For the full versions of these articles see bmj.com CLINICAL REVIEW

Diagnosis and management of Barrett’s oesophagus Janusz Jankowski,1 2 3 Hugh Barr,4 5 Ken Wang,6 Brendan Delaney7

See also Barrett’s oesophagus affects 2% of the adult population What is Barrett’s oesophagus and who gets it? EDITORIAL, p 564 in the West, which makes it one of the most common Barrett’s oesophagus is a change in the lining of the RESEARCH, p 595 premalignant lesions after colorectal polyps. Conversion oesophagus from normal stratified (multilayered) squa- 1Gastrointestinal Oncology Group, University of Oxford, Oxford to oesophageal adenocarcinoma is the most important mous mucosa to single layered, inflamed, premalignant, 2Centre for Digestive Disease, complication of the condition, with a lifetime risk of mucin secreting mucosa with variable degrees of goblet Blizard Institute, Queen Mary 5% in men and 3% in women.1-4 A diagnosis of Bar- cell differentiation, termed intestinal metaplasia.3 University of London, London rett’s oesophagus has important ramifications for the It develops in 5% of people with gastro-oesophageal 3Digestive Disease Centre, University Hospitals of Leicester, patient because of the uncertainty of prognosis, possible reflux disease, which affects as many as 30% of adults 5 6 Leicester anxiety about cancer in the future, the need for repeated in the Western world. Evidence from one case series 4Cranfield Health, Cranfield endoscopy in a surveillance programme, and the costs suggests that at least 60% of patients with Barrett’s University, Cranfield, Bedfordshire of drugs and repeated investigations.2 4 Several large tri- oesophagus develop the disease as a result of chronic 5 Department of Surgery, als investigating surveillance, chemoprevention, genetic reflux, although other forms of mucosal inflammation in Gloucestershire Royal Hospital, Gloucestershire stratification, and endotherapy for high risk individuals the lower oesophagus (such as from damage by chemo- 6Advanced Endoscopy Group and are under way to determine the best way to prevent pro- therapy, non-steroidal anti-inflammatory drugs, and Esophageal Neoplasia, Mayo Clinic, gression to ad­enocarcinoma. viral infections) could be linked to the condition.3 6 7 Rochester, Minnesota, USA Endoscopic alternatives to radical surgical Community studies have estimated the prevalence of 7Department of Primary Care and Public Health Sciences, King’s oesophagectomy now exist for treating high grade dys- ­Barrett’s oesophagus to be just under 2% among adults College London, London plasia and early mucosal cancer, which avoid the mortal- in the West, which corresponds with approximately one Correspondence to: J Jankowski ity and morbidity of surgery. We review evidence from [email protected] epidemiological studies, observational studies, and ran- SOURCES AND SELECTION CRITERIA Cite this as: BMJ 2010;341:c4551 domised trials, and draw on expert opinion, to discuss We searched Medline using the keywords “Barrett’s doi: 10.1136/bmj.c4551 the importance of early recognition and optimal treat- oesophagus,” “epidemiology,” “high grade dysplasia,” ment of Barrett’s oesophagus. “medical therapy,” “surgery,” “histology,” and “endoscopic ablation,” and found 12 000 relevant articles. We also searched the Cochrane central register of controlled trials and the BMJ Clinical Evidence database. We went through bmj.com archive SUMMARY POINTS Previous articles in the reference lists of articles identified from the Medline this series Barrett’s oesophagus usually occurs as a consequence of search to identify further relevant papers. Observational chronic gastro-oesophageal reflux disease studies, epidemiological studies, and randomised controlled ЖЖManaging anaemia in trials were extracted, and expert opinion was sought in critically ill adults The incidence of Barrett’s oesophagus is increasing: the condition is present in 2% of the adult population in the West areas where no trials existed. In addition, we consulted (BMJ 2010;341:c4551) national and international guidelines on the management of The incidence of oesophageal adenocarcinoma related ЖЖManaging gastro- to Barrett’s oesophagus is also increasing. In the United Barrett’s oesophagus, including guidelines from the British oesophageal reflux in Kingdom, especially Scotland, oesophageal adenocarcinoma Society of Gastroenterology and the American College of infants rates are higher than anywhere else in the world Gastroenterology. (BMJ 2010;341:c4420) Patients