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1
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Hasan AM, Cavalu S, Kira AY, Hamad RS, Abdel-Reheim MA, Elmorsy EA, El-kott AF, Morsy K, AlSheri AS, Negm S, Saber S. Localized Drug Delivery in Different Gastrointestinal Cancers: Navigating Challenges and Advancing Nanotechnological Solutions. Int J Nanomedicine 2025; 20:741-770. [PMID: 39845772 PMCID: PMC11752831 DOI: 10.2147/ijn.s502833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Different types of cancers affect the gastrointestinal tract (GIT), starting from the oral cavity and extending to the colon. In general, most of the current research focuses on the systemic delivery of the therapeutic agents, which leads to undesired side effects and a limited enhancement in the therapeutic outcomes. As a result, localized delivery within gastrointestinal (GI) cancers is favorable in overcoming these limitations. However, the localized delivery via oral administration faces many challenges related to the complex structure of GIT (varied pH levels and transit times) as well as the harsh environment within tumor cells (hypoxia, efflux pumps, and acidity). To overcome these obstacles, nano-drug delivery systems (NDDs) have been designed and proved their potential by exploiting these challenges in favor of offering a specific delivery to the desired target. The current review begins with an overview of different GI cancers and their impact globally. Then, it discusses the current treatment approaches and their corresponding limitations. Additionally, the different challenges associated with localized drug delivery for GI cancers are summarized. Finally, the review discusses in detail the recent therapeutic and diagnostic applications of NDDs that have been conducted in oral, esophageal, gastric, colon, and liver cancers, aiming to offer valuable insights into the current and future state of utilizing NDDs for the local treatment of GI cancers.
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Affiliation(s)
- Alexandru Madalin Hasan
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410087, Romania
| | - Simona Cavalu
- Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410087, Romania
| | - Ahmed Y Kira
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia
| | - Elsayed A Elmorsy
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, 51452, Saudi Arabia
| | - Attalla F El-kott
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Kareem Morsy
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt
| | - Ali S AlSheri
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Sally Negm
- Department of Life Sciences, College of Science and Art, Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt
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Zheng Y, Niu X, Wei Q, Li Y, Li L, Zhao J. Familial Esophageal Cancer in Taihang Mountain, China: An Era of Personalized Medicine Based on Family and Population Perspective. Cell Transplant 2022; 31:9636897221129174. [PMID: 36300368 PMCID: PMC9618747 DOI: 10.1177/09636897221129174] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In the Taihang Mountain areas, known as the “esophageal cancer zone” in China, the incidence of esophageal cancer (ESCA) ranks the first in the country and shows a familial and regional clustering trend. Taihang Mountain areas are located in a mountainous area, with inconvenient transportation, limited living conditions, unbalanced diet, and poor nutrition. Ninety percent of the pathological types of ESCA in Taihang Mountain areas are squamous cell carcinoma, among which the risk factors have not been well understood. These areas are usually remote villages and mountains with low population mobility, large family members, similar environmental factors, and a clear and stable genetic background. Therefore, according to the current situation, second-generation sequencing and multigroup analysis technology are used to analyze the familial ESCA patients; disease-related genetic variation are located; and then disease-related susceptibility genes associated with ESCA are screened and analyzed. Health education, tobacco control, endoscopic screening, and other health management projects for suspected and high-risk patients in areas with a high incidence of ESCA can be carried out for screening and early diagnosis, and the incidence of ESCA in Taihang Mountain areas can be reduced. A comprehensive continuous care pattern based on traditional medical nursing to track, monitor, evaluate, and intervene with patients diagnosed with ESCA to facilitate them with medications guidance, dietary guidance, and timely health problem-solving is established. Furthermore, statistical analysis of epidemiology, gene sequencing, and family genetics information can be performed on patients with ESCA in the Taihang Mountains areas to clarify the relationship between genetic phenotype and genotype during the occurrence of ESCA.
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Affiliation(s)
- Yuanyuan Zheng
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Niu
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Qian Wei
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yijing Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lifeng Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Biological Cell Therapy Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Zhao
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Jie Zhao, National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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Schmidt M, Hackett RJ, Baker AM, McDonald SAC, Quante M, Graham TA. Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy. Nat Rev Gastroenterol Hepatol 2022; 19:95-111. [PMID: 34728819 DOI: 10.1038/s41575-021-00531-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Cancer development is a dynamic evolutionary process characterized by marked intratumoural heterogeneity at the genetic, epigenetic and phenotypic levels. Barrett oesophagus, the pre-malignant condition to oesophageal adenocarcinoma (EAC), is an exemplary system to longitudinally study the evolution of malignancy. Evidence has emerged of Barrett oesophagus lesions pre-programmed for progression to EAC many years before clinical detection, indicating a considerable window for therapeutic intervention. In this Review, we explore the mechanisms underlying clonal expansion and contraction that establish the Barrett oesophagus clonal mosaicism over time and space and discuss intrinsic genotypic and extrinsic environmental drivers that direct the evolutionary trajectory of Barrett oesophagus towards a malignant phenotype. We propose that understanding and exploiting the evolutionary dynamics of Barrett oesophagus will identify novel therapeutic targets, improve prognostic tools and offer the opportunity for personalized surveillance programmes geared to prevent progression to EAC.
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Affiliation(s)
- Melissa Schmidt
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Richard J Hackett
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ann-Marie Baker
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stuart A C McDonald
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
- Department of Medicine II, Universitaetsklinikum Freiburg, Freiburg, Germany
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Dhillon VS, Deo P, Bonassi S, Fenech M. Lymphocyte micronuclei frequencies in skin, haematological, prostate, colorectal and esophageal cancer cases: A systematic review and meta-analysis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2021; 787:108372. [PMID: 34083057 DOI: 10.1016/j.mrrev.2021.108372] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/17/2021] [Accepted: 01/31/2021] [Indexed: 01/07/2023]
Abstract
Micronucleus (MN) assay has been widely used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging in many epidemiological studies. In this narrative review and meta-analysis we assessed the association between lymphocyte micronuclei (MNi) and cancers of the skin, blood, digestive tract, and prostate. The review identified nineteen studies with 717 disease subjects and 782 controls. Significant increases in MRi for MNi were observed in the following groups: subjects with blood cancer (MRi = 3.98; 95 % CI: 1.98-7.99; p = 0.000) and colorectal cancer (excluding IBD) (MRi = 2.69; 95 % CI: 1.82-3.98, p < 0.000). The results of this review suggest that lymphocyte MNi are a biomarker of DNA damage and chromosomal instability in people with haematological or colorectal cancers. However, the MRi for lymphocyte MNi in subjects with cancers of skin, prostate, esophagus was not significantly increased. More case-control and prospective studies are warranted to further verify the observed trends and to better understand the role of lymphocyte MNi as a biomarker of cancer risk in blood, skin, digestive tract and prostate.
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Affiliation(s)
- Varinderpal S Dhillon
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, 5000, Australia.
| | - Permal Deo
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, 5000, Australia
| | - Stefano Bonassi
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Rome, Italy; Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Michael Fenech
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, 5000, Australia; Faculty of Health Sciences, National University of Malaysia, Kuala Lumpur, Malaysia
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Balmus IM, Ciobica A, Cojocariu R, Luca AC, Gorgan L. Irritable Bowel Syndrome and Neurological Deficiencies: Is There A Relationship? The Possible Relevance of the Oxidative Stress Status. ACTA ACUST UNITED AC 2020; 56:medicina56040175. [PMID: 32295083 PMCID: PMC7230401 DOI: 10.3390/medicina56040175] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022]
Abstract
Background: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, exhibiting complex and controversial pathological features. Both oxidative stress and inflammation-related reactive oxygen species production may be involved in IBS pathological development. Thus, we focused on several aspects regarding the causes of oxidative stress occurrence in IBS. Additionally, in the molecular context of oxidative changes, we tried to discuss these possible neurological implications in IBS. Methods: The literature search included the main available databases (e.g., ScienceDirect, Pubmed/Medline, Embase, and Google Scholar). Articles in the English language were taken into consideration. Our screening was conducted based on several words such as “irritable bowel syndrome”, “gut brain axis”, “oxidative stress”, “neuroendocrine”, and combinations. Results: While no consistent evidence suggests clear pathway mechanisms, it seems that the inflammatory response may also be relevant in IBS. The mild implication of oxidative stress in IBS has been described through clinical studies and some animal models, revealing changes in the main markers such as antioxidant status and peroxidation markers. Moreover, it seems that the neurological structures involved in the brain-gut axis may be affected in IBS rather than the local gut tissue and functionality. Due to a gut-brain axis bidirectional communication error, a correlation between neurological impairment, emotional over-responsiveness, mild inflammatory patterns, and oxidative stress can be suggested. Conclusions: Therefore, there is a possible correlation between neurological impairment, emotional over-responsiveness, mild inflammatory patterns, and oxidative stress that are not followed by tissue destruction in IBS patients. Moreover, it is not yet clear whether oxidative stress, inflammation, or neurological impairments are key determinants or in which way these three interact in IBS pathology. However, the conditions in which oxidative imbalances occur may be an interesting research lead in order to find possible explanations for IBS development.
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Affiliation(s)
- Ioana-Miruna Balmus
- Department of Interdisciplinary Research in Science, “Alexandru Ioan Cuza” University of Iasi, Carol I Avenue, No. 11, 700506 Iași, Romania;
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Carol I Avenue, 20A, 700506 Iași, Romania
| | - Alin Ciobica
- Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Carol I Avenue, 20A, 700506 Iași, Romania
- Correspondence: (A.C.); (A.-C.L.)
| | - Roxana Cojocariu
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Carol I Avenue, 20A, 700506 Iași, Romania; (R.C.); (L.G.)
| | - Alina-Costina Luca
- Faculty of Medicine, “Gr. T. Popa” University of Medicine and Pharmacy, 16th University Street, 700115 Iași, Romania
- Correspondence: (A.C.); (A.-C.L.)
| | - Lucian Gorgan
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, Carol I Avenue, 20A, 700506 Iași, Romania; (R.C.); (L.G.)
