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Momayez Sanat Z, Vahedi H, Malekzadeh R, Kasaeian A, Mohammadi Ganjaroudi N, Sima A, Mansour Ghanaei F, Ghadir M, Tirgar Fakheri H, Nasseri Moghaddam S, Alatab S, Sadeghi A, Anushiravani A, Maleki I, Yazdanbod A, Vossoughinia H, Seyyedmajidi M, Naghshbandi SJ, Baniasadi N, Parhizkar B, Matinkhah S, Gheibi S, Hosseini Hemmat Abadi RS, Valizadeh Toosi S. Causes of Colectomy in Patients with Ulcerative Colitis: Findings from an Iranian National Registry. ARCHIVES OF IRANIAN MEDICINE 2024; 27:350-356. [PMID: 39072382 PMCID: PMC11316182 DOI: 10.34172/aim.28887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/05/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) marked by rectal and colon inflammation, leading to relapsing symptoms. Its prevalence is increasing, particularly in developed nations, impacting patients' health. While its exact cause remains unclear, genetic and environmental factors are implicated, elevating the risk of colorectal cancer (CRC). Colectomy, though declining, is still performed in select UC cases, necessitating further study. METHODS We analyzed data from the Iranian Registry of Crohn's and Colitis (IRCC) to examine UC patients undergoing colectomy. We collected demographic and clinical data from 91 patients, focusing on dysplasia. Statistical analyses assessed dysplasia risk factors. RESULTS Patients with dysplasia were older at diagnosis and surgery compared to those without dysplasia. Age emerged as a significant risk factor for dysplasia in UC patients undergoing colectomy. No significant associations were found between dysplasia and other factors. CONCLUSION Age plays a crucial role in dysplasia risk among UC patients undergoing colectomy. Older age at diagnosis and surgery may indicate a higher risk of dysplasia and CRC. Clinicians should consider age when managing UC patients and implementing screening protocols. Further research with larger samples is needed to confirm these findings.
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Affiliation(s)
- Zahra Momayez Sanat
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Homayoon Vahedi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Malekzadeh
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Kasaeian
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Chronic Inflammatory Diseases, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Clinical Research Development Unit, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Alireza Sima
- Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Center, Tehran, Iran
| | - Fariborz Mansour Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Guilan, Iran
| | - Mohammadreza Ghadir
- Gastroenterology and Hepatology Diseases Research Center, Qom University of Medical Science, Qom, Iran
| | - Hafez Tirgar Fakheri
- Gut and Liver Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Siavosh Nasseri Moghaddam
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sudabeh Alatab
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Anahita Sadeghi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Iradj Maleki
- Gut and Liver Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abbas Yazdanbod
- Digestive Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Hassan Vossoughinia
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sayed Jalaleddin Naghshbandi
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nadieh Baniasadi
- Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran
| | - Baran Parhizkar
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Shahsanam Gheibi
- Maternal and Childhood Obesity Research center, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Seyedmohamad Valizadeh Toosi
- Gut and Liver Research Center, Non-communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
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Uchino M, Ikeuchi H, Noguchi T, Okabayashi K, Futami K, Tanaka S, Ohge H, Watanabe K, Itabashi M, Okamoto K, Okita Y, Mizushima T, Mizuuchi Y, Yamada K, Shimada Y, Sato Y, Kimura H, Takahashi K, Hida K, Kinugasa Y, Okuda J, Daito K, Koyama F, Ueno H, Yamamoto T, Hanai T, Kono T, Kobayashi H, Ajioka Y, Sugihara K, Ishihara S. Histological differentiation between sporadic and colitis-associated intestinal cancer in a nationwide study: A propensity-score-matched analysis. J Gastroenterol Hepatol 2024; 39:893-901. [PMID: 38273469 DOI: 10.1111/jgh.16496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/05/2023] [Accepted: 01/07/2024] [Indexed: 01/27/2024]
Abstract
BACKGROUND AND AIM Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.
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MESH Headings
- Humans
- Propensity Score
- Male
- Female
- Middle Aged
- Colitis, Ulcerative/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/epidemiology
- Aged
- Japan/epidemiology
- Crohn Disease/pathology
- Crohn Disease/epidemiology
- Crohn Disease/complications
- Colitis-Associated Neoplasms/pathology
- Colitis-Associated Neoplasms/etiology
- Colitis-Associated Neoplasms/epidemiology
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/epidemiology
- Colorectal Neoplasms/etiology
- Adult
- Adenocarcinoma/pathology
- Adenocarcinoma/epidemiology
- Adenocarcinoma/etiology
- Neoplasm Staging
- Neoplasm Grading
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Mucinous/epidemiology
- Adenocarcinoma, Mucinous/etiology
- Carcinoma, Signet Ring Cell/pathology
- Carcinoma, Signet Ring Cell/epidemiology
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/epidemiology
- Carcinoma, Squamous Cell/etiology
- Diagnosis, Differential
- Prevalence
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Affiliation(s)
- Motoi Uchino
- Department of Gastroenterological Surgery, Division of Inflammatory Bowel Disease, Hyogo Medical University, Nishinomiya, Japan
| | - Hiroki Ikeuchi
- Department of Gastroenterological Surgery, Division of Inflammatory Bowel Disease, Hyogo Medical University, Nishinomiya, Japan
| | - Tatsuki Noguchi
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Okabayashi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kitaro Futami
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michio Itabashi
- Department of Surgery, Division of Inflammatory Bowel Disease Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Kinya Okamoto
- Department of Coloproctology, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Yoshiki Okita
- Department of Gastrointestinal and Pediatric Surgery, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yusuke Mizuuchi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazutaka Yamada
- Department of Surgery, Coloproctology Center Takano Hospital, Kumamoto, Japan
| | - Yoshifumi Shimada
- Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yu Sato
- Department of Surgery, Toho University Sakura Medical Center, Chiba, Japan
| | - Hideaki Kimura
- Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Kenichi Takahashi
- Department of Colorectal Surgery, Tohoku Rosai Hospital, Sendai, Japan
| | - Koya Hida
- Department of Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Junji Okuda
- Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Koji Daito
- Department of Surgery, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Fumikazu Koyama
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Japan
| | - Tsunekazu Hanai
- Department of Surgery, School of Medicine, Fujita Health University, Toyoake, Japan
| | - Toru Kono
- Advanced Surgery Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Hirotoshi Kobayashi
- Department of Surgery, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | | | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
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Jamil OK, Shaw D, Deng Z, Dinardi N, Fillman N, Khanna S, Krugliak Cleveland N, Sakuraba A, Weber CR, Cohen RD, Dalal S, Jabri B, Rubin DT, Pekow J. Inflammation in the proximal colon is a risk factor for the development of colorectal neoplasia in inflammatory bowel disease patients with primary sclerosing cholangitis. Therap Adv Gastroenterol 2023; 16:17562848231184985. [PMID: 37692199 PMCID: PMC10486214 DOI: 10.1177/17562848231184985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 06/12/2023] [Indexed: 09/12/2023] Open
Abstract
Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have an increased risk of developing colorectal neoplasia (CRN) in the proximal colon. Objectives To evaluate whether duration and severity of inflammation are linked to the development of CRN in this population. Design Retrospective, case-control chart review of patients with PSC and IBD at a tertiary care center. Methods Disease activity was scored per colonic segment at each colonoscopy prior to the first instance of observed CRN using a modified Mayo endoscopic sub-score and histologic assessment. Patients in the CRN-positive group were compared to controls that did not. Results In all, 72 PSC-IBD patients with no history of CRN were identified, 13 of whom developed CRN after at least one colonoscopy at our institution. Patients in the CRN-positive group had significantly more endoscopic (p < 0.01) and histologic (p < 0.01) inflammation in the right compared to the control group prior to the development of dysplasia. There was significantly greater endoscopic inflammation in the segment of the colon with a dysplastic lesion than other segments of the colon (p = 0.018). Patients with moderate/severe lifetime endoscopic (p = 0.02) or histologic inflammation (p = 0.04) score had a lower probability of remaining free of dysplasia during follow-up. Nearly half of the patients with dysplasia had invisible lesions found on random biopsy. Conclusions Endoscopic and histologic inflammation in the proximal colon are risk factors for CRN in patients with PSC-IBD. PSC-IBD patients frequently have subclinical inflammation, and these findings support the practice of regular assessment of disease activity and random biopsy of inflamed and uninflamed areas in patients with PSC with the goal of reducing inflammation to prevent the development of CRN.