detected with early cancer related to Barrett’s Two of the authors (JJ and HB) served on the National ЖEvaluating the child oesophagus might have surgically or endoscopically Institute for Health and Clinical Excellence review board Ж for the management of dysplastic Barrett’s oesophagus, who presents with an curable disease. Endoscopic therapy is recommended as an alternative to oesophagectomy for patients with dysplasia which allowed us to do an extensive data search and seek acute limp The value of protocol based endoscopic surveillance to detect independent advice on the robustness of the evidence (BMJ 2010;341:c4250) early cancer is yet to be established and is the subject of a available. All four authors are members of the consensus ЖЖA guide to imaging for major randomised clinical trial panel for the BArrett’s Dysplasia and CAncer Taskforce common neurological (BAD CAT), which is composed of approximately 100 Other cancer prevention strategies being tested are 4 problems chemoprevention of Barrett’s oesophagus by aspirin in the individuals and endorsed by 14 international societies. Although this taskforce has not completed its deliberations, (BMJ 2010;341:c4113) 2513 patient AspECT trial and genome-wide identification of the four authors exploited a small part of this resource to ЖThe vegetative state inherited risk factors in the 4500 patient EAGLE consortium Ж study compile sections of this review. (BMJ 2010;341:c3765)

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risk could be 14%—a 30-100-fold higher risk of adeno- Conditions associated with the development of Barrett’s oesophagus carcinoma of the oesophagus compared with the general population’s risk of 0.1%.1-3 8 Once a patient is in a sur- Chronic oesophageal reflux (>60% of cases) veillance programme, the risk of developing oesophageal Congenital retardation syndromes (1%) adenocarcinoma varies from 0.4% a year in the US to 1% Non-steroidal anti-inflammatory drugs (1%) a year in the UK.8 Chemotherapy (<1%) Viral oesophagitis (<1%) How does Barrett’s oesophagus progress to adenocarcinoma of the oesophagus? million cases in the United Kingdom and four million Figure 1 illustrates the stages of progression of Barrett’s in the United States. It is especially prevalent in middle oesophagus, from oesophagitis through metaplasia and aged to older men of Anglo-Saxon origin.3 7 The UK is dysplasia to adenocarcinoma.12-14 the centre of the Barrett’s oesophagus “epidemic”—rates The steps of progression to cancer all involve genetic of oesophageal adenocarcinoma related to Barrett’s (damage to the DNA in cells) and epigenetic (revers- oesophagus in Scotland are the highest in the world (16 ible alterations to cell function) changes. For exam- per 100 000 population) compared with lower rates in ple, the development of metaplasia is associated with Eastern Europe, Africa, and Asia.8 9 ­alterations in genes controlling stem cells, and progres- The annual incidence of Barrett’s oesophagus in the sion to dysplasia is reflected by loss of heterozygos- adult population is about one per 1000. Evidence from ity or methylation of the adenomatous polyposis coli case series suggests that the global rate of diagnosis is (APC) gene. Further progression entails loss of expres- increasing by 2% a year, which may reflect increased sion or ­mutations in P16 and P53, which decrease endoscopic recognition but probably reflects a true their ­function.12 13 ­However, none of these biological increased incidence.6 7 10 ­alterations can yet replace conventional histology for diagnosis and staging, because their exact relationship What is the natural history of the condition? with clinical progression has not been robustly tested in The majority of cases of Barrett’s oesophagus stay con- large randomised clinical trials.14 stant, neither progressing to oesophageal adenocarci- noma nor regressing. Complete resolution of Barrett’s What influences the risk of developing oesophagus is rare, although it is not uncommon to adenocarcinoma? see modest shrinkage of the segment length in patients The major factors associated with progression to cancer treated with acid suppression. are: male gender; white ethnicity; length of Barrett’s The risk of progression from Barrett’s oesophagus to segment in centimetres, as seen during endoscopy oesophageal adenocarcinoma is small in absolute terms (higher risk for length greater than 8 cm); diet poor in (~5% lifetime risk in men and ~3% in women) according ­vegetables and fruit