Gastroesophageal reflux disease and Barrett esophagus: an overview of evidence-based guidelines.

Gastroesophageal reflux disease is an extremely common condition worldwide, with the published prevalence rates varying from 2.5% in China to 51.2% in Greece. Its economic and morbidity burden is vast, and optimizing care for this condition carries huge financial and patient­related benefits. The disease can be complicated by progression to Barrett esophagus (BE), a precancerous condition that affects approximately 2% of the population and remains undiagnosed in many individuals. The National Institute of Clinical Excellence has produced guidelines on cost­effective management of gastroesophageal reflux disease in patients in the United Kingdom, and the Benign Barrett's and Cancer Taskforce consensus was the largest international review of evidence known on the management of benign BE complications. This paper is a review of these guidelines with updates on new evidence. Areas for future development involve risk­stratifying patients to surveillance, chemoprevention agents, and genetic biomarkers to help decide who will be at highest risk of malignant progression. Evidence supports the safety of proton pump inhibitors for symptom control in the medium term (ie, 9 years) and reducing the risk of progression of BE, while surgical options are cost­effective treatments for certain patients. Barrett esophagus surveillance should be directed towards high­risk groups, while those at lower risk may benefit from chemoprevention strategies.

Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial.

BACKGROUND: Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus. METHODS: The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77. FINDINGS: Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2-9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01-1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98-1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01-1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14-2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events. INTERPRETATION: High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus. FUNDING: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

Management of Barrett esophagus: a practical guide for clinicians based on the BADCAT and BoB CAT recommendations.

We undertook two of the largest evidence-based reviews in clinical medicine to assess the rationale for the management of gastroesophageal reflux disease, Barrett esophagus (BE), dysplasia, and early invasive esophageal adenocarcinoma. These reviews involved over 150 world experts in 4 continents, and over 20 000 papers were assessed. Quality assessment of the publications was made using Grading of Recommendations Assessment, Development and Evaluation, and of over 240 questions formulated, we were able to answer 30% with an agreement of at least 80%. We agreed on a unique global definition of BE meaning that the presence both of hiatus hernia endoscopically and of intestinal metaplasia histologically should be noted. In addition, we devised an escalation and deescalation pathway for the management of esophagitis, metaplasia, dysplasia, and adenocarcinoma sequence. Endoscopic resection (ER) is recommended for visible mucosal lesions. Moreover, we endorsed the early use of ablation therapy for persistent dysplasia of any degree. In this regard, ER may be both diagnostic and therapeutic and may be sufficient even in early mucosal lesions (T1m). In conclusion, fewer people should be surveyed but those that do will require more detailed mapping and endoscopic interventions than currently. In addition, patients accumulating other potentially life-threaten-ing comorbidities should be offered cessation of surveillance. In the future, chemoprevention may be the game-changing solution but results from large randomized trials, including AspECT and BOSS, are awaited.

Trefoil Factor Expression in a Human Model of the Early Stages of Barrett's Esophagus.

BACKGROUND: Trefoil proteins are believed to have an important role in mucosal protection and repair in the gastrointestinal tract. They are well recognized in Barrett's esophagus and considered a potential biomarker for the condition. Metaplasia occurring in the esophageal remnant after esophagectomy is a human model for the early stages of development of Barrett's esophagus. AIMS: To assess expression of trefoil proteins in post-esophagectomy columnar epithelium and to use trefoils as a molecular tool to understand regenerative mucosa in the esophagus. METHODS: Patients with columnar metaplasia in the esophageal remnant were recruited from a large esophago-gastric cancer center. Trefoil factor expression was determined using immunohistochemical techniques. RESULTS: Samples were obtained from 37 patients. TFF1 and TFF2 were expressed by all samples in a similar pattern to that described in studies of sporadic Barrett's esophagus. TFF3 was less widely expressed and was significantly associated with time elapsed between surgery and endoscopy. Median time from surgery to endoscopy was 8.1 years for patients with TFF3 expression versus 3.4 years for those without (p = 0.004). CONCLUSIONS: Widespread expression of trefoils in this environment suggests that these proteins have an important role in development of Barrett's metaplasia. TFF3 expression may be absent in the early stages of metaplasia and may represent more established columnar epithelium. Biopsy samples from post-esophagectomy patients provide a valuable resource to study the early stages of Barrett's esophagus.