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Affiliation(s)
- Omar K. Jamil
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Dustin Shaw
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA Digestive Diseases Research Core Center, University of Chicago Medicine, Chicago, IL, USA
| | - Zifeng Deng
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Nicholas Dinardi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Natalie Fillman
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Shivani Khanna
- Department of Allergy and Immunology, Johns Hopkins University, Baltimore, MD, USA
| | | | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | | | - Russell D. Cohen
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Sushila Dalal
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Bana Jabri
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA Digestive Diseases Research Core Center, University of Chicago Medicine, Chicago, IL, USA
| | - David T. Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Joel Pekow
- Inflammatory Bowel Disease Center, University of Chicago Medicine, 900 East 57th Street, MB #9, Chicago, IL 60637, USA
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Luo X, Zheng Y, Bao YR, Wang S, Li TJ, Leng JP, Meng XS. Potential effects of fructus aurantii ethanol extracts against colitis-associated carcinogenesis through coordination of Notch/NF-κB/IL-1 signaling pathways. Biomed Pharmacother 2022; 152:113278. [PMID: 35709655 DOI: 10.1016/j.biopha.2022.113278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 11/18/2022] Open
Abstract
Colitis-associated cancer (CAC) is the colorectal cancer (CRC) subtype that is difficult to treat, and shows high mortality. The consumption of flavonoid-rich fructus aurantii extracts (FAE) has been associated with multiple beneficial effects including anti-inflammatory and anti-cancer properties, but the potential effects on the colitis-associated carcinogenesis have not been thoroughly investigated. Recent clinical data show that, as yet, few agents clearly inhibited CRC development in long-standing inflammatory bowel diseases. Here, we identified that FAE showed significant efficiency to inhibit HT-29 cell proliferation. The potential of FAE in vivo was further evaluated in an AOM/DSS-induced CAC mouse model. Intriguingly, FAE diminished the number of polyps in mice. Furthermore, FAE inhibited CAC by regulating the gene expression of Notch/ NF-κB/IL-1 signaling pathways. Collectively, these results were indicative of FAE has great potential in CAC prevention and treatment.
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Affiliation(s)
- Xi Luo
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Yi Zheng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Yong-Rui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Liaoning Multi-dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian 116600, China; Liaoning Province Modern Traditional Chinese Medicine Research and Engineering Laboratory, Dalian 116600, China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Liaoning Multi-dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian 116600, China; Liaoning Province Modern Traditional Chinese Medicine Research and Engineering Laboratory, Dalian 116600, China
| | - Tian-Jiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Liaoning Multi-dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian 116600, China; Liaoning Province Modern Traditional Chinese Medicine Research and Engineering Laboratory, Dalian 116600, China
| | - Jia-Peng Leng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
| | - Xian-Sheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China; Liaoning Multi-dimensional Analysis of Traditional Chinese Medicine Technical Innovation Center, Dalian 116600, China; Liaoning Province Modern Traditional Chinese Medicine Research and Engineering Laboratory, Dalian 116600, China.
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Modulation of Mismatch Repair and the SOCS1/p53 Axis by microRNA-155 in the Colon of Patients with Primary Sclerosing Cholangitis. Int J Mol Sci 2022; 23:ijms23094905. [PMID: 35563301 PMCID: PMC9100906 DOI: 10.3390/ijms23094905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 12/10/2022] Open
Abstract
Deficient mismatch repair (MMR) proteins may lead to DNA damage and microsatellite instability. Primary sclerosing cholangitis (PSC) is a risk factor for colitis-associated colon cancer. MiR-155 is suggested to act as a key regulating node, linking inflammation and tumorigenesis. However, its involvement in the chronic colitis of PSC-UC patients has not been examined. We investigated the involvement of miR-155 in the dysregulation of MMR genes and colitis in PSC patients. Colon tissue biopsies were obtained from patients with PSC, PSC with concomitant ulcerative colitis (PSC-UC), uncomplicated UC, and healthy controls (n = 10 per group). In the ascending colon of PSC and PSC-UC patients, upregulated miR-155 promoted high microsatellite instability and induced signal transducer and activator of transcription 3 (STAT-3) expression via the inhibition of suppressors of cytokine signalling 1 (SOCS1). In contrast, the absence of miR-155 overexpression in the sigmoid colon of PSC-UC patients activated the Il-6/S1PR1 signalling pathway and imbalanced the IL17/FOXP3 ratio, which reinforces chronic colitis. Functional studies on human intestinal epithelial cells (HT-29 and NCM460D) confirmed the role of miR-155 over-expression in the inhibition of MMR genes and the modulation of p53. Moreover, those cells produced more TNFα upon a lipopolysaccharide challenge, which led to the suppression of miR-155. Additionally, exposure to bile acids induced upregulation of miR-155 in Caco-2 cell lines. Thus, under different conditions, miR-155 is involved in either neoplastic transformation in the ascending colon or chronic colitis in the sigmoid colon of patients with PSC. New insight into local modulation of microRNAs, that may alter the course of the disease, could be used for further research on potential therapeutic applications.
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6
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Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology 2022; 162:715-730.e3. [PMID: 34757143 PMCID: PMC9003896 DOI: 10.1053/j.gastro.2021.10.035] [Citation(s) in RCA: 372] [Impact Index Per Article: 124.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, University of California San Diego, San Diego, California; GI Section, VA San Diego Healthcare Center, San Diego, California
| | - Steven H Itzkowitz
- The Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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Reznicek E, Arfeen M, Shen B, Ghouri YA. Colorectal Dysplasia and Cancer Surveillance in Ulcerative Colitis. Diseases 2021; 9:86. [PMID: 34842672 PMCID: PMC8628786 DOI: 10.3390/diseases9040086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative colitis (UC) is a risk factor for the development of inflammation-associated dysplasia or colitis-associated neoplasia (CAN). This transformation results from chronic inflammation, which induces changes in epithelial proliferation, survival, and migration via the induction of chemokines and cytokines. There are notable differences in genetic mutation profiles between CAN in UC patients and sporadic colorectal cancer in the general population. Colonoscopy is the cornerstone for surveillance and management of dysplasia in these patients. There are several modalities to augment the quality of endoscopy for the better detection of dysplastic or neoplastic lesions, including the use of high-definition white-light exam and image-enhanced colonoscopy, which are described in this review. Clinical practice guidelines regarding surveillance strategies in UC have been put forth by various GI societies, and overall, there is agreement between them except for some differences, which we highlight in this article. These guidelines recommend that endoscopically detected dysplasia, if feasible, should be resected endoscopically. Advanced newer techniques, such as endoscopic mucosal resection and endoscopic submucosal dissection, have been utilized in the treatment of CAN. Surgery has traditionally been the mainstay of treating such advanced lesions, and in cases where endoscopic resection is not feasible, a proctocolectomy, followed by ileal pouch-anal anastomosis, is generally recommended. In this review we summarize the approach to surveillance for cancer and dysplasia in UC. We also highlight management strategies if dysplasia is detected.
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Affiliation(s)
- Emily Reznicek
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Mohammad Arfeen
- Department of Gastroenterology, Franciscan Health, Olympia Fields, IL 60461, USA
| | - Bo Shen
- Interventional IBD Center, Department of Medicine and Surgery, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY 10032, USA
| | - Yezaz A. Ghouri
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO 65212, USA
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8
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Bhama AR, Kapadia MR. Management of Dysplasia in Ulcerative Colitis. J Laparoendosc Adv Surg Tech A 2021; 31:855-860. [PMID: 34252316 DOI: 10.1089/lap.2020.0974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Surveillance colonoscopies for patients with ulcerative colitis (UC) are necessary to monitor for the development of cancer and its precursor, dysplasia. The management of dysplasia in the setting of UC has been evolving over the past two decades. This is in large part due to higher resolution colonoscopes and development of advanced endoscopic techniques, such as chromoendoscopy, endoscopic mucosal resection, and endoscopic submucosal dissection. Mucosal evaluation, as well as identification and removal of dysplastic tissue, has improved markedly, such that the majority of dysplasia is now considered visible. Whereas previously random biopsies were deemed necessary for surveillance, currently their value is uncertain. Surveillance with high-definition colonoscopes is recommended and consideration of chromoendoscopy is suggested. During colonoscopy, if visible dysplasia is identified and removed completely, continued surveillance is appropriate. If dysplasia is unresectable or there are other high-risk factors such as primary sclerosing cholangitis or multifocality, patients should undergo colectomy. If random biopsies are taken and high-grade dysplasia is identified, that is, invisible dysplasia, patients should similarly consider colectomy. Surgical options include total proctocolectomy with end ileostomy versus ileal pouch-anal anastomosis. Patients undergoing pouch surgery must continue surveillance for dysplasia of the rectal cuff and the pouch. Although surgical management remains an important option for dysplasia in the setting of UC, endoscopic surveillance and resection have improved tremendously, leading to a shift in the overall management strategies for these patients.
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Affiliation(s)
- Anuradha R Bhama
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Muneera R Kapadia
- Division of Gastrointestinal Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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9
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Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini MT, Gad M, Al-Husseini M, Saad A. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets 2021; 22:998-1009. [PMID: 33208072 DOI: 10.2174/1389450121999201117115717] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/30/2020] [Accepted: 10/05/2020] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related deaths in the world with an estimated number of 1.8 million new cases and about 881,000 deaths worldwide in 2018. The epidemiology of CRC varies significantly between different regions in the world as well as between different age, gender and racial groups. Multiple factors are involved in this variation, including risk factor exposure, demographic variations in addition to genetic susceptibility and genetic mutations and their effect on the prognosis and treatment response. In this mini-review, we discuss the recent epidemiological trend including the incidence and mortality of colorectal cancer worldwide and the factors affecting these trends.
