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Zhang H, Shi Y, Lin C, He C, Wang S, Li Q, Sun Y, Li M. Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota. Front Immunol 2024; 14:1338918. [PMID: 38288125 PMCID: PMC10822953 DOI: 10.3389/fimmu.2023.1338918] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Inflammatory bowel disease (IBD), characterized primarily by gastrointestinal inflammation, predominantly manifests as Crohn's disease (CD) and ulcerative colitis (UC). It is acknowledged that Inflammation plays a significant role in cancer development and patients with IBD have an increased risk of various cancers. The progression from inflammation to carcinogenesis in IBD is a result of the interplay between immune cells, gut microbiota, and carcinogenic signaling pathways in epithelial cells. Long-term chronic inflammation can lead to the accumulation of mutations in epithelial cells and the abnormal activation of carcinogenic signaling pathways. Furthermore, Immune cells play a pivotal role in both the acute and chronic phases of IBD, contributing to the transformation from inflammation to tumorigenesis. And patients with IBD frequently exhibit dysbiosis of the intestinal microbiome. Disruption of the gut microbiota and subsequent immune dysregulation are central to the pathogenesis of both IBD and colitis associated colorectal cancer (CAC). The proactive management of inflammation combined with regular endoscopic and tumor screenings represents the most direct and effective strategy to prevent the IBD-associated cancer.
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Affiliation(s)
- Haonan Zhang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chanchan Lin
- Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Chengcheng He
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shanping Wang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Sun
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingsong Li
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Nishiguchi R, Basu S, Staab HA, Ito N, Zhou XK, Wang H, Ha T, Johncilla M, Yantiss RK, Montrose DC, Dannenberg AJ. Dietary interventions to prevent high-fructose diet-associated worsening of colitis and colitis-associated tumorigenesis in mice. Carcinogenesis 2021; 42:842-852. [PMID: 33513602 PMCID: PMC8215596 DOI: 10.1093/carcin/bgab007] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/06/2021] [Accepted: 01/25/2021] [Indexed: 12/22/2022] Open
Abstract
Diet is believed to be an important factor in the pathogenesis of inflammatory bowel disease. High consumption of dietary fructose has been shown to exacerbate experimental colitis, an effect mediated through the gut microbiota. This study evaluated whether dietary alterations could attenuate the detrimental effects of a high-fructose diet (HFrD) in experimental colitis. First, we determined whether the procolitic effects of a HFrD could be reversed by switching mice from a HFrD to a control diet. This diet change completely prevented HFrD-induced worsening of acute colitis, in association with a rapid normalization of the microbiota. Second, we tested the effects of dietary fiber, which demonstrated that psyllium was the most effective type of fiber for protecting against HFrD-induced worsening of acute colitis, compared with pectin, inulin, or cellulose. In fact, supplemental psyllium nearly completely prevented the detrimental effects of the HFrD, an effect associated with a shift in the gut microbiota. We next determined whether the protective effects of these interventions could be extended to chronic colitis and colitis-associated tumorigenesis. Using the azoxymethane/dextran sodium sulfate model, we first demonstrated that HFrD feeding exacerbated chronic colitis and increased colitis-associated tumorigenesis. Using the same dietary changes tested in the acute colitis setting, we also showed that mice were protected from HFrD-mediated enhanced chronic colitis and tumorigenesis, upon either diet switching or psyllium supplementation. Taken together, these findings suggest that high consumption of fructose may enhance colon tumorigenesis associated with long-standing colitis, an effect that could be reduced by dietary alterations.
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Affiliation(s)
| | - Srijani Basu
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Hannah A Staab
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Naotake Ito
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Xi Kathy Zhou
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Hanhan Wang
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Taehoon Ha
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Melanie Johncilla
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - David C Montrose
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.,Stony Brook Cancer Center, Stony Brook, NY, USA
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Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis. Cancer Epidemiol 2018; 58:52-62. [PMID: 30472477 DOI: 10.1016/j.canep.2018.11.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/13/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023]
Abstract
There is still insufficient data about the risk-benefit profile about recommending non-aspirin, non-steroidal anti-inflammatory drugs (NA-NSAIDs) for colorectal cancer (CRC) prevention, especially in people aged 40 years or older. This study specifically addressed the association between regular NA-NSAIDs use and CRC risk in the population aged 40 years or older, performing a comprehensive systematic review and meta-analysis of all published studies on this topic until April 2018, by a search of PubMed, Scopus and Web of science databases and clinical trial registries. Two reviewers independently selected studies based on predefined inclusion criteria and assessed study quality using the Newcastle-Otawa scale. The data was combined with the random effects model. Potential heterogeneity was calculated as Q statistic and I2 value. A total of 23 studies involving more than 1 million subjects contributed to the analysis. Pooled odds ratio (OR) of NA-NSAIDs effects on CRC risk was 0.74 (0.67-0.81), I2 = 75.9%, p < 0.001. Heterogeneity was explained by a number of variables including the quality of the studies. Significant protective effects of NA-NSAIDs use were found for women (risk reduction of 19%), higher doses (risk reduction of 18%), distal colon cancer (risk reduction of 22%) and white people (risk reduction from 31% to 41%). From the results NA-NSAIDs use appears to be CRC chemopreventive for a specific subgroup of the population.
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Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, Burisch J, Gecse KB, Hart AL, Hindryckx P, Langner C, Limdi JK, Pellino G, Zagórowicz E, Raine T, Harbord M, Rieder F. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis 2017; 11:649-670. [PMID: 28158501 DOI: 10.1093/ecco-jcc/jjx008] [Citation(s) in RCA: 1267] [Impact Index Per Article: 158.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 02/01/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Fernando Magro
- Department of Pharmacology and Therapeutics, University of Porto; MedInUP, Centre for Drug Discovery and Innovative Medicines; Centro Hospitalar São João, Porto, Portugal
| | | | - Rami Eliakim
- Department of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Sandro Ardizzone
- Gastrointestinal Unit ASST Fatebenefratelli Sacco-University of Milan-Milan, Italy
| | - Alessandro Armuzzi
- IBD Unit Complesso Integrato Columbus, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli Universita' Cattolica del Sacro Cuore, Rome, Italy
| | - Manuel Barreiro-de Acosta
- Department of Gastroenterology, IBD Unit, University Hospital Santiago De Compostela (CHUS), A Coruña, Spain
| | - Johan Burisch
- Department of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark
| | - Krisztina B Gecse
- First Department of Medicine, Semmelweis University, Budapest,Hungary
| | | | - Pieter Hindryckx
- Department of Gastroenterology, University Hospital of Ghent, Ghent, Belgium
| | - Cord Langner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Jimmy K Limdi
- Department of Gastroenterology, Pennine Acute Hospitals NHS Trust; Institute of Inflammation and Repair, University of Manchester, Manchester, UK
| | - Gianluca Pellino
- Unit of General Surgery, Second University of Naples,Napoli, Italy
| | - Edyta Zagórowicz
- Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Oncological Gastroenterology Warsaw; Medical Centre for Postgraduate Education, Department of Gastroenterology, Hepatology and Clinical Oncology, Warsaw, Poland
| | - Tim Raine
- Department of Medicine, University of Cambridge, Cambridge,UK
| | - Marcus Harbord
- Imperial College London; Chelsea and Westminster Hospital, London,UK
| | - Florian Rieder
- Department of Pathobiology /NC22, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition/A3, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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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: 87] [Impact Index Per Article: 10.9] [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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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: 91] [Impact Index Per Article: 11.4] [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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Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, Karlson EW, Murphy SN, Liao KP, Kohane I. Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2016; 14:973-9. [PMID: 26905907 PMCID: PMC4912917 DOI: 10.1016/j.cgh.2016.02.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/01/2016] [Accepted: 02/10/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Chemopreventive strategies have produced weak or inconsistent results. Statins have been associated inversely with sporadic CRC. We examined their role as chemopreventive agents in patients with IBD. METHODS We collected data from 11,001 patients with IBD receiving care at hospitals in the Greater Boston metropolitan area from 1998 through 2010. Diagnoses of CRC were determined using validated International Classification of Diseases, 9th revision, Clinical Modification codes. Statin use before diagnosis was assessed through analysis of electronic prescriptions. We performed multivariate logistic regression analyses, adjusting for potential confounders including primary sclerosing cholangitis, smoking, increased levels of inflammation markers, and CRC screening practices to identify an independent association between statin use and CRC. We performed sensitivity analyses using propensity score adjustment and variation in the definition of statin use. RESULTS In our cohort, 1376 of the patients (12.5%) received 1 or more prescriptions for a statin. Patients using statins were more likely to be older, male, white, smokers, and have greater comorbidity than nonusers. Over a follow-up period of 9 years, 2% of statin users developed CRC compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). On multivariate analysis, statin use remained independently and inversely associated with CRC (odds ratio, 0.42; 95% confidence interval, 0.28-0.62). Our findings were robust on a variety of sensitivity and subgroup analyses. CONCLUSIONS Statin use was associated inversely with the risk of CRC in a large IBD cohort. Prospective studies on the role of statins as chemopreventive agents are warranted.