and high in fats; cigarette smoking; to data from case series.1-3 8 11 A recent decision analysis and ­obesity.3 suggested that in secondary referral centres the lifetime Case-control studies have shown that symptoms of gastro-oesophageal reflux disease are associated with Alternative model BStandard model Alternative model A a significant increase in the risk of developing cancer Micrometaplasia Squamous oesophagitis Submucosal glands (odds ratio 40±15), but also that as many as 40% of those with adenocarcinoma do not report a history of reflux Environmental Internal cellular genetic and epigenetic changes ­symptoms.7 9 10 triggers Alterations in genes controlling stem cells Oesophageal ↑ Metaplasia How is Barrett’s oesophagus diagnosed? acid and bile DNA damage Current guidelines on the management of dyspep- ↑ Cytokines and Loss of heterozygosity or methylation of APC sia from the National Institute for Health and Clinical growth factors Excellence (NICE) advise that patients with symptoms Loss of heterozygosity or mutations in p16 of reflux for more than 5-10 years should be referred Dysplasia Mutations in p53 for screening endoscopy to check for Barrett’s oesopha- gus or its ­complications.15 16 On endoscopy, if the distal Multiple aneuploidy oesophagus looks pink or crimson in colour and is clearly distinguishable from the appearance of a hiatal hernia Adenocarcinoma (fig 2) using accepted criteria such as the Prague endo- scopic criteria,16 then mucosal biopsies should be exam- Fig 1 | The standard and alternative models of progression of Barrett’s oesophagus to ined ­histopathologically. Biopsy samples are graded as adenocarcinoma of the oesophagus. The standard pathway to cancer is through the oesophagitis- metaplasia-dysplasia-adenocarcinoma sequence. Recently, however, it has been recognised that “diagnostic of Barrett’s oesophagus,” “corroborative submucosal glands can also develop into metaplastic cells (alternative pathway A). In addition, of Barrett’s oesophagus,” “consistent with Barrett’s squamous oesophagitis can conceivably develop directly into adenocarcinoma via “microscopic oesophagus,” or “Barrett’s oesophagus not present.” metaplasia” without apparently transitioning through endoscopically evident metaplasia The first three­classifications should qualify the patient (alternative pathway B). The column on the left shows the environmental factors that help facilitate for entry into an endoscopic surveillance programme.17 progression of the Barrett’s oesophagus. The column on the right shows the genetic (blue) and Protocols for surveillance programmes vary but usu- epigenetic (red) changes in the evolution of cancer. APC, adenomatous polyposis coli gene ally consist of endoscopies every two years with random

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Surveillance related prevention of oesophageal adeno- carcinoma might not dramatically increase the longevity of patients because Barrett’s oesophagus has also been associated with an increased risk of other potentially fatal conditions. For example, Barrett’s oesophagus might be associated with obesity and gastropulmonary aspiration, which increase the risk of ischaemic heart disease and bronchopneumonia, respectively.11

What treatments can prevent progression of Barrett’s oesophagus to adenocarcinoma? Case series have suggested that as many as 10% Fig 2 | Endoscopic image of Barrett’s oesophagus. The two pictures are from the same patient of patients with Barrett’s oesophagus develop high grade but were taken five seconds apart. The panel on the right shows correct air insufflation during 3 endoscopy, whereas the panel on the left shows the oesophagus suboptimally distended. As a dysplasia in their lifetime. Cohort studies have shown consequence, the picture on the left may be misdiagnosed by inexperienced endoscopists as that such patients have an increased risk of progres- a hiatal hernia, because the folds in the oesophageal lining extend to the gastro-oesophageal sion to adenocarcinoma compared with those who have junction (dashed arrow). The panel on the right indicates circumferential Barrett’s oesophagus, non-dysplastic Barrett’s oesophagus (30-55% in 8 which can easily be seen above the folds of the hiatal hernia (solid arrow). Pictures taken with years).17 full informed written consent Data from several case-control series indicate that man- agement of multifocal areas of high grade dysplasia can circumferential biopsies. If dysplasia is found, more be technically difficult and may require multiple interven- frequent intervals of endoscopy a few months apart tions.18 19 Experts agree that because of their increased coupled with more intensive endoscopic pinch biopsies risk of cancer, such patients warrant intervention with will usually occur. Those who are no longer fit for any either several sessions of endoscopic ablation therapy intervention may be discharged. However, age alone or, in exceptional cases, oesophagectomy.4 17 26 Arguably should not be the sole criterion for removing patients these patients represent a bigger burden to healthcare from ­surveillance.9 17-21 providers than those with cancer.4