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Affiliation(s)
- Firas Baidoun
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | | | - Yasmine Elkeraie
- High institute of Public Health, Alexandria University, Alexandria, Egypt
| | - Zahi Merjaneh
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - George Khoudari
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Muhammad Talal Sarmini
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Mohamed Gad
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Muneer Al-Husseini
- Department of Medicine, Ascension St John Hospital, Detroit, Michigan, United States
| | - Anas Saad
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
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10
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Mäki-Nevala S, Ukwattage S, Olkinuora A, Almusa H, Ahtiainen M, Ristimäki A, Seppälä T, Lepistö A, Mecklin JP, Peltomäki P. Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer. Int J Cancer 2021; 148:2997-3007. [PMID: 33521965 DOI: 10.1002/ijc.33492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/22/2022]
Abstract
Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n = 27) were investigated for microsatellite instability, CpG island methylator phenotype and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n = 28). Mutational loads and signatures stratified CA-CRCs into three subgroups: hypermutated microsatellite-unstable (Group 1, n = 1), hypermutated microsatellite-stable (Group 2, n = 9) and nonhypermutated microsatellite-stable (Group 3, n = 17). The Group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency-associated Signatures 21 and 15. Signatures 30 and 32 characterized Group 2, whereas no prominent single signature existed in Group 3. TP53, the most common mutational target in CA-CRC (16/27, 59%), was similarly affected in Groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in Group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA-CRC Groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, Groups 1 (4%) and 3 (63%) comply with published studies, whereas Group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA-CRC may guide clinical management, such as therapy options.
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Affiliation(s)
- Satu Mäki-Nevala
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Sanjeevi Ukwattage
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Henrikki Almusa
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Maarit Ahtiainen
- Department of Education and Research, Central Finland Central Hospital, Jyväskylä, Finland
| | - Ari Ristimäki
- Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Toni Seppälä
- Department of Gastrointestinal Surgery, Helsinki University Hospital and Helsinki University, Helsinki, Finland
| | - Anna Lepistö
- Department of Gastrointestinal Surgery, Helsinki University Hospital and Helsinki University, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Sport and Health Sciences, University of Jyväskylä and Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
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11
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Recommendations of the Spanish Working Group on Crohn's disease and Ulcerative Colitis (Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa - GETECCU) on dysplasia screening in inflammatory bowel disease patients. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 44:435-447. [PMID: 33592179 DOI: 10.1016/j.gastrohep.2020.12.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022]
Abstract
Colonic inflammatory bowel diseases have a higher risk of developing colorectal cancer compared to the general population, which is why they require endoscopic screening techniques with specific follow-up intervals based on the different risk factors described on the literature. This position paper analyzes the current scientific evidence for the different endoscopic techniques available today, how their implementation should be carried out in endoscopic units and describes in detail how their implementation should be carried out, in which patients and with what interval, and finally, what should be the response to finding dysplasia, proposing a specific follow-up algorithm.
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12
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Lee SA, Wang Y, Liu F, Riordan SM, Liu L, Zhang L. Escherichia coli K12 Upregulates Programmed Cell Death Ligand 1 (PD-L1) Expression in Gamma Interferon-Sensitized Intestinal Epithelial Cells via the NF-κB Pathway. Infect Immun 2020; 89:e00618-20. [PMID: 33046511 PMCID: PMC7927934 DOI: 10.1128/iai.00618-20] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 10/06/2020] [Indexed: 01/09/2023] Open
Abstract
Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein which is used by tumor cells for immune evasion. PD-L1 is upregulated in inflamed intestinal tissues. The intestinal tract is colonized by millions of bacteria, most of which are commensal bacterial species. We hypothesized that under inflammatory conditions, some commensal bacterial species contribute to increased PD-L1 expression in intestinal epithelium and examined this hypothesis. Human intestinal epithelial HT-29 cells with and without interferon (IFN)-γ sensitization were incubated with six strains of four enteric bacterial species. The mRNA and protein levels of PD-L1 in HT-29 cells were examined using quantitative real-time PCR and flow cytometry, respectively. The levels of interleukin (IL)-1β, IL-18, IL-6, IL-8, and tumor necrosis factor (TNF)-α secreted by HT-29 cells were measured using enzyme-linked immunosorbent assay. Apoptosis of HT-29 cells was measured using a caspase 3/7 assay. We found that Escherichia coli K12 significantly upregulated both PD-L1 mRNA and protein in IFN-γ-sensitized HT-29 cells. E. coli K12 induced the production of IL-8 in HT-29 cells, however, IL-8 did not affect HT-29 PD-L1 expression. Inhibition of the nuclear factor-kappa B pathway significantly reduced E. coli K12-induced PD-L1 expression in HT-29 cells. The other two E. coli strains and two enteric bacterial species did not significantly affect PD-L1 expression in HT-29 cells. Enterococcus faecalis significantly inhibited PD-L1 expression due to induction of cell death. Data from this study suggest that some gut bacterial species have the potential to affect immune function under inflammatory conditions via upregulating epithelial PD-L1 expression.
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Affiliation(s)
- Seul A Lee
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Yiming Wang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
- Infection & Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Fang Liu
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Stephen M Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital, University of New South Wales, Sydney, Australia
| | - Lu Liu
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
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13
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A young woman who developed ascending colon cancer 2 years after the onset of ulcerative colitis. Clin J Gastroenterol 2020; 13:1189-1195. [PMID: 32780275 DOI: 10.1007/s12328-020-01207-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/08/2020] [Indexed: 10/23/2022]
Abstract
Guidelines recommend surveillance colonoscopy for patients with an ulcerative colitis (UC) duration of 8-10 years. We experienced a patient who had not undergone UC surveillance. A 35-year-old Japanese woman developed diarrhea and abdominal pain in January 2018 and was diagnosed with UC. She underwent medical therapy, and 18 months after onset of UC colonoscopy indicated that her UC activity was remission and showed no cancer lesions. Twenty-four months after onset, colonoscopy revealed a tumor in the ascending colon, and the biopsy revealed tubular adenocarcinoma. She had no family history of colorectal cancer. There were no findings of distant metastases or primary sclerosing cholangitis. Laparoscopy-assisted anus-preserving total proctocolectomy, the creation of a J-type ileal pouch, ileal pouch anal anastomosis, and the creation of an ileostomy were performed. The pathological report was type 3, 30 × 27-mm, adenocarcinoma (por2 > tub2), pT4a, Ly1a, V1a, budding grade 3, pN0, M0, Stage IIb. Some colitic cancers such as our patient's may not conform to the existing guidelines. When a colonoscopy is being performed for a UC patient, even if its timing is less < 8 years since the UC onset, suspicious lesions should be biopsied considering the possibility of cancer.
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14
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Liu XH, Wu XR, Lan N, Zheng XB, Zhou C, Hu T, Chen YF, Cai ZR, Chen ZX, Lan P, Wu XJ. CD73 promotes colitis-associated tumorigenesis in mice. Oncol Lett 2020; 20:1221-1230. [PMID: 32724362 PMCID: PMC7377052 DOI: 10.3892/ol.2020.11670] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 04/29/2020] [Indexed: 12/26/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumorigenesis. A mouse model of colitis-associated tumorigenesis (CAT) induced by azoxymethane and dextran sulfate sodium was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumor formation were assessed macroscopically. Inflammatory cytokine measurement and RNA sequencing on colon tissues were performed. Inhibition of CD73 by adenosine 5′-(α,β-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumor number and smaller tumor size compared with the model group. Activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranuronamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced, while activation of adenosine receptors exacerbated, the histological damage of the colon. Increased expression of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to RNA sequencing results, potential oncogenes such as arachidonate 15-lipoxygenase (ALOX15), Bcl-2-like protein 15 (Bcl2l15) and N-acetylaspartate synthetase (Nat8l) were downregulated in the APCP group and upregulated in the NECA group compared with the model group. Therefore, inhibition of CD73 attenuated IBD-associated tumorigenesis, while activation of adenosine receptors exacerbated tumorigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.
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Affiliation(s)
- Xuan-Hui Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xian-Rui Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong 510655, P.R. China
| | - Nan Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xiao-Bin Zheng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Chi Zhou
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Tuo Hu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Yu-Feng Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Ze-Rong Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Ze-Xian Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Xiao-Jian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China.,Department of Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
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15
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Zhou Q, Shen ZF, Wu BS, Xu CB, He ZQ, Chen T, Shang HT, Xie CF, Huang SY, Chen YG, Chen HB, Han ST. Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract 2019; 2019:5363261. [PMID: 31781191 PMCID: PMC6874962 DOI: 10.1155/2019/5363261] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ulcerative colitis (UC) patients have an increased risk for the development of colorectal cancer (CRC). Our aim was to assess the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation. METHODS In this systematic review and meta-analysis, we searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to 2018, and assessed the risk of CRC in UC patients. Patients with Crohn's disease, family history of CRC, and colorectal adenomatous polyp (CAP) were excluded from this research. The study was registered with PROSPERO, number CRD42018102213. FINDINGS We included 58 studies that included 267566 UC patients. Extensive UC and left-sided UC had a higher risk of CRC than proctitis UC. Geography also played a role in UC-associated CRC development. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration. CONCLUSION In a systematic review of the literature, we found that disease extent, disease duration, and geography were strong, independent risk factors in UC-associated CRC development.
