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Ko MT, Thomas T, Holden E, Beales ILP, Alexandre L. The Association Between Obesity and Malignant Progression of Barrett's Esophagus: A Systematic Review and Dose-Response Meta-Analysis. Clin Gastroenterol Hepatol 2025; 23:726-738.e28. [PMID: 39237080 DOI: 10.1016/j.cgh.2024.07.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND AND AIMS Obesity is a risk factor for both Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). However, it is unclear whether obesity drives the malignant progression of BE. We aimed to assess whether obesity is associated with high-grade dysplasia (HGD) or cancer in patients with BE. METHODS We searched MEDLINE and EMBASE from inception through April 2024 for studies reporting the effect of body mass index (BMI) on the progression of nondysplastic BE or low-grade dysplasia (LGD) to HGD or EAC. A 2-stage dose-response meta-analysis was performed to estimate the dose-response relationship between BMI with malignant progression. Study quality was appraised using a modified Newcastle-Ottawa scale. RESULTS Twenty studies reported data on 38,565 patients (74.4% male) in total, of whom 1684 patients were diagnosed with HGD/cancer. Nineteen studies were considered moderate to high quality. Eight cohort studies reported data on 6647 male patients with baseline nondysplastic BE/LGD, of whom 555 progressed to HGD/EAC (pooled annual rate of progression, 0.02%; 95% confidence interval [CI], 0.01%-0.03%), and 1992 female patients with baseline nondysplastic BE/LGD, with 110 progressors (pooled annual rate of progression, 0.01%; 95% CI, 0.01%-0.02%). There was no significant difference in pooled annual rate of progression between males and females (P = .15). Each 5-kg/m2 increase in BMI was associated with a 6% increase in the risk of malignant progression (adjusted odds ratio, 1.06; 95% CI, 1.02-1.10; P < .001; I2= 0%). CONCLUSION Our meta-analysis provides some evidence that obesity as measured by BMI is associated with malignant progression of BE with a dose-response relationship. This finding requires confirmation in future high-quality cohort studies. Future risk prediction models could incorporate measures of obesity to potentially improve risk stratification in patients with BE. PROSPERO, Number: CRD42017051046.
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Affiliation(s)
- Mie Thu Ko
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - Tom Thomas
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Emily Holden
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Ian L P Beales
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - Leo Alexandre
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom.
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Jankowski J, Denholm M. Chemoprevention: can we prevent esophageal cancer? ESOPHAGEAL CANCER AND BARRETT'S ESOPHAGUS 2015:199-208. [DOI: 10.1002/9781118655153.ch21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett's esophagus [BE]) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done, but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (ie, changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia-EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel therapeutic targets.
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Affiliation(s)
- Antonio Galvao Neto
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - April Whitaker
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - Zhiheng Pei
- Department of Veterans Affairs New York Harbor Healthcare System, New York, NY, USA; Departments of Medicine and Pathology, New York University School of Medicine, New York, NY, USA.