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Iwaya Y, Shimamura Y, Mosko JD, Kandel G, Kortan PP, May GR, Marcon NE, Teshima CW. Clinical characteristics may distinguish patients with esophageal adenocarcinoma arising from long- versus short-segment Barrett's esophagus. Dig Liver Dis 2019; 51:1470-1474. [PMID: 31147211 DOI: 10.1016/j.dld.2019.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 04/13/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Patients with long-segment Barrett's esophagus (LSBE; ≧3 cm) have higher risk of developing esophageal adenocarcinoma (EAC) than those with short-segment Barrett's esophagus (SSBE; <3 cm). However, it is unclear whether patients developing EAC from LSBE or SSBE differ significantly according to baseline clinical characteristics. METHODS We conducted a retrospective analysis of a prospectively maintained database comprising consecutive patients with early EAC treated by endoscopic mucosal resection at a single, tertiary-referral center. Information regarding baseline clinical characteristics were determined. Univariate and multivariate logistic regression were performed to identify factors that differed significantly between patients with EAC arising from SSBE and LSBE. RESULTS A total of 145 LSBE EAC and 179 SSBE EAC cases were identified. The LSBE EAC patients had a stronger association with having a hiatal hernia compared to the SSBE EAC patients. In contrast, inverse associations were observed in LSBE EAC patients with statin use and smoking pack-years relative to SSBE EAC patients. CONCLUSIONS Patients who developed EAC on a background of LSBE were more likely to have a hiatus hernia compared to patients with SSBE EAC, who were more likely to have higher smoking pack-years and higher rates of statin use.
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Affiliation(s)
- Yugo Iwaya
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada.
| | - Yuto Shimamura
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Jeffrey D Mosko
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Gabor Kandel
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Paul P Kortan
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Gary R May
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Norman E Marcon
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
| | - Christopher W Teshima
- Advanced Therapeutic Endoscopy Centre, St Michael's Hospital, University of Toronto, Canada
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Caspa Gokulan R, Garcia-Buitrago MT, Zaika AI. From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2019; 1872:37-48. [PMID: 31152823 PMCID: PMC6692203 DOI: 10.1016/j.bbcan.2019.05.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/10/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett's esophagus to esophageal adenocarcinoma are also discussed.
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Affiliation(s)
| | | | - Alexander I Zaika
- Department of Surgery, University of Miami, Miami, FL, United States of America; Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, United States of America.
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8
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Cook MB, Barnett MJ, Bock CH, Cross AJ, Goodman PJ, Goodman GE, Haiman CA, Khaw KT, McCullough ML, Newton CC, Boutron-Ruault MC, Lund E, Rutegård M, Thornquist MD, Spriggs M, Giffen C, Freedman ND, Kemp T, Kroenke CH, Le Marchand L, Park JY, Simon M, Wilkens LR, Pinto L, Hildesheim A, Campbell PT. Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: a study within the National Cancer Institute Cohort Consortium. Gut 2019; 68:960-968. [PMID: 30121626 PMCID: PMC6379150 DOI: 10.1136/gutjnl-2018-316678] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 07/02/2018] [Accepted: 08/02/2018] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.
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Affiliation(s)
- Michael B. Cook
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA
| | - Matthew J. Barnett
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Cathryn H. Bock
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Amanda J. Cross
- Department of Epidemiology and Biostatistics, Imperial College London, UK
| | - Phyllis J. Goodman
- Southwest Oncology Group (SWOG) Statistics & Data Management Center (SDMC), Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Gary E. Goodman
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
- Swedish Medical Center, Swedish Cancer Institute, Seattle, WA 98104
| | - Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kay-Tee Khaw
- Department of Public Health and Primary Care, University of Cambridge, United Kingdom
| | - Marjorie L. McCullough
- Behavioral and Epidemiology Research Program, American Cancer Society Inc., Atlanta, GA 30303, USA
| | - Christine C. Newton
- Behavioral and Epidemiology Research Program, American Cancer Society Inc., Atlanta, GA 30303, USA
| | - Marie-Christine Boutron-Ruault
- CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, 94805, Villejuif, France
- Generations and Health, Gustave Roussy, F-94805, Villejuif, France
| | - Eiliv Lund
- Department of Community Medicine, UiT The Arctic University of Norway, 9037 Tromsø, Norway
| | - Martin Rutegård
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Mark D. Thornquist
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Michael Spriggs
- Information Management Services (IMS), Rockville, MD 20852, USA
| | - Carol Giffen
- Information Management Services (IMS), Rockville, MD 20852, USA
| | - Neal D. Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA
| | - Troy Kemp
- Human Papilloma Virus (HPV) Immunology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA
| | - Candyce H. Kroenke
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo St., Honolulu, HI 96817, USA
| | - Jin Young Park
- Prevention and Implementation Group, International Agency for Research on Cancer, Lyon, France
| | - Michael Simon
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Lynne R. Wilkens
- Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
| | - Ligia Pinto
- Information Management Services (IMS), Rockville, MD 20852, USA
| | - Allan Hildesheim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA
| | - Peter T. Campbell
- Behavioral and Epidemiology Research Program, American Cancer Society Inc., Atlanta, GA 30303, USA
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Kresty LA, Fromkes JJ, Frankel WL, Hammond CD, Seeram NP, Baird M, Stoner GD. A phase I pilot study evaluating the beneficial effects of black raspberries in patients with Barrett's esophagus. Oncotarget 2018; 9:35356-35372. [PMID: 30450163 PMCID: PMC6219678 DOI: 10.18632/oncotarget.10457] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 05/23/2016] [Indexed: 12/11/2022] Open
Abstract
Black raspberries inhibit a broad range of cancers in preclinical models which has led to clinical evaluations targeting premalignant lesions of the colon, oral cavity and esophagus. A phase I pilot study was conducted in twenty Barrett's esophagus (BE) patients to investigate the effect of lyophilized black raspberries (LBR) on urinary metabolites and markers of lipid peroxidation, DNA damage and tissue markers of cellular proliferation, detoxification, and inflammation. Surveys, biopsies, blood and urine samples were collected before and after 6 months of LBR treatment (32 or 45 g). LBR significantly reduced urinary excretion of 8-epi-prostaglandin F2α, a marker of lipid peroxidation linked to oxidative stress and free radical damage. Urinary levels of the ellagitannin metabolites, urolithin A-glucuronide, urolithin A-sulfate and dimethylellagic acid glucuronide were significantly increased following 12 and 26 weeks of LBR consumption and may prove useful as indicators of compliance in future clinical studies. Immunohistochemical staining of BE biopsies following LBR treatment showed significant increases in mean GST-pi levels, with 55.6% of subjects responding favorably. In summary, LBR significantly decreased urinary lipid peroxidation levels and significantly increased GST-pi, a marker of detoxification, in BE epithelium. Still, LBR may need to be formulated differently, administered at higher concentrations or multiple times a day to increase efficacy.
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Affiliation(s)
- Laura A Kresty
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John J Fromkes
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Cynthia D Hammond
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Navindra P Seeram
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Maureen Baird
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Gary D Stoner
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Krishnamoorthi R, Singh S, Ragunathan K, Visrodia K, Wang KK, Katzka DA, Iyer PG. Factors Associated With Progression of Barrett's Esophagus: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018; 16:1046-1055.e8. [PMID: 29199147 DOI: 10.1016/j.cgh.2017.11.044] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 09/21/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endoscopic surveillance of patients with Barrett's esophagus (BE) is inefficient. Risk stratification of patients might improve the effectiveness of surveillance. We performed a systematic review and meta-analysis to identify factors associated with progression of BE without dysplasia or BE with low-grade dysplasia (LGD) to high-grade dysplasia or esophageal adenocarcinoma. METHODS We performed a systematic search of databases through May 2016 to identify cohort studies of patients with baseline BE without dysplasia or BE with LGD that reported predictors of progression. Pooled estimates (odds ratios) of associations of age, sex, smoking, alcohol use, obesity, baseline LGD, segment length, and medication use with progression were calculated. RESULTS We identified 20 studies, reporting 1231 events in 74943 patients. The studies associated BE progression with increasing age (12 studies; odds ratio [OR], 1.03; 95% CI, 1.01-1.05), male sex (11 studies; OR, 2.16; 95% CI, 1.84-2.53), ever smoking (current or past, 8 studies; OR, 1.47; 95% CI, 1.09-1.98), and increasing BE segment length (10 studies; OR, 1.25; 95% CI, 1.16-1.36), with a low degree of heterogeneity. LGD was associated with a 4-fold increase in risk of BE progression (11 studies; OR, 4.25; 95% CI, 2.58-7.0). Use of proton pump inhibitors (4 studies; OR, 0.55; 95% CI, 0.32-0.96) or statins (3 studies; OR, 0.48; 95% CI, 0.31-0.73) were associated with lower risk of BE progression. Alcohol use and obesity did not associate with risk of progression. CONCLUSIONS In a systematic review and meta-analysis, we associated older age, male sex, smoking, longer BE segment, and LGD with risk of progression of BE. Individuals with these features should undergo more intensive surveillance or endoscopic therapy. Smoking is a modifiable risk factor for cancer prevention in patients with BE.
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Affiliation(s)
- Rajesh Krishnamoorthi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Siddharth Singh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Karthik Ragunathan
- Department of Internal Medicine, University of Illinois College of Medicine, Peoria, Illinois
| | - Kavel Visrodia
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kenneth K Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - David A Katzka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
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11
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Coleman HG, Xie SH, Lagergren J. The Epidemiology of Esophageal Adenocarcinoma. Gastroenterology 2018; 154:390-405. [PMID: 28780073 DOI: 10.1053/j.gastro.2017.07.046] [Citation(s) in RCA: 377] [Impact Index Per Article: 53.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 12/18/2022]
Abstract
The incidence of esophageal adenocarcinoma (EAC) has increased in many Western countries and is higher in men than women. Some risk factors for EAC have been identified-mainly gastroesophageal reflux disease, Barrett's esophagus, obesity, and tobacco smoking. It is not clear whether interventions to address these factors can reduce risk of EAC, although some evidence exists for smoking cessation. Although consumption of alcohol is not associated with EAC risk, other exposures, such as physical activity, nutrition, and medication use, require further study. Genetic variants have been associated with risk for EAC, but their overall contribution is low. Studies are needed to investigate associations between risk factors and the molecular subtypes of EAC. The prognosis for patients with EAC has slightly improved, but remains poor-screening and surveillance trials of high-risk individuals are needed.