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Affiliation(s)
- Qing Zhou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhao-Feng Shen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ben-sheng Wu
- Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, China
| | - Cheng-biao Xu
- Xuyi Hospital of Traditional Chinese Medicine, Huaian, Jiangsu, China
| | - Zhong-qi He
- Suzhou Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, China
| | - Tuo Chen
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hong-tao Shang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chao-fan Xie
- Shishi General Hospital, Quanzhou, Fujian, China
| | - Si-yi Huang
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Yu-gen Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hai-bo Chen
- Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Shu-tang Han
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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16
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Shah SC, Itzkowitz SH. Management of Inflammatory Bowel Disease-Associated Dysplasia in the Modern Era. Gastrointest Endosc Clin N Am 2019; 29:531-548. [PMID: 31078251 PMCID: PMC7354094 DOI: 10.1016/j.giec.2019.02.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This article begins with a brief overview of risk factors for colorectal neoplasia in inflammatory bowel disease to concretize the approach to risk stratification. It then provides an up-to-date review of diagnosis and management of dysplasia in inflammatory bowel disease, which integrates new and emerging data in the field. This is particularly relevant in an era of increased attention to cost- and resource-containment from the health systems vantage point, coupled with a heightened prioritization of patient quality of life and shared decision-making. Also provided is a brief discussion of the status of newer therapeutic techniques, such as endoscopic submucosal dissection.
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Affiliation(s)
- Shailja C. Shah
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Steven H. Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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17
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Baker AM, Cross W, Curtius K, Al Bakir I, Choi CHR, Davis HL, Temko D, Biswas S, Martinez P, Williams MJ, Lindsay JO, Feakins R, Vega R, Hayes SJ, Tomlinson IPM, McDonald SAC, Moorghen M, Silver A, East JE, Wright NA, Wang LM, Rodriguez-Justo M, Jansen M, Hart AL, Leedham SJ, Graham TA. Evolutionary history of human colitis-associated colorectal cancer. Gut 2019; 68:985-995. [PMID: 29991641 PMCID: PMC6580738 DOI: 10.1136/gutjnl-2018-316191] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/01/2018] [Accepted: 06/02/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. DESIGN Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. RESULTS 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase. CONCLUSIONS Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
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Affiliation(s)
- Ann-Marie Baker
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - William Cross
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kit Curtius
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ibrahim Al Bakir
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Chang-Ho Ryan Choi
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | | | - Daniel Temko
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Computer Science, University College London, London, UK
- Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK
| | - Sujata Biswas
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Pierre Martinez
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Marc J Williams
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK
- Department of Cell and Developmental Biology, University College London, London, UK
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Roger Feakins
- Department of Histopathology, The Royal London Hospital, London, UK
| | - Roser Vega
- Department of Gastroenterology, University College London Hospital, London, UK
| | - Stephen J Hayes
- Department of Histopathology, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Ian P M Tomlinson
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Stuart A C McDonald
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Morgan Moorghen
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Andrew Silver
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - James E East
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Nicholas A Wright
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lai Mun Wang
- Cellular Pathology, John Radcliffe Hospital, Oxford, UK
| | | | - Marnix Jansen
- Department of Histopathology, University College London Hospital, London, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Simon J Leedham
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Trevor A Graham
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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18
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Khalid S, Abbass A, Khetpal N, Shen B, Navaneethan U. Endoscopic detection and resection of dysplasia in inflammatory bowel disease-techniques with videos. Int J Colorectal Dis 2019; 34:569-580. [PMID: 30854573 DOI: 10.1007/s00384-019-03269-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Patients with ulcerative colitis and Crohn's colitis have an increased risk of developing dysplasia and colorectal cancer as compared to the general population; surveillance colonoscopy is recommended in this patient population. METHODS This review of the published literature aimed to assess the published evidence. RESULTS Detection of dysplasia requires examination of mucosa with targeted biopsies of the visible lesions as well as random biopsies to detect invisible lesions. Newer endoscopic techniques, in particular chromoendoscopy, increase the yield of identifying dysplastic lesions. The surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients International Consensus (SCENIC) guidelines recommends that colonoscopy using chromoendoscopy is the optimal endoscopic surveillance strategy to detect dysplasia. Once dysplastic lesions are discovered on surveillance endoscopic examination, careful and meticulous descriptions of lesions is mandatory to aid in further decision making. Management of dysplastic lesions in inflammatory bowel disease patients depends on endoscopic (morphological) and histologic findings and patient characteristics such as age, general condition of the patient, and patient preferences. Endoscopic mucosal resection, endoscopic submucosal dissection, and surgery are different therapeutic options for colonic dysplastic lesions detected in the setting of inflammatory bowel disease. CONCLUSIONS In this review, we discuss the various techniques for endoscopic resection of dysplasia in patients with inflammatory bowel disease. Further research is required to determine the optimal approach to diagnosis and management of dysplasia in patients with inflammatory bowel disease.
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Affiliation(s)
- Sameen Khalid
- Department of Internal Medicine, Advent Health, Orlando, FL, USA
| | - Aamer Abbass
- Department of Internal Medicine, Advent Health, Orlando, FL, USA
| | - Neelam Khetpal
- Department of Internal Medicine, Advent Health, Orlando, FL, USA
| | - Bo Shen
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH, USA
| | - Udayakumar Navaneethan
- Center for Interventional Endoscopy, Advent Health, University of Central Florida College of Medicine, 601 E Rollins Street, Orlando, FL, 32803, USA.
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19
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Landerholm K, Wood C, Bloemendaal A, Buchs N, George B, Guy R. The rectal remnant after total colectomy for colitis - intra-operative,post-operative and longer-term considerations. Scand J Gastroenterol 2018; 53:1443-1452. [PMID: 30451043 DOI: 10.1080/00365521.2018.1529195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Acute severe colitis requires surgery in around 30% of the cases. Total colectomy with ileostomy is the standard procedure with distinct advantages to a laparoscopic approach. Less agreement exists regarding the formation or configuration of the retained rectal stump and its short-term and long-term management. In this review, aspects of management of the rectal remnant, including perioperative considerations, potential complications, medical treatment, surveillance and implications for proctectomy and reconstructive surgery are explored. METHODS A thorough literature review exploring the PubMed and EMBASE databases was undertaken to clarify the evidence base surrounding areas of controversy in the surgical approach to acute severe colitis. In particular, focus was given to evidence surrounding management of the rectal remnant. RESULTS There is a paucity of high quality evidence for optimal management of the rectal stump following colectomy, and randomised trials are lacking. Establishment of laparoscopic colectomy has been associated with distinct advantages as well as the emergence of unique considerations, including those specific to rectal remnant management. CONCLUSIONS Early surgical involvement and a multidisciplinary approach to the management of acute severe colitis are advocated. Laparoscopic subtotal colectomy and ileostomy should be the operation of choice, with division of the rectum at the pelvic brim leaving a closed intraperitoneal remnant. If the rectum is severely inflamed, a mucus fistula may be useful, and an indwelling rectal catheter is probably advantageous to reduce the complications associated with stump dehiscence. Patients electing not to proceed to proctectomy should undergo surveillance for dysplasia of the rectum.
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Affiliation(s)
- Kalle Landerholm
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
| | - Christopher Wood
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
| | - Alexander Bloemendaal
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
| | - Nicolas Buchs
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
| | - Bruce George
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
| | - Richard Guy
- a Department of Colorectal Surgery , Oxford University Hospital NHS Foundation Trust , Oxford , UK
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Ünal NG, Özütemiz Ö, Tekin F, Turan İ, Osmanoğlu N. Colorectal cancer and dysplasia risk of ulcerative colitis patients in a tertiary referral center in Turkey. TURKISH JOURNAL OF GASTROENTEROLOGY 2018; 30:139-147. [PMID: 30460897 DOI: 10.5152/tjg.2018.18221] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Patients with ulcerative colitis (UC) are at increased risk of colorectal cancer (CRC). High-grade dysplasia (HGD) and low-grade dysplasia (LGD) are premalignant conditions. The aim of this study is to evaluate the risk of CRC/dysplasia in patients with UC, and the related risk factors. MATERIALS AND METHODS Medical records of 1659 patients dating between 1993 and 2016 were scanned from an inflammatory bowel disease database. A total of 801 patients with UC who underwent at least one colonoscopic procedure with at least 1-year follow-up period were included in the study. Clinical, endoscopic, and histopathological data were assessed. RESULTS The mean disease duration was 6.7±6.6 years. The total disease duration was 5334 person-years duration (pyd), and 34% of patients had the disease for 8 years or longer. The prevalence of UC-associated CRC was 0.7%, and the prevalence of dysplasia was 0.85%. The overall incidence of CRC was determined to be 1.1/1000 pyd. The cumulative risk of CRC was 0.3% at 10 years, 1.3% at 20 years, and 5.9% at 30 years. The Cox regression analysis indicated that primary sclerosing cholangitis (HR:13.677, 95% CI:2.6-70.8, p = 0.012) was an independent risk factor for developing UC-associated CRC. CONCLUSION This study underlined the low risk of CRC and dysplasia in patients with UC in a tertiary referral center in the western part of Turkey. Primary sclerosing cholangitis was found to be the most important risk factor for the development of CRC in patients with UC. Identification of risk factors is important to categorize patients into subgroups to know which patients will require frequent surveillance.
