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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

To commemorate Edkins’ discovery of gastrin in 1905, we review a century of progress in the physiology and pathobiology of gastrin and acid secretion especially as it pertains to clinical aspects of gastro-oesophageal reflux disease.

Although initially ignored, Edkins’ observations eventually led to the enthusiastic investigation of gastrin and acid regulation in peptic ulcer disease, culminating in important therapeutic advances in the management of acid peptic disease. Following the improved understanding of gastric secretory physiology, and the development of acid suppressants with increasing efficacy, the use of surgical intervention for peptic ulcer disease was almost eliminated. Surgery became obsolete with the discovery of Helicobacter pylori.

Three other advances are also influencing modern practice: the gastrotoxicity of aspirin and non-steroidal anti-inflammatory drugs is now increasingly appreciated, the role of endoscopy in the diagnosis and therapy of upper gastrointestinal bleeding, and the use of intravenous acid-suppressive agents.

The major issue for the future resides within the epidemic of gastro-oesophageal reflux disease. How to diagnose, categorize and treat this condition and how to identify and prevent neoplasia, are the challenges of the new century.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

The year 2005 marks the 100th anniversary of the discovery of gastrin by John Sydney Edkins.1 This study represents the synthesis of the thoughts of 40 distinguished gastroenterologists and scientists (see Appendix) from around the globe who assembled on 8–10 April 2005 at Tylney Hall, Hampshire, UK, to commemorate the occasion and to opine upon the current critical issues in acid-related disease.

Edkins’ seminal finding led to a century of progress in unravelling the acid peptic disorders, highlighted by an increasingly sophisticated understanding of the role of gastrin in the regulation of acid secretion and the rational development of potent medications to suppress gastric acid secretion and treat acid peptic disorders – from the H2-receptor antagonists to proton-pump inhibitors (PPIs) and acid pump antagonists.1 The century that has elapsed has seen the description of rare gastrin-secreting tumours that cause ulcer disease and the belated recognition in the 1980s that Helicobacter pylori was the major cause of the peptic ulcer diathesis. More recently the increasing role chronic aspirin and non-steroidal anti-inflammatory drug (NSAID) use play in the aetiology of peptic ulcer bleeding in developed countries has been recognized. Dominating the latter part of the century has been the ever-increasing burden of gastro-oesophageal reflux disease (GERD) and the widespread use of acid suppression medications for its treatment.

It is instructive to recall that Edkins’ discovery, reported by Sherrington in 1905 to the Physiological Society of London,2 was originally strongly refuted by the eminent physiologist of the day, Henry Dale, who believed histamine to be the dominant acid secretagogue. Edkins was vindicated in 1938 by Komarov, and subsequently by Gregory and Tracey in the 1960s when the structure of gastrin was elucidated.1 Thus, Edkins’ finding was ignored and rediscovered after many decades – an interesting parallel with the history of gastric bacteria.3 Perhaps there are lessons here for the decline and fall and subsequent resurrection of the hiatal hernia in the aetiology of GERD (discussed below), and a reminder that what is dogma today may be derided tomorrow. Indeed we have seen the rise and fall of the histamine receptor and may well live to see the ebb and flow of the pump. A century ago therapy of acid peptic disease embraced bismuth and milk or gastrectomy – now it is antibiotics and acid pump inactivation or wrapping a sphincter.

In respect of the passage of time and the growth of intellect this overview seeks to place in perspective the oesophago-gastric issues of 2005. The comments should be viewed within the context of the philosophical recognition that our knowledge may be little more than an ephemeral distillation of the glimpse of the brief video clip that represents the clinical and scientific span of our individual lives. As Michel de Montaigne so aptly framed it –‘Que sais-je'? (what do I know…).

A century of progress in the biology and pathobiology of gastrin

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

Gastrin was initially identified as an antrally located bioactive mucosal agent based on its ability to stimulate gastric acid secretion.2 As such it represented the confirmation of Bayliss and Starling's hypothesis that there existed chemical messengers in the gut mucosa that could activate other cells.4 The focus of clinical investigation in the second half of the ‘gastrin century’ was thus chiefly on gastrin as a chemical secretagogue responsible for most of the acid-secretory response to food and acting through gastrin receptors on parietal and enterochromaffin-like (ECL) cells. Considerable attention was also addressed to the pathophysiological role of gastrin as the biological agent responsible for the Zollinger–Ellison syndrome, and the enthusiastic investigation of abnormalities of gastrin and acid regulation in peptic ulcer disease as well as the (much) later appreciation that H. pylori (the cause of most peptic ulcers) subtly influences gastrin secretion and thus gastric secretory biology.5