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Affiliation(s)
- Helen G Coleman
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, UK.
| | - Shao-Hua Xie
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Division of Cancer Studies, King's College London, United Kingdom
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12
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Song JH, Han YM, Kim WH, Park JM, Jeong M, Go EJ, Hong SP, Hahm KB. Oxidative stress from reflux esophagitis to esophageal cancer: the alleviation with antioxidants. Free Radic Res 2016; 50:1071-1079. [DOI: 10.1080/10715762.2016.1181262] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Ji Hyun Song
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
| | - Young-Min Han
- CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea
| | - Won Hee Kim
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
| | - Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea
| | - Migyeong Jeong
- CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea
| | - Eun Jin Go
- CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
- CHA Cancer Prevention Research Center, CHA Bio Complex, Seongnam, Korea
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13
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Balmus IM, Ciobica A, Trifan A, Stanciu C. The implications of oxidative stress and antioxidant therapies in Inflammatory Bowel Disease: Clinical aspects and animal models. Saudi J Gastroenterol 2016; 22:3-17. [PMID: 26831601 PMCID: PMC4763525 DOI: 10.4103/1319-3767.173753] [Citation(s) in RCA: 209] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/20/2015] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder characterized by alternating phases of clinical relapse and remission. The etiology of IBD remains largely unknown, although a combination of patient's immune response, genetics, microbiome, and environment plays an important role in disturbing intestinal homeostasis, leading to development and perpetuation of the inflammatory cascade in IBD. As chronic intestinal inflammation is associated with the formation of reactive oxygen and reactive nitrogen species (ROS and RNS), oxidative and nitrosative stress has been proposed as one of the major contributing factor in the IBD development. Substantial evidence suggests that IBD is associated with an imbalance between increased ROS and decreased antioxidant activity, which may explain, at least in part, many of the clinical pathophysiological features of both CD and UC patients. Hereby, we review the presently known oxidant and antioxidant mechanisms involved in IBD-specific events, the animal models used to determine these specific features, and also the antioxidant therapies proposed in IBD patients.
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Affiliation(s)
- Ioana Miruna Balmus
- Department of Biology, Alexandru Ioan Cuza University, Bulevardul Carol, Iaşi, Romania
| | - Alin Ciobica
- Department of Biology, Alexandru Ioan Cuza University, Bulevardul Carol, Iaşi, Romania
- Department of Animal Physiology, Center of Biomedical Research of the Romanian Academy, Iaşi, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Gr. T. Popa” University of Medicine and Pharmacy, Iaşi, Romania
| | - Carol Stanciu
- Department of Animal Physiology, Center of Biomedical Research of the Romanian Academy, Iaşi, Romania
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14
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Xu Q, Guo W, Shi X, Zhang W, Zhang T, Wu C, Lu J, Wang R, Zhao Y, Ma X, He J. Association Between Alcohol Consumption and the Risk of Barrett's Esophagus: A Meta-Analysis of Observational Studies. Medicine (Baltimore) 2015; 94:e1244. [PMID: 26266354 PMCID: PMC4616710 DOI: 10.1097/md.0000000000001244] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The association between alcohol consumption and Barrett's esophagus (BE) remained uncertain and controversial in the previous studies. We performed a meta-analysis of observational studies to clarify the association.We searched PubMed, Web of Science, and Embase for studies on alcohol consumption and risk of BE published before February 2015. A total of 20 studies reporting the association between alcohol consumption and the risk of BE were identified. Subgroup analyses, meta-regression analyses, sensitivity analyses, and publication bias tests were also performed. Several results from individual studies were pooled using a dose-response meta-analysis.A total of 20 studies involving 45,181 participants and 4432 patients of BE were included in the meta-analysis. No association was found between alcohol consumption and BE (relative risk [RR] = 1.10, 95% confidence interval [CI] 0.96-1.27, I = 48.60%) in our study. In subgroup analysis, alcohol consumption was associated with an increased risk of BE in men (RR = 1.35, 95% CI 1.13-1.61, I = 0.00%) and Asian population (RR = 1.60, 95% CI 1.03-2.49, I = 60.60%). In beverage-specific consumption analysis, liquor was associated with an increased risk of BE (RR = 1.16, 95% CI 1.02-1.32, I = 0.00%). Multivariate meta-regression analysis suggested that geographic area, and adjusted age, sex, body mass index, and smoke, might explain 70.75% of the heterogeneity between the studies. We also found the inverse association (RR = 0.84, 95% CI 0.72-0.98, I = 0.00%) between alcohol consumption and BE among subjects when compared with population controls.Overall, there was no significant association between alcohol consumption and BE. Alcohol consumption may be a risk factor of BE in men and Asian population, and liquor consumption may also increase the risk of BE. Significant inverse association was observed between alcohol consumption and BE, for comparisons with population controls.
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Affiliation(s)
- Qin Xu
- From the Department of Health Statistics (QX, WG, TZ, CW, JL, RW, YZ, XM, JH), Second Military Medical University; Department of Gastroenterology (XS), Changhai Hospital, Second Military Medical University; and Department of Heath Services Management (WZ), Second Military Medical University, Shanghai, China
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15
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Brown CS, Ujiki MB. Risk factors affecting the Barrett's metaplasia-dysplasia-neoplasia sequence. World J Gastrointest Endosc 2015; 7:438-445. [PMID: 25992184 PMCID: PMC4436913 DOI: 10.4253/wjge.v7.i5.438] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/27/2014] [Accepted: 01/20/2015] [Indexed: 02/05/2023] Open
Abstract
Esophageal adenocarcinoma has the fastest growing incidence rate of any cancer in the United States, and currently carries a very poor prognosis with 5 years relative survival rates of less than 15%. Current curative treatment options are limited to esophagectomy, a procedure that suffers from high complication rates and high mortality rates. Metaplasia of the esophageal epithelium, a condition known as Barrett’s esophagus (BE), is widely accepted as the precursor lesion for adenocarcinoma of the esophagus. Recently, radio-frequency ablation has been shown to be an effective method to treat BE, although there is disagreement as to whether radio-frequency ablation should be used to treat all patients with BE or whether treatment should be reserved for those at high risk for progressing to esophageal adenocarcinoma while continuing to endoscopically survey those with low risk. Recent research has been targeted towards identifying those at greater risk for progression to esophageal adenocarcinoma so that radio-frequency ablation therapy can be used in a more targeted manner, decreasing the total health care cost as well as improving patient outcomes. This review discusses the current state of the literature regarding risk factors for progression from BE through dysplasia to esophageal adenocarcinoma, as well as the current need for an integrated scoring tool or risk stratification system capable of differentiating those patients at highest risk of progression in order to target these endoluminal therapies.
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16
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Falk GW. Barrett's oesophagus: frequency and prediction of dysplasia and cancer. Best Pract Res Clin Gastroenterol 2015; 29:125-38. [PMID: 25743461 PMCID: PMC4352690 DOI: 10.1016/j.bpg.2015.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 01/08/2015] [Accepted: 01/12/2015] [Indexed: 02/07/2023]
Abstract
The incidence of oesophageal adenocarcinoma is continuing to increase at an alarming rate in the Western world today. Barrett's oesophagus is a clearly recognized risk factor for the development of oesophageal adenocarcinoma, but the overwhelming majority of patients with Barrett's oesophagus will never develop oesophageal cancer. A number of endoscopic, histologic and epidemiologic risk factors identify Barrett's oesophagus patients at increased risk for progression to high-grade dysplasia and oesophageal adenocarcinoma. Endoscopic factors include segment length, mucosal abnormalities as seemingly trivial as oesophagitis and the 12 to 6 o'clock hemisphere of the oesophagus. Both intestinal metaplasia and low grade dysplasia, the latter only if confirmed by a pathologist with expertise in Barrett's oesophagus pathologic interpretation are the histologic risk factors for progression. Epidemiologic risk factors include ageing, male gender, obesity, and smoking. Factors that may protect against the development of adenocarcinoma include a diet rich in fruits and vegetables, and the use of proton pump inhibitors, aspirin/NSAIDs and statins.
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Affiliation(s)
- Gary W. Falk
- Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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17
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Dai C, Liu WX, Wang K, Jiang HK, Jiang M, Sun MJ. Alcohol consumption and the risk of Barrett’s esophagus: A meta-analysis. World J Meta-Anal 2014; 2:204-211. [DOI: 10.13105/wjma.v2.i4.204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 10/05/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate the possible association between alcohol consumption and Barrett’s esophagus (BE).
METHODS: We performed a systematic literature search of multiple online electronic databases. Inclusion criteria entailed studies about alcohol and BE. Meta-analysis was conducted to evaluate odds ratio (OR) and 95%CIs for the association between alcohol consumption and BE.
RESULTS: Twenty studies comprising 4758 patients with BE were included in the meta-analysis. The risk of BE in patients with alcohol consumption was increased compared with control groups (OR = 1.01; 95%CI: 1.00-1.02), especially in case-control and cohort, European and Asian, and hospital studies, but there was a decreased risk of BE associated with alcohol consumption from American studies (OR = 0.86; 95%CI: 0.77-0.96). At the same time, there was no significant association between BE and alcohol consumption in community studies (OR = 0.97; 95%CI: 0.84-1.12) and the type of alcohol (wine, beer and liquor) studies.
CONCLUSION: Our meta-analysis found that alcohol consumption was associated with an increased risk of BE, especially for European and Asian drinkers.
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18
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Lou Z, Xing H, Li D. Alcohol consumption and the neoplastic progression in Barrett's esophagus: a systematic review and meta-analysis. PLoS One 2014; 9:e105612. [PMID: 25299129 PMCID: PMC4191954 DOI: 10.1371/journal.pone.0105612] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Accepted: 07/25/2014] [Indexed: 01/11/2023] Open
Abstract
Purpose In the developed countries, the incidence of esophageal adenocarcinoma (EAC) is increasing over recent decades. The purpose of this meta-analysis was to arrive at quantitative conclusions about the contribution of alcohol intakes and the progression of Barrett's esophagus. Methods A comprehensive, systematic bibliographic search of medical literature published up to Oct 2013 was conducted to identify relevant studies. A meta-analysis was conducted for alcohol consumption on the Barrett's esophagus progression. Results A total of 882 cases in 6,867 individuals from 14 observational studies were indemnified in this meta-analysis. The result of this current meta-analysis, including 10 case-control and 4 cohort studies, indicated that alcohol consumption was not associated with the neoplastic progression in Barrett's esophagus (RR, 1.17; 95% CI, 0.93–1.48). When stratified by the study designs, no significant association was detected in either high vs low group or ever vs never group. Conclusions Alcohol drinking is not associated with risk of neoplastic progression in Barrett's esophagus. Further well designed studies are needed in this area.