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Affiliation(s)
- Nalan Gülşen Ünal
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - Ömer Özütemiz
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - Fatih Tekin
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - İlker Turan
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
| | - Necla Osmanoğlu
- Department of Gastroenterology, Ege University School of Medicine, İzmir, Turkey
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Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk. Biochem Biophys Rep 2018; 17:17-22. [PMID: 30519644 PMCID: PMC6260414 DOI: 10.1016/j.bbrep.2018.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 10/07/2018] [Accepted: 11/09/2018] [Indexed: 12/28/2022] Open
Abstract
Single-nucleotide polymorphisms (SNPs) located in the promoter region of the receptor for advanced glycation end products (RAGE) gene have been linked to the activity of RAGE. However, contrary to our expectation, we previously detected no correlation between SNPs within the RAGE promoter and ulcerative colitis (UC) risk in a case-control study. Here, we investigated the methylation of the RAGE promoter and analyzed the collective contribution of methylation and SNPs to UC risk. We found that RAGE promoter hypomethylation was more common in UC patients compared to controls (70% vs. 30%, respectively), as determined via bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP). Furthermore, we investigated the cooperativity of promoter methylation and SNPs and found that either of two SNPs (rs1800624 or rs1800625) and promoter methylation jointly contributed to UC risk (30 UC patients vs. 30 controls, P < 0.05). There was no correlation between UC risk and either methylation or SNPs when analyzed separately. This lack of correlation is likely due to promoter methylation repressing gene transcription, whereas SNPs in the RAGE promoter region activate RAGE transcription. We found that variant allele carriers with promoter hypomethylation were at an increased risk for UC (rs1800624, OR = 10, 95% CI: 1.641-60.21, P = 0.009; rs1800625, OR = 4.8, 95% CI: 1.074-21.447, P = 0.039). Furthermore, our data revealed that the RAGE mRNA levels in variant allele carriers with promoter hypomethylation were significantly higher compared to those with promoter hypermethylation (P < 0.05) as well as to those in wild-type allele individuals exhibiting promoter hypomethylation (P < 0.05). We therefore speculate that the methylation status and SNPs present in the RAGE promoter region alter RAGE transcription, thereby impacting UC risk. We also propose that the methylation status and RAGE promoter genotype could jointly serve as clinical biomarkers to assist in UC risk assessment.
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Surgery in ulcerative colitis: When? How? Best Pract Res Clin Gastroenterol 2018; 32-33:71-78. [PMID: 30060941 DOI: 10.1016/j.bpg.2018.05.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/25/2018] [Indexed: 02/07/2023]
Abstract
Ulcerative Colitis (UC) is an idiopathic chronically-remitting inflammatory bowel disorder characterized by a contiguous inflammation of the colonic mucosa affecting the rectum that generally extends proximally in a continuous manner through the entire colon. Patients typically experience intermittent exacerbations, with symptoms characterized by bloody diarrhea associated with urgency and tenesmus. The anatomical extent of mucosal involvement is the most important factor determining disease course and is an important predictor of colectomy. The precise etiology of UC is unknown. However, a combination of genetic predisposition and environmental factors seems to have a key role in the development of the disease. UC usually is mildly active but it can be a life-threatening condition because of colonic and systemic complications, and later in the disease course due to the development of colorectal cancer. Interestingly, even if pathogenetic features detected in patients with sporadic CRC can be also found in UC-related colorectal cancer (UC-CRC), this latter is, usually, driven by an inflammation-driven pathway rising from a non-neoplastic inflammatory epithelium to dysplasia to cancer. Thus, a long-term follow-up with colonoscopy surveillance has been recommended. Approximately 15% of UC patients develop an acute attack of severe colitis, and 30% of these patients require colectomy. The initial treatment strategy in UC typically follows the traditional step-up approach. One third of the patients will not respond to steroid therapy and cyclosporine and infliximab are the most common salvage agents employed in these cases in order to avoid emergent surgery. Unfortunately, although a significant short-term benefit have been observed after infliximab treatment, the colectomy rate have remained stable. Surgery in UC depends on the stage of the disease as well as patient's status and is divided into the following settings: urgent, emergent and elective. Despite many efforts the surgical management of UC remains a significant challenge. A multidisciplinary management of UC is key in order to define the best timing and the best procedure for each patient in an individualized basis.
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Cromer WE, Zawieja DC. Acute exposure to space flight results in evidence of reduced lymph Transport, tissue fluid Shifts, and immune alterations in the rat gastrointestinal system. LIFE SCIENCES IN SPACE RESEARCH 2018; 17:74-82. [PMID: 29753416 DOI: 10.1016/j.lssr.2018.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/09/2018] [Accepted: 03/19/2018] [Indexed: 06/08/2023]
Abstract
Space flight causes a number of alterations in physiological systems, changes in the immunological status of subjects, and altered interactions of the host to environmental stimuli. We studied the effect of space flight on the lymphatic system of the gastrointestinal tract which is responsible for lipid transport and immune surveillance which includes the host interaction with the gut microbiome. We found that there were signs of tissue damage present in the space flown animals that was lacking in ground controls (epithelial damage, crypt morphological changes, etc.). Additionally, morphology of the lymphatic vessels in the tissue suggested a collapsed state at time of harvest and there was a profound change in the retention of lipid in the villi of the ileum. Contrary to our assumptions there was a reduction in tissue fluid volume likely associated with other fluid shifts described. The reduction of tissue fluid volume in the colon and ileum is a likely contributing factor to the state of the lymphatic vessels and lipid transport issues observed. There were also associated changes in the number of MHC-II+ immune cells in the colon tissue, which along with reduced lymphatic competence would favor immune dysfunction in the tissue. These findings help expand our understanding of the effects of space flight on various organ systems. It also points out potential issues that have not been closely examined and have to potential for the need of countermeasure development.
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Affiliation(s)
- W E Cromer
- Department of Medical Physiology, Texas A&M University Health Science Center, United States.
| | - D C Zawieja
- Department of Medical Physiology, Texas A&M University Health Science Center, United States
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24
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Younus N, Abid M, Hashmi AA, Aijaz S, Edhi MM, Sheikh AK, Khan A. Colorectal dysplasia and adenocarcinoma in patients with ulcerative colitis: an experience from a tertiary care hospital. World J Surg Oncol 2018; 16:81. [PMID: 29673364 PMCID: PMC5909273 DOI: 10.1186/s12957-018-1385-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/05/2018] [Indexed: 12/16/2022] Open
Abstract
Background The rationale behind this study was to find out the frequency of dysplasia and colorectal cancer (CRC) in young patients with ulcerative colitis (UC) using histopathological examination. This facilitated early detection of dysplasia and CRC by regular endoscopic biopsies and also guided physicians on appropriate surveillance and management, thus improved outcome. Methods It was a prospective cross-sectional study conducted at the Department of Pathology, PIMS, Islamabad. Seventy-six biopsies of already diagnosed cases of UC of young patients aged between 15 and 40 years of either gender were included. Specimens were fixed in 10% buffer formalin, paraffin embedded followed by cutting, slide preparation, and staining with hematoxylin and eosin (H&E) stain, and examined under light microscope. Statistical package for social sciences (SPSS 21) was used for data compilation and analysis. Mean and standard deviation were calculated for quantitative variables. Frequency and percentage were calculated for qualitative variables. Results There were 13 (17.2%) patients who were diagnosed with colorectal dysplasia, 3 (4.0%) with indefinite for dysplasia, 8 (10.5%) with low-grade dysplasia, and 2 (2.6%) with high-grade dysplasia. There were three (3.9%) patients who were diagnosed for colorectal carcinoma, one (1.3%) with grade 1, one (1.3%) with grade 2, and one (1.3%) with grade 3 CRC. Conclusion Routine biopsies can identify dysplastic epithelium, which is an established sign for synchronized carcinoma with ulcerative colitis, and give the rationale for surveillance of the patients.
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Affiliation(s)
- Naila Younus
- Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Mariam Abid
- Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Atif Ali Hashmi
- Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Saher Aijaz
- Shaheed Zulfiqar Ali Institute of Science and Technology, Karachi, Pakistan
| | | | | | - Amir Khan
- Kandahar University, Kandahar, Afghanistan.
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Friedman AB, Brown SJ, Bampton P, Barclay ML, Chung A, Macrae FA, McKenzie J, Reynolds J, Gibson PR, Hanauer SB, Sparrow MP. Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). Aliment Pharmacol Ther 2018; 47:1092-1102. [PMID: 29468701 DOI: 10.1111/apt.14571] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/26/2017] [Accepted: 01/25/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. AIMS To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. DESIGN In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x108 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. RESULTS Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). CONCLUSIONS Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.