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Cooper S, Menon S, Nightingale P, Trudgill N. Risk factors for the development of oesophageal adenocarcinoma in Barrett's oesophagus: a UK primary care retrospective nested case-control study. United European Gastroenterol J 2014; 2:91-8. [PMID: 24918013 DOI: 10.1177/2050640614523596] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 01/20/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Oesophageal adenocarcinoma (OAC) incidence is rising rapidly and prognosis remains poor. Endoscopic surveillance of Barrett's oesophagus (BO) remains controversial. OBJECTIVE A nested case-control study was undertaken to evaluate risk factors for progression of BO to OAC, potentially guiding surveillance efforts. METHODS The Health Improvement Network database includes general practitioner consultations from 5 million UK subjects. BO subjects with 1-year minimum of follow up were followed until development of OAC or end of time on database. Demographic variables (age, gender, smoking, body mass index) and data on medication considered negatively (aspirin/nonsteroidal anti-inflammatory drugs/proton pump inhibitors) or positively associated (lower oesophageal sphincter-relaxing and asthma drugs) with OAC development were studied. Cox regression analysis-derived hazard ratios with 95% confidence intervals estimated the relative risk for OAC progression. RESULTS A total of 3749 BO subjects were studied: 55 developed OAC during 17,743 patient years of follow up, a progression rate of 0.3% per annum. There was 96.7% of the cohort who took proton-pump inhibitors, with no association observed. Increasing age (1.03, 95% CI 1.01-1.05, p = 0.005), male gender (3.06, 95% CI 1.50-6.24, p = 0.002), and having ever smoked (2.36, 95% CI 1.13-4.93, p = 0.023) were associated with progression to OAC, (although smoking lost association on multivariate analysis). Increasing number of drugs used for asthma (2.91, 95% CI 1.10-7.68, p= 0.0314) was also associated. CONCLUSION In this nested case-control study of BO, male gender, increasing age, and increasing use of asthma drugs were associated with progression to OAC.
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Affiliation(s)
- Sc Cooper
- Department of Gastroenterology, Sandwell and West Birmingham Hospitals NHS Trust, West Midlands, UK ; Department of Gastroenterology, Dudley Group NHS Foundation Trust, West Midlands, UK
| | - S Menon
- Department of Gastroenterology, Sandwell and West Birmingham Hospitals NHS Trust, West Midlands, UK
| | - Pg Nightingale
- Wolfson Computer Laboratory, University Hospital Birmingham NHS Foundation Trust, West Midlands, UK
| | - Nj Trudgill
- Department of Gastroenterology, Sandwell and West Birmingham Hospitals NHS Trust, West Midlands, UK
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Pavlov K, Meijer C, van den Berg A, Peters FTM, Kruyt FAE, Kleibeuker JH. Embryological signaling pathways in Barrett's metaplasia development and malignant transformation; mechanisms and therapeutic opportunities. Crit Rev Oncol Hematol 2014; 92:25-37. [PMID: 24935219 DOI: 10.1016/j.critrevonc.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 03/24/2014] [Accepted: 05/02/2014] [Indexed: 01/07/2023] Open
Abstract
Barrett's metaplasia of the esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EAC), a deadly disease with a 5-year overall survival of less than 20%. The molecular mechanisms of BE development and its transformation to EAC are poorly understood and current surveillance and treatment strategies are of limited efficacy. Increasing evidence suggests that aberrant signaling through pathways active in the embryological development of the esophagus contributes to BE development and progression to EAC. We discuss the role that the Bone morphogenetic protein, Hedgehog, Wingless-Type MMTV Integration Site Family (WNT) and Retinoic acid signaling pathways play during embryological development of the esophagus and their contribution to BE development and malignant transformation. Modulation of these pathways provides new therapeutic opportunities. By integrating findings in developmental biology with those from translational research and clinical trials, this review provides a platform for future studies aimed at improving current management of BE and EAC.
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Affiliation(s)
- K Pavlov
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - C Meijer
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - A van den Berg
- Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - F T M Peters
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - F A E Kruyt
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J H Kleibeuker
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Cyclooxygenase inhibitors use is associated with reduced risk of esophageal adenocarcinoma in patients with Barrett's esophagus: a meta-analysis. Br J Cancer 2014; 110:2378-88. [PMID: 24651385 PMCID: PMC4007227 DOI: 10.1038/bjc.2014.127] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/10/2014] [Accepted: 02/13/2014] [Indexed: 12/20/2022] Open
Abstract
Background: Esophageal adenocarcinoma (EAC) has high mortality and is increasing in incidence. Barrett's esophagus (BE) increases the risk for EAC. Studies have reported inconsistent findings on the association between use of cyclooxygenase (COX) inhibitors and the risk of neoplastic progression in BE patients. Therefore, we performed a meta-analysis to investigate this association. Methods: A meta-analysis was undertaken among a total of 9 observational studies using fixed- and random-effects models, comprising 5446 participants; 605 had EAC or high-grade dysplasia (HGD). Results: Overall, COX inhibitors use was associated with a reduced risk of EAC/HGD among BE patients (relative risk (RR)=0.64, 95% confidence interval (CI)=0.53–0.77). Aspirin use also reduced the risk of EAC/HGD (RR=0.63, 95% CI=0.43–0.94), as well as non-aspirin COX inhibitors (RR=0.50, 95% CI=0.32–0.78). The chemopreventive effect seemed to be independent of duration response. Conclusions: Cyclooxygenase inhibitors use is associated with a reduced risk of developing EAC in patients with BE. Both low-dose aspirin and non-aspirin COX inhibitors are associated with a reduced risk of neoplasia. More well-designed randomised controlled trials are needed to increase our understanding of the chemopreventive effect of COX inhibitors.