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Affiliation(s)
- Ashwin N. Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA,Harvard Medical School, Boston, MA,Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Andrew Cagan
- Research IS and Computing, Partners HealthCare, Charlestown, MA
| | - Tianxi Cai
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | | | - Stanley Y Shaw
- Harvard Medical School, Boston, MA,Department of Medicine, Massachusetts General Hospital, Boston, MA,Center for Systems Biology, Massachusetts General Hospital, Boston, MA
| | | | - Elizabeth W. Karlson
- Harvard Medical School, Boston, MA,Division of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Boston, MA
| | - Shawn N. Murphy
- Harvard Medical School, Boston, MA,Department of Neurology, Massachusetts General Hospital, Boston, MA
| | - Katherine P. Liao
- Harvard Medical School, Boston, MA,Division of Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Boston, MA
| | - Isaac Kohane
- Harvard Medical School, Boston, MA,Department of Biomedical Informatics, Harvard Medical School,Children’s Hospital Boston, Boston, MA
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Gordillo J, Cabré E, Garcia-Planella E, Ricart E, Ber-Nieto Y, Márquez L, Rodríguez-Moranta F, Ponferrada Á, Vera I, Gisbert JP, Barrio J, Esteve M, Merino O, Muñoz F, Domènech E. Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry. J Crohns Colitis 2015; 9:1063-70. [PMID: 26351379 DOI: 10.1093/ecco-jcc/jjv145] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 08/06/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), but recent studies suggest a lower risk than previously reported. The aim was to evaluate the incidence of dysplasia, CRC and related risk factors in UC patients from a Spanish nationwide database. METHODS All UC patients were identified and retrospectively reviewed. Clinical-epidemiological data and the finding of dysplasia and/or CRC were collected. RESULTS A total of 831 UC patients were included. Twenty-six cases of CRC in 26 patients and 29 cases of high-grade dysplasia (HGD) in 24 patients were found, accounting for 55 diagnoses of advanced neoplasia (AN = CRC and/or HGD) in 45 patients (33% of them within the first 8 years after UC diagnosis). The cumulative risk of AN was 2, 5.3 and 14.7% at 10, 20 and 30 years, respectively. Concomitant primary sclerosing cholangitis (odds ratio [OR] 10.90; 95% confidence interval [CI] 3.75-31.76, p < 0.001), extensive UC (OR 2.10, 95% CI 1.01-4.38, p = 0.048), UC diagnosis at an older age (OR 2.23, 95% CI 1.03-4.83, p = 0.043) and appendectomy prior to UC diagnosis (OR 2.66, 95% CI 1.06-6.71, p = 0.038) were independent risk factors for AN. Use of thiopurines (OR 0.21, 95% CI 0.06-0.74, p = 0.015) and being in a surveillance colonoscopy programme (OR 0.33; 95% CI 0.16-0.67; p = 0.002) were independent protective factors for AN. CONCLUSIONS The risk of AN among UC patients is lower than previously reported but steadily increases from the time of UC diagnosis. The widespread use of thiopurines may have influenced this reduced incidence of UC-related neoplasias.
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Affiliation(s)
- Jordi Gordillo
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eduard Cabré
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | - Elena Ricart
- Hospital Clínic i Provincial, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Yolanda Ber-Nieto
- Hospital Universitario Lozano Blesa, Zaragoza, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | | | - Isabel Vera
- Hospital Universitario Puerta del Hierro, Madrid, Spain
| | - Javier P Gisbert
- Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jesús Barrio
- Hospital Universitaro Rio Hortega, Valladolid, Spain
| | - Maria Esteve
- Hospital Mútua de Terrassa, Terrassa, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | | | | | - Eugeni Domènech
- Hospital Universitari Germans Trias i Pujol, Badalona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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9
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van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollón F, Häuser W, Herrlinger K, Oldenburg B, Panes J, Portela F, Rogler G, Stein J, Tilg H, Travis S, Lindsay JO. [Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 3: Special situations (Spanish version)]. REVISTA DE GASTROENTEROLOGIA DE MEXICO 2015; 80:74-106. [PMID: 25769216 DOI: 10.1016/j.rgmx.2014.10.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 12/12/2022]
Affiliation(s)
- G van Assche
- En nombre de la ECCO; G.V.A. y A.D. actúan como coordinadores del consenso y han contribuido igualmente para este trabajo.
| | - A Dignass
- G.V.A. y A.D. actúan como coordinadores del consenso y han contribuido igualmente para este trabajo.
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10
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Bae SI, Kim YS. Colon cancer screening and surveillance in inflammatory bowel disease. Clin Endosc 2014; 47:509-15. [PMID: 25505716 PMCID: PMC4260098 DOI: 10.5946/ce.2014.47.6.509] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 08/05/2014] [Indexed: 12/13/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Accordingly, the duration and anatomic extent of the disease have been known to affect the development of IBD-related CRC. When CRC occurs in patients with IBD, unlike in sporadic CRC, it is difficult to detect the lesions because of mucosal changes caused by inflammation. In addition, the tumor types vary with ill-circumscribed lesions, and the cancer is difficult to diagnose and remedy at an early stage. For the diagnosis of CRC in patients with IBD, screening endoscopy is recommended 8 to 10 years after the IBD diagnosis, and surveillance colonoscopy is recommended every 1 to 2 years thereafter. The recent development of targeted biopsies using chromoendoscopy and relatively newer endoscopic techniques helps in the early diagnosis of CRC in patients with IBD. A total proctocolectomy is advisable when high-grade dysplasia or multifocal low-grade dysplasia is confirmed by screening endoscopy or surveillance colonoscopy or if a nonadenoma-like dysplasia-associated lesion or mass is detected. Currently, pharmacotherapies are being extensively studied as a way to prevent IBD-related CRC.
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Affiliation(s)
- Song I Bae
- Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - You Sun Kim
- Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
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11
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Bezzio C, Furfaro F, de Franchis R, Maconi G, Asthana AK, Ardizzone S. Ulcerative colitis: current pharmacotherapy and future directions. Expert Opin Pharmacother 2014; 15:1659-70. [DOI: 10.1517/14656566.2014.925445] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Zhao LN, Li JY, Yu T, Chen GC, Yuan YH, Chen QK. 5-Aminosalicylates reduce the risk of colorectal neoplasia in patients with ulcerative colitis: an updated meta-analysis. PLoS One 2014; 9:e94208. [PMID: 24710620 PMCID: PMC3978022 DOI: 10.1371/journal.pone.0094208] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 03/13/2014] [Indexed: 12/20/2022] Open
Abstract
Background Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis. Methods Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed. Results Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48–0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35–0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53–1.89]. Conclusion Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited.