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Affiliation(s)
- A B Friedman
- Department of Gastroenterology, The Alfred Hospital and Monash University, Melbourne, Australia
| | - S J Brown
- St Vincent's Hospital, Melbourne, Australia
| | - P Bampton
- Flinders medical Centre, Adelaide, Australia
| | - M L Barclay
- Christchurch Hospital, Christchurch, New Zealand
| | - A Chung
- Eastern Health and Monash University, Melbourne, Australia
| | - F A Macrae
- Royal Melbourne Hospital, Melbourne, Australia
| | - J McKenzie
- The Alfred Hospital and Monash University, Melbourne, Australia
| | - J Reynolds
- The Alfred Hospital and Monash University, Melbourne, Australia
| | - P R Gibson
- The Alfred Hospital and Monash University, Melbourne, Australia
| | | | - M P Sparrow
- The Alfred Hospital and Monash University, Melbourne, Australia
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Aardoom MA, Joosse ME, de Vries ACH, Levine A, de Ridder L. Malignancy and Mortality in Pediatric-onset Inflammatory Bowel Disease: A Systematic Review. Inflamm Bowel Dis 2018. [PMID: 29522170 DOI: 10.1093/ibd/izx104] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cancer and death are the most severe outcomes that affect patients with inflammatory bowel disease (IBD). These outcomes are even more severe if they occur at a young age but are rare, even in the general population. We conducted a systematic review to provide an overview of all reported pediatric (PIBD) patients with severe outcome. METHODS A literature search identified publications that reported development of cancer or fatal outcome in PIBD patients. Studies were eligible for inclusion when (1) article written in English, (2) original data, (3) individual patient information, (4) full text available, (5) study population consisting of patients diagnosed with IBD under the age of 19 years, and (6) who developed malignancy or fatality at any point later in life. RESULTS A total of 98 included studies comprised data of 271 PIBD patients who developed cancer and/or fatal outcome at any point later in life. Meta-analysis demonstrated an increased risk for cancer in PIBD patients (pooled standardized incidence ratio 2.23, 95% CI: 1.98-2.52). The most frequent type of non-fatal cancer was lymphoma, whereas colorectal carcinomas were the most frequently reported type of fatal cancer in PIBD patients and were particularly associated with primary sclerosing cholangitis. The majority of patients with noncancer-related fatal outcomes were diagnosed with ulcerative colitis and most often died due to infectious complications or severe disease-associated complications. CONCLUSIONS The data in this review confirm that PIBD associated malignancy and mortality are rare and detailed clinical characteristics are limited. Prospective and international collaborations are needed to obtain more detailed patient-specific information, which is necessary to investigate the relationship between severe outcomes in PIBD patients and the currently used therapeutic strategies. 10.1093/ibd/izx104_video1izx104_Video5754026434001.
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Affiliation(s)
- Martine A Aardoom
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Maria E Joosse
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Andrica C H de Vries
- Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Arie Levine
- Department of Pediatric Gastroenterology, The Wolfson Medical Center, Tel-Aviv University, Tel-Aviv, Israel
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
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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: 1250] [Impact Index Per Article: 156.3] [Reference Citation Analysis] [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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Newly Diagnosed Colonic Adenocarcinoma: The Presenting Sign in a Young Woman with Undiagnosed Crohn's Disease in the Absence of Primary Sclerosing Cholangitis and a Normal Microsatellite Instability Profile. Case Rep Pathol 2017; 2017:2758769. [PMID: 28255489 PMCID: PMC5306990 DOI: 10.1155/2017/2758769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 11/03/2016] [Accepted: 01/12/2017] [Indexed: 11/18/2022] Open
Abstract
Ulcerative colitis has long been linked with an increased risk for colonic adenocarcinoma, whereas Crohn's disease (CD) has recently been reported to pose a similar increased risk. We report a 33-year-old healthy female with no family history who presented with abdominal pain and a colon mass. Histopathology revealed a moderately differentiated adenocarcinoma extending through the muscularis propria with metastatic lymph nodes and intact mismatch repair proteins by immunohistochemical expression and gene sequencing. The nonneoplastic grossly uninvolved background mucosa showed marked crypt distortion, crypt abscesses, CD-like lymphoid hyperplasia, transmural inflammation, and reactive epithelial atypia. Additional patient questioning revealed frequent loose stools since she was a teenager leading to diagnosis of a previously undiagnosed CD without primary sclerosing cholangitis (PSC). The adenocarcinoma is suspected to be related to the underlying CD. Newly diagnosed adenocarcinoma in a young female as the presenting sign for CD in the absence of PSC is extremely rare.
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Dore MP, Davoli A, Longo N, Marras G, Pes GM. Glucose-6-phosphate dehydrogenase deficiency and risk of colorectal cancer in Northern Sardinia: A retrospective observational study. Medicine (Baltimore) 2016; 95:e5254. [PMID: 27858887 PMCID: PMC5591135 DOI: 10.1097/md.0000000000005254] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with a lower cancer risk, possibly via a reduction of mutagenic oxygen-free radicals and by reducing nicotinamide-adeninedinucleotide-phosphate for replicating cells. In Sardinia, the enzyme defect is frequent as a consequence of selection by malaria in the past. This study investigated the relationship between G6PD deficiency and colorectal cancer (CRC).A retrospective case-control study of 3901 patients from Sardinia, who underwent a colonoscopy between 2006 and 2016, was performed. G6PD phenotype was assessed for each subject. The proportion of pre and malignant colorectal lesions was compared in cases (G6PD-deficient) and controls (G6PD-normal). Data concerning age, sex, family history of CRC, smoking habits, body height, and weight, and also associated diseases were collected.The CRC risk reduction was 43.2% among G6PD-deficient compared with G6PD-normal subjects (odds ratio 0.57, 95% confidence interval 0.37-0.87, P = 0.010). Age, sex, family history of CRC, and also comorbidities such as type 1 diabetes and ischemic heart disease, were significantly associated with CRC risk. The protective effect of G6PD deficiency remained significant after adjusting for all covariates by logistic regression analysis, and was consistently lower across all age groups.Glucose-6-phosphate dehydrogenase enzyme deficiency is associated with a reduced risk of CRC.
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Affiliation(s)
- Maria P. Dore
- Dipartimento di Medicina Clinica e Sperimentale, University of Sassari, Italy
- Baylor College of Medicine, Houston, TX, USA
- Correspondence: Maria Pina Dore, Clinica Medica, Dipartimento di Medicina Clinica e Sperimentale, Viale San Pietro 8, 07100 Sassari, Italy (e-mail: )
| | - Agnese Davoli
- Dipartimento di Medicina Clinica e Sperimentale, University of Sassari, Italy
| | - Nunzio Longo
- Dipartimento di Medicina Clinica e Sperimentale, University of Sassari, Italy
| | - Giuseppina Marras
- Dipartimento di Medicina Clinica e Sperimentale, University of Sassari, Italy
| | - Giovanni M. Pes
- Dipartimento di Medicina Clinica e Sperimentale, University of Sassari, Italy
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Connelly TM, Devane L, Kelly JC, Wrafter P, Messaris E. The 100 classic papers in ulcerative colitis: a bibliometric analysis. Expert Rev Gastroenterol Hepatol 2016; 10:1187-1195. [PMID: 27531253 DOI: 10.1080/17474124.2016.1216786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The identification of the top 100 papers in ulcerative colitis (UC) using citation analysis provides a unique insight into the advancement of disease understanding and subsequent treatment innovations that have progressed over time. METHODS The Thomson Reuters Web of Knowledge was used to identify the 100 most cited UC manuscripts. Title, first and senior authors, institution and department of first author, journal, country of origin, year and topic of each manuscript were analyzed. RESULTS The top 100 manuscripts were published between 1955-2012. Thirty eight percent of the manuscripts originated from the US followed by the UK (26%). Genetics was the topic with the most publications (n = 27), followed by treatment (n = 22) and immunological pathways (n = 17). Truelove had the highest amount of authorships. The institutions with the highest number of publications were St. Mark's, London and the Radcliffe Infirmary. CONCLUSION This list of highly cited papers identifies the topics and authors that have made the most impact in the study of UC over the last century. This paper provides a reference of what could be considered as the most influential UC papers and serves as a reference of what comprises a 'highly citable' manuscript for both researchers and clinicians.
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Affiliation(s)
- Tara M Connelly
- a Department of Surgery , University Hospital Waterford , Waterford , Ireland
| | - Liam Devane
- a Department of Surgery , University Hospital Waterford , Waterford , Ireland
| | - John C Kelly
- b Department of Surgery , University Hospital Galway , Galway , Ireland
| | - Paula Wrafter
- b Department of Surgery , University Hospital Galway , Galway , Ireland
| | - Evangelos Messaris
- c Division of Colon and Rectal Surgery, Milton Hershey Medical Center , Pennsylvania State College of Medicine , Hershey , PA , USA
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Large bowel cancer in the setting of inflammatory bowel disease. Eur Surg 2016. [DOI: 10.1007/s10353-016-0434-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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32
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Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan. Anticancer Drugs 2016; 27:457-63. [DOI: 10.1097/cad.0000000000000338] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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33
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Sengupta N, Yee E, Feuerstein JD. Colorectal Cancer Screening in Inflammatory Bowel Disease. Dig Dis Sci 2016; 61:980-9. [PMID: 26646250 DOI: 10.1007/s10620-015-3979-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/24/2015] [Indexed: 12/20/2022]
Abstract
Patients with long-standing ulcerative colitis (UC) or Crohn's colitis are at increased risk of developing colorectal cancer (CRC). Given that most cases of CRC are thought to arise from dysplasia, previous guidelines have recommended endoscopic surveillance with random biopsies obtained from all segments of the colon involved by endoscopic or microscopic inflammation. However, recent evidence has suggested that the majority of dysplastic lesions in patients with inflammatory disease (IBD) are visible, and data have been supportive of chromoendoscopy with targeted biopsies of visible lesions versus traditional random biopsies. This review article will discuss the risk of colon cancer in patients with IBD, as well as current recommendations for CRC screening and surveillance in patients with UC or Crohn's colitis.
