John deCaestecker

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Management of Barrett's esophagus in the UK: Overtreated and underbiopsied but improved by the introduction of a national randomized trial

OBJECTIVES:To assess the variation in practice of Barretts esophagus (BE) management in comparison with accepted international guidelines before and after the introduction of a large BE randomized controlled trial (RCT) with protocols including those of tissue sampling.DESIGN:A validated anonymized questionnaire was sent to 401 senior attending gastroenterologists asking for details of their current management of BE, especially histological sampling. Of the 228 respondents, 57 individuals (each from a different center) were in the first group to enter the ASPirin Esomeprazole (BE) Chemoprevention Trial (AspECT), and we assessed change in practice in these centers.RESULTS:Ninety percent of specialists did not take adequate biopsies for histological diagnosis. Furthermore, 74% would consider aggressive surgical resection for prevalent cases of high-grade dysplasia in BE as their first-line choice despite the associated perioperative mortality. Ninety-two percent claim their lack of adherence to guidelines is because there is a need for stronger evidence for surveillance and medical interventions.Effect of the AspECT trial: Those clinicians in centers where the AspECT trial has started have improved adherence to ACG guidelines compared with their previous practice (P < 0.05). BE patients now get 18.8% more biopsies compared with previous practice, and 37.7% if the patient is entered into the AspECT trial (P < 0.01).CONCLUSIONS:This large study indicates both wide variation in practice and poor compliance with guidelines. Because optimal histology is arguably the most important facet of BE management, the improvement in practice in centers taking part in the AspECT trial indicates an additional value of large international RCTs.

BOB CAT: a Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

OBJECTIVES:Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).METHODS:We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.RESULTS:In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.CONCLUSIONS:In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

Background & Aims Barretts esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barretts and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

An Epidemiological Study of Achalasia Among the South Asian Population of Leicester, 1986–2005

Achalasia is an uncommon esophageal motility disorder of unknown etiology that predominantly affects people over the age of 50. The overall incidence in this study was 0.89 cases/105/year. There was no significant difference in the proportion of South Asian women with achalasia compared to the proportion of men affected in the whole population nor between the male-to-female ratio in the patient group compared to the healthy population. Throughout the twentieth century there have been sporadic attempts to find any etiological link but to date none have been confirmed. However, there is evidence that environmental factors may be important and these are reflected in geographical differences in the distribution of the disease. In this study we were also unable to identify any triggering factor responsible for the development of achalasia.

Aspirin in the prevention of cancer

Peter Rothwell and colleagues, in their meta-analysis of randomised trials (Jan 1, p 31), show that low-dose long-term aspirin use reduces the risk of several cancers. Before this information was available, the balance of benefi t and harm in taking aspirin in the primary prevention of coronary heart disease and stroke (cardiovascular disease [CVD]) was uncertain. The new data on cancer help to clarify the net benefi t of aspirin, particularly if aspirin were included with a statin and bloodpressure-lowering drugs in a combined formulation (Polypill). The table shows the estimated number of fi rst CVD events and cancer deaths prevented in England and Wales in 1 year on the basis of a Polypill (composed of three blood-pressurelowering drugs at half standard dose and a statin at standard dose such as simvastatin 40 mg), with or without aspirin. In people aged 55–89 years, for example, 186 000 CVD events and cancer deaths would be prevented. The table shows that 120 such outcomes would be prevented in 1000 people over a period of 20 years (or 170 per 1000 over 35 years). Aspirin causes substantially fewer major extracranial bleeds that require a blood transfusion than the number of CVD events and cancer deaths prevented (table). However, the risk of an aspirin-induced major extracranial bleed increases with age. The estimates for such bleeds shown in the table among people aged 55 years over a period of 20 years are based on observed data and are likely to be accurate, but the numbers in people older than 75 years are uncertain— they would be twice those shown if the age trend to 75 years continues to 90 years. Given the results published by Rothwell and colleagues, the balance of the evidence is in favour of including aspirin in a Polypill strategy to prevent CVD and cancer. NW and ML hold a European and Canadian patent (pend ing in the USA) for the Polypill, fi led in April 2000.

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Objective Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barretts oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. Design We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. Results We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. Conclusions This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.