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Affiliation(s)
- Zhifeng Lou
- The department of stomatology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China
| | - Haibo Xing
- The department of intensive care unit, Xiasha Hospital, Hangzhou, Zhejiang, P. R. China
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China
- * E-mail:
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19
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Balasubramanian G, Gupta N, Giacchino M, Singh M, Kanakadandi V, Gaddam S, Wani SB, Higbee AD, Rastogi A, Bansal A, Sharma P. Cigarette smoking is a modifiable risk factor for Barrett's oesophagus. United European Gastroenterol J 2014; 1:430-7. [PMID: 24917994 DOI: 10.1177/2050640613504917] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 08/19/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cigarette smoking has been associated with an increased risk of oesophageal adenocarcinoma (OAC). However, the impact of smoking and more importantly smoking cessation on Barrett's oesophagus (BO) is unclear. OBJECTIVE The aim of the study is to evaluate the association between cigarette smoking and presence of BO in a large prospective cohort of patients with gastro-oesophageal reflux disease (GORD). METHODS Patients presenting to the endoscopy unit for upper endoscopy completed a validated GORD questionnaire and information on demographics (age, gender, and ethnicity), cigarette smoking [status (current/past), amount (pack years) and duration of smoking cessation], clinical data [medication history, body mass index (BMI), and family history] and endoscopic findings [BO and hiatal hernia] were recorded. Cigarette smokers (current and past) and nonsmokers were compared using Fisher's Exact test for categorical variables and Mann-Whitney test for continuous variables. Effects of cigarette smoking and smoking cessation on BO risk was assessed by stepwise logistic regression analysis. RESULTS A total of 1056 patients were included in the analysis [mean age: 57.2 ± 12.7years, Caucasian 880 (83.3%), male 985 (93.3%), and mean BMI 29.6 (SD: ± 5.6)]. 827 (78.3%) were smokers and 229 (21.6%) were nonsmokers. 474 subjects (44.9%) had a previous history of smoking. Anytime smokers were more likely to have BO (adjusted OR: 3.3; 95 CI: 1.7-6.3; p < 0.01). Higher smoking burden (pack years) was associated with higher risk of BO in this GORD cohort (p for trend < 0.01). Duration of smoking cessation was inversely associated with risk of BO (p for trend: 0.01). CONCLUSION This study shows that smokers with reflux symptoms have about threefold higher risk of BO compared with nonsmokers, whereas discontinuing smoking is associated with a significant reduced risk. Smoking cessation appears to be a viable option to reduce BO risk in patients with reflux disease.
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Affiliation(s)
| | - Neil Gupta
- Gastroenterology and Hepatology, Loyola University Medical Center, Maywood, IL, USA
| | - Maria Giacchino
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA
| | - Mandeep Singh
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA ; Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, KS, USA
| | - Vijay Kanakadandi
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA
| | - Srinivas Gaddam
- Gastroenterology and Hepatology, Washington University in St.Louis, St.Louis, MO, USA
| | - Sachin B Wani
- Gastroenterology and Hepatology, University of Colorado, Denver, CO, USA
| | - April D Higbee
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA
| | - Amit Rastogi
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA ; Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, KS, USA
| | - Ajay Bansal
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA ; Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, KS, USA
| | - Prateek Sharma
- Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA ; Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, KS, USA
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20
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Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146:357-373. [PMID: 24315827 PMCID: PMC3978703 DOI: 10.1053/j.gastro.2013.11.051] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/30/2013] [Accepted: 11/14/2013] [Indexed: 02/06/2023]
Abstract
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
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Affiliation(s)
| | - Leonardo H. Eusebi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, and Center for Applied Biomedical Research (CRBA), University of Bologna, Italy
| | - Kavish Patidar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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21
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Thrift AP, Kramer JR, Richardson PA, El-Serag HB. No significant effects of smoking or alcohol consumption on risk of Barrett's esophagus. Dig Dis Sci 2014; 59:108-16. [PMID: 24114046 PMCID: PMC3976430 DOI: 10.1007/s10620-013-2892-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 09/14/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Smoking, but not higher alcohol consumption, is associated with increased risk of esophageal adenocarcinoma (EAC) and progression from Barrett's esophagus (BE) to EAC. However, it is still unclear whether smoking or alcohol is implicated in the development of BE. AIM To evaluate the associations between smoking, alcohol and the risk of BE. METHODS The study included eligible patients scheduled for elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics. We compared 258 patients with definitive BE with two separate control groups: 453 patients from the primary care group ("colonoscopy controls") and 1,145 patients from the elective EGD group ("endoscopy controls") with no endoscopic or histopathologic BE. We calculated odds ratios (OR) and 95 % confidence intervals (95 % CI) using multivariable logistic regression models. RESULTS Seventy-seven percent of BE cases, 75 % of colonoscopy controls and 72 % of endoscopy controls were ever smokers. Of these, approximately 45 % were current smokers. Overall, 91 % of study participants were ex or current alcohol drinkers, with the majority drinking beer. We found no association between various measure of smoking exposure (status, intensity, age at initiation, duration, pack-years and cessation) and risk of BE. Alcohol consumption was not associated with increased risk of BE. Conversely, moderate intake was associated with lower risk (14 to <28 drinks/week, OR 0.39, 95 % CI 0.15-1.00). CONCLUSION Smoking and alcohol were not strong or consistent risk factors for BE. The likely role of smoking in increasing risk of EAC is through promoting progression from BE to cancer.
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Affiliation(s)
- Aaron P. Thrift
- Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Royal Brisbane Hospital, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Brisbane, QLD 4029, Australia
| | - Jennifer R. Kramer
- Houston VA HSR&D Center of Excellence, Health Services Research and Development Service, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Peter A. Richardson
- Houston VA HSR&D Center of Excellence, Health Services Research and Development Service, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Hashem B. El-Serag
- Houston VA HSR&D Center of Excellence, Health Services Research and Development Service, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA, Department of Medicine, Baylor College of Medicine, Houston, TX, USA, Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
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22
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Lin D, Kramer JR, Ramsey D, Alsarraj A, Verstovsek G, Rugge M, Parente P, Graham DY, El-Serag HB. Oral bisphosphonates and the risk of Barrett's esophagus: case-control analysis of US veterans. Am J Gastroenterol 2013; 108:1576-83. [PMID: 23857477 PMCID: PMC4046950 DOI: 10.1038/ajg.2013.222] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 06/11/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study examined Barrett's esophagus (BE) risk factors in veterans to determine the association between risk of BE and use of oral bisphosphonates. METHODS We conducted a case-control study among eligible patients scheduled for an elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics from a single VA Medical Center. Cases with definitive BE were compared with controls; all underwent study EGD. Use of oral bisphosphonates was ascertained by reviewing filled prescriptions in electronic pharmacy records. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs), using multivariate logistic regression modeling while adjusting for sex, age, race, proton-pump inhibitor use, hiatal hernia, waist-to-hip ratio, Helicobacter pylori infection, and gastroesophageal reflux disorder (GERD) symptoms. RESULTS There were 285 BE cases, 1,122 endoscopy controls, and 496 primary care controls. Alendronate and risedronate were the only oral bisphosphonates prescribed. The proportion of BE cases with filled prescription of oral bisphosphonates (4.6%) was greater than in endoscopy controls (1.6%) or primary care controls (2.9%). In the adjusted analysis, oral bisphosphonate use was significantly associated with BE risk (OR=2.33; 95% CI: 1.11-4.88) compared with the combined control groups. This association remained significant when BE cases were compared with endoscopy controls only (OR=2.74; 95% CI: 1.28-5.87) but was attenuated when compared with primary care controls only (OR=2.60; 95% CI: 0.99-6.84). The association was observed in patients with GERD symptoms (OR=3.29; 95% CI: 1.36-7.97) but not in those without GERD symptoms. CONCLUSION Oral bisphosphonate use may increase the risk for BE, especially among patients with GERD.
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Affiliation(s)
- Derek Lin
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Jennifer R. Kramer
- Houston VA HSR&D Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - David Ramsey
- Houston VA HSR&D Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Abeer Alsarraj
- Houston VA HSR&D Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Gordana Verstovsek
- Department of Pathology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA, Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
| | - Massimo Rugge
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Paola Parente
- Casa Sollievo della Sofferenza, Department of Pathology, San Giovanni Rotondo, Italy
| | - David Y. Graham
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA, Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Hashem B. El-Serag
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA, Houston VA HSR&D Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA, Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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Zaïr ZM, Johnson GE, Griffiths AP, Jenkins GJ. Diagnostic correlation between the expression of the DNA repair enzyme N-methylpurine DNA glycosylase and esophageal adenocarcinoma onset: a retrospective pilot study. Dis Esophagus 2013; 26:644-50. [PMID: 23137018 DOI: 10.1111/dote.12003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
EAC in its early stages, when it can potentially be cured, is rarely symptomatic and is associated with high mortality rates because in part of late-stage diagnosis. Given that DNA repair is an important contributory factor of early-stage malignancy, our study focused on the expression of the base excision repair enzyme N-methylpurine DNA glycosylase (MPG) in EAC disease onset. MPG messenger RNA (mRNA) expression levels were determined using quantitative reverse transcriptase polymerase chain reaction from a maximum of 72 patient samples. Immunohistochemistry was further utilized for the detection of MPG protein, and semiquantitative analysis performed using an H-score approach was carried out on a total of 130 archival tissue samples of different esophageal pathologies. Nuclear localized MPG protein was detected in all nonmalignant tissues derived from the enterohepatic system, with H-score values of 3.9-5.5 ± 0.4-1.0. In cancerous tissues derived from the enterohepatic system, a 9.5-fold increase in the level of MPG mRNA expression was specifically observed in the malignant regions located within the esophagus region. Further analysis revealed a 9- and 14-fold increase in MPG mRNA expression in EAC tumor, node, metastasis stages II and III, respectively, suggesting MPG expression to correlate with EAC disease progression. Immunohistochemistry analysis further showed a sevenfold significant increase in MPG protein expression in EAC tissues. Intriguingly, there was a fivefold significant decrease in nuclear localized MPG protein expression in tissues derived from Barrett's esophagus and low-grade dysplasia. Such findings highlight a complex regulatory pattern governing DNA glycosylase base excision repair initiation, as normal tissue undergoes Barrett's metaplasia and later dedifferentiates to EAC. Indeed, disease-stage-specific alterations in the expression of MPG may highlight a potential role for MPG in determining EAC onset and thus potentially be of clinical relevance for early disease detection and increased patient survival.