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Affiliation(s)
- Neil Sengupta
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, 110 Francis St 8E Gastroenterology, Boston, MA, 02215, USA
| | - Eric Yee
- Division of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Joseph D Feuerstein
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, 110 Francis St 8E Gastroenterology, Boston, MA, 02215, USA.
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34
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Althumairi AA, Lazarev MG, Gearhart SL. Inflammatory bowel disease associated neoplasia: A surgeon’s perspective. World J Gastroenterol 2016; 22:961-973. [PMID: 26811640 PMCID: PMC4716048 DOI: 10.3748/wjg.v22.i3.961] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is associated with increased risk of colorectal cancer (CRC). The risk is known to increase with longer duration of the disease, family history of CRC, and history of primary sclerosing cholangitis. The diagnosis of the neoplastic changes associated with IBD is difficult owing to the heterogeneous endoscopic appearance and inter-observer variability of the pathological diagnosis. Screening and surveillance guidelines have been established which aim for early detection of neoplasia. Several surgical options are available for the treatment of IBD-associated neoplasia. Patients’ morbidities, risk factors for CRC, degree and the extent of neoplasia must be considered in choosing the surgical treatment. A multidisciplinary team including the surgeon, gastroenterologist, pathologist, and the patient who has a clear understanding of the nature of their disease is needed to optimize outcomes.
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35
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Kilcoyne A, Kaplan JL, Gee MS. Inflammatory bowel disease imaging: Current practice and future directions. World J Gastroenterol 2016; 22:917-932. [PMID: 26811637 PMCID: PMC4716045 DOI: 10.3748/wjg.v22.i3.917] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 09/18/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
The purpose of this paper is to evaluate the role of imaging in inflammatory bowel disease (IBD), including detection of extraluminal complications and extraintestinal manifestations of IBD, assessment of disease activity and treatment response, and discrimination of inflammatory from fibrotic strictures. IBD is a chronic idiopathic disease affecting the gastrointestinal tract that is comprised of two separate, but related intestinal disorders; Crohn’s disease and ulcerative colitis. The paper discusses, in detail the pros and cons of the different IBD imaging modalities that need to be considered in order to optimize the imaging and clinical evaluation of patients with IBD. Historically, IBD evaluation of the bowel has included imaging to assess the portions of the small bowel that are inaccessible to optical endoscopic visualization. This traditionally was performed using barium fluoroscopic techniques; however, cross-sectional imaging techniques (computed tomography and magnetic resonance imaging) are being increasingly utilized for IBD evaluation because they can simultaneously assess mural and extramural IBD manifestations. Recent advances in imaging technology, that continue to improve the ability of imaging to noninvasively follow disease activity and treatment response, are also discussed. This review article summarizes the current imaging approach in inflammatory bowel disease as well as the role of emerging imaging modalities.
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36
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Abstract
Our understanding of colitis-associated carcinoma (CAC) has benefited substantially from mouse models that faithfully recapitulate human CAC. Chemical models, in particular, have enabled fast and efficient analysis of genetic and environmental modulators of CAC without the added requirement of time-intensive genetic crossings. Here we describe the Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) mouse model of inflammatory colorectal cancer.
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37
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Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Muschel R. Macrophage migration inhibitory factor: a key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev 2015; 26:451-61. [PMID: 25882738 DOI: 10.1016/j.cytogfr.2015.03.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/25/2015] [Indexed: 02/07/2023]
Abstract
Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients.
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Affiliation(s)
- A N Gordon-Weeks
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK.
| | - S Y Lim
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - A E Yuzhalin
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - K Jones
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
| | - R Muschel
- CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK
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38
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Parian A, Lazarev M. Who and how to screen for cancer in at-risk inflammatory bowel disease patients. Expert Rev Gastroenterol Hepatol 2015; 9:731-46. [PMID: 25592672 DOI: 10.1586/17474124.2015.1003208] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel diseases (IBDs) include both Crohn's disease and ulcerative colitis and both diseases are marked by inflammation within the gastrointestinal tract. Due to long-standing inflammation, IBD patients are at increased risk of colorectal cancer, especially patients with chronic inflammation, pancolitis, co-diagnosis of primary sclerosing cholangitis and a longer duration of disease. Small bowel inflammation places Crohn's patients at an increased risk of small bowel cancer. A higher risk of skin cancers, lymphomas and cervical abnormalities is also seen in IBD patients; this is likely related to both disease factors and the presence of immunosuppressive medication. This article reviews which patients are at an increased risk of IBD-associated or IBD treatment-associated cancers, when to begin screening and which screening methods are recommended.
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Affiliation(s)
- Alyssa Parian
- Department of Gastroenterology, Johns Hopkins University, 4940 Eastern Avenue, Building A, Baltimore, MD 21224, USA
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39
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Shergill AK, Lightdale JR, Bruining DH, Acosta RD, Chandrasekhara V, Chathadi KV, Decker GA, Early DS, Evans JA, Fanelli RD, Fisher DA, Fonkalsrud L, Foley K, Hwang JH, Jue TL, Khashab MA, Muthusamy VR, Pasha SF, Saltzman JR, Sharaf R, Cash BD, DeWitt JM. The role of endoscopy in inflammatory bowel disease. Gastrointest Endosc 2015; 81:1101-21.e1-13. [PMID: 25800660 DOI: 10.1016/j.gie.2014.10.030] [Citation(s) in RCA: 253] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 10/27/2014] [Indexed: 02/08/2023]
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40
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Pellino G, Selvaggi F. From colon-sparing techniques to pelvic ileal pouch: history and evolution of surgery for ulcerative colitis. Eur Surg 2015. [DOI: 10.1007/s10353-015-0309-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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41
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Prabhakar N, Kalra N, Bhasin DK, Rana SS, Gupta V, Singh R, Khandelwal N. Comparison of CT colonography with conventional colonoscopy in patients with ulcerative colitis. Acad Radiol 2015; 22:296-302. [PMID: 25435187 DOI: 10.1016/j.acra.2014.09.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/21/2014] [Accepted: 09/26/2014] [Indexed: 02/01/2023]
Abstract
RATIONALE AND OBJECTIVE Patients with ulcerative colitis require recurrent conventional colonoscopy (CC) to define the extent of the disease. Computed tomography (CT) colonography (CTC) can be used as an alternative technique for studying the colon in these patients. The purpose of the study was to compare the findings of CTC to CC in patients with ulcerative colitis. MATERIALS AND METHODS Twenty patients proven to have ulcerative colitis on biopsy and in clinical remission state were enrolled in the study. They underwent CTC and CC within 1 week of each test. The investigators performing CTC and CC were blinded to the findings of each other. The chi-square test, kappa test, sensitivity, and specificity were used to compare the findings on CTC and CC. In addition, patient acceptance for both the procedures was compared. RESULTS Sensitivity and specificity on CTC for detecting granular appearance were 81.0% and 73.8%, respectively, and for pseudopolyps were 82.1% and 84.5%, respectively. Good correlation was seen between CTC and CC for detection of granular appearance and pseudopolyps. Loss of haustral folds, wall thickening, pericolonic vascularity, and pericolonic lymph nodes seen on CTC were found to correlate with intraluminal findings seen on CC. Patient acceptance for CTC was better than that for CC. CONCLUSIONS CTC can be used for evaluating patients with ulcerative colitis who are in remission.
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Affiliation(s)
- Nidhi Prabhakar
- Department of Radiodiagnosis, PGIMER, Chandigarh 160012, India
| | - Naveen Kalra
- Department of Radiodiagnosis, PGIMER, Chandigarh 160012, India.
| | | | | | - Vikas Gupta
- Department of General Surgery, PGIMER, Chandigarh, India
| | - Rajinder Singh
- Department of General Surgery, PGIMER, Chandigarh, India
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42
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Fazeli MS, Keramati MR. Rectal cancer: a review. Med J Islam Repub Iran 2015; 29:171. [PMID: 26034724 PMCID: PMC4431429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 12/24/2014] [Indexed: 11/22/2022] Open
Abstract
Rectal cancer is the second most common cancer in large intestine. The prevalence and the number of young patients diagnosed with rectal cancer have made it as one of the major health problems in the world. With regard to the improved access to and use of modern screening tools, a number of new cases are diagnosed each year. Considering the location of the rectum and its adjacent organs, management and treatment of rectal tumor is different from tumors located in other parts of the gastrointestinal tract or even the colon. In this article, we will review the current updates on rectal cancer including epidemiology, risk factors, clinical presentations, screening, and staging. Diagnostic methods and latest treatment modalities and approaches will also be discussed in detail.
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Affiliation(s)
- Mohammad Sadegh Fazeli
- 1 Associate Professor of Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Reza Keramati
- 2 Assistant Professor of Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
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43
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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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44
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Abstract
Patients with inflammatory bowel diseases (IBDs) are at increased risk of colorectal cancer (CRC), but the risk varies between different studies and seems to be decreasing. The cumulative risk of CRC has been reported to be 1%, 2%, and 5% after 10, 20, and over 20 years of disease duration, respectively, in recent meta-analysis. Disease duration and grade of inflammation are the main driving forces of dysplasia and CRC development. Also, the risk of extraintestinal cancers is increased in IBD, where the degree of immunosuppression and its duration are the most important risk factors. Most important extraintestinal malignancies are lymphomas and non-melanoma skin cancers, both of which are increased in patients receiving thiopurines. Also, extraintestinal manifestations or concomitant diseases such as primary sclerosing cholangitis predispose IBD patients to malignancies such as cholangiocarcinoma. History of previous cancer increases the risk of developing either new or recurrent cancers and should be taken into account when choosing therapy and planning surveillance. Dysplasia and cancer screening and surveillance must be individualized according to patients' risk factors. Malignancies are the second most common cause of death after cardiovascular diseases in both genders in patients with IBD.