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Affiliation(s)
- Li-Na Zhao
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Jie-Yao Li
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Tao Yu
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
- * E-mail:
| | - Guang-Cheng Chen
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yu-Hong Yuan
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
| | - Qi-Kui Chen
- Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China
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Sebastian S, Hernández V, Myrelid P, Kariv R, Tsianos E, Toruner M, Marti-Gallostra M, Spinelli A, van der Meulen-de Jong AE, Yuksel ES, Gasche C, Ardizzone S, Danese S. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J Crohns Colitis 2014; 8:5-18. [PMID: 23664897 DOI: 10.1016/j.crohns.2013.04.008] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 04/05/2013] [Indexed: 02/08/2023]
Abstract
Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop.
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Affiliation(s)
- Shaji Sebastian
- Hull & East Yorkshire Hospitals NHS Trust, Hull York Medical School, Hull, United Kingdom.
| | - Vincent Hernández
- Gastroenterology Department, Complexo Hospitalario Universitario de Vigo, Vigo, Spain
| | - Pär Myrelid
- Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden
| | - Revital Kariv
- Service for Gastrointestinal Malignancies, Department of Gastroenterology & Liver Disease, Tel Aviv Sourasky Medical Center, Israel
| | - Epameinondas Tsianos
- University of Ioannina, 1st Division of Internal Medicine and Hepato-Gastroenterology Unit, Greece
| | - Murat Toruner
- Ankara University Medical School, Ibni Sina Hospital, Division of Gastroenterology, Ankara, Turkey
| | - Marc Marti-Gallostra
- Department of Colorectal Surgery, University Hospital of Valle de Hebron, Barcelona, Spain
| | - Antonino Spinelli
- Dipartimento e Cattedra di Chirurgia Generale, Istituto Clinico Humanitas IRCCS, Università degli Studi di Milano, Rozzano, Milano, Italy
| | | | - Elif Sarıtas Yuksel
- Department of Gastroenterology, Katip Celebi University, Ataturk Research and Teaching Hospital, Izmir, Turkey
| | - Christoph Gasche
- Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Division of Gastroenterology, Medical University of Vienna, Vienna, Austria
| | - Sandro Ardizzone
- Chair of Gastroenterology, "L. Sacco" University Hospital, Milan, Italy
| | - Silvio Danese
- Department of Gastroenterology, Istituto Clinico Humanitas, Milan, Italy.
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14
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Abstract
5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease (IBD). Intestinal inflammation is the main risk factor for colorectal cancer (CRC) in IBD. Hence, all drugs that are able to induce and maintain mucosal healing (MH) may prevent CRC risk in IBD. In patients with mild to moderate ulcerative colitis (UC), a recent systematic review of 5-ASA trials demonstrated that MH was achieved in nearly 50% of patients. A systematic review including 48 studies linked 5-ASA chemopreventive properties to five distinct pathways: cell cycle progression, scavenging of reactive oxygen- or nitrogen-derived metabolites, TNF-α/TGF-ss signaling, WNT/β-catenin signaling and antibacterial properties. Therefore, in addition to their overall anti-inflammatory activity on the intestinal mucosa, 5-ASA compounds have specific effects on colorectal carcinogenesis at the molecular level. In 2005, a landmark meta-analysis of observational studies found a protective association between 5-ASA and CRC or a combined end point of CRC/dysplasia in UC patients. More recently, a meta-analysis failed to identify a protective effect of 5-ASA on CRC risk in non-referral populations, but in a separate analysis of 9 clinic-based studies, the pooled odds ratio was 0.58 (95% confidence interval: 0.45-0.75), further highlighting the chemopreventive effect of 5-ASA on CRC risk. In conclusion, 5-ASA therapy may reduce CRC risk by healing the mucosa of UC patients and via specific mechanisms of action at the molecular level. Conducting a clinical trial providing the best level of evidence by comparing UC patients receiving 5-ASA treatment versus those included in a placebo arm would be unethical.
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15
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Rousseaux C, El-Jamal N, Fumery M, Dubuquoy C, Romano O, Chatelain D, Langlois A, Bertin B, Buob D, Colombel JF, Cortot A, Desreumaux P, Dubuquoy L. The 5-aminosalicylic acid antineoplastic effect in the intestine is mediated by PPARγ. Carcinogenesis 2013; 34:2580-6. [PMID: 23843037 PMCID: PMC3810841 DOI: 10.1093/carcin/bgt245] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Epidemiological evidences suggested that 5-aminosalicylic acid (5-ASA) therapy may prevent the development of colorectal cancer in inflammatory bowel disease patients. Our aim is to investigate whether peroxisome proliferator-activated receptor-γ (PPARγ) mediates the antineoplastic effects of 5-ASA. HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARγ ligand) or etoposide (anticarcinogenic drug). Epithelial cell growth, proliferation and apoptosis were assessed by cell count, Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. The antineoplastic effect of 5-ASA was evaluated in a xenograft tumor model in SCID mice and in azoxymethane (AOM)-induced colon carcinogenesis in A/JOlaHsd mice. The role of PPARγ was examined by administration of PPARγ antagonist, GW9662 and in PPAR knockdown cells. Compared with untreated cells, treatment of HT-29 cells by 5-ASA inhibited significantly cell growth and cell proliferation (respectively, 60% and 63%) and induced apoptosis in 75% of cells. These effects were abolished by co-treatment with GW9662 and blunted in PPAR knockdown cells. Contrarily to etoposide, similar inhibitory effects of GW9662 were obtained in HT-29 cells treated with rosiglitazone. In the xenograft model, GW9662 abolished the therapeutic effect of 5-ASA, which decreased tumor weight and volume by 80% in SCID mice compared with untreated mice. In A/JOlaHsd mice, 5-ASA suppressed colon carcinogenesis by decreasing the number of aberrant crypt foci (75%) and aberrant crypts (22%) induced by AOM treatment with an absence of 5-ASA response after GW9662 administration. In conclusion, 5-ASA exerts potent antineoplastic effects that are mediated through PPARγ. These data provide new rational for designing more effective and safe antineoplastic PPARγ ligands with topical effects.
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Affiliation(s)
- Christel Rousseaux
- Department of Project Management, Intestinal Biotech Development, 59045 Lille, France
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16
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Van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollón F, Häuser W, Herrlinger K, Oldenburg B, Panes J, Portela F, Rogler G, Stein J, Tilg H, Travis S, Lindsay JO. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis 2013; 7:1-33. [PMID: 23040453 DOI: 10.1016/j.crohns.2012.09.005] [Citation(s) in RCA: 334] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 09/03/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Gert Van Assche
- Division of Gastroenterology, Department of Medicine, Mt. Sinai Hospital and University Health Network,University of Toronto and University of Leuven, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
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17
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Abstract
5-aminosalicylates (5-ASA) are widely used to treat patients with ulcerative colitis. Experimental data suggest that these agents can potentially be used in a chemopreventive fashion to inhibit the development of colitis-associated colorectal cancer (CRC); however, observational studies investigating a possible risk reduction of CRC by 5-ASA therapy have revealed conflicting results. Currently, it appears that 5-ASA have no or only a very limited effect as a deterrence against CRC. Thus, a general recommendation for long-term use of 5-ASA solely for chemopreventive measures is not warranted.
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Affiliation(s)
- Hans Herfarth
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC 27599, USA.
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18
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Tanaka T. Preclinical cancer chemoprevention studies using animal model of inflammation-associated colorectal carcinogenesis. Cancers (Basel) 2012; 4:673-700. [PMID: 24213461 PMCID: PMC3712717 DOI: 10.3390/cancers4030673] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 06/14/2012] [Accepted: 07/06/2012] [Indexed: 12/21/2022] Open
Abstract
Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.