Recently, there has been considerable interest on the effects of gastrin that are unrelated to gastric acid secretion. Evaluating the biologically active non-amidated products of the gastrin gene has revealed that such species, including progastrins and glycine-extended species, have trophic effects on the gastric and colonic mucosa and may influence the growth of tumours. Gastrin-sensitive neoplasms include gastric carcinoids (predictably so, by extrapolation from conventional gastrin physiology) and possibly gastric cancer, as well as extra-gastric tumours in the colon, pancreas and lung.6 Furthermore, components of an entirely autocrine gastrin regulatory loop have also been reported in some studies of human colon cancer.6 Further understanding of this field has been greatly aided by several types of genetically engineered mice exhibiting specific defects in gastrin signalling pathways. Thus knock-outs, knock-ins and a variety of permutations of such have led to almost as many interpretations of the role of gastrin as commentaries on the Talmud or explanations of Genesis. Gastrins probably stimulate pro-proliferative and potentially carcinogenic pathways in epithelial cells indirectly by crosstalk between multiple diverse epithelial and stromal cell types through pathways mediated by members of the epidermal growth factor family, regenerating gene (Reg) family proteins, matrix metalloproteinases and cytokines.7 Determining whether abnormalities of gastrin secretion or processing are involved in the pathogenesis of human tumours remains a challenge. Nevertheless, rodent models of gastrin responsive xenografts and colonic tumorigenesis do suggest the potential for treating some human cancers by inhibiting gastrin-mediated pathways, for example, by targeting gastrin itself or the gastrin receptor.8 Although such therapies could also be applied to managing the hypergastrinaemia of the Zollinger–Ellison syndrome, the therapeutic efficacy of PPIs in this condition would be difficult to better. Interestingly, it is now over 30 years since James Black discovered the histamine (H2)-receptor antagonists9 (leading to his Nobel laureate in 1988) and 20 years since the first PPI was tested in humans. Yet while these agents effectively inhibit much gastric acid secretion and led to a substantial improvement of quality of life for a large number of patients, many years of work on the delineation of an antigastrin by Sir James and others has failed to yield a clinically viable therapeutic agent.

Chronically sustained increased plasma gastrin concentrations leads to increased numbers of ECL cells, and results occasionally in the formation of gastric carcinoid tumours. There is some evidence that gastric carcinoids are being increasingly identified clinically, although this rise may reflect, at least in part, increased recognition or altered diagnostic criteria. Predicting the behaviour of gastric carcinoids and thereby devising optimal treatment strategies remains a significant challenge. Thus, it is important to develop better biomarkers of malignancy in this disease, for example, by characterizing changes in the molecular signatures of human ECL cell tumours and rodent gastric carcinoid models during disease progression.10

Acid suppression and other therapeutic strategies in ulcer management

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

The major agents injurious to the upper gastrointestinal (GI) tract are gastric acid, H. pylori infection, aspirin and NSAIDs. Helicobacter pylori is the most important risk factor for peptic ulcer disease, while aspirin and NSAIDs are the biggest culprits in peptic ulcer bleeding.11 Fortunately, potent acid suppression with PPIs heals NSAID ulcers and continued PPI use provides good long-term prophylaxis. The widespread practice of H. pylori eradication together with the natural decrease in H. pylori prevalence in western countries has led to a relative decline in peptic ulcers attributable to H. pylori infection alone. Consequently, there has been a rise in the proportion of ulcers that are ‘non-H. pylori, non-NSAID ulcers’ and a recognition of the importance of preventive strategies in aspirin or NSAID users at high risk of ulcer disease and bleeding. These high-risk patients (particularly the elderly with a history of ulcers and significant comorbidity) had been under-represented in early clinical trials evaluating the GI side-effects of NSAIDs and aspirin, but they incur the majority of fatal and near-fatal GI bleeding episodes. In such patients, H. pylori should be actively sought and eradicated and aspirin or NSAIDS only continued if clinically imperative and with the co-prescription of PPIs. The alternative strategy of substituting a selective cyclo-oxygenase 2 inhibitory NSAID is now a much less attractive option after the withdrawal of two of the three formerly available agents from the US market because of concern over adverse cardiovascular safety profiles.