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Affiliation(s)
- Urpo Nieminen
- Helsinki University Hospital, Department of Medicine, Division of Gastroenterology , Helsinki , Finland
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45
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Yashiro M. Ulcerative colitis-associated colorectal cancer. World J Gastroenterol 2014; 20:16389-16397. [PMID: 25469007 PMCID: PMC4248182 DOI: 10.3748/wjg.v20.i44.16389] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 09/02/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
The association between ulcerative colitis (UC) and colorectal cancer (CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC (UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, low-grade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.
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Abstract
AbstractColitis-associated colorectal cancer (CACRC) constitutes a severe complication of inflammatory bowel diseases (IBD) and occurs in more than one third of IBD patients. In this short review we focus on the mechanisms underlying CACRC pathogenesis, and discuss the approaches for prevention and therapy in CACRC.
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47
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Allende D, Elmessiry M, Hao W, DaSilva G, Wexner SD, Bejarano P, Berho M, Al-Qadasi M. Inter-observer and intra-observer variability in the diagnosis of dysplasia in patients with inflammatory bowel disease: correlation of pathological and endoscopic findings. Colorectal Dis 2014; 16:710-8; discussion 718. [PMID: 24836541 DOI: 10.1111/codi.12667] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 04/17/2014] [Indexed: 01/21/2023]
Abstract
AIM Colonic epithelial dysplasia is deemed the precursor lesion of cancer arising in inflammatory bowel disease (IBD). It has been suggested that many dysplastic lesions could be endoscopically detected to obtain target biopsies, leading to better yield. However, the clinical impact of a diagnosis of dysplasia may be hampered by a significant degree of histological and endoscopic intra-observer and inter-observer variability. This study aimed to evaluate intra-observer and inter-observer variability in the microscopic diagnosis of dysplasia in IBD and correlate endoscopic and histological findings. METHOD In total, 158 cases of ulcerative colitis and 14 of Crohn's disease with dysplasia were selected from a pathology database. Slides were blindly reviewed twice by two expert gastrointestinal pathologists. Results of endoscopic examinations were extracted from the reports. The degree of intra-observer and inter-observer variability was determined by kappa statistics. RESULTS Overall, there was an excellent degree of histopathological inter-observer agreement (κ = 0.786). The lowest level of agreement in the dysplasia group was for indefinite dysplasia (κ = 0.251). Negative and high grade dysplasia diagnosis reached the highest level of agreement with κ values of 0.822 [95% confidence interval (CI) 0.673-0.971] and 1.00 (95% CI 0.850-1.149), respectively. Intra-observer agreement was good and increased during the latter period of the study (κ = 0.734, 95% CI 0.642-0.826). Endoscopic-histological correlation was poor among the negative endoscopies, as up to 43% of cases were diagnosed with at least focal high grade dysplasia. The endoscopic-histological correlation improved when evaluating suspicious endoscopic lesions. CONCLUSION Dysplasia is reliably diagnosed by expert gastrointestinal pathologists but has poor correlation with an endoscopic diagnosis of dysplasia.
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Affiliation(s)
- D Allende
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA
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48
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Zhiqin W, Palaniappan S, Raja Ali RA. Inflammatory Bowel Disease-related Colorectal Cancer in the Asia-Pacific Region: Past, Present, and Future. Intest Res 2014; 12:194-204. [PMID: 25349593 PMCID: PMC4204722 DOI: 10.5217/ir.2014.12.3.194] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 07/01/2014] [Accepted: 07/01/2014] [Indexed: 12/17/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and key contributing factors include chronic colonic inflammation and the extent and duration of disease. This increase in risk is more likely to result from chronic inflammation of the colonic mucosa than from any clearly defined genetic predisposition. However, globally, the true magnitude of this risk is debatable, since results from different studies are heterogeneous in terms of geographical and methodological variables. The prevalence of IBD-related CRC in the Asia-Pacific region ranges from 0.3% to 1.8% and a recent study found that the cumulative incidence of IBD-related CRC is comparable to that in Western countries. However, the CRC mortality rate in the Asia-Pacific region is on the rise compared with that in Western countries, and a few Asian countries show particularly rapid upward trends in CRC incidence. Although our understanding of the molecular and clinical basis for IBD-related CRC has improved substantially, our means of prevention, endoscopic surveillance, chemoprevention, and prophylactic surgery remain modest at best. Furthermore, published data on IBD-related CRC in the Asia-Pacific region is lacking, and this review addresses many aspects including epidemiology, natural history, etiopathogenesis, morphology, and biological behaviors of IBD-related CRC and sporadic CRC in the Asia-Pacific region. In this review, we will also discuss the risk factors for CRC in IBD patients, endoscopic technology screening, and surveillance programs and management strategies for IBD-related CRC.
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Affiliation(s)
- Wong Zhiqin
- Department of Gastroenterology and Hepatology, National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Shanthi Palaniappan
- Department of Gastroenterology and Hepatology, National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- Department of Gastroenterology and Hepatology, National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia. ; Medical Molecular Biology Institute, National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia
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49
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Coviello LC, Stein SL. Surgical management of nonpolypoid colorectal lesions and strictures in colonic inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24:447-54. [PMID: 24975535 DOI: 10.1016/j.giec.2014.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Patients with inflammatory bowel disease (IBD) and dysplasia have pathologic characteristics and risks different from those of patients with sporadic carcinomas. Therefore, surgical interventions need to be more aggressive than in sporadic cases. This article reviews the surgical management of nonpolypoid lesions, dysplasia, and strictures found in patients with IBD.
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Affiliation(s)
- Lisa C Coviello
- Colorectal Surgery and Endoscopy, Department of Surgery, William Beaumont Army Medical Center, 5005 North Piedras Street, El Paso, TX 79920, USA.
| | - Sharon L Stein
- Section of Colon and Rectal Surgery, Department of Surgery, University Hospitals/Case Medical Center, 11100 Euclid Avenue, LKS 5047, Cleveland, OH 44106, USA
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50
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Nguyen GC, Devlin SM, Afif W, Bressler B, Gruchy SE, Kaplan GG, Oliveira L, Plamondon S, Seow CH, Williams C, Wong K, Yan BM, Jones J. Defining quality indicators for best-practice management of inflammatory bowel disease in Canada. Can J Gastroenterol Hepatol 2014; 28:275-85. [PMID: 24839622 PMCID: PMC4049258 DOI: 10.1155/2014/941245] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 02/23/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There is a paucity of published data regarding the quality of care of inflammatory bowel disease (IBD) in Canada. Clinical quality indicators are quantitative end points used to guide, monitor and improve the quality of patient care. In Canada, where universal health care can vary significantly among provinces, quality indicators can be used to identify potential gaps in the delivery of IBD care and standardize the approach to interprovincial management. METHODS The Emerging Practice in IBD Collaborative (EPIC) group generated a shortlist of IBD quality indicators based on a comprehensive literature review. An iterative voting process was used to select quality indicators to take forward. In a face-to-face meeting with the EPIC group, available evidence to support each quality indicator was presented by the EPIC member aligned to it, followed by group discussion to agree on the wording of the statements. The selected quality indicators were then ratified in a final vote by all EPIC members. RESULTS Eleven quality indicators for the management of IBD within the single-payer health care system of Canada were developed. These focus on accurate diagnosis, appropriate and timely management, disease monitoring, and prevention or treatment of complications of IBD or its therapy. CONCLUSIONS These quality indicators are measurable, reflective of the evidence base and expert opinion, and define a standard of care that is at least a minimum that should be expected for IBD management in Canada. The next steps for the EPIC group involve conducting research to assess current practice across Canada as it pertains to these quality indicators and to measure the impact of each of these indicators on patient outcomes.
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Affiliation(s)
- Geoffrey C Nguyen
- Mount Sinai Hospital Centre for Inflammatory Bowel Disease, University of Toronto, Toronto, Ontario
| | - Shane M Devlin
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta
| | - Waqqas Afif
- Department of Gastroenterology and Hepatology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec
| | - Brian Bressler
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia
| | - Steven E Gruchy
- Division of Gastroenterology, Dalhousie University, Halifax, Nova Scotia
| | - Gilaad G Kaplan
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta
| | | | - Sophie Plamondon
- Division of Gastroenterology, Centre Hospitalier Universitaire de Sherbrooke and Centre de Recherche Étienne-LeBel, Université de Sherbrooke, Sherbrooke, Québec
| | - Cynthia H Seow
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta
| | - Chadwick Williams
- Division of Gastroenterology, Saint John Regional Hospital, Saint John, New Brunswick
| | - Karen Wong
- Mount Saint Joseph Hospital, Vancouver, British Columbia
| | - Brian M Yan
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario
| | - Jennifer Jones
- Multidisciplinary IBD Program, Division of Gastroenterology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan
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