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Tsibouris P, Vlachou E, Isaacs PET. Role of chemoprophylaxis with either NSAIDs or statins in patients with Barrett's esophagus. World J Gastrointest Pharmacol Ther 2014; 5:27-39. [PMID: 24605249 PMCID: PMC3944467 DOI: 10.4292/wjgpt.v5.i1.27] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 11/09/2013] [Accepted: 11/15/2013] [Indexed: 02/06/2023] Open
Abstract
The incidence of esophageal adenocarcinoma, a poor prognosis neoplasia, has risen dramatically in recent decades. Barrett's esophagus represents the best-known risk factor for esophageal adenocarcinoma development. Non-steroidal anti-inflammatory drugs through cyclooxygenase-2 inhibition and prostaglandin metabolism regulation could control cell proliferation, increase cell apoptosis and regulate the expression of growth and angiogenic factors. Statins can achieve equivalent effects through prenylation and subsequently control of cellular signaling cascades. At present, epidemiological studies are small and underpowered. Their data could not justify either medication as a chemo-preventive agent. Population based studies have shown a 43% reduction of the odds of developing an esophageal adenocarcinoma, leaving out or stating a 25% reduction in patients consuming non-aspirin nonsteroidal anti-inflammatory drugs and a 50% reduction in those patients consuming aspirin. They have also stated a 19% reduction of esophageal cancer incidence when statins have been used. Observational studies have shown that non-steroidal anti-inflammatory drugs could reduce the adenocarcinoma incidence in patients with Barrett's esophagus by 41%, while statins could reduce the risk by 43%. The cancer preventive effect has been enhanced in those patients taking a combination of non-steroidal anti-inflammatory drugs and statins (a 74% decrease). Observational data are equivocal concerning the efficacy of non-steroidal anti-inflammatory drug subclasses. Non-steroidal anti-inflammatory drugs clearly have substantial potential for toxicity, while statins are rather safe drugs. In conclusion, both non-steroidal anti-inflammatory drugs and statins are promising chemopreventive agents and deserve further exploration with interventional studies. In the meanwhile, their use is justified only in patients with cardiovascular disease.
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Watari J, Oshima T, Fukui H, Tomita T, Miwa H. Carcinogenesis of Barrett's esophagus: a review of the clinical literature. Clin J Gastroenterol 2013; 6:399-414. [PMID: 26182128 DOI: 10.1007/s12328-013-0412-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 07/25/2013] [Indexed: 11/25/2022]
Abstract
Barrett's esophagus (BE) is a premalignant condition of esophageal adenocarcinoma (EAC). Although the incidence of BE has risen rapidly in the West, it is rare in Asia despite a recent increase in the prevalence of gastroesophageal reflux disease. Controversies over the definition of BE are presented because most cases show short-segment BE, especially ultra-short BE, in Asia. Here we review possible risk factors for the development of EAC, particularly possible roles of ethnicity, specialized intestinal metaplasia (SIM), BE length, and environmental factors, such as Helicobacter pylori infection and obesity. Additionally, we summarize recent studies on the effect of chemoprevention including proton pump inhibitors, nonsteroidal anti-inflammatory drugs or aspirin in order to reduce the risk of neoplastic progression in BE patients. Although substantial knowledge of risk factors of dysplasia/EAC in BE is shown, the risk for neoplastic development may be influenced by geographic variation, study population, the presence or absence of SIM or dysplasia at baseline, and the small number of BE patients investigated. Recently, the efficiency of surveillance for BE patients has been discussed from the standpoint of cost-effectiveness. It may be too difficult to draw conclusions because no randomized clinical trials of BE surveillance have been performed.
