Nigel Trudgill

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus

These guidelines provide a practical and evidence-based resource for the management of patients with Barretts oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barretts oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barretts oesophagus and related neoplasia.

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.

Risk factors in the aetiology of hiatus hernia: a meta-analysis.

Objective Hiatus hernia (HH) is commonly associated with gastro-oesophageal reflux disease, particularly reflux oesophagitis and Barretts oesophagus. HH may increase with age as a result of fibromuscular degeneration. Obesity increases intra-abdominal pressure and may increase the risk of HH. A meta-analysis was undertaken to assess the influence of risk factors for HH. Methods Studies that included HH and potential aetiological factors (e.g. age, sex and BMI) as keywords were extracted from Medline. Studies and were required to define HH endoscopically and include unselected study populations. Data on a number of HH in relation to aetiological factors were extracted and a meta-analysis was performed, provided at least two suitable studies for each factor were available. Results From 2953 abstracts, 29 studies contained information on HH in relation to age, sex and BMI. Seven studies provided data for meta-analysis of the effect of age and HH was associated with age above 50 years [odds ratio 2.17, 95% confidence interval (CI): 1.35–3.51, P=0.001, I2=97.3]. Four studies provided data for meta-analysis of the effect of obesity and HH was associated with BMI above 25 kg/m2 (odds ratio 1.93, 95% CI: 1.10–3.39, P=0.002, I2=80.5). Eighteen studies provided data for meta-analysis of the effect of sex and HH was more common among men (odds ratio 1.36, 95% CI: 1.10–1.68, P=0.005, I2=89.5). Publication bias was assessed by the Classic fail-safe N test and no significant evidence of publication bias was noted. Conclusion The prevalence of HH increases with age and increasing BMI and HH is more common among men.

How commonly is upper gastrointestinal cancer missed at endoscopy? A meta-analysis.

Background and study aims: Upper gastrointestinal (UGI) cancer in the Western world usually presents at an advanced stage, when opportunities for curative therapy are limited. The failure to detect subtle, early-stage UGI cancer at endoscopy may contribute to a poor prognosis. We undertook a meta-analysis of studies of endoscopic miss rates for UGI cancer to quantify how often opportunities to diagnose cancer at an earlier stage are missed. Patients and methods: A MEDLINE search was conducted to identify relevant studies, and a meta-analysis was conducted. “Missed” UGI cancer was defined as cancer that had not been diagnosed by UGI endoscopy performed within 3 years before the diagnosis. Random effects meta-analysis was used to determine the event rate of missed UGI cancer. Results: Ten studies were identified that included 3,787 patients with UGI cancer. Four hundred eighty-seven UGI cancers were missed at endoscopy within 3 years before diagnosis. Marked heterogeneity was observed between studies (I 2, 94.4 %; P < 0.001). On random effects meta-analysis, the pooled miss rates were 6.4 % (95 % confidence interval [CI], 4.3 % – 9.5 %) within 1 year and 11.3 % (95 % CI, 7.5 % – 16.6 %) within 3 years before diagnosis. There appeared to be no difference between the miss rates of oesophageal (44 %) and gastric (51 %) cancer (P = 0.42). Conclusion It appears that 11.3 % of UGI cancers are missed at endoscopy up to 3 years before diagnosis. To ameliorate the poor prognosis of patients with UGI cancer in the Western world, efforts should be made to improve the quality of UGI endoscopy and create opportunities for earlier diagnosis.

Patients with prostate cancer are less likely to develop oesophageal adenocarcinoma: could androgens have a role in the aetiology of oesophageal adenocarcinoma?

Oesophageal adenocarcinoma (OAC) is more common in men. Androgens may therefore contribute to the pathogenesis of OAC. Prostate cancer (PC), an androgen sensitive tumor with a long natural history, may allow insights into this putative association. West Midlands Cancer Intelligence Unit data from 1977 to 2004 were examined to identify patients with a first malignant primary of PC. Patients were followed until diagnosis of a second primary cancer, death or end of the time period. Age- and period-adjusted standardized incidence ratios (SIR) were calculated as an estimate of the relative risk of a second malignant primary of the oesophagus. Between 1977 and 2004, 44,819 men within the West Midlands developed PC as a first primary malignancy. After exclusion for lack of follow-up, 38,627 men were eligible, providing 143,526 person years at risk for analysis. 86 second primary oesophageal cancers were observed, compared with 110 expected, resulting in an SIR of 0.78 (95% CI 0.62–0.96). There was a reduced risk of OAC 0.7 (0.5–0.95) but not of oesophageal squamous cell carcinoma (OSCC) 1.03 (0.69–1.47). The risk of developing OAC, but not OSCC, is lower than expected in patients with PC. A diagnosis of PC may be associated with aetiological factors that are negatively associated with OAC, or anti-androgen therapy may influence the development of OAC.