Endoscopic therapies for the prevention and treatment of early esophageal neoplasia

Esophageal cancers have traditionally been diagnosed late and prognosis has been dire. For many years the only real treatment option was esophagectomy with substantial morbidity and mortality. This situation has now changed dramatically. Improvements have been achieved in surgical outcomes and there is an array of new effective treatment options now available, particularly for the increasing proportion diagnosed with early-stage disease. Minimally invasive endoscopic therapies can now prevent, cure or palliate esophageal cancers. This article aims to investigate the role and evidence base for these new therapeutic options.

Erratum: Addendum: BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia (The American journal of gastroenterology (2015) 110 5 (662-682))

Bennett, Cathy, Moayyedi, Paul, Corley, Douglas A, DeCaestecker, John, Falck-Ytter, Yngve, Falk, Gary, Vakil, Nimish, Sanders, Scott, Vieth, Michael, Inadomi, John, Aldulaimi, David, Ho, Khek-Yu, Odze, Robert, Meltzer, Stephen J, Quigley, Eamonn, Gittens, Stuart, Watson, Peter, Zaninotto, Giovanni, Iyer, Prasad G, Alexandre, Leo, Ang, Yeng, Callaghan, James, Harrison, Rebecca, Singh, Rajvinder, Bhandari, Pradeep, Bisschops, Raf, Geramizadeh, Bita, Kaye, Philip, Krishnadath, Sheila, Fennerty, M Brian, Manner, Hendrik, Nason, Katie S, Pech, Oliver, Konda, Vani, Ragunath, Krish, Rahman, Imdadur, Romero, Yvonne, Sampliner, Richard, Siersema, Peter D, Tack, Jan, Tham, Tony C K, Trudgill, Nigel, Weinberg, David S, Wang, Jean, Wang, Kenneth, Wong, Jennie Y Y, Attwood, Stephen, Malfertheiner, Peter, MacDonald, David, Barr, Hugh, Ferguson, Mark K and Jankowski, Janusz

PWE-086 What Motivates Patients to Enter Clinical Trials Involving Endoscopic or Surgical Treatment? Qualitative Interviews of Patients Approached for The Bride Study (NCT01733719)

Introduction Poor recruitment is an issue for randomised trials. We aimed to explore patient attitudes towards recruitment in an RCT comparing ablative therapies in Barrett’s early neoplasia (BRIDE) & to a proposed trial comparing surgery to endotherapy. Methods Patients sampled from among 100 entering/declining BRIDE in each of 6 UK centres, had telephone interviews by an experienced qualitative researcher using a topic guide developed with patients, audio-recorded, anonymised & transcribed verbatim. Transcript analysis used the constant comparative approach, managed by NVivo software. Scrutiny of initial transcripts during 3–4 intensive readings generated open codes (short descriptors summarising points), grouped into themes. Data from other transcripts contradicting the codes/themes were explored & the coding frame revised, resulting in a set of issues important to patients that can help/hinder recruitment and retention. Results 18 (16 men, age 47–85) were interviewed. Main findings: 1) Gaining informed consent is time-consuming, but necessary as there is potential for misunderstanding. 2) Some patients received information about BRIDE before results of investigations. Recruitment process should be designed to prevent this. 3) Recruiters need a pleasant attitude, honesty, respect for potential participants, & good interpersonal skills. If not their own doctor, the approach should be from someone suitably qualified & introduced by the doctor/their team. 4) Presence of others during recruitment (eg Macmillan nurse or multiple professionals) may frighten patients into interpreting their diagnosis as serious/terminal. 5) Some believed that treatment had been chosen based on individual need, & others that trial participation was the only route to a particular treatment & better follow up, misunderstanding randomisation. 6) The expectation that taking part could benefit people like themselves or their descendants facilitated successful recruitment. 7) Inconvenience/additional costs to patients and their families should be minimised (e.g. many more visits to hospital). 8) Recruitment was facilitated by awareness that outcomes & side effects of the 2 treatments were roughly equivalent. Surgery was not seen as equivalent, but for most was riskier, involving additional suffering & longer recovery. It was seen as less preferable & would need to offer some probability of advantage over endoscopy. Conclusion Communication, openness & trust are key; patients need to understand randomisation does not ensure a particular treatment. Reducing expense/inconvenience assists recruitment. Randomisation to surgery requires clear potential benefits to be acceptable. (NIHR RfPB Grant No PB-PG-0711-25066) Disclosure of Interest None Declared