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Affiliation(s)
- Jiro Watari
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Tadayuki Oshima
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hirokazu Fukui
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Toshihiko Tomita
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroto Miwa
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: current state-of-the science. Cancer Lett 2013; 345:249-57. [PMID: 24021750 DOI: 10.1016/j.canlet.2013.09.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Revised: 08/28/2013] [Accepted: 09/02/2013] [Indexed: 12/16/2022]
Abstract
Growing evidence from epidemiologic and preclinical studies suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal (GI) cancers, including esophageal, gastric, pancreatic, colorectal cancer, and hepatocellular carcinoma. However, there is also evidence indicating the absence of this benefit. The exact mechanism of NSAIDs' action on GI tumors is not known. Although some studies have suggested inhibition of carcinogenesis by NSAIDs through suppression effect on inflammation-associated cyclooxygenase-2 (COX-2) expression, other studies have suggested COX-2-independent mechanisms. Herein, we summarize the current state of-the-science regarding NSAID benefit for patients with GI cancers.
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Beales ILP, Hensley A, Loke Y. Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition. World J Gastrointest Pharmacol Ther 2013; 4:69-79. [PMID: 23919219 PMCID: PMC3729870 DOI: 10.4292/wjgpt.v4.i3.69] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 05/22/2013] [Accepted: 06/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the association between statin use and the development of esophageal cancer METHODS We performed a systematic review and meta-analysis. Multiple databases (Pubmed, EMBASE, Cochrane Library, Web of Science, Wiley Interscience and Google Scholar) were systematically searched for studies reporting the association of statin use and the development of esophageal cancer. Literature searching and data abstraction were performed independently by two separate researchers. The quality of studies reviewed was evaluated using the Newcastle-Ottawa Quality assessment scale. Meta-analysis on the relationship between statin use and cancer incidence was performed. The effect of the combination of statin plus a cyclo-oxygenase inhibitor was also examined. RESULTS Eleven studies met eligibility criteria, 9 high and 2 medium quality. All were observational studies. Studies examining adenocarcinoma development in Barrett's esophagus included 317 cancers and 1999 controls, population-based studies examining all esophageal cancers included 371203 cancers and 6083150 controls. In the Barrett's population the use of statins (OR = 0.57; 95%CI: 0.43-0.75) and cyclo-oxygenase inhibitors (OR = 0.59; 95%CI: 0.45-0.77) were independently associated with a reduced incidence of adenocarcinoma. Combined use of a statin plus cyclo-oxygenase inhibitor was associated with an even lower adenocarcinoma incidence (OR = 0.26; 95%CI: 0.1-0.68). There was more heterogeneity in the population-based studies but pooled adjusted data showed that statin use was associated with a lower incidence of all combined esophageal cancers (OR = 0.81; 95%CI: 0.75-0.88). CONCLUSION Statin use in patients with Barrett's oesophagus is associated with a significantly lower incidence of adenocarcinoma. The chemopreventive actions of statins, especially combined with cyclo-oxygenase inhibitors deserve further exploration.