The correlation between reading and mathematics ability at age twelve has a substantial genetic component.

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.

The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.

OBJECTIVE: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. METHODS: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. RESULTS: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. CONCLUSIONS: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.

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 Barrett's 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 Barrett's 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 Barrett's oesophagus and related neoplasia.

Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus.

BACKGROUND & AIMS: The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. METHODS: Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m(2) body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. RESULTS: No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). CONCLUSIONS: LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required.

Why is there a change in patterns of GE cancer?

Recent decades have seen a worrying trend in incidence rates of distal oesophageal and proximal gastric cancers. Fuelled by radical changes in lifestyle, diet, physical activity and environmental exposures, as well as an ageing population and host genetic predisposition, the incidence of oesophageal adenocarcinoma (OAC) is on the rise in Western populations. While overall incidence of gastric cancers is declining, the ageing of society means that an increase in absolute numbers is expected over coming years. Both cancers tend to present at an advanced stage, hence prognosis remains poor despite increasingly effective screening and treatment strategies. The development of gastric and oesophageal malignancies is influenced by myriad factors, not least geographical, racial and socioeconomic differences in addition to lifestyle choices. The multidimensional nature of these risk factors requires a holistic understanding of their net influence in the development of malignancy. This review explores the evidence base for established and putative risk factors in the development of gastric and oesophageal cancers. It is hoped that with a clear understanding of important risk factors, a multidisciplinary approach including effective primary prevention, regular screening of high-risk groups and continued research into the molecular biology of gastrointestinal carcinogenesis may facilitate a reduction in incidence rates, as well as early detection and optimal management of upper gastrointestinal malignancies.

Aspirin and NSAIDs; benefits and harms for the gut.

Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett's oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose.

Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor.

BACKGROUND: Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations. METHODS: Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry. RESULTS: The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 µm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett's metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett's metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett's metaplasia stem cells. Patches of clonally mutated Barrett's metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell. CONCLUSION: In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett's metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity.

The clonal origins of dysplasia from intestinal metaplasia in the human stomach.

BACKGROUND & AIMS: Studies of the clonal architecture of gastric glands with intestinal metaplasia are important in our understanding of the progression from metaplasia to dysplasia. It is not clear if dysplasias are derived from intestinal metaplasia or how dysplasias expand. We investigated whether cells within a metaplastic gland share a common origin, whether glands clonally expand by fission, and determine if such metaplastic glands are genetically related to the associated dysplasia. We also examined the clonal architecture of entire dysplastic lesions and the genetic changes associated with progression within dysplasia. METHODS: Cytochrome c oxidase-deficient (CCO⁻) metaplastic glands were identified using a dual enzyme histochemical assay. Clonality was assessed by laser capture of multiple cells throughout CCO⁻ glands and polymerase chain reaction sequencing of the entire mitochondrial DNA (mtDNA) genome. Nuclear DNA abnormalities in individual glands were identified by laser capture microdissection polymerase chain reaction sequencing for mutation hot spots and microsatellite loss of heterozygosity analysis. RESULTS: Metaplastic glands were derived from the same clone-all lineages shared a common mtDNA mutation. Mutated glands were found in patches that had developed through gland fission. Metaplastic and dysplastic glands can be genetically related, indicating the clonal origin of dysplasia from metaplasia. Entire dysplastic fields contained a founder mutation from which multiple, distinct subclones developed. CONCLUSIONS: There is evidence for a distinct clonal evolution from metaplasia to dysplasia in the human stomach. By field cancerization, a single clone can expand to form an entire dysplastic lesion. Over time, this field appears to become genetically diverse, indicating that gastric cancer can arise from a subclone of the founder mutation.

Chemoprevention in Barrett's esophagus: A pill a day?

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.

Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence.

Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world's first proven chemopreventive agent is currently unknown but the evidence looks hopeful.