Does surveillance prevent the development of Proton pump inhibitors adenocarcinoma? A recent large randomised controlled trial found that Several medium sized case series have found that patients early effective therapy for gastro-oesophageal reflux with Barrett’s oesophagus enrolled in surveillance pro- disease with proton pump inhibitors both manages grammes have cancer detected at an earlier (and hence symptoms effectively and heals oesophageal ulcera- more curable) stage than patients not in a surveillance tion.27 These findings support the use of acid suppres- programme who present with symptoms of oesophageal sant drugs such as proton pump inhibitors not only to cancer, but other evidence suggests that patients with heal and maintain healing of oesophagitis but also for cancer related to Barrett’s oesophagus do not benefit ­“chemoprevention” in patients with Barrett’s oesopha- from surveillance endoscopy.18 19 22-23 In addition, several gus. Case-control studies and randomised control- audits have shown that many ­specialists do not adhere led trials have shown that proton pump inhibitor to international guidelines.22-23 The Barrett’s Oesopha- therapy is well tolerated and safe in patients with B­arrett’s gus Surveillance Study (BOSS) of 2500 patients aims oesophagus, despite initial fears that they may promote to strengthen the evidence base by identifying both the elongation of Barrett’s oesophagus through hypergastri- objective value of endoscopic surveillance in preventing naemia.28 29 oesophageal cancer, and the best protocol (regular two However, case reports have speculated about a possible year upper gastrointestinal endoscopic surveillance pro- link between use of proton pump inhibitors and intestinal gramme versus endoscopy at time of need).19 infections—especially Clostridium difficile—deficiencies

The cost effectiveness of surveillance is still highly of nutrients like folate and vitamin B12, and osteoporo- uncertain in the absence of real cost estimates from ran- sis. Proton pump inhibitors also reduce the effectiveness domised controlled trials such as BOSS. Costs have been of clopidogrel, and co-administration of the two drugs estimated to be about £40 000 (€50 000; $60 000) per should be avoided if possible. cancer diagnosed for less than one quality adjusted life Some practitioners have attempted to reduce costs and year (QALY) gained.24 25 The cost effectiveness is arguably potential for side effects by treating patients who have better in the US because the country has a lower incidence gastro-oesophageal reflux disease with on demand pro- of oesophageal adenocarcinoma than in the UK and endo- ton pump inhibitor therapy.17 However, this approach scopic surveillance is undertaken less often (three yearly might be the worst of all options because intermittent in the USA compared with two yearly in the UK). In addi- treatment could increase the risk of Barrett’s oesopha- tion, endoscopic surveillance is more cost effective when gus and adenocarcinoma. Partial treatment might prevent undertaken only in patients with proven intestinal meta- the oesophagitis from healing completely and might also plasia on biopsy, because such patients are three times conceivably allow the metaplastic Barrett’s cells at the more likely to develop cancer than those without proven ulcer base, which can tolerate a low pH, to colonise the intestinal ­metaplasia.1 22 23 25 residual ulcerated oesophageal mucosa.30 31