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Abstract
INTRODUCTION Barrett's oesophagus (BO) is a common premalignant condition, which carries a risk of progression to oesophageal adenocarcinoma. Recent advances include quantifying the risk of neoplasia progression, novel diagnostic tools and development of new endoscopic techniques to treat early Barrett's cancer. SOURCES OF DATA A selective search was performed on recent advances in BO and this was supplemented with guidelines from the American and British Society of Gastroenterology. AREAS OF AGREEMENT All cases of dysplasia should be confirmed by a second expert histopathologist. Endoscopic therapy is the preferred option for high-grade dysplasia and intra-mucosal (T1a) carcinoma using endomucosal resection (EMR) and/or radiofrequency ablation. EMR also provides accurate staging information and any remaining Barrett segment should be ablated to reduce the risk of metachronous lesions. AREAS OF CONTROVERSY The cell of origin for BO is not certain. The merits and cost effectiveness of endoscopic screening and surveillance still remain controversial. The risk of neoplasia progression in low-grade dysplasia is inconsistently reported. The role of chemoprevention remains unclear. GROWING POINTS The use of radical endotherapy in early Barrett's neoplasia is promising with some data supporting long-term durability. AREAS TIMELY FOR DEVELOPING RESEARCH The development of non-endoscopic diagnostic tools and radical endotherapy to treat early cancer strengthens the argument for surveillance and suggests the possibility of screening in the near future. Identification of a biomarker may help to select high-risk patients.
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Affiliation(s)
- Yean Cheant Lim
- Addenbrooke's Hospital, Hills Road, PO Box 133, Cambridge CB2 0QQ, UK
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Mayne GC, Watson DI, Hussey DJ. COX-2 mRNA is increased in oesophageal mucosal cells by a proton pump inhibitor. ANZ J Surg 2012; 82:691-696. [PMID: 22758658 DOI: 10.1111/j.1445-2197.2012.06124.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Barrett's oesophagus develops in some individuals with gastro-oesophageal reflux and is the precursor to oesophageal adenocarcinoma. Proton pump inhibitors (PPIs) suppress gastric acid production and are used to treat reflux. Clinical trials suggest that cyclooxygenase (COX) inhibitors might prevent oesophageal cancer, although PPIs could offset this by increasing COX-2 expression in Barrett's oesophagus. To investigate this, we evaluated the impact of a PPI on COX expression in oesophageal mucosal cells. METHODS The effect of the PPI esomeprazole on COX-1 and COX-2 mRNA levels in oesophageal cells was determined. Oesophageal cell lines OE33 (adenocarcinoma-derived) and HET-1A (immortalized squamous cells) and a control intestinal cell line HT29 (colon carcinoma) were treated for 24 h, with increasing concentrations of the esomeprazole. RESULTS COX-2, but not COX-1, mRNA levels dose-dependently increased in OE33 and HET-1A cells versus esomeprazole concentration. COX-2 mRNA levels did not increase in HT29 cells. CONCLUSIONS Exposure to esomeprazole increases COX-2 mRNA in oesophageal cells. This might contribute to the lack of benefit for COX inhibitors for oesophageal cancer prevention in recent clinical studies.
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Affiliation(s)
- George C Mayne
- Department of Surgery, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia.
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Winberg H, Lindblad M, Lagergren J, Dahlstrand H. Risk factors and chemoprevention in Barrett's esophagus--an update. Scand J Gastroenterol 2012; 47:397-406. [PMID: 22428928 DOI: 10.3109/00365521.2012.667145] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Barrett's esophagus (BO) is a precursor of esophageal adenocarcinoma (OAC), a cancer with a poor prognosis and an increasing incidence. Hence there is an interest in mapping causal factors underlying BO and finding strategies to reduce the risk of dysplasia progression in patients with BO. Here we review current knowledge on established as well as less risk factors for the development of BO. Additionally, we summarize today's status on the use of chemoprevention aiming to reduce the risk of cancer progression in BO patients. METHODS We searched Medline and the Cochrane Library using the MeSH terms "Barrett's esophagus" and "Barrett esophagus," both alone and combined with the terms "risk factor," "aetiology," "diet," or "prevention." Focus was on original contributions, systematic reviews, and meta-analyses. RESULTS Established risk factors for the development of BO include gastro-esophageal reflux, obesity, male gender, Caucasian ethnicity, and increasing age. Smoking might increase the risk of BO, while aspirin/NSAIDs, Helicobacter pylori infection, and specific "healthy" dietary factors may lower the risk. The potential value of using chemoprevention with proton pump inhibitors, aspirin/NSAIDs, or statins is still uncertain. CONCLUSIONS There is today a substantial knowledge of risk factors of BO. Certain diet may be protective of BO, albeit yet to be proven. The efficiency of chemoprevention in BO is currently addressed further in randomized clinical trials.