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Affiliation(s)
- Z M Zaïr
- Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK.
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24
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Andrici J, Cox MR, Eslick GD. Cigarette smoking and the risk of Barrett's esophagus: a systematic review and meta-analysis. J Gastroenterol Hepatol 2013; 28:1258-1273. [PMID: 23611750 DOI: 10.1111/jgh.12230] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Barrett's esophagus (BE) is a premalignant condition to esophageal adenocarcinoma. It is currently not clear whether cigarette smoking increases the risk of developing BE, and no meta-analysis has been performed on the topic. We conducted a systematic review and meta-analysis, providing a quantitative estimate of the increased risk of BE associated with cigarette smoking, to help clarify whether a relationship exists between smoking and BE. METHODS Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to May 17, 2013, for observational studies of BE patients. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using a random effects model for the association of smoking with BE. BE patients were compared with non-gastroesophageal reflux disease (GERD) controls as well as with population-based and GERD controls. RESULTS Thirty-nine studies comprising 7069 BE patients were included in the meta-analysis. Having ever-smoked was associated with an increased risk of BE compared with non-GERD controls (OR 1.44; 95% CI 1.20-1.74), population-based controls (OR 1.42; 95% CI 1.15-1.76), but not GERD controls (OR 1.18; 95% CI 0.75-1.86). The meta-analyses of the studies reporting the lowest and highest number of pack-years smoked showed an increased risk of BE (OR 1.41; 95% CI 1.22-1.63) and (OR 1.53; 95% CI 1.27-1.84), respectively. CONCLUSION Cigarette smoking was associated with an increased risk of BE. Being an ever-smoker was associated with an increased risk of BE in all control groups. A greater number of pack-years smoked was associated with a greater risk of BE.
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Affiliation(s)
- Juliana Andrici
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Penrith, New South Wales, Australia
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25
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Cardin R, Piciocchi M, Tieppo C, Maddalo G, Zaninotto G, Mescoli C, Rugge M, Farinati F. Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation. Ann Surg Oncol 2013; 20 Suppl 3:S583-9. [PMID: 23744553 DOI: 10.1245/s10434-013-3043-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Barrett esophagus develops in a scenario of chronic inflammation, linked to free radical formation and oxidative DNA damage. Eight-hydroxydeoxyguanosine, the main oxidative DNA adduct, is partially repaired by a glycosylase (OGG1) whose polymorphism is associated to a reduced repair capacity. Telomeres are particularly prone to oxidative damage, which leads to shortening and cell senescence, while elongation, by telomerase activity, is linked to cell immortalization and cancer. Limited data are available on this point with respect to Barrett esophagus. This study aimed to evaluate the link among 8-hydroxydeoxyguanosine, OGG1 polymorphism, telomerase activity, telomere length, and p53 mutation in Barrett progression. METHODS Forty consecutive patients with short- and long-segment Barrett esophagus and 20 controls with gastroesophageal reflux disease without Barrett esophagus were recruited. Analysis of biopsy samples was undertaken to study 8-hydroxydeoxyguanosine levels, OGG1 polymorphism, telomerase activity, and telomere length. Serum samples were obtained for p53 mutation. RESULTS Controls had significantly lower levels of 8-hydroxydeoxyguanosine and telomerase activity, with normal telomere length and no p53 mutation. In short-segment Barrett esophagus, 8-hydroxydeoxyguanosine levels were higher and telomeres underwent significant shortening, with stimulation of telomerase activity but no p53 mutations. In long-segment Barrett esophagus, 8-hydroxydeoxyguanosine reached maximal levels, with telomere elongation, and 42 % of the patients showed p53 mutation. CONCLUSIONS In Barrett patients, with disease progression, oxidative DNA damage accumulates, causing telomere instability, telomerase activation, and, in a late phase, mutations in the p53 gene, thus abrogating its activity as the checkpoint of proliferation and apoptosis, and facilitating progression to cancer.
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Affiliation(s)
- Romilda Cardin
- Section of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University, Padua, Italy
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Kim YJ, Kim EH, Hahm KB. Oxidative stress in inflammation-based gastrointestinal tract diseases: challenges and opportunities. J Gastroenterol Hepatol 2012; 27:1004-10. [PMID: 22413852 DOI: 10.1111/j.1440-1746.2012.07108.x] [Citation(s) in RCA: 171] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Oxygen free radicals in excessively high amounts are all very reactive chemically and can impose a detrimental influence on living organisms by provoking "oxidative stress" that can damage major cellular constituents. The latter includes the cell membrane, cytoplasmic proteins, and nuclear DNA. Conversely, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) when present in low amounts play an important role as regulatory mediators in signaling processes, through which, paradoxically, many ROS-mediated responses can protect the cells against oxidative stress by induction of "redox homeostasis." Therefore, diseases associated with free radical overproduction are provoked by "blazed ROS productions" far beyond the host's capacity to quench. Free radicals have been implicated in the pathogenesis of diverse gastrointestinal (GI) diseases including gastroesophageal reflux disease (GERD), gastritis, enteritis, colitis and associated cancers as well as pancreatitis and liver cirrhosis. This article provides an overview of the role of oxidative stress in inflammation-based GI tract diseases, including reflux esophagitis, Helicobacter pylori-associated gastritis, non-steroidal anti-inflammatory drug-induced enteritis, ulcerative colitis, and associated colorectal cancer. The challenging issue that ROS can contribute to diverse gastrointestinal dysfunction, or manifest dual roles in cancer promotion or cancer suppression will also be discussed for the opportunity to enhance understanding of inflammation-based GI diseases.
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Affiliation(s)
- Yoon Jae Kim
- Department of Gastroenterology, Gachon University Gil Medical Center, Incheon, Korea
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27
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Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan TL, Whiteman DC, Corley DA. Cigarette smoking increases risk of Barrett's esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium. Gastroenterology 2012; 142:744-53. [PMID: 22245667 PMCID: PMC3321098 DOI: 10.1053/j.gastro.2011.12.049] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 12/07/2011] [Accepted: 12/31/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Cigarette smoking has been implicated in the etiology of esophageal adenocarcinoma, but it is not clear if smoking is a risk factor for Barrett's esophagus. We investigated whether tobacco smoking and other factors increase risk for Barrett's esophagus. METHODS We analyzed data from 5 case-control studies included in the international Barrett's and Esophageal Adenocarcinoma Consortium. We compared data from subjects with Barrett's esophagus (n = 1059) with those from subjects with gastroesophageal reflux disease (gastroesophageal reflux disease controls, n = 1332), and population-based controls (n = 1143), using multivariable logistic regression models to test associations with cigarette smoking. We also tested whether cigarette smoking has synergistic effects with other exposures, which might further increase risk for Barrett's esophagus. RESULTS Subjects with Barrett's esophagus were significantly more likely to have ever smoked cigarettes than the population-based controls (odds ratio [OR] = 1.67; 95% confidence interval [CI]: 1.04-2.67) or gastroesophageal reflux disease controls (OR = 1.61; 95% CI: 1.33-1.96). Increasing pack-years of smoking increased the risk for Barrett's esophagus. There was evidence of a synergy between ever-smoking and heartburn or regurgitation; the attributable proportion of disease among individuals who ever smoked and had heartburn or regurgitation was estimated to be 0.39 (95% CI: 0.25-0.52). CONCLUSIONS Cigarette smoking is a risk factor for Barrett's esophagus. The association was strengthened with increased exposure to smoking until ∼20 pack-years, when it began to plateau. Smoking has synergistic effects with heartburn or regurgitation, indicating that there are various pathways by which tobacco smoking might contribute to development of Barrett's esophagus.
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Affiliation(s)
| | | | | | | | - Wong-Ho Chow
- Division of Cancer Epidemiology and Genetics, NCI
| | - Thomas L. Vaughan
- Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Douglas A. Corley
- Division of Research and Oakland Medical Center, Kaiser Permanente, CA
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Coleman HG, Bhat S, Johnston BT, McManus D, Gavin AT, Murray LJ. Tobacco smoking increases the risk of high-grade dysplasia and cancer among patients with Barrett's esophagus. Gastroenterology 2012; 142:233-240. [PMID: 22062359 DOI: 10.1053/j.gastro.2011.10.034] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 09/28/2011] [Accepted: 10/24/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Esophageal adenocarcinoma arises from Barrett's esophagus (BE); patients with this cancer have a poor prognosis. Identification of modifiable lifestyle factors that affect the risk of progression from BE to esophageal adenocarcinoma might prevent its development. We investigated associations among body size, smoking, and alcohol use with progression of BE to neoplasia. METHODS We analyzed data from patients with BE identified from the population-based Northern Ireland BE register, diagnosed between 1993 and 2005 with specialized intestinal metaplasia (n = 3167). Data on clinical, demographic, and lifestyle factors related to diagnosis of BE were collected from hospital case notes. We used the Northern Ireland Cancer Registry to identify which of these patients later developed esophageal adenocarcinoma, adenocarcinomas of the gastric cardia, or esophageal high-grade dysplasia. Cox proportional hazards models were used to associate lifestyle factors with risk of progression. RESULTS By December 31, 2008, 117 of the patients with BE developed esophageal high-grade dysplasia or adenocarcinomas of the esophagus or gastric cardia. Current tobacco smoking was significantly associated with an increased risk of progression (hazard ratio = 2.03; 95% confidence interval, 1.29-3.17) compared with never smoking, and across all strata of smoking intensity. Alcohol consumption was not related to risk of progression. Measures of body size were infrequently reported in endoscopy reports, and body size was not associated with risk of progression. CONCLUSIONS Smoking tobacco increases the risk of progression to cancer or high-grade dysplasia 2-fold among patients with BE, compared with patients with BE that have never smoked. Smoking cessation strategies should be considered for patients with BE.