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cheaper than proton pump inhibitors when drug use over TIPS FOR NON-SPECIALISTS 27 many years is anticipated. Other randomised trials have Who should be referred for routine endoscopy? confirmed that surgery controls reflux more completely Patients with reflux for more than five years and who are than does medical therapy. aged over 50 years15 21 Furthermore, fundoplication may prevent all constitu- What are the alarm symptoms for immediate referral for ents of the refluxate, including contents of the duodenum endoscopy? such as bile, from entering the oesophagus, which may 15 21 not occur with proton pump inhibitor therapy according Dysphagia to evidence from case series.3 Weight loss15 21 15 21 Vomiting blood Newer endoscopic therapies 15 21 Anaemia Endoscopic mucosal resection for the eradication of What other comorbid diseases should be screened for? early cancers (by definition confined to the mucosal Ischemic heart disease4 35 lining) is highly effective—five year survival is 98% in Hypercholesterolaemia4 35 patients with early adenocarcinoma confined to the mucosa and high grade dysplasia.1 18 20 23 24 The type of What is the best treatment approach for patients diagnosed with Barrett’s oesophagus? epithelium that re-grows is in part determined by the depth of injury that occurs as a consequence of treat- 90% can be managed by acid suppression therapy 1 5 27 ment. In order to ensure squamous cell regeneration as 5% may benefit from Nissen fundoplication 1 5 27 opposed to recurrence of Barrett’s oesophagus, some of 5% may develop oesophageal adenocarcinoma after at 1 3 27 the superficial squamous lined ducts of the oesopha- least 15 years 30 geal mucus glands must ­survive. What dose of proton pump inhibitors should be used? Photodynamic therapy comprises systemic admin- Use the lowest effective dose that suppresses symptoms istration of photosensitising agents that are retained 16 21 so that heartburn occurs less than once a week selectively in malignant tissue. When exposed to When should patients be reviewed? appropriate wavelength laser light, a cytotoxic reaction Primary care physician—Dose of proton pump inhibitors occurs that causes cellular destruction. The strongest should be reviewed annually, and healthy living evidence for the effectiveness of photodynamic therapy messages—such as maintaining a low fat diet, exercising, comes from the five year follow-up of a randomised, and maintaining a BMI of less than 30—should be multicentre, multinational, pathology blinded trial that reinforced regularly evaluated the usefulness of the technique to eradicate Secondary care physician—Patients should be reviewed dysplasia. Photodynamic therapy was significantly endoscopically every two years in the UK and every three more effective at eradicating high grade dysplasia than years elsewhere (because of higher incidence of cancer in omeprazole only (odds ratio 2±0.7) and reduced the 21 the UK) likelihood of developing cancer by half, with a signifi- cantly longer time to progression in the photodynamic Detecting significant differences between interven- therapy group compared with the omeprazole group.33 tions for relatively rare outcomes in Barrett’s oesopha- It may be necessary to repeat ablation at intervals, and gus such as adenocarcinoma would need a controlled patients treated this way should remain in lifelong study with a very large number of subjects. Future ­surveillance.4 developments in linking routine clinical data with A further randomised trial compared thermal ablation research in the community could potentially facilitate and argon plasma coagulation with surveillance in 40 this type of large scale study. A large randomised trial patients who had undergone surgical reflux control.34 in secondary care—the Aspirin Esomeprazole Chemo- Significant reversal of Barrett’s oesophagus occurred in prevention Trial (AspECT)—is currently evaluating the patients treated by argon plasma coagulation ablation long term value of low dose (20 mg) esomeprazole (a (63% v 15% in patients under surveillance (odds ratio proton pump inhibitor) compared with high dose (80 4.1±1.2)). Most recently, a randomised trial showed that mg) esomeprazole, either with or without aspirin (aspi- radiofrequency ablation is effective in ablating both rin may help to prevent cancers of the gastrointestinal non-dysplastic and dysplastic Barrett’s oesophagus, tract).32 So far 2513 patients have been recruited into with complete eradication in 90.5% and 81.0% of cases, the trial, and an interim analysis in one large centre has respectively.20 found a low rate of major side effects, suggesting that The immediate side effects of ablation are minor any interaction between esomeprazole and aspirin is ­retrosternal discomfort in 30% of patients, but full func- acceptable.32 tional activity is possible in almost all patients. Stricture, bleeding, and perforation occur in 10%, 1%, and less Nissen fundoplication than 1% of patients, respectively. Randomised controlled trials have shown that surgical Recently published NICE guidelines from the UK rec- repair of the oesophageal sphincter by buttressing the ommend that clinicians consider offering endoscopic stomach onto the oesophagus (fundoplication) offers good ablative therapy as an alternative to oesophagectomy symptom control in patients with severe reflux disease and for people with high grade dysplasia and intramucosal Barrett’s oesophagus. In addition, this approach might be cancer, according to individual patient preferences