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Affiliation(s)
- Takuji Tanaka
- Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285, Japan.
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19
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Devlin SM. Do thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease or is this an unanswerable question? Inflamm Bowel Dis 2012; 18:1184-5. [PMID: 22271441 DOI: 10.1002/ibd.21869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Accepted: 07/28/2011] [Indexed: 12/09/2022]
Affiliation(s)
- Shane M Devlin
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
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20
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Kisiel JB, Loftus EV, Harmsen WS, Zinsmeister AR, Sandborn WJ. Outcome of sporadic adenomas and adenoma-like dysplasia in patients with ulcerative colitis undergoing polypectomy. Inflamm Bowel Dis 2012; 18:226-35. [PMID: 21416564 DOI: 10.1002/ibd.21687] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 01/20/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) patients are at increased risk of colorectal dysplasia and cancer. Few studies have examined the clinical outcomes of dysplastic polyps resembling sporadic adenomas that are removed with endoscopic polypectomy. METHODS A centralized diagnostic index identified patients evaluated between 1994 and 2004 with UC and polypoid dysplasia who were followed from the time of polypectomy until the most recent colonoscopy. They were stratified into two groups by polyp occurrence, either within (adenoma-like dysplasia) or outside (sporadic adenoma) the most proximal endoscopic or histologic extent of colitis. The endpoints of interest were the development of subsequent colorectal neoplasia, flat dysplasia, or cancer. The cumulative probabilities of these endpoints were estimated using the Kaplan-Meier method, and the association with clinical factors assessed using Cox proportional hazards regression. RESULTS Ninety-five patients were found to have polypoid dysplasia; of these, 77 underwent polypectomy. The cumulative probability of subsequent colorectal neoplasia in polypectomy patients was 18% at 1 year and 69% at 5 years. After polypectomy, cumulative incidence of cancer or flat dysplasia was 2% at 1 year and 13% at 5 years. The proportional hazards models indicated that these outcomes were not significantly associated with polyp type, primary sclerosing cholangitis, family history of colorectal cancer, 5-aminosalicylate use, extent of colitis, or duration of disease. CONCLUSIONS While polypectomy may be safe for the management of adenomas occurring in most UC patients, the 5-year cumulative incidence of a combined endpoint (cancer or flat dysplasia) was 13%. Such patients should be followed closely.
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Affiliation(s)
- John B Kisiel
- Division of Gastroenterology & Hepatology, Rochester, Minnesota 55905, USA
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21
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Gong W, Lv N, Wang B, Chen Y, Huang Y, Pan W, Jiang B. Risk of ulcerative colitis-associated colorectal cancer in China: a multi-center retrospective study. Dig Dis Sci 2012; 57:503-7. [PMID: 21938485 DOI: 10.1007/s10620-011-1890-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 08/17/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND The number of patients with ulcerative colitis (UC) in China has increased in the past 10 years. Thus, it is anticipated that the incidence of UC-associated colorectal cancer (UC-CRC) will also increase. However, the risk of CRC in UC patients is still unknown in Chinese. The aim of this study was to identify the risk and risk factors of UC-CRC in Chinese. METHODS A total of 3,922 patients with UC were retrospectively collected from five central teaching hospitals in China, in which high-quality endoscopic and histological diagnoses were available from 1998 to 2009. The database of the UC and UC-associated CRC patients was evaluated. RESULTS CRC was diagnosed 34 in patients, and the overall prevalence of CRC in patients with UC was 0.87%. The cumulative risk of developing CRC after a disease duration of 10 years was 1.15% (95% confidence interval [CI] 0.71-1.84%); 20 years, 3.56% (95% CI 2.14-5.89%); and 30 years, 14.36% (95% CI 7.57-26.3%). Longer disease duration, extensive colitis, and dysplasia found in the biopsy specimen were identified as risk factors for developing CRC. 5-ASA use was identified as a protective factor of UC-CRC. CONCLUSIONS The period prevalence of CRC was lower than that reported from the West. However, the cumulative risk was found to be comparable to that of Western countries, which suggests that the period prevalence of UC-CRC in China may be growing in the future.
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Affiliation(s)
- Wei Gong
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
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22
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Efthymiou M, Taylor ACF, Kamm MA. Cancer surveillance strategies in ulcerative colitis: the need for modernization. Inflamm Bowel Dis 2011; 17:1800-13. [PMID: 21089179 DOI: 10.1002/ibd.21540] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The risk of colorectal cancer is increased in patients with long-standing ulcerative colitis. Traditional surveillance has centered around regular standard white-light colonoscopy, with multiple biopsies aimed at detecting dysplasia or the identification of early cancer. This has resulted in only a modest reduction in cancer incidence and mortality. A better understanding of disease risk factors may allow endoscopic resources to be more focused on patients at higher risk. In addition, advanced endoscopic techniques have the potential to improve dysplasia detection, minimize the need for routine biopsies, and allow for the removal of dysplastic lesions, avoiding the need for surgery. Techniques such as magnification colonoscopy, chromoendoscopy, narrow band imaging, autofluorescence, and confocal endomicroscopy may all have a role to play in improving the benefits of endoscopic surveillance. Revised endoscopic surveillance strategies are proposed, incorporating aspects of risk stratification, a well-established practice in noncolitis-related colorectal cancer screening, and some of these new technologies.
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Affiliation(s)
- Marios Efthymiou
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia
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23
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Terdiman JP. The prevention of colitis-related cancer by 5-aminosalicylates: an appealing hypothesis that remains unproven. Am J Gastroenterol 2011; 106:737-40. [PMID: 21468069 DOI: 10.1038/ajg.2011.56] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Whether or not 5-aminosalicylates can prevent colorectal cancer among patients with colitis remains an open question. The observational studies examining this question have provided conflicting results, but none of these studies have been of sufficient quality to provide a definitive answer one way or another.
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24
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5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol 2011; 106:731-6. [PMID: 21407180 DOI: 10.1038/ajg.2011.50] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES We aimed to determine if use of 5-aminosalicylates (5-ASA) was associated with a reduced risk of colorectal cancer (CRC) in people with inflammatory bowel disease (IBD). METHODS We used the population-based University of Manitoba IBD Epidemiology Database that tracks all health-care visits from 1984 to 2008 of all Manitobans with IBD and all prescription medication use since 1995. In 2008, there were 8,744 subjects with IBD (ulcerative colitis 4,325, Crohn's disease 4,419, females 4,851, males 3,893). In study I, we assessed the incidence of CRC among 5-ASA users (≥1 year, ≥5 years of cumulative use) compared with nonusers. In study II, we assessed a cohort of those with CRC (n=101) diagnosed in 1995-2008, matched to a control cohort by age, sex, disease duration, and disease diagnosis without CRC (n=303), and logistic analysis was undertaken. RESULTS For study I, the hazard ratio for CRC among 5-ASA users was 1.04 (95% confidence interval (CI) 0.67-1.62, P=0.87) at ≥1 year of use and 2.01 (95% CI 1.04-3.9, P=0.038) at ≥ 5 years of use with no difference when assessing by diagnosis. Males, but not females, using 5-ASA for ≥ 5 years had an increased risk of CRC. In study II, CRC cases had similar use of any 5-ASA compared with controls for ≥ 1 year of use (1.02, 95% CI 0.60-1.74) or ≥ 5 years (1.96, 95% CI 0.84-4.55), and a similar mean number of 5-ASA prescriptions at 10 vs. 11 (P=0.8) and a similar mean number of dose days at 330 vs. 410 (P=0.69). CONCLUSIONS Our results support the majority of studies to date that 5-ASA is not chemoprophylactic in IBD for CRC.