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Affiliation(s)
- Helen G Coleman
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Northern Ireland, UK.
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Fikrová P, Stětina R, Hronek M, Hyšpler R, Tichá A, Zadák Z. Application of the comet assay method in clinical studies. Wien Klin Wochenschr 2011; 123:693-9. [PMID: 22024999 DOI: 10.1007/s00508-011-0066-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Accepted: 08/04/2011] [Indexed: 12/21/2022]
Abstract
The comet assay or single-cell gel electrophoresis (SCGE) assay is now widely accepted as a standard method for assessing DNA damage in individual cells. It finds use in a broad variety of applications including human biomonitoring, genotoxicology, ecological monitoring and as a tool for investigation of DNA damage and repair in different cell types in response to a range of DNA-damaging agents. The comet assay should be eminently suitable for use in clinical practice since it is a relatively simple and inexpensive technique which requires only a few cells, and results can be obtained within a matter of hours. This method can be used in the study of cancer as well as in lifestyle and dietary studies. In cancer it is useful for measuring DNA damage before, throughout and after therapy (either radiotherapy or chemotherapy). Another use of this method is in lifestyle study, such as investigation of the effect on DNA of common human activities (e.g. smoking, or working with a potentially genotoxic agent). The final use of comet assay in this paper is dietary study. In this type of study we observe the effects of consumption of specific foods or supplements which may be protective for DNA against damage.
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Affiliation(s)
- Petra Fikrová
- Charles University, Department of Biological Sciences, Hradec Králové, Czech Republic.
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30
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Jacobson BC, Giovannucci EL, Fuchs CS. Smoking and Barrett's esophagus in women who undergo upper endoscopy. Dig Dis Sci 2011; 56:1707-17. [PMID: 21448698 PMCID: PMC3100531 DOI: 10.1007/s10620-011-1672-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2010] [Accepted: 03/08/2011] [Indexed: 01/11/2023]
Abstract
BACKGROUND Cigarette use is associated with esophageal adenocarcinoma, and cross-sectional studies suggest an association between smoking and Barrett's esophagus. AIMS We sought to examine prospectively the effect of smoking on the risk for Barrett's esophagus. METHODS This was a prospective cohort study among 20,863 women within the Nurses' Health Study who underwent upper gastrointestinal endoscopy for any reason between 1980 and 2006. We assessed the association between smoking and pathologically-confirmed Barrett's esophagus (n = 377). Self-reported data on smoking and potential confounding variables were collected from biennial questionnaires. RESULTS Compared with women who never smoked, former smokers of 1-24 cigarettes/day had a multivariate odds ratio for Barrett's esophagus of 1.25 (95% CI 0.99-1.59), former smokers of ≥ 25 cigarettes/day had a multivariate odds ratio of 1.52 (95% CI 1.04-2.22), current smokers of 1-24 cigarettes/day had a multivariate odds ratio of 0.89 (95% CI 0.54-1.45), and current smokers of ≥ 25 cigarettes/day had a multivariate odds ratio of 0.92 (95% CI 0.34-2.54). The risk for Barrett's esophagus increased significantly with increasing pack-years smoked among former (P = 0.008) but not current smokers (P = 0.99), especially when considering exposure ≥ 25 years before index endoscopy. Results were similar among women reporting regular heartburn/acid-reflux one or more times a week, and were not accounted for by changes in weight. CONCLUSIONS Heavy, remote smoking is associated with an increased risk for Barrett's esophagus. This finding suggests a long latency period between exposure and development of the disease, even after discontinuation of smoking.
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Affiliation(s)
- Brian C Jacobson
- Section of Gastroenterology, Department of Medicine, Boston University Medical Center, 85 East Concord Street, Room 7721, Boston, MA 02118, USA.
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Lonkar P, Dedon PC. Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates. Int J Cancer 2011; 128:1999-2009. [PMID: 21387284 PMCID: PMC3334345 DOI: 10.1002/ijc.25815] [Citation(s) in RCA: 220] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer.
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Affiliation(s)
- Pallavi Lonkar
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Peter C. Dedon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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Johanson JF, Frakes J, Eisen D. Computer-assisted analysis of abrasive transepithelial brush biopsies increases the effectiveness of esophageal screening: a multicenter prospective clinical trial by the EndoCDx Collaborative Group. Dig Dis Sci 2011; 56:767-72. [PMID: 21132367 DOI: 10.1007/s10620-010-1497-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 11/10/2010] [Indexed: 12/25/2022]
Abstract
BACKGROUND The sensitivity of screening for Barrett's esophagus (BE) and esophageal dysplasia (ED) is hampered by the limited amount of tissue that can be sampled by forceps biopsy (FB). AIM The aim of this study was to evaluate computer assisted analysis of an abrasive, transepithelial brush biopsy as an adjunct to FB to increase detection of BE and ED. METHODS This was a multicenter prospective trial of patients being screened for BE and ED. Each patient had two brush biopsies (BB) and then random four-quadrant FB every 1-2 cm of the esophagus. All BB were examined with computer assistance by pathologists at CDx Laboratories (Suffern, NY), and all FB were examined by the investigators' local pathologists. RESULTS Of 1,266 patients enrolled, 363 were diagnosed with BE by FB alone and 146 additional cases of BE were identified by adding BB. The addition of BB to FB increased the overall detection of BE by 39.8% (95% CI 32-48%). This added detection of BE in 11.5% of all patients tested with the BB (146/1266) resulted in a number of patients needed to test (NNT) to obtain each additional positive finding of Barrett's esophagus of 8.7. Among a subset of 848 patients with gastroesophageal reflux disease and no prior history of BE, the addition of BB to FB identified an additional 105 patients with BE increasing the overall detection of BE by 70.5% (95% CI 54-90%). Dysplasia was diagnosed in 16 patients by FB alone, with an additional 14 cases detected by adding BB. The addition of BB to FB thus increased the detection of ED by 87.5%. CONCLUSION These results suggest that adjunctive computer-assisted analysis of an abrasive brush biopsy has the potential to substantially improve the detection of Barrett's esophagus and dysplasia in screening populations.
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Affiliation(s)
- J F Johanson
- Rockford Gastroenterology Associates, Ltd., Rockford, IL, USA.
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The pathogenesis of Barrett's metaplasia and the progression to esophageal adenocarcinoma. Recent Results Cancer Res 2010; 182:39-63. [PMID: 20676870 DOI: 10.1007/978-3-540-70579-6_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The most important risk factor for the development of Barrett's esophagus is the reflux of both gastric and duodenal contents into the esophagus. The reason why Barrett's metaplasia develops only in a minority of patients suffering from gastroesophageal reflux disease remains unknown.The exact mechanism behind the transition of normal squamous epithelium into specialized columnar epithelium is also unclear. It is likely that stem cells are involved in this metaplastic change, as they are the only permanent residents of the epithelium. Several tumorigenic steps that lead to the underlying genetic instability, which is indispensable in the progression from columnar metaplasia to esophageal adenocarcinoma have been described. This review outlines the process of pathogenesis of Barrett's metaplasia and its progression to esophageal adenocarcinoma.
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Cook MB, Kamangar F, Whiteman DC, Freedman ND, Gammon MD, Bernstein L, Brown LM, Risch HA, Ye W, Sharp L, Pandeya N, Webb PM, Wu AH, Ward MH, Giffen C, Casson AG, Abnet CC, Murray LJ, Corley DA, Nyrén O, Vaughan TL, Chow WH. Cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction: a pooled analysis from the international BEACON consortium. J Natl Cancer Inst 2010; 102:1344-53. [PMID: 20716718 PMCID: PMC2935475 DOI: 10.1093/jnci/djq289] [Citation(s) in RCA: 221] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2009] [Revised: 07/12/2010] [Accepted: 07/13/2010] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation. METHODS We used primary data from 10 population-based case-control studies and two cohort studies from the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided. RESULTS The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar. CONCLUSIONS Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.
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Affiliation(s)
- Michael B Cook
- Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health/DHHS, 6120 Executive Blvd., Bethesda, MD 20852-7234, USA.
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Karaman A, Binici DN, Kabalar ME, Koca T, Dursun H. Genomic instability in patients with Barrett's esophagus. ACTA ACUST UNITED AC 2010; 201:88-93. [DOI: 10.1016/j.cancergencyto.2010.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Revised: 04/08/2010] [Accepted: 05/04/2010] [Indexed: 12/12/2022]
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Vasavi M, Vedicherala B, Vattam KK, Ahuja YR, Hasan Q. Assessment of Genetic Damage in Inflammatory, Precancerous, and Cancerous Pathologies of the Esophagus Using the Comet Assay. Genet Test Mol Biomarkers 2010; 14:477-82. [DOI: 10.1089/gtmb.2010.0006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Mohan Vasavi
- Department of Genetics and Molecular Medicine, Kamineni Hospital, Hyderabad, India
| | - Bhavani Vedicherala
- Department of Genetics, Bhagwan Mahavir Medical Research Centre, Hyderabad, India
| | - Kiran K. Vattam
- Department of Genetics and Molecular Medicine, Kamineni Hospital, Hyderabad, India
| | - Yog R. Ahuja
- Department of Genetics, Vasavi Medical and Research Centre, Hyderabad, India
| | - Qurratulain Hasan
- Department of Genetics and Molecular Medicine, Kamineni Hospital, Hyderabad, India
- Department of Genetics, Bhagwan Mahavir Medical Research Centre, Hyderabad, India
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Fenech MF. Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: current status and a road map to the future. Am J Clin Nutr 2010; 91:1438S-1454S. [PMID: 20219957 DOI: 10.3945/ajcn.2010.28674d] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Damage to the genome is recognized as a fundamental cause of developmental and degenerative diseases. Several micronutrients play an important role in protecting against DNA damage events generated through endogenous and exogenous factors by acting as cofactors or substrates for enzymes that detoxify genotoxins as well as enzymes involved in DNA repair, methylation, and synthesis. In addition, it is evident that either micronutrient deficiency or micronutrient excess can modify genome stability and that these effects may also depend on nutrient-nutrient and nutrient-gene interaction, which is affected by genotype. These observations have led to the emerging science of genome health nutrigenomics, which is based on the principle that DNA damage is a fundamental cause of disease that can be diagnosed and nutritionally prevented on an individual, genetic subgroup, or population basis. In this article, the following topics are discussed: 1) biomarkers used to study genome damage in humans and their validation, 2) evidence for the association of genome damage with developmental and degenerative disease, 3) current knowledge of micronutrients required for the maintenance of genome stability in humans, 4) the effect of nutrient-nutrient and nutrient-genotype interaction on DNA damage, and 5) strategies to determine dietary reference values of single micronutrients and micronutrient combinations (nutriomes) on the basis of DNA damage prevention. This article also identifies important knowledge gaps and future research directions required to shed light on these issues. The ultimate goal is to match the nutriome to the genome to optimize genome maintenance and to prevent pathologic amounts of DNA damage.