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and their suitability for the procedure.4 5 NICE guide- might allow risk stratification for individual patients lines consider endoscopic therapy—especially endo- based on ethnicity, gender, and mucosal phenotype and scopic resection and radiofrequency ablation—to be may facilitate individually tailored treatment. The first ­particularly suitable for patients who are considered genome-wide assessment study of Barrett’s oesophagus unsuitable for surgery and those who do not wish to will be published in 2011. Several genetic consortiums undergo ­oesophagectomy.20 26 are being set up to replicate these genetic data once ­published and validate them for clinical use. Perhaps Support for patients the largest in Europe is the Esophageal Adenocarcinoma Patients with Barrett’s oesophagus are strongly Genetic LinkagE (EAGLE) consortium, which incorporates ­recommended to join patient support organisations with both the Chemoprevention Of Premalignant Intestinal expertise in this disease, such as Fight Oesophageal Neoplasia (ChOPIN) trial and the Inherited ­Predisposition Reflux Together (FORT), so they can be helped to form of Oesophageal Diseases (IPOD) study. an informed opinion of their options at each stage in the A large specialist and patient international consensus pathway.35 on the management of high grade dysplasia (BArretts’s Dysplasia and CAncer Taskforce (BAD CAT)) is due in What does the future hold? 2011. There is not yet consensus on the value of either tissue We thank Cathy Bennett of the Cochrane Collaboration Upper or blood biomarkers to stratify patients with Barrett’s Gastrointestinal and Pancreatic Diseases Group and the BArrett’s oesophagus in terms of risk of developing cancer.13 14 Dysplasia CAncer Taskforce (BAD CAT) for her help. We also thank Researchers hope that data from genome-wide associa- Rebecca Harrison, Leicester, UK, for discussions during writing and proof reading. tion studies may further understanding of the inherited Contributors: JJ came up with the concept for this article and undertook basis of Barrett’s oesophagus and its progression, which the research, writing, and coordination. HB contributed to researching and writing the article, whereas KW and BD both contributed to the writing. ADDITIONAL EDUCATIONAL RESOURCES JJ and HB contributed equally to the manuscript. JJ acts as the guarantor and accepts full responsibility for the work, had full access to the data, and For healthcare professionals controlled the decision to publish. CORE (www.corecharity.org.uk)—Charity specifically Funding: The authors received funding for this review from the following geared towards funding research into gastrointestinal organisations: AstraZeneca; Cancer Research UK; the National Institute diseases for Health Research Health Technology Assessment programme; National Institutes of Health; BAD CAT; Queen Mary University of London; and the National Institute for Health and Clinical Excellence Wellcome Trust. (www.nice.org.uk)—National body providing evidence Competing interests: All authors have completed the Unified Competing based guidance on specific diseases and conditions Interest form at www.icmje.org/coi_disclosure.pdf (available on request Barrett’s Dysplasia and Cancer Taskforce (www. from the corresponding author) and declare: (1) Financial support worldgastroenterology.org/international-consensus- from AstraZeneca; Cancer Research UK; the National Institute for of-management-of-dysplastic-barretts-and-cancer. Health Research Health Technology Assessment programme; National html)—Taskforce producing evidence based guidelines Institutes of Health; BAD CAT; Queen Mary University of London; and the Wellcome Trust for the submitted work. (2) JJ has acted as a consultant to for best clinical and cost effective