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25
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Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Risk factors are extent and severity of colonic inflammation, concurrent primary sclerosing cholangitis, and a positive family history of sporadic CRC. The chromosomal instability, microsatellite instability and hypermethylation pathways form the molecular background of IBD-related carcinogenesis, which is not different from sporadic CRC. The dysplasia-carcinoma sequence of IBD-related colorectal carcinogenesis makes patients suitable for endoscopic surveillance. In the future, new molecular biomarkers and endoscopic techniques may improve early detection of precursor lesions of IBD-related CRC. The potential of aminosalicylates and ursodeoxycholic acid as chemopreventive agents needs to be studied in randomized clinical trials. Patients with IBD who are being treated with thiopurines have a slightly increased risk of developing lymphoproliferative disorders, whereas patients with small bowel Crohn's disease have a high relative risk and a small absolute risk of developing small bowel adenocarcinoma.
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Affiliation(s)
- M M H Claessen
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
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26
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Baars JE, Looman CWN, Steyerberg EW, Beukers R, Tan ACITL, Weusten BLAM, Kuipers EJ, van der Woude CJ. The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study. Am J Gastroenterol 2011; 106:319-28. [PMID: 21045815 DOI: 10.1038/ajg.2010.428] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. METHODS IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. RESULTS A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. CONCLUSIONS We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.
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Affiliation(s)
- Judith E Baars
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
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27
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Viennot S, Deleporte A, Moussata D, Nancey S, Flourié B, Reimund JM. Colon cancer in inflammatory bowel disease: recent trends, questions and answers. ACTA ACUST UNITED AC 2010; 33 Suppl 3:S190-201. [PMID: 20117342 DOI: 10.1016/s0399-8320(09)73154-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with chronic colitis (ulcerative colitis or colonic Crohn's disease) have an increased risk of colorectal cancer (CRC). Although most of the molecular alterations reported in sporadic CRC have also been observed in colitis-associated CRC, they do not occur at the same timing and frequency, indicating a different pathophysiology. In particular, recent work highlighted the importance of chronic mucosal inflammation as a key factor favouring colorectal carcinogenesis in these patients. This may also be one of the reasons explaining the role of 5-aminosalicylates as chemopreventive agents for CRC in inflammatory bowel disease (IBD) patients with colonic involvement. Beside chemoprevention, colonoscopic screening and surveillance have been shown to be the cornerstone for CRC prevention and early detection in this particular patients' population. Periodic surveillance colonoscopy to detect dysplasia has been shown to decrease the mortality attributed to CRC. More recently, progress in imaging techniques increased our ability to identify dysplasia, and should probably now be considered to be an integral part of surveillance colonoscopy. In the future, further improvement of our knowledge of CRC biology, refinement of imaging techniques, as well as molecular discovery (e.g. identification of specific mutations in stool DNA extracts), might lead to develop more accurate diagnostic strategies to reduce the morbidity and mortality related to CRC in patients with ulcerative colitis or colonic Crohn's disease.
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Affiliation(s)
- S Viennot
- Centre Hospitalier Universitaire de Caen, Service d'Hépato-Gastroentérologie et Nutrition, Pôle Reins-Digestif-Nutrition, Hôpital Côte de Nacre, B.P. 95182, 14033 Caen cedex 9, France
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28
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Abstract
OBJECTIVES Colorectal cancer (CRC), developing from dysplastic lesions, is the main long-term complication of pancolitis. The aims of the present study were to assess the risks for neoplasia and advanced neoplasia (AN), respectively, in ulcerative colitis (UC) and Crohn's disease (CD) patients with pancolitis, and to search for protective and risk factors for colorectal neoplasia. METHODS A total of 855 inflammatory bowel disease (IBD) patients with longstanding pancolitis (276 UC, 56 IBD unclassified (IBDu), and 523 CD) had pathological examination of a proctocolectomy specimen (n=255) or multiple biopsy samples from a surveillance colonoscopy (n=600) after median disease duration of 115 months. Risk factors for low-grade dysplasia (LGD) and AN, respectively, were searched for in the whole group of patients and in a case-control comparison after matching for IBD phenotype. RESULTS A total of 75 patients eventually developed colorectal neoplasia: 14 adenomas, 28 nonadenomatous LGD, and 33 ANs. The 25-year cumulative risks for neoplasia and AN, respectively, were 32.8±5.7% and 25.9±5.7% in UC and IBDu vs. 12.1±2.7% and 3.9±2.0% in CD (P<0.0001). In CD, patients with UC-like endoscopic appearance (n=126) had an increased risk for AN compared with those with discrete lesions (at 25 years, 10.6±7.2 vs. 1.5±0.9%). In the case-control comparison, factors associated with an increased risk of AN were primary sclerosing cholangitis (hazard ratio (HR) 4.72 (1.54-14.52)) and family history of CRC (HR 3.37 (1.02-11.14)), whereas previous segmental colectomy was protective (HR 0.25 (0.07-0.88)). CONCLUSIONS The risk of AN in longstanding pancolitis is higher in UC or IBDu than in CD. In CD, this risk is significantly increased in patients with UC-like endoscopic lesions. The surveillance program should focus on these latter patients.
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Abstract
OBJECTIVES We sought to describe the characteristics of health-care utilization (HCU) among patients with Crohn's disease using infliximab (IFX). METHODS Using the University of Manitoba Inflammatory Bowel Disease Epidemiology Database (UMIBDED), we extracted all subjects with newly prescribed IFX, newly prescribed purine analogs (azathioprine, AZA) (without IFX), newly prescribed steroids (Ster) (without IFX or purine analogs) after 2001, and those not prescribed any of these drugs (ND). All of the subjects must have had HCU data available for 5 years before initial prescription and for 3 years afterward. We analyzed the number of physician visits, hospital visits, and surgeries. RESULTS IBD-associated physician visits were consistently higher for IFX, both pre- and post-initial dosing, although overall physician visits were similar between IFX, AZA, and Ster. There was a steep rise in hospitalizations in the 6 months before initial prescription of IFX, AZA, or Ster, and hospitalizations were higher in the IFX cohort until 18-24 months after the first prescription, at which point levels fell to those evident 2-5 years before initiating IFX and to levels in the other drug groups. Likelihood of surgery post-dosing was greater in IFX than in AZA or ND for up to 36 months but was not different than Ster. CONCLUSIONS In a "step-up" approach to IFX use, it takes 2 years for the physician visits to reduce to 2-year pre-dosing rates and 18-24 months to reach hospitalization rates at 2 years pre-dosing and hospitalization rates of the AZA and Ster groups. Surgical rates to 3 years post-dosing were still higher than in AZA or ND groups.
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Mesalamine protects against colorectal cancer in inflammatory bowel disease. Dig Dis Sci 2010; 55:1696-703. [PMID: 19705280 DOI: 10.1007/s10620-009-0942-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2009] [Accepted: 08/06/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support. AIM Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients. METHODS IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves. RESULTS Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose of >or=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose of >or=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose of >or=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose of >or=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002). CONCLUSIONS Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.