Influence of age and sex on endoscopic findings of gastrooesophageal reflux disease: an endoscopy database study

Background Barretts oesophagus (BO) and oesophageal adenocarcinoma are more common with increasing age and among men. Symptoms of gastrooesophageal reflux disease are equally common in both sexes and at all ages. We hypothesized that reduced postmenopausal female sex hormone levels may remove protection from acid reflux injury, leading to increased oesophagitis and its complications in older women. Aim To examine the incidence of gastrooesophageal reflux disease and its complications in men and women in a large endoscopy database. Methods Anonymized data were extracted from endoscopy databases covering an 11-year period. Patients with an endoscopic diagnosis of reflux oesophagitis (RO), BO, hiatus hernia and benign oesophageal stricture and total number and indications for endoscopies were identified. Results Out of 154 406 upper gastrointestinal endoscopies, 24 240 (15.7%) patients had RO {13 148 male, 11 092 female, mean age 59 [standard deviation (SD) 17] years}. The incidence of RO increased with age {odds ratio 1.029 [95% confidence interval (CI) 1.026–1.032], P<0.001} but this increase was more marked in women with increasing age [1.01 (1.01–1.02), P<0.001] compared with men. Increasing age was associated with an increased incidence of benign oesophageal stricture [1.02 (1.017–1.023)] and BO [1.02 (1.019–1.021)]. Although the increase in benign oesophageal stricture was more marked in women [1.024 (1.02–1.028) P<0.001] than in men, this was not the case in BO. Conclusion RO and its complications, BO and benign oesophageal stricture increase with age. RO, BO and stricture are more common in absolute and relative terms among younger men than younger women. RO and stricture increase more rapidly in women than men so that the prevalence in elderly patients is similar in both sexes.

The influence of deprivation and ethnicity on the incidence of esophageal cancer in England

The incidence of esophageal cancer (EC), particularly esophageal adenocarcinoma (EAC), has been rising dramatically. In the USA, esophageal squamous cell carcinoma (ESCC) is associated with deprivation and black ethnicity, while EAC is more common among whites. The influence of social deprivation and ethnicity has not been studied in England. West Midlands Cancer Intelligence Unit data were used to study the incidence of ESCC and EAC, and the influence of age, sex, socioeconomic status (Townsend quintiles by postcode) and ethnicity (to individual patients from Hospital Episode Statistics). From 1977 to 2004, a total of 15,138 EC were identified. Five-year directly age standardized incidence rates per 100,000 (95% CI) for men increased from 8.6 (8.0–9.1) in 1977–1981 to 13.7 (13.1–14.3) in 2000–2004 and for women from 5.0 (4.7–5.4) to 6.3 (5.9–6.6). ESCC incidence did not alter, but EAC incidence rose rapidly in males [2.1 (1.9–2.4) to 8.5 (8.1–9.0)] and in females [0.5 (0.4–0.6) to 1.7 (1.5–1.9)]. ESCC was strongly associated with the most socially deprived quintile. EAC was not associated with differences in socioeconomic status. EAC was significantly more common in white men 7.3 (6.9–7.7) and women 1.5 (1.3–1.6) when compared with black and Asian populations. In England the incidence of EAC has rapidly risen, particularly in men over the last three decades. ESCC was strongly associated with social deprivation. EAC was more common in white populations, but no association with the socioeconomic status was found.

Studies of autonomic function in patients with achalasia and nutcracker oesophagus.

BACKGROUND Post-mortem studies in patients with achalasia reveal degenerative changes in the vagus and its dorsal motor nuclei suggesting the possibility of widespread autonomic dysfunction. AIMS To study a broad range of autonomic function in patients with achalasia and nutcracker oesophagus and in asymptomatic volunteers. SUBJECTS Patients with a manometric diagnosis of achalasia and nutcracker oesophagus and age- and sex-matched asymptomatic volunteers. METHODS Subjects underwent measurement of: (1) pupil cycle time estimation; (2) heart rate response to the Valsalva manoeuvre, standing and deep breathing; (3) systolic blood pressure response to standing; (4) diastolic response to sustained handgrip; (5) spectral analysis of heart rate variability; and (6) heart rate and blood pressure during the Valsalva manoeuvre. RESULTS No significant differences were found between patients with achalasia and asymptomatic volunteers. Patients with nutcracker oesophagus, however, had longer pupil cycle times (1.2 (0.9-1.4) s versus 0.9 (0.8-1.2) s, P= 0.02) and had attenuation of both the rise in the low frequency peak of heart rate variability and the fall in the high frequency peak on standing (rise in low frequency peak - patients 26.6 (10.4-52.3)% to 42.2 (15.5-54.0)%, P = 0.46, volunteers 16.9 (8.4-37.2)% to 47.4 (21.1-66.3)%, P = 0.03; fall in high frequency peak - patients 18.1 (0.9-43.3)% to 10.1 (0.5-26.6)%, P= 0.46, volunteers 24.8 (8.5-44.4)% to 9.3 (2.6-35.6)%, P= 0.03). The rise in blood pressure during the Valsalva manoeuvre was also attenuated in patients with nutcracker oesophagus compared with asymptomatic volunteers (6.9 (1.0-9.3) mmHg versus 12.9 (11 -23.0) mmHg, P < 0.01). CONCLUSIONS Whereas tests of cardiovascular and pupillary autonomic function are normal in patients with achalasia, patients with nutcracker oesophagus show defects in both parasympathetic and sympathetic function.

Quality standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS)

This document represents the first position statement produced by the British Society of Gastroenterology and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, setting out the minimum expected standards in diagnostic upper gastrointestinal endoscopy. The need for this statement has arisen from the recognition that while technical competence can be rapidly acquired, in practice the performance of a high-quality examination is variable, with an unacceptably high rate of failure to diagnose cancer at endoscopy. The importance of detecting early neoplasia has taken on greater significance in this era of minimally invasive, organ-preserving endoscopic therapy. In this position statement we describe 38 recommendations to improve diagnostic endoscopy quality. Our goal is to emphasise practices that encourage mucosal inspection and lesion recognition, with the aim of optimising the early diagnosis of upper gastrointestinal disease and improving patient outcomes.