management of high AstraZeneca, has received educational grants, and is chief investigator for grade dysplasia and early mucosal cancer in Barrett’s the AspECT and ChOPIN trials; HB has been a consultant for AstraZeneca oesophagus and Axcan Pharma, and is chief investigator for the BOSS trial; and KW is a consultant to various companies. (3) No spouses, partners, or children For patients with relationships with commercial entities that might have an interest in Oesophageal Patients Association (www.opa.org. the submitted work. (4) No non-financial interests that may be relevant to uk)—Largest patients’ support group dedicated to the submitted work. oesophageal cancer Provenance and peer review: Commissioned; externally peer reviewed. Patient UK (www.patient.co.uk)—Comprehensive source 1 Shaheen NJ, Richter JE. Barrett’s oesophagus. Lancet 2009;373: of health and disease information for patients 850-61. 2 Spechler SJ, Fitzgerald RC, Prasad GA, Wang KK. History, molecular Fight Oesophageal Reflux Together (refluxhelp. mechanisms, and endoscopic treatment of Barrett’s esophagus. org)—Largest UK patients’ support group, with online Gastroenterology 2010;138:854-69. 3 Jankowski J, Harrison RF, Perry I, Balkwill F, Tselepis C. Seminar: resources Barrett’s metaplasia. Lancet 2000;356:2079-85. American College of Gastroenterology (www.gi.org/ 4 Barrett’s Dysplasia and Cancer Taskforce ‘BAD CAT’ consensus patients/patientinfo/barretts.asp)—Patient information group. International consensus of the management of dysplastic Barrett’s and cancer. World Gastroenterology Organisation. http:// on Barrett’s oesophagus from one of the largest clinical www.worldgastroenterology.org/international-consensus-of- organisations dealing with digestive care management-of-dysplastic-barretts-and-cancer.html. 5 Moayyedi P, Talley NJ. Gastro-oesophageal reflux disease. Lancet MacMillan Cancer Support and Cancer Backup (www. 2006;367:2086-100. macmillan.org.uk/Cancerinformation/Cancertypes/ 6 Ronkainen J, Pertti A, Storskrubb T, Johansson SE, Lind T, Bolling- Gulletoesophagus/Pre-cancerousconditions/ Sternevald E, et al. Prevalence of Barrett’s esophagus in the general Barrettsoesophagus.aspx)—Patient information from population: an endoscopic study. Gastroenterology 2005;129: 1825-31. one of the largest cancer patient information websites 7 Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R for the Global British Society of Gastroenterology (www.bsg.org. Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based uk/patients/patients/general/oesophageal-cancer. consensus. Am J Gastroenterol 2006;101:1900-20. html)—Patient information from one of the largest 8 Jankowski JA, Provenzale D, Moayyedi P. Esophageal gastroenterology organisations in Europe adenocarcinoma arising from Barrett’s metaplasia has regional variations in the West. Gastroenterology 2002;122:588-90.

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9 Peng S, Cui Y, Xiao YL, Xiong LS, Hu PJ, Li CJ, et al. Prevalence of 23 Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, erosive esophagitis and Barrett’s esophagus in the adult Chinese surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol population. Endoscopy 2009;41:1011-7. 2008;103:788-97. 10 Gerson LB, Banerjee S. Screening for Barrett’s esophagus in 24 Inadomi JM, Somsouk M, Madanick RD, Thomas JP, Shaheen NJ. A asymptomatic women. Gastrointest Endosc 2009;70:867-73. cost-utility analysis of ablative therapy for Barrett’s esophagus. 11 Moayyedi P, Burch N, Akhtar-Danesh N, Enaganti SK, Harrison Gastroenterology 2009;136:2101-14. R, Talley NJ, et al. Mortality rates in patients with Barrett’s 25 Cook MB, Wild CP, Everett SM, Hardie LJ, Bani-Hani KE, Martin IG, et oesophagus. Aliment Pharmacol Ther 2008;27:316-20. al. Risk of mortality and cancer incidence in Barrett’s esophagus. 12 Jankowski J, Wright NA, Meltzer S, Triadafilopoulos G, Geboes K, Cancer Epidemiol Biomarkers Prev 2007;16:2090-6. Casson A, et al. Molecular evolution of the metaplasia dysplasia 26 National Institute for Health and Clinical Excellence. Ablative adenocarcinoma sequence in the esophagus (MCS). Am J Pathol therapy for the treatment of Barrett’s oesophagus (clinical guideline 1999;154:965-74. CG106). NICE, 2010. 13 Robertson EV, Jankowski JA. Genetics of gastroesophageal cancer: 27 Epstein D, Bojke L, Sculpher MJ for the REFLUX trial group. paradigms, paradoxes and prognostic utility. Am J Gastroenterol Laparoscopic fundoplication compared with medical management 2008;103:443-9. for gastro-oesophageal reflux disease: cost effectiveness study. 