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Chromik AM, Huss S, Osseili H, Daigeler A, Kersting S, Sülberg D, Mittelkötter U, Herdegen T, Uhl W, Müller AM. Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium induced colitis-associated carcinogenesis in mice. J Carcinog 2010; 9:5. [PMID: 20442801 PMCID: PMC2862504 DOI: 10.4103/1477-3163.62536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Accepted: 03/14/2010] [Indexed: 12/11/2022] Open
Abstract
Background: New chemopreventive strategies for ulcerative colitis (UC)-associated dysplasia and cancer have to be evaluated. Taurolidine (TRD) has anti-inflammatory, anti-proliferative and anti-neoplastic properties with almost absent toxicity. The aim of the study was to determine whether TRD decreases dysplasia in the well-characterized Dextran Sulfate Sodium – Azoxymethane (DSS-AOM) animal model for UC-associated carcinogenesis. Material and Methods: The DSS-AOM model of carcinogenesis was induced in female inbred C57BL/6 mice. Half of the mice were treated with TRD, the other served as control. After 100 days macroscopic, histological and immunhistochemical (β-Catenin, E-Cadherin, SOX9, Ki-67, Cyclin-D1) examination of the colon was performed. Results: Incidence, multiplicity, grading and growth pattern of adenomas did not differ significantly between TRD and control group. In all animals, inflammatory changes were absent. Immunhistochemistry revealed increased expression of Ki-67, β-catenin, SOX9 and Cyclin-D1 in adenomas compared to normal mucosa – without significant difference between TRD and control treatment. Conclusion: Oral administration of TRD has no impact on DSS-induced colitis-associated carcinogenesis. However, SOX9 and Cyclin-D1 representing key members of the Wnt pathway have not yet been described in the DSS-AOM model of carcinogenesis – underlining the importance of this oncogenic pathway in this setting.
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Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105:501-23; quiz 524. [PMID: 20068560 DOI: 10.1038/ajg.2009.727] [Citation(s) in RCA: 935] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the field, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case-control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.
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Affiliation(s)
- Asher Kornbluth
- Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
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Low A, Love M, Walt R, Kane K, Eksteen B, Goh J. Understanding of chemoprophylaxis and concordance in inflammatory bowel disease. World J Gastroenterol 2010; 16:578-82. [PMID: 20128025 PMCID: PMC2816269 DOI: 10.3748/wjg.v16.i5.578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess patients’ understanding for the reasons for taking 5-aminosalicylic acid or ursodeoxycholic acid as chemoprophylaxis against colorectal carcinoma associated with inflammatory bowel disease (IBD).
METHODS: A questionnaire-based study using a 5-point opinion scale was performed. One hundred and ninety-two patients with colitis only and 74 patients with primary sclerosing cholangitis and IBD were invited to take part.
RESULTS: Overall response rate was 58%. Sixty-four percent of patients claimed full concordance with chemoprophylaxis for maintenance of remission. Eighty-four percent of patients considered daily concordance during remission to be very important. Seventy-five percent stated they understood the reasons for taking the drugs. However, only 50% of the patients were aware of any link of their condition to bowel cancer. Seventy-nine percent of patients felt their concordance and understanding would be improved if they were informed of the chemoprophylactic potential of the medication.
CONCLUSION: Despite good self-reported concordance, half of the patients were unaware of an association between colitis and bowel cancer. Explaining the potential chemoprophylactic benefits may enhance patients’ overall concordance to 5-aminosalicylic acid and ursodeoxycholic acid and help maintain remission.
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Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138:746-74, 774.e1-4; quiz e12-3. [PMID: 20141809 DOI: 10.1053/j.gastro.2009.12.035] [Citation(s) in RCA: 339] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Francis A Farraye
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
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Bernstein CN, Nugent Z, Longobardi T, Blanchard JF. Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study. Am J Gastroenterol 2009; 104:2774-8. [PMID: 19623167 DOI: 10.1038/ajg.2009.417] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES There is anecdotal evidence that isotretinoin use is associated with development of colitis. We aimed at determining whether there is an association between isotretinoin use and development of inflammatory bowel disease (IBD). METHODS The population-based University of Manitoba IBD Epidemiology Database and a control group matched by age, sex, and geographical residence were linked to the provincial prescription drug registry, a registry that was initiated in 1995. The number of users and duration of isotretinoin use were identified in both IBD cases and controls. RESULTS We found that 1.2% of IBD cases used isotretinoin before IBD diagnosis, which was statistically similar to controls (1.1% users). This was also similar to the number of IBD patients who used isotretinoin after a diagnosis of IBD (1.1%). There was no difference between isotretinoin use before Crohn's disease compared with its use before ulcerative colitis. CONCLUSIONS Patients with IBD were no more likely to have used isotretinoin before diagnosis than were sex-, age-, and geography-matched controls. Although there may be anecdotes of isotretinoin causing acute colitis, our data suggest that isotretinoin is not likely to cause chronic IBD.
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Affiliation(s)
- Charles N Bernstein
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.
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Terdiman JP, Johnson LK, Kim YS, Sleisenger MH, Gum JR, Hayes A, Weinberg VK, McQuaid KR. Chemoprevention of colonic polyps with balsalazide: an exploratory, double-blind, placebo-controlled study. Dig Dis Sci 2009; 54:2488-96. [PMID: 19757048 PMCID: PMC2762046 DOI: 10.1007/s10620-009-0966-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Accepted: 08/20/2009] [Indexed: 01/19/2023]
Abstract
BACKGROUND A number of agents, including aspirin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, folic acid, calcium, and vitamins, have been evaluated for their potential in chemoprevention of sporadic colorectal adenomas or cancer. Preclinical data suggest that 5-aminosalicylates also may have a chemopreventive effect. AIM To investigate chemoprevention of colonic polyps with balsalazide, a 5-aminosalicylate prodrug. METHODS In this randomized, double-blind, placebo-controlled study, adults diagnosed with small polyps in the rectosigmoid colon were treated with either balsalazide 3 g/d or placebo for 6 months. Follow-up lower endoscopy was performed, and all polyps were measured and analyzed histologically. The primary endpoint was reduction in mean size of the largest polyp per subject. RESULTS Among 241 participants screened, 86 were randomized to treatment, with 75 subjects evaluable. Balsalazide 3 g/d (n = 38) did not significantly reduce the mean size of the largest colonic polyp or the number of polyps compared with placebo (n = 37). Although not significant, post-hoc analysis revealed that total adenoma burden per subject, calculated as the sum of the volumes of all adenomas in mm3, increased by 55% in the balsalazide group compared with 95% in the placebo group. CONCLUSIONS Although balsalazide did not have significant chemopreventive effects on established colonic polyps, these results can aid in designing future prospective studies.
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Affiliation(s)
- Jonathan P. Terdiman
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA
| | | | - Young S. Kim
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Marvin H. Sleisenger
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - James R. Gum
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Ann Hayes
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
| | - Vivian K. Weinberg
- Helen Diller Family Cancer Center Biostatistics Core, University of California, San Francisco, Box 1623, San Francisco, CA 94143 USA
| | - Kenneth R. McQuaid
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA USA ,Department of Veterans Affairs Medical Center, San Francisco, CA USA
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The long journey of salicylates in ulcerative colitis: The past and the future. J Crohns Colitis 2009; 3:149-56. [PMID: 21172263 DOI: 10.1016/j.crohns.2009.05.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2009] [Revised: 05/05/2009] [Accepted: 05/05/2009] [Indexed: 02/08/2023]
Abstract
The advent of salicylates in the treatment of ulcerative colitis started in 1938 with the discovery of Salazopyrin by Nanna Svartz. This drug offered for the first time a therapeutic chance to patients with ulcerative colitis. In this paper we describe the fascinating history of Salazopyrin and salicylates from the first serendipitous observations to the last randomized clinical trials. Attention was paid to the pharmacokinetics and the mechanism of action of 5-aminosalicylates and, in particular, to the issue of the mucosal concentrations of 5-aminosalicylates and its therapeutic efficacy. Moreover a look at the new oral mesalazine formulations that allow the homogenous distribution of 5-aminosalicylate through all the large bowel was taken. Lastly, the possible use of mesalazine in the prevention of colorectal cancer was reviewed.