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Affiliation(s)
- Hanna Winberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Upper Gastrointestinal Research (UGIR), Stockholm, Sweden
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Thrift AP, Pandeya N, Smith KJ, Green AC, Webb PM, Whiteman DC. The use of nonsteroidal anti-inflammatory drugs and the risk of Barrett's oesophagus. Aliment Pharmacol Ther 2011; 34:1235-44. [PMID: 21967506 DOI: 10.1111/j.1365-2036.2011.04855.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Epidemiological studies have consistently reported inverse associations between nonsteroidal anti-inflammatory drugs (NSAIDs) and oesophageal adenocarcinoma, but few have investigated associations with the precursor lesion, Barrett's oesophagus. AIM To investigate the relationship between NSAID use and risk of Barrett's oesophagus. METHODS We conducted a large population-based case-control study that collected information on patterns of intake for aspirin and non-aspirin NSAIDs during the past 5 years and other exposures from 285 patients with nondysplastic Barrett's oesophagus, 108 patients with dysplastic Barrett's oesophagus, and two separate control groups: 313 endoscopy patients with acute inflammatory changes ('inflammation controls') and 644 population controls. We calculated odds ratios (ORs) and 95% CIs using unconditional logistic regression. RESULTS Use of aspirin was not associated with nondysplastic Barrett's oesophagus when compared with population (OR=1.01, 95% CI 0.71-1.43) or inflammation controls (OR=1.16, 95% CI 0.80-1.68). Whereas we observed significant risk reductions for use of non-aspirin NSAIDs when nondysplastic Barrett's oesophagus cases were compared with population controls (OR=0.69, 95% CI 0.49-0.97), the effect was weaker and nonsignificant when cases were compared with inflammation controls (OR=0.82, 95% CI 0.57-1.18), and no dose-response effects were present in either analysis. We found no evidence that aspirin or non-aspirin NSAID use conferred risk reductions for dysplastic Barrett's oesophagus, regardless of the control series. We excluded effect modification by known risk factors as an explanation for these null findings. CONCLUSIONS We found little support for an inverse association between use of NSAIDs and Barrett's oesophagus. The question of whether or not these medications prevent the onset of Barrett's oesophagus remains open.
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Affiliation(s)
- A P Thrift
- School of Population Health, The University of Queensland, Public Health Building, Herston, Brisbane, Australia
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15
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Wiseman EF, Ang YS. Risk factors for neoplastic progression in Barrett’s esophagus. World J Gastroenterol 2011; 17:3672-83. [PMID: 21990948 PMCID: PMC3181452 DOI: 10.3748/wjg.v17.i32.3672] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 10/11/2010] [Accepted: 10/18/2010] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a “metaplasia-dysplasia-carcinoma” (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available.