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Affiliation(s)
- Michael F Fenech
- Commonwealth Scientific and Industrial Research Organisation Food and Nutritional Sciences, Adelaide BC SA 5000, Australia.
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Kadioglu E, Sardas S, Ergun M, Unal S, Karakaya AE. The role of oxidative DNA damage, DNA repair, GSTM1, SOD2 and OGG1 polymorphisms in individual susceptibility to Barrett’s esophagus. Toxicol Ind Health 2010; 26:67-79. [DOI: 10.1177/0748233709359278] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Determination of the genetic alterations, which play a role in the etiology of Barrett’s esophagus (BE), could help identify high-risk individuals for esophageal adenocarcinoma (EA). The aim of the present study was to investigate the role of oxidative DNA damage, glutathione (GSH) concentration as oxidative stress parameters and DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms as individual susceptibility parameters in the etiology of BE. The study groups comprised BE patients who were clinically diagnosed (n = 40) and a healthy control group (n = 40). Basal DNA damage, pyrimidine and purine base damage after H2O2 induction, H 2O2 sensitivity, DNA repair capacity, oxidized pyrimidine and purine base damage repair were evaluated in peripheral blood lymphocytes with a modified comet assay using specific endonucleases (Endo III and Fpg). Polymerase chain reaction—restriction length polymorphism (PCR-RFLP)-based assays were used for genotyping. The patient group showed elevated levels of basal DNA damage, pyrimidine base damage and H2O2 sensitivity as compared to controls (p < .05). DNA repair capacity, oxidized pyrimidine and purine base damage repair capacity, were not statistically different between patients and controls. GSH concentration was found to be significantly lower in smoking patients than in the controls (p < .05). None of the genetic variations changed the risk of having BE disease. However, patients carrying the variant OGG1 Cys allele showed elevated levels of pyrimidine base damage as compared to patients carrying the wild-type OGG1 Ser (p < .05). The results of this study point to a role of oxidative DNA damage in BE. However, DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms appeared to play no role in the individual susceptibility to this disease.
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Affiliation(s)
- Ela Kadioglu
- Toxicology Department, Faculty of Pharmacy, Gazi University, Hipodrom, Ankara, Turkey,
| | - Semra Sardas
- Toxicology Department, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
| | - Meltem Ergun
- Gastroenterology Department, Faculty of Medicine, Gazi University, Beşevler, Ankara, Turkey
| | - Selahattin Unal
- Gastroenterology Department, Faculty of Medicine, Gazi University, Beşevler, Ankara, Turkey
| | - Ali Esat Karakaya
- Toxicology Department, Faculty of Pharmacy, Gazi University, Hipodrom, Ankara, Turkey
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Zhang HY, Hormi-Carver K, Zhang X, Spechler SJ, Souza RF. In benign Barrett's epithelial cells, acid exposure generates reactive oxygen species that cause DNA double-strand breaks. Cancer Res 2009; 69:9083-9. [PMID: 19920191 DOI: 10.1158/0008-5472.can-09-2518] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cells that sustain double-strand breaks (DSB) can develop genomic instability, which contributes to carcinogenesis, and agents that cause DSBs are considered potential carcinogens. We looked for evidence of acid-induced DNA damage, including DSBs, in benign Barrett's epithelial (BAR-T) cell lines in vitro and in patients with Barrett's esophagus in vivo. In BAR-T cells, we also explored the mechanisms underlying acid-induced DNA damage. We exposed BAR-T cells to acid in the presence of a fluorescent probe for reactive oxygen species (ROS) and in the presence or absence of disodium 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (which prevents intracellular acidification) and N-acety-l-cysteine (a scavenger of ROS). DSBs were detected by Western blotting and immunofluorescence for histone H2AX phosphorylation and by CometAssay. During endoscopy in patients with Barrett's esophagus, we took biopsy specimens from the metaplastic mucosa before and after esophageal perfusion with 0.1 N HCl for 3 min and sought DSBs by Western blotting for histone H2AX phosphorylation. In BAR-T cells, acid exposure resulted in ROS production and caused a time-dependent increase in levels of phospho-H2AX that continued for at least 48 h. Pretreatment with disodium 4,4'-diisothiocyanatostilbene-2,2'-disulfonate or N-acety-l-cysteine prevented the acid-induced increase in phospho-H2AX levels. DSBs also were detected in biopsy specimens of Barrett's metaplasia following esophageal acid perfusion in all of 6 patients with Barrett's esophagus. Acid exposure causes DSBs in Barrett's epithelial cells through ROS produced as a consequence of intracellular acidification. These findings suggest that acid can be considered a carcinogen in Barrett's esophagus.
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Affiliation(s)
- Hui Ying Zhang
- Department of Medicine, VA North Texas Health Care System, Dallas, Texas 75216, USA
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Abstract
The incidence of esophageal adenocarcinoma (EAC) has increased dramatically in the western world, and there also appears to have been an increase in the incidence of Barrett's esophagus and gastroesophageal reflux disease in recent years. The contemporaneous increase in obesity has focused interest on whether obesity is a risk factor for EAC and its precursors. This article reviews current evidence for the role that overweight/obesity and body fat distribution have in development of the esophagitis metaplasia-dysplasia-adenocarcinoma sequence. Particular attention is paid to the stage at which adiposity may act to influence the risk of EAC, because this determines the importance of weight control and weight loss at each stage in the disease spectrum for the prevention of EAC.
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Affiliation(s)
- Liam Murray
- Centre for Public Health, The Queen's University of Belfast, Mulhouse Building, Grosvenor Road, Belfast B12 6BJ, UK.
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Abstract
Barrett's esophagus (BE) is a metaplastic premalignant disorder in which the normal stratified squamous epithelium of the lower esophagus is replaced by a columnar lined epithelium with intestinal differentiation. BE generally occurs in the context of chronic gastroesophageal reflux disease and it is the primary risk factor for the development of esophageal adenocarcinoma, with a conversion rate of 0.5% to 1% per annum. The dramatic increase of esophageal adenocarcinoma incidence in the western world over the last two decades justifies the strong interest in BE and its development with the aim to improve preventative and therapeutic clinical strategies.
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Pan J, Lin J, Izzo JG, Liu Y, Xing J, Huang M, Ajani JA, Wu X. Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis 2009; 30:785-92. [PMID: 19270000 PMCID: PMC2675653 DOI: 10.1093/carcin/bgp058] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Revised: 03/02/2009] [Accepted: 03/03/2009] [Indexed: 12/14/2022] Open
Abstract
In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3' untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19-0.86). The heterozygous AG genotype of XPA 5' UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10-fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97), whereas the poly-AT-/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57-4.52) and > or = 2 (OR = 2.74, 95% CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
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Affiliation(s)
- Jennifer Pan
- Department of Epidemiology
- Department of Gastrointestinal Medical Oncology
| | | | - Julie G. Izzo
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Abstract
Esophageal cancer is a significant worldwide health problem because of its poor prognosis and high incidence in certain parts of the world. Tobacco smoke and alcohol consumption are significant risk factors for esophageal squamous cell carcinoma, whereas frequent gastroesophageal reflux and subsequent inflammatory reactions play a role in causing the adenocarcinoma. Esophageal carcinogenesis involves multiple genetic alterations. A large body of knowledge has been generated regarding molecular alterations associated with esophageal carcinogenesis. These alterations include aberrant cell cycle control, DNA repair, cellular enzymes, growth factor receptors, and nuclear receptors. This chapter reviews the most frequent gene alterations and their correlation with risk factors as well as the prevention strategies in esophageal cancer.
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Affiliation(s)
- Xiao-chun Xu
- Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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Masannat YA, Hanby A, Horgan K, Hardie LJ. DNA damaging effects of the dyes used in sentinel node biopsy: possible implications for clinical practice. J Surg Res 2008; 154:234-8. [PMID: 19181339 DOI: 10.1016/j.jss.2008.07.039] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Revised: 07/29/2008] [Accepted: 07/31/2008] [Indexed: 11/16/2022]
Abstract
OBJECTIVE This study investigates whether methylene blue (MB), patent blue V (PBV), and indigo carmine (IDC) commonly used in sentinel node biopsy cause DNA damage to breast epithelial cells in vitro. METHODS MCF-7 and HB-2 cells were exposed for 5 minutes to the above dyes at the same concentrations used in clinical practice. Following exposure, the comet assay was performed to detect DNA damage. The enzyme, Fapy-DNA glycosylase (FpG) was incorporated to enable the detection of additional oxidative damage. RESULTS Both PBV and MB stimulated DNA strand breaks in both MCF-7 and HB2 cell lines (P < 0.05). Levels were elevated over 3-fold (P < 0.05) in MCF-7 and HB2 cells treated with 2.5% PBV and 1% MB, compared with untreated control cells. In contrast, IDC did not stimulate DNA strand break damage at clinically relevant concentrations in either cell line. Addition of Fapy-DNA glycosylase enzyme also revealed significantly (P < 0.05) increased levels of oxidative DNA lesions (ODL) in MCF-7 cells treated with PBV (17.6% ODL) compared with control cells (5.9% ODL). CONCLUSIONS This study shows, for the first time, that certain dyes (MB and PBV) commonly used in SLNB have genotoxic effects on breast cells at clinically relevant concentrations in vitro. In vivo studies are now warranted to assess and minimize DNA damage caused by these dyes during SLNB.