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Rubenstein JH, Waljee AK, Jeter JM, Velayos FS, Ladabaum U, Higgins PDR. Cost effectiveness of ulcerative colitis surveillance in the setting of 5-aminosalicylates. Am J Gastroenterol 2009; 104:2222-32. [PMID: 19491824 PMCID: PMC2764368 DOI: 10.1038/ajg.2009.264] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Colorectal cancer (CRC) is a feared complication of chronic ulcerative colitis (UC). Annual endoscopic surveillance is recommended for the detection of early neoplasia. 5-Aminosalicylates (5-ASAs) may prevent some UC-associated CRC. Therefore, in patients prescribed 5-ASAs for maintenance of remission, annual surveillance might be overly burdensome and inefficient. We aimed to determine the ideal frequency of surveillance in patients with UC maintained on 5-ASAs. METHODS We performed systematic reviews of the literature, and created a Markov computer model simulating a cohort of 35-year-old men with chronic UC, followed until the age of 90 years. Twenty-two strategies were modeled: natural history (no 5-ASA or surveillance), surveillance without 5-ASA at intervals of 1-10 years, 5-ASA plus surveillance every 1-10 years, and 5-ASA alone. The primary outcome was the ideal interval of surveillance in the setting of 5-ASA maintenance, assuming a third-party payer was willing to pay $100,000 for each quality-adjusted life-year (QALY) gained. RESULTS In the natural history strategy, the CRC incidence was 30%. Without 5-ASA, annual surveillance was the ideal strategy, preventing 89% of CRC and costing $69,100 per QALY gained compared with surveillance every 2 years. 5-ASA alone prevented 49% of CRC. In the setting of 5-ASA, surveillance every 3 years was ideal, preventing 87% of CRC. 5-ASA with surveillance every 2 years cost an additional $147,500 per QALY gained, and 5-ASA with annual surveillance cost nearly $1 million additional per QALY gained compared with every 2 years. In Monte Carlo simulations, surveillance every 2 years or less often was ideal in 95% of simulations. CONCLUSIONS If 5-ASA is efficacious chemoprevention for UC-associated CRC, endoscopic surveillance might be safely performed every 2 years or less often. Such practice could decrease burdens to patients and on endoscopic resources with a minimal decrease in quality-adjusted length of life, because 5-ASA with annual surveillance may cost nearly $1 million per additional QALY gained.
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Affiliation(s)
- Joel H Rubenstein
- The Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
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Ullman T, Odze R, Farraye FA. Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn's disease of the colon. Inflamm Bowel Dis 2009; 15:630-8. [PMID: 18942763 PMCID: PMC2753500 DOI: 10.1002/ibd.20766] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
To minimize the possibility of developing lethal colorectal cancer (CRC) in ulcerative colitis (UC) and Crohn's colitis, patients are usually enrolled in a program of dysplasia surveillance. The success of a surveillance program depends on the identification of patients with dysplasia and timely referral for colectomy. While a number of issues might stand in the way of a surveillance system achieving its maximal effect (less than ideal agreement in the interpretation of biopsy specimens, sampling error by endoscopists, delays in referral to surgery, and patient drop-out among others), circumstantial evidence supports the concept that colonoscopic dysplasia surveillance is an effective means of reducing CRC mortality and morbidity while minimizing the application of colectomy for cancer prevention. This review critically appraises key issues in the diagnosis and management of dysplasia in UC and Crohn's disease as well as adjunct efforts to prevent CRC in inflammatory bowel disease.
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Affiliation(s)
- Thomas Ullman
- Mount Sinai School of Medicine, New York, New York, USA
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Andrews JM, Travis SPL, Gibson PR, Gasche C. Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes? Aliment Pharmacol Ther 2009; 29:459-69. [PMID: 19077129 DOI: 10.1111/j.1365-2036.2008.03915.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND With greater use of immunomodulators in inflammatory bowel disease (IBD), it is uncertain whether concurrent therapy with both 5-aminosalicylic acid [5-ASA, mesalazine (mesalamine)] and an immunomodulator is necessary. AIM To determine whether concurrent therapy with both 5-ASA and immunomodulator(s) improves outcomes in IBD. METHODS Systematic review with search terms 'azathioprine, 6-mercaptopurine, thiopurine(s), 5 aminosalicylic acid, mesalazine, inflammatory bowel disease, ulcerative colitis, Crohn's disease, immunosuppressant(s), immunomodulator and methotrexate' in November 2007 to identify clinical trials on concurrent 5-ASA and immunomodulator therapy. RESULTS Two small controlled studies were found. Neither showed a benefit on disease control beyond immunomodulator monotherapy. Potential pharmacological interactions exist between 5-ASA and thiopurines. Whilst circumstantial, epidemiological and laboratory evidence suggests that 5-ASA may assist colorectal cancer (CRC) chemoprevention, it may simply be via anti-inflammatory effects. With changes in practice, ethical issues and the long lead-time needed to demonstrate or disprove an effect, no clinical studies can/will directly answer this. The costs of avoiding one CRC in IBD may be as low as 153 times the annual cost of 5-ASA therapy. CONCLUSIONS It is unclear whether concurrent 5-ASA and immunomodulator therapy improves outcomes of disease control, drug toxicity or compliance. Concurrent therapy of 5-ASA and immunomodulators may decrease CRC risk at 'acceptable' cost.
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Affiliation(s)
- J M Andrews
- Departments of Gastroenterology and Hepatology, Royal Adelaide Hospital and School of Medicine, University of Adelaide, Adelaide, SA, Australia.
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Ahmadi A, Polyak S, Draganov PV. Colorectal cancer surveillance in inflammatory bowel disease: The search continues. World J Gastroenterol 2009; 15:61-6. [PMID: 19115469 PMCID: PMC2653296 DOI: 10.3748/wjg.15.61] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk for colorectal cancer (CRC). Risk factors for the development of CRC in the setting of IBD include disease duration, anatomic extent of disease, age at time of diagnosis, severity of inflammation, family history of colon cancer, and concomitant primary sclerosing cholangitis. The current surveillance strategy of surveillance colonoscopy with multiple random biopsies most likely reduces morbidity and mortality associated with IBD-related CRC. Unfortunately, surveillance colonoscopy also has severe limitations including high cost, sampling error at time of biopsy, and interobserver disagreement in histologically grading dysplasia. Furthermore, once dysplasia is detected there is disagreement about its management. Advances in endoscopic imaging techniques are already underway, and may potentially aid in dysplasia detection and improve overall surveillance outcomes. Management of dysplasia depends predominantly on the degree and focality of dysplasia, with the mainstay of management involving either proctocolectomy or continued colonoscopic surveillance. Lastly, continued research into additional chemopreventive agents may increase our arsenal in attempting to reduce the incidence of IBD-associated CRC.
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Ullman T, Croog V, Harpaz N, Hossain S, Kornbluth A, Bodian C, Itzkowitz S. Progression to colorectal neoplasia in ulcerative colitis: effect of mesalamine. Clin Gastroenterol Hepatol 2008; 6:1225-30; quiz 1177. [PMID: 18848502 DOI: 10.1016/j.cgh.2008.05.020] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Revised: 05/13/2008] [Accepted: 05/26/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Some studies have suggested that mesalamine can prevent the development of colorectal cancer in patients with ulcerative colitis (UC). The aim of this study was to compare rates of progression with advanced neoplasia in patient cohorts with UC taking low and high doses of mesalamine and to determine where in the process of neoplastic progression mesalamine might act. METHODS Three cohorts of UC patients were identified from an institutional database: 311 patients with no dysplasia (NoD), 56 with indefinite dysplasia (IND), and 26 with flat low-grade dysplasia (fLGD). The impact of mesalamine exposure on the subsequent development of advanced neoplasia (high-grade dysplasia or colorectal cancer) was assessed using life-table methods. RESULTS Seventeen of 311 patients with NoD progressed to advanced neoplasia (5-year rate, 1.1%). This rate was lower than the 5-year rate for the IND (9%; P = .02 vs NoD) and fLGD (45%; P < .001 vs NoD and P = .001 vs IND) cohorts. Among the NoD cohort, the hazard ratio for mesalamine users versus nonusers was 0.70 (95% confidence interval, 0.20-2.44), and for each 1 g/d increase in dose, the hazard ratio was 0.92 (95% confidence interval, 0.58-1.47). For patients with IND, no patients on greater than 2 g/d progressed versus 13.8% on low-dose mesalamine (P = .11). For fLGD, 62.5% on high dose progressed, versus 27.8% on low dose (P = .054). CONCLUSIONS In long-standing UC, patients with fLGD have a higher rate of progression to advanced neoplasia than those with NoD or IND. However, at none of these stages of disease did mesalamine use show definitive chemopreventive activity.