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Wang F, Lv ZS, Fu YK. Nonsteroidal anti-inflammatory drugs and esophageal inflammation - Barrett's esophagus - adenocarcinoma sequence: a meta-analysis. Dis Esophagus 2011; 24:318-24. [PMID: 21166737 DOI: 10.1111/j.1442-2050.2010.01153.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The incidence of esophageal adenocarcinoma has markedly increased in the last few decades and Barrett's esophagus is regarded as the precursor lesion of this cancer. The aim of the study was to quantify the adenocarcinoma risk associated with nonsteroidal anti-inflammatory drug use and to determine at which stage chemoprevention with this drug is the most effective in esophageal inflammation - Barrett's esophagus - adenocarcinoma sequence. A literature search was performed to identify studies published between 1998 and 2009 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, and all nonsteroidal anti-inflammatory drugs. Four cohort and 10 case-control studies were included. Use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs in normal population was associated with a reduced risk of adenocarcinoma (odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.65-0.83; OR: 0.84, 95% CI: 0.72-0.98, respectively). The use of all nonsteroidal anti-inflammatory drugs was associated with a reduced risk of adenocarcinoma (relative risk [RR]: 0.64, 95% CI: 0.42-0.96) in Barrett's esophagus patients. However, no obvious dose-effect relationships were found. In addition, we discovered a reverse association between drugs use and adenocarcinoma risk in people without a history of upper gastrointestinal tract disorders (OR: 0.57, 95% CI: 0.43-0.77, P= 0.12). Our meta-analyses suggest a protective effect of nonsteroidal anti-inflammatory drugs on the risk of adenocarcinoma. Our results also suggest that the drugs might act after the formation of Barrett's epithelium in the esophageal inflammation - Barrett's esophagus - adenocarcinoma sequence.
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Affiliation(s)
- F Wang
- Department of Gastroenterology, General Hospital of Tianjin Medical University, andDepartment of Metabolic Gastroenterology, Metabolic Diseases Hospital of Tianjin Medical University, Tianjin, China
| | - Z S Lv
- Department of Gastroenterology, General Hospital of Tianjin Medical University, andDepartment of Metabolic Gastroenterology, Metabolic Diseases Hospital of Tianjin Medical University, Tianjin, China
| | - Y K Fu
- Department of Gastroenterology, General Hospital of Tianjin Medical University, andDepartment of Metabolic Gastroenterology, Metabolic Diseases Hospital of Tianjin Medical University, Tianjin, China
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Meta-analysis on the relationship between nonsteroidal anti-inflammatory drug use and gastric cancer. Eur J Cancer Prev 2011; 19:288-98. [PMID: 20386312 DOI: 10.1097/cej.0b013e328339648c] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, show chemopreventive effects on several types of cancer, their role in the development of gastric cancer remains controversial. The objective of this study is to assess the quantitative association between NSAIDs and gastric cancer by meta-analysis using both crude data and adjusted data. A search of Medline, Embase, Web of science, and citations from relevant articles was conducted for eligible articles published up to March 2009. A meta-analysis was developed. Pooled risk ratio and odds ratio with 95% confidence intervals were calculated, based on both crude and adjusted data from the selected studies and using random or fixed effects models based on heterogeneity analysis. Overall, 21 individual epidemiological studies (13 case-control studies with 29 560 participants and 8 cohort studies with 2 199 227 participants) were examined. The summary crude and adjusted risk ratios were 0.89 (0.83-0.97) and 0.81 (0.73-0.89) when the case-control and cohort studies were pooled, respectively. Significant protective effects of NSAIDs against gastric cancer appeared in all subgroups (study design, type of drug, site of cancer, and sample source), but only the site of cancer and sample source can substantially influence the estimate of effect. The chemopreventive effect of NSAIDs in gastric cancer was stronger based on the adjusted data than that based on crude data. Therefore, we conclude that NSAID use is associated with a decrease in the development of gastric cancer. The associations were more obvious after we adjusted for several risk factors that are known to contribute to the development of gastric cancer.