14 Jankowski J, Odze R. Biomarkers in gastroenterology; between BMJ 2009;339:b2576. hype and hope comes histopathology. Am J Gastroenterol 28 Obszynska J, Atherfold P, Nanji M, Glancy D, Santander S, Graham 2009;104:1093-6. T, et al. Long-term proton pump induced hypergastrinaemia does 15 National Institute for Health and Clinical Excellence. Dyspepsia: induce lineage-specific restitution but not clonal expansion in managing dyspepsia in adults in primary care (clinical guideline benign Barrett’s oesophagus in vivo. Gut 2010;59:156-63. CG17). NICE, 2005. 29 Leedham S, Jankowski J. The evidence base of proton pump 16 Sharma P, Dent J, Armstrong D, Bergman J, Gossner L, Hoshihara inhibitor chemopreventative agents in Barrett’s esophagus: the Y, et al. The development and validation of an endoscopic grading good, the bad and the flawed. Am J Gastroenterol 2007;102:21-3. system for Barrett’s esophagus—the Prague C and M criteria. 30 Leedham SJ, Preston SL, McDonald SAC, Elia G, Bhandari P, Poller Gastroenterology 2006;131:1392-9. D, et al. Individual crypt genetic heterogeneity and the origin of 17 Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R, Spechler S, et al. A critical review of the diagnosis and management of Barrett’s metaplastic glandular epithelium in human Barrett’s oesophagus. esophagus. Gastroenterology 2004;127:310-30. Gut 2008;57:1041-8. 18 Wong T, Tian J, Nagar AB. Barrett’s surveillance identifies patients 31 Tselepis C, Perry I, Dawson C, Hardy R, Darnton J, McConkey C, et with early esophageal adenocarcinoma. Am J Med 2010;123:462-7. al. Tumour necrosis factor alpha in Barrett’s metaplasia: a novel 19 Rubenstein JH, Sonnenberg A, Davis J, McMahon L, Inadomi mechanism of action. Oncogene 2002;39:6071-81. JM. Effect of a prior endoscopy on outcomes of esophageal 32 Das D, Chilton A, Jankowski J. Oesophageal cancer prevention and adenocarcinoma among United States veterans. Gastrointest the AspECT trial. In: Senn HJ, Kapp U, Otto F eds. Cancer Prevention Endosc 2008;68:849-55. II. Springer, 2009. pp 161-72. 20 Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, 33 Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava Wang KK, et al. Radiofrequency ablation in Barrett’s esophagus with HR, et al for the International Photodynamic Group for High-Grade dysplasia. N Engl J Med 2009;360:2277-88. Dysplasia in Barrett’s Esophagus. Five-year efficacy and safety 21 British Society of Gastroenterology. Guidelines for the diagnosis of photodynamic therapy with Photofrin in Barrett’s high-grade and management of Barrett’s columnar-lined oesophagus. BSG, dysplasia. Gastrointest Endosc 2007;66:460-8. 2005. 34 Hage M, Siersema PD, van Dekken H, Steyerberg EW, Haringsma 22 Das D, Ishaq S, Harrison R, Kosuri K, Harper E, deCaestecker J, et al. J, van de Vrie W, et al. 5-aminolevulinic acid photodynamic Management of Barrett’s oesophagus in the UK: over treated, and therapy versus argon plasma coagulation for ablation of Barrett’s under biopsied but improved by a national randomised trial. Am J oesophagus: a randomised trial. Gut 2004;53:785-90. Gastroenterol 2008;103:1079-89. 35 Fight Oesophageal Reflux Together (FORT). http://refluxhelp.org/.

ANSWERS TO ENDGAMES, p 611. For long answers go to the Education channel on bmj.com

ANATOMY QUIZ CASE REPORT Coronal magnetic resonance image An agitated man with earache of the right wrist 1 The most likely diagnosis is bacterial meningitis. 2 To establish the diagnosis of bacterial meningitis A Hamate a lumbar puncture should be performed. Cranial B Triquetral imaging before lumbar puncture is needed in C Lunate selected cases to rule out brain shift but should not D Capitate delay initiation of appropriate treatment. E Scaphoid 3 The most common causative micro-organisms in bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. Predisposing conditions ON EXAMINATION QUIZ are otitis media, sinusitis, pneumonia, and Medication side effects immunocompromise. Answer A is correct. 4 Antimicrobial treatment for adults with bacterial meningitis of unknown cause consists of intravenous vancomycin and ceftriaxone. Adjunctive STATISTICAL QUESTION dexamethasone should be started with the first dose of antibiotics. Immediate empirical treatment Odds ratios II is potentially life saving and must not be delayed by Answers a, b, and d are all true, whereas c is false. diagnostic procedures.

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