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Affiliation(s)
- Thomas Ullman
- Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
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Clapper ML, Gary MA, Coudry RA, Litwin S, Chang WCL, Devarajan K, Lubet RA, Cooper HS. 5-aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis 2008; 14:1341-7. [PMID: 18452197 DOI: 10.1002/ibd.20489] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The impact of the antiinflammatory agent 5-aminosalicylic acid (5-ASA) on the risk for colitis-associated colorectal cancer remains controversial. The chemopreventive activity of 5-ASA was evaluated in the Swiss Webster model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated neoplasia. METHODS Mice were injected with AOM (7.4 mg/kg i.p.) and randomized to receive either vehicle or 5-ASA (75, 150, and 225 mg/kg) for the remainder of the study. DSS treatment began at 9 weeks of age and continued for 3 cycles. At the time of sacrifice (18 weeks of age), the entire colon and rectum were processed for histopathologic examination. RESULTS An inverse trend was observed between dose and multiplicity of colonic dysplasias in all drug-treated groups (P = 0.03), with animals receiving 75 mg/kg 5-ASA exhibiting 56% of the number of dysplasias of the AOM/DSS controls (mean +/- SEM: 7.6 +/- 1.4 and 13.6 +/- 2.7, respectively). Administration of 75 mg/kg 5-ASA decreased both the mean multiplicity of flat dysplasias (1.8 +/- 0.4 for drug-treated versus 5.6 +/- 1.2 for AOM/DSS control) and the burden of polypoid dysplasias (tumor burden: 6.7 +/- 2.7 for drug-treated versus 14.9 +/- 3.9 units for AOM/DSS controls) significantly (P = 0.002 and 0.04, respectively). Inflammation was least severe in the 75 mg/kg group, which exhibited the fewest number of colorectal tumors. CONCLUSIONS These data suggest that low-dose 5-ASA may be efficacious in preventing colitis-associated dysplasias and provide strong support for optimizing this therapy for the prevention of colonic neoplasms in patients with ulcerative colitis.
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Affiliation(s)
- Margie L Clapper
- Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
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Stolfi C, Pellegrini R, Franzè E, Pallone F, Monteleone G. Molecular basis of the potential of mesalazine to prevent colorectal cancer. World J Gastroenterol 2008; 14:4434-9. [PMID: 18680220 PMCID: PMC2731267 DOI: 10.3748/wjg.14.4434] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with ulcerative colitis (UC) and Crohn's disease (CD) are at increased risk for developing colorectal cancer (CRC), and this is believed to be a result of chronic inflammation. Although conclusive evidence is still missing, both epidemiological and experimental observations suggest that certain drugs used to treat inflammation, such as mesalazine, can reduce the incidence of colitis-associated CRC. Therefore, in recent years, several studies have been conducted to dissect the mechanisms by which mesalazine interferes with CRC cell growth and survival. This review summarizes the current information on the molecular mechanisms that underlie the antineoplastic action of mesalazine.
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Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 2008; 14:3937-3947. [PMID: 18609676 PMCID: PMC2725331 DOI: 10.3748/wjg.14.3937] [Citation(s) in RCA: 318] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2008] [Revised: 04/18/2008] [Accepted: 04/25/2008] [Indexed: 02/06/2023] Open
Abstract
The risk of colorectal cancer for any patient with ulcerative colitis is known to be elevated, and is estimated to be 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. Risk factors for cancer include extent and duration of ulcerative colitis, primary sclerosing cholangitis, a family history of sporadic colorectal cancer, severity of histologic bowel inflammation, and in some studies, young age at onset of colitis. In this review, the authors discuss recent epidemiological trends and causes for the observed changes. Population-based studies published within the past 5 years suggest that this risk has decreased over time, despite the low frequency of colectomies. The crude annual incidence rate of colorectal cancer in ulcerative colitis ranges from approximately 0.06% to 0.16% with a relative risk of 1.0-2.75. The exact mechanism for this change is unknown; it may partly be explained by the more widespread use of maintenance therapy and surveillance colonoscopy.
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Konda A, Duffy MC. Surveillance of patients at increased risk of colon cancer: inflammatory bowel disease and other conditions. Gastroenterol Clin North Am 2008; 37:191-213, viii. [PMID: 18313546 DOI: 10.1016/j.gtc.2007.12.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the United States. Colonoscopic screening with removal of adenomatous polyps in individuals at average risk is known to decrease the incidence and associated mortality from colon cancer. Certain conditions, notably inflammatory bowel disease involving the colon, a family history of polyps or cancer, a personal history of colon cancer or polyps, and other conditions such as acromegaly, ureterosigmoidostomy, and Streptococcus bovis bacteremia are associated with an increased risk of colonic neoplasia. This article reviews the CRC risks associated with these conditions and the currently recommended surveillance strategies.
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Affiliation(s)
- Amulya Konda
- Division of Gastroenterology, William Beaumont Hospital, 3535 West 13 Mile Road, Royal Oak, MI 48076, USA
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Rubin DT, Cruz-Correa MR, Gasche C, Jass JR, Lichtenstein GR, Montgomery EA, Riddell RH, Rutter MD, Ullman TA, Velayos FS, Itzkowitz S. Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review and update. Inflamm Bowel Dis 2008; 14:265-74. [PMID: 17932965 DOI: 10.1002/ibd.20297] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A roundtable consensus meeting was held to consolidate current knowledge on the etiology of colorectal cancer in patients with inflammatory bowel disease and to review current strategies, both diagnostic and preventive, specifically addressing the role of 5-aminosalicylic acid. Specific topics that were addressed included: the epidemiology of colorectal cancer, including an assessment of risk factors and the impact of colonoscopy on colorectal cancer incidence and mortality; the origin and evolution of dysplasia nomenclature and the natural history of dysplasia; review of the experience of St. Mark's Hospital (London) as gleaned from its surveillance database; mechanisms by which 5-aminosalicylic acid is thought to exert a chemopreventive effect; the potential future role of 5-aminosalicylic acid in chemopreventive strategies; chemoprevention in familial adenomatous polyposis; and other future research directions. This article provides a comprehensive overview of the issues discussed and should act as a guide to shaping the design of future studies in this area.
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Affiliation(s)
- David T Rubin
- University of Chicago Medical Center, Chicago, IL 60637, USA.
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Colon, Rectum, and Anus. Surgery 2008. [DOI: 10.1007/978-0-387-68113-9_52] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Levine JS, Burakoff R. Chemoprophylaxis of colorectal cancer in inflammatory bowel disease: current concepts. Inflamm Bowel Dis 2007; 13:1293-8. [PMID: 17567870 DOI: 10.1002/ibd.20186] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Ulcerative colitis and Crohn's disease both confer an increased risk of developing colorectal cancer. The use of 5-aminosalicylate as a remission-inducing agent has been long accepted. Its use as a potential chemoprophylactic agent has been proposed and is used by some practitioners. This review examines the most recent data on 5-aminosalicylate as a chemoprophylactic drug as well as ursodeoxycholic acid, folic acid, azathioprine, and 6-mercaptopurine.
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Affiliation(s)
- Jonathan S Levine
- Center for Crohn's and Colitis, Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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