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Dent J. Barrett's esophagus: A historical perspective, an update on core practicalities and predictions on future evolutions of management. J Gastroenterol Hepatol 2011; 26 Suppl 1:11-30. [PMID: 21199510 DOI: 10.1111/j.1440-1746.2010.06535.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Interpretation of exploding knowledge about Barrett's esophagus is impaired by use of several conflicting definitions. Because any histological type of esophageal columnar metaplasia carries risk for esophageal adenocarcinoma, the diagnosis of Barrett's esophagus should no longer require demonstration of intestinal-type metaplasia. Endoscopic recognition and grading of Barrett's esophagus remains a significant source of ambiguity. Reflux disease is a key factor for development of Barrett's esophagus, but other factors must underlie its development, since it occurs in only a minority of reflux disease patients. Neither antireflux surgery nor proton pump inhibitor (PPI) therapy has major impacts on cancer risk. Within a year, a major trial should indicate whether low-dose aspirin usefully reduces cancer risk. The best referral centers have transformed the accuracy of screening and surveillance for early curable esophageal adenocarcinoma by use of enhanced and novel endoscopic imaging, visually-guided, rather than blind biopsies and by partnership with expert pathologists. General endoscopists now need to upgrade their skills and equipment so that they can rely mainly on visual targeting of biopsies on mucosal areas of concern in their surveillance practice. General pathologists need to greatly improve their interpretation of biopsies. Endoscopic therapy now achieves very high rates of cure of high-grade dysplasia and esophageal adenocarcinoma with minimal morbidity and risk. Such results will only be achieved by skilled interventional endoscopists. Esophagectomy should now be mainly restricted to patients whose cancer has extended into and beyond the submucosa. Weighing risks and benefits in the management of Barrett's esophagus is difficult, as is the process of adequately informing patients about their specific cancer risk.
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Affiliation(s)
- John Dent
- Department of Gastroenterology & Hepatology, Royal Adelaide Hospital, University of Adelaide, South Australia, Australia.
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Abstract
Esophageal adenocarcinoma is increasing in incidence. The main risk factor is the premalignant condition of Barrett's esophagus. There is great interest in chemoprevention to prevent or slow malignant transformation. There are many agents proposed as playing a role in chemoprevention; however, none is licensed for this role as yet. Aspirin possesses many favorable qualities for chemoprevention and is the focus of the largest randomized control trial in this field.
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Affiliation(s)
- Janusz A Jankowski
- Digestive Diseases Centre, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK.
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20
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Abstract
Barrett’s esophagus (BE) is a change in the esophageal mucosa as a result of long-standing gastroesophageal reflux disease. The importance of BE is that it is the main risk factor for the development of esophageal adenocarcinoma, whose incidence is currently growing faster than any other cancer in the Western world. The aim of this review was to compare the common treatment modalities of BE, with the focus on proton pump inhibitors and operative fundoplication. We performed a literature search on medical and surgical treatment of BE to determine eligible studies for this review. Studies on medical and surgical treatment of BE are discussed with regard to treatment effect on progression and regression of disease. Although there is some evidence for control of reflux with either medical or surgical therapy, there is no definitive evidence that either treatment modality decreases the risk of progression to dysplasia or cancer. Even though there is a trend toward antireflux surgery being superior, there are no definitive studies to prove this.
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Decreased risk of squamous cell carcinoma of the head and neck in users of nonsteroidal anti-inflammatory drugs. Int J Otolaryngol 2010; 2010:424161. [PMID: 20628564 PMCID: PMC2902018 DOI: 10.1155/2010/424161] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Revised: 03/17/2010] [Accepted: 03/27/2010] [Indexed: 11/18/2022] Open
Abstract
We evaluated the chemopreventive effect of nonsteroidal anti-inflammatory drug (NSAID) use in head and neck squamous cell carcinomas (HNSCC) by conducting a case-control study based on the administration of a standardized questionnaire to 71 incident HNSCC cases and same number of healthy controls. NSAID use was associated with a 75% reduction in risk of developing HNSCC. A significant risk reduction was noted in association with frequency of NSAID use. Restricting the analysis to aspirin users revealed a significant 90% reduction in risk of developing HNSCC. This study provides evidence for a significant reduction in the risk of developing HNSCC in users of NSAIDs, and specifically aspirin users.
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