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Affiliation(s)
- Yazan Adnan Masannat
- The Breast Unit, Department of Surgery, Leeds General Infirmary, Great George Street, Leeds, United Kingdom
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Reddy Thavanati PK, Kanala KR, de Dios AE, Cantu Garza JM. Age-Related Correlation Between Antioxidant Enzymes and DNA Damage With Smoking and Body Mass Index. J Gerontol A Biol Sci Med Sci 2008; 63:360-4. [DOI: 10.1093/gerona/63.4.360] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Guy NC, Garewal H, Holubec H, Bernstein H, Payne CM, Bernstein C, Bhattacharyya AK, Dvorak K. A novel dietary-related model of esophagitis and Barrett's esophagus, a premalignant lesion. Nutr Cancer 2008; 59:217-27. [PMID: 18001217 DOI: 10.1080/01635580701499529] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Barrett's esophagus (BE) is a premalignant lesion in which columnar epithelium (containing goblet cells) replaces esophageal squamous cells. Previous evidence suggested that hydrophobic bile acids and zinc deficiency each play a role in BE development. We fed wild-type C57BL/6 mice a zinc-deficient diet containing the hydrophobic bile acid, deoxycholic acid for various times up to 152 days. All mice fed this diet developed esophagitis by 69 days on the diet and 63% of the mice on this diet for 88 to 152 days also developed a BE-like lesion. Esophageal tissues showed thickened mucosa, increased proliferation, and increased expression of markers associated with oxidative and nitrosative stress. The newly formed BE-like lesions expressed Mucin-2, a marker of columnar differentiation. They also showed translocation of the p65 subunit of nuclear factor-kappaB and beta -catenin to the nucleus and typical histological changes associated with BE lesions. This mouse model of esophagitis and BE is expected to contribute to a deeper understanding of BE pathogenesis and to strategies for prevention of BE progression to cancer.
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Affiliation(s)
- Naihsuan C Guy
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
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Räsänen JV, Sihvo EIT, Ahotupa MO, Färkkilä MA, Salo JA. The expression of 8-hydroxydeoxyguanosine in oesophageal tissues and tumours. Eur J Surg Oncol 2007; 33:1164-8. [PMID: 17467227 DOI: 10.1016/j.ejso.2007.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2006] [Accepted: 03/02/2007] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The most common marker of oxidative DNA damage is 8-hydroxydeoxyguanosine (8-OHdG), which is linked with several malignancies. In the present study we investigated whether DNA damage linked to oxidative stress (as 8-OHdG) is present in Barrett's mucosa with or without associated adenocarcinoma or high-grade dysplasia and in normal controls' squamous mucosa. EXPERIMENTAL DESIGN We measured 8-OHdG in 51 patients (13 Barrett's metaplasia, six Barrett's oesophagus with high-grade dysplasia, 18 adenocarcinoma of the distal oesophagus/oesophagogastric junction and 14 normal controls). The amount of DNA damage was determined by high-performance liquid chromatography in oesophagus samples obtained either from endoscopy or as samples from surgery. The median 8-OHdG concentration was expressed as the ratio of 8-OHdG per 10(5) deoxyguanosine. RESULTS Analysis revealed that 8-OHdG was present in both Barrett's metaplasia with and without dysplasia as well as in adenocarcinoma of the oesophagus/oesophagogastric junction. Although the study group was small the amount of 8-OHdG was significantly increased in the distal oesophagus both in Barrett's epithelium 1.26 (0.08-29.47) and in high-grade dysplasia 1.35 (1.04-1.65) as well as in adenocarcinoma of oesophagus/oesophagogastric junction 1.08 (0.59-1.94) compared to controls 0.06 (0-4.08) (p=0.002, p=0.012, p=0.001, respectively). Barrett's patients had no significant difference in 8-OHdG levels between their distal and proximal oesophageal samples. CONCLUSIONS Our results show the presence of oxidative DNA damage in the distal oesophagus of patients with Barrett's oesophagus and adenocarcinoma of the oesophagus/oesophagogastric junction. This may have a connection to carcinogenesis in Barrett's oesophagus.
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Affiliation(s)
- J V Räsänen
- Division of General Thoracic and Oesophageal Surgery, Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 340, FIN-00029 HUS, Helsinki, Finland
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Zhang HY, Zhang X, Hormi-Carver K, Feagins LA, Spechler SJ, Souza RF. In non-neoplastic Barrett's epithelial cells, acid exerts early antiproliferative effects through activation of the Chk2 pathway. Cancer Res 2007; 67:8580-7. [PMID: 17875697 DOI: 10.1158/0008-5472.can-07-2023] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Acid exerts pro-proliferative effects in Barrett's-associated esophageal adenocarcinoma cells. In non-neoplastic Barrett's epithelial (BAR-T) cells, in contrast, we have shown that acid exposure has antiproliferative effects. To explore our hypothesis that the acid-induced, antiproliferative effects are mediated by alterations in the proteins that regulate the G(1)-S cell cycle checkpoint, we exposed non-neoplastic Barrett's cells to acidic media (pH 4.0) and analyzed G(1)-S checkpoint proteins' expression, phosphorylation, and activity levels by Western blot. We studied acid effects on growth (by cell counts), proliferation (by flow cytometry and bromodeoxyuridine incorporation), cell viability (by trypan blue staining), and apoptosis (by annexin V staining), and we used caffeine and small interfering RNA to assess the effects of checkpoint kinase 2 (Chk2) inhibition on G(1)-S progression. Acid exposure significantly decreased cell numbers without affecting cell viability and with only a slight increase in apoptosis. Within 2 h of acid exposure, there was a delay in progression through the G(1)-S checkpoint that was associated with increased phosphorylation of Chk2, decreased levels of Cdc25A, and decreased activity of cyclin E-cyclin-dependent kinase 2; by 4 h, a continued delay at G(1)-S was associated with increased expression of p53 and p21. Caffeine and Chk2 siRNA abolished the acid-induced G(1)-S delay at 2 but not at 4 h. We conclude that acid exposure in non-neoplastic BAR-T cells causes early antiproliferative effects that are mediated by the activation of Chk2. Thus, we have elucidated a mechanism whereby acid can exert disparate effects on proliferation in neoplastic and non-neoplastic BAR-T cells.
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Affiliation(s)
- Hui-Ying Zhang
- Department of Medicine, Dallas Veterans Affairs Medical Center, University of Texas Southwestern Medical School, Dallas, Texas, USA
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Anderson LA, Watson RGP, Murphy SJ, Johnston BT, Comber H, Mc Guigan J, Reynolds JV, Murray LJ. Risk factors for Barrett’s oesophagus and oesophageal adenocarcinoma: Results from the FINBAR study. World J Gastroenterol 2007; 13:1585-94. [PMID: 17461453 PMCID: PMC4146903 DOI: 10.3748/wjg.v13.i10.1585] [Citation(s) in RCA: 180] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate risk factors associated with Barrett’s oesophagus and oesophageal adenocarcinoma.
METHODS: This all-Ireland population-based case-control study recruited 224 Barrett’s oesophagus patients, 227 oesophageal adenocarcinoma patients and 260 controls. All participants underwent a structured interview with information obtained about potential lifestyle and environmental risk factors.
RESULTS: Gastro-oesophageal reflux was associated with Barrett’s [OR 12.0 (95% CI 7.64-18.7)] and oesophageal adenocarcinoma [OR 3.48 (95% CI 2.25-5.41)]. Oesophageal adenocarcinoma patients were more likely than controls to be ex- or current smokers [OR 1.72 (95% CI 1.06-2.81) and OR 4.84 (95% CI 2.72-8.61) respectively] and to have a high body mass index [OR 2.69 (95% CI 1.62-4.46)]. No significant associations were observed between these risk factors and Barrett's oesophagus. Fruit but not vegetables were negatively associated with oesophageal adenocarcinoma [OR 0.50 (95% CI 0.30-0.86)].
CONCLUSION: A high body mass index, a diet low in fruit and cigarette smoking may be involved in the progression from Barrett’s oesophagus to oesophageal adenocarcinoma.
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Affiliation(s)
- Lesley A Anderson
- Centre for Clinical and Population Sciences, Queen's University, Mulhouse Building, Grosvenor Road, Belfast, BT12 6BJ, Northern Ireland.
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Herszenyi L, Hritz I, Pregun I, Sipos F, Juhasz M, Molnar B, Tulassay Z. Alterations of glutathione S-transferase and matrix metalloproteinase-9 expressions are early events in esophageal carcinogenesis. World J Gastroenterol 2007; 13:676-682. [PMID: 17278189 PMCID: PMC4065999 DOI: 10.3748/wjg.v13.i5.676] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2006] [Revised: 11/13/2006] [Accepted: 12/15/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of glutathione S-transferase (GST) and matrix metalloproteinase-9 (MMP-9) expressions in the development and progression of reflux esophagitis-Barrett's metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. METHODS GST and MMP-9 expressions were analyzed in 51 paraffin-embedded tissue samples by immunohistochemistry including patients with reflux esophagitis (n = 7), Barrett's metaplasia (n = 14), Barrett and esophagitis (n = 8), Barrett and dysplasia (n = 7), esophageal adenocarcinoma (n = 8) and a control group without any histological changes (n = 7). Immunostaining was determined semiquantitatively. Statistical analysis with one-way ANOVA, LSD test and correlation analysis were performed. P value of < 0.05 was considered significant. RESULTS GST expression was significantly higher while MMP-9 expression was significantly lower in control group compared to Barrett's metaplasia and the other groups. No major changes were observed between Barrett, esophagitis, and Barrett and concomitant esophagitis. Barrett and concomitant dysplasia, and adenocarcinoma revealed a significant lower expression of GST and higher levels of MMP-9 compared to all other groups. Adenocarcinoma showed almost no expression of GST and significantly higher levels of MMP-9 than Barrett and concomitant dysplasia. Alterations of GST and MMP-9 were inversely correlated (r = -0.82). CONCLUSION Decreased GST and increased expression of MMP-9 in Barrett's metaplasia-dysplasia-adenocarcinoma sequence as compared to normal tissue suggest their association with esophageal tumorigenesis. Loss of GST and gain of MMP-9 in Barrett with dysplasia compared to non-dysplastic metaplasia indicate that these alterations may be early events in carcinogenesis. Quantification of these parameters in Barrett's esophagus might be useful to identify patients at higher risk for progression to cancer.
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Affiliation(s)
- Laszlo Herszenyi
- 2nd Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkiralyi u. 46, Hungary.
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