The management of bleeding ulcers has also become more uniform recently. Aggressive resuscitation followed by early endoscopy (to treat bleeding lesions and to establish the likely rebleeding risk) is now standard medical practice. Increasing evidence supports the widespread practice of immediate intravenous PPI use (probably with an initial loading dose and a subsequent continuous infusion) followed through the period of endoscopy to the time of refeeding.12, 13 Optimal endoscopic management of the bleeding lesion includes saline combined with adrenaline injection, completed with either thermal energy application or hemoclips. Adherent clots should be washed off if possible to treat the underlying lesion. For clots that cannot be shifted with irrigation, shaving them off with a snare has been proposed by some authors to allow access for endotherapy;14 whether this is appropriate in the current era where intravenous PPIs are used to enhance clot stability has not been tested. A ‘second look’ endoscopy is not advisable routinely but may be helpful in certain high-risk patients.15 If rebleeding occurs, a repeat endoscopy is recommended and in cases with further rebleeding a critical and joint evaluation by gastroenterologists and surgeons is essential. For subsequent episodes, and for initial bleeding that cannot be controlled endoscopically, surgery will usually be necessary. Unfortunately, most such patients are not ideal surgical candidates – they are characteristically older, have considerable comorbidity and may be hemodynamically unstable. For these reasons, an attempt at selective arterial embolization may be a suitable alternative, providing expert angiographic facilities are available – adequate controlled data in this area are lacking. If surgery is undertaken, it is best performed by an experienced surgeon using the minimal necessary intervention. Vagal dissection and pyloroplasty should be relegated to history, although gastrectomy may rarely still be needed for obscure or diffuse lesions. As for all peptic ulcers, evidence of underlying H. pylori infection should be sought (by serology, breath or stool test if initial biopsy-based tests were negative in spite of sufficient numbers of biopsies) and the organism eradicated if found. Assessing whether eradication was achieved by the use of appropriate test protocols is mandatory prior to withdrawal of long-term acid suppression after bleeding episodes in these patients and is strongly advisable in patients with an increased risk for ulcer complications but who have not yet bled, such as patients on anticoagulation.

The rise of GERD and current management dilemmas

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

The final quarter of the ‘gastrin century’ has witnessed a striking shift in acid-related disorders from below to above the gastro-oesophageal (GE) junction. The epidemic of GERD in the western world is beginning to be seen also in developing countries and has contributed to the phenomenal growth in the worldwide use of potent acid-suppressing medications. The causes of this continuing increase in GERD prevalence are multifactorial, with the most important contribution likely to be obesity – increased body mass consistently tracks closely with GERD in associative studies.16 Other postulated cofactors include the adoption of an increasingly sedentary lifestyle, herniation of the upper stomach through the diaphragmatic hiatus and loss of H. pylori infection (though this is unlikely to be causal).17 However, relatively little attention has been paid to changes in the preparation and composition of foods and the dietary constituents that may be particularly associated with the increased incidence of GERD.

Exactly how and why hiatal hernias develop is not certain. Increasing evidence supports the long popular, subsequently rejected and more recently resurrected concept of the hernia being of pathophysiological importance in gastro-oesophageal reflux. The presence of a hiatal hernia is associated with a further widening of the relaxed GE junction18 that is likely to promote the reflux of liquid during transient lower oesophageal sphincter relaxations, increase the volume of the refluxate and, lead, postprandially, to the migration upward of the ‘acid pocket’ that sits atop the ingested meal. As the refluxate rises higher towards the upper oesophagus and larynx, sensory mechanoreceptors in the oesophageal wall may be stimulated too.19, 20

It is becoming evident that the definitions we commonly use to categorize patients with GERD [into erosive GERD, non-erosive reflux disease (NERD) and functional heartburn] and our current concepts of symptom generation in GERD have major deficiencies for patient management. The long-held belief that ‘heartburn’ is a dependable or dominant symptom is probably incorrect or overemphasized and has led to the proposal that a beneficial response to acid inhibition be a necessary part of this definition.21 Non-oesophageal symptoms, including lower GI symptoms, nausea and dyspeptic or sleep-related complaints are remarkably frequent in GERD patients,22 as they are in those diagnosed with irritable bowel syndrome,23, 24 suggesting that generalized visceral hypersensitivity may be involved in the generation of many oesophageal symptoms; such patients would likely derive little overall benefit from potent acid suppression alone. Our ignorance of the mechanisms involved in the generation of oesophageal pain is evidenced by a recent population-based study from Sweden that demonstrated the frequent occurrence of erosive GERD in patients without any oesophageal symptoms at all.25

Recent surveys have confirmed that insomnia and daytime somnolence may be not so ‘atypical’ in GERD after all. At least half of all GERD patients polled, reported being wakened by reflux episodes,26 as did 25% of a population-based sample.27 It is conceivable that very short reflux episodes may fragment sleep even further, leading to an insidious decline in sleep quality. In view of these problems with reliance on the presence or absence of specific symptoms in GERD and the realization that doctors underestimate their patients’ GERD symptoms,28 self-reported GERD questionnaires are likely to be extremely helpful in clinical studies and perhaps also of importance in clinical practice. The need to define an individual patient's symptomatology and be able to appreciate its waxing and waning or response to a medication is a critical requirement. Particularly, given the appreciation that endoscopy is both a relatively insensitive as well as an impractical tool for this purpose. As there are deficiencies of the existing GERD questionnaires29, 30 a new instrument (termed ‘ReQuest’) has been specifically developed with the intention of being inclusive, patient-oriented and self-administered.30 The tool was designed specifically to monitor the response to GERD therapy in clinical trials31 and has proved to be reliable and responsive in erosive GERD and NERD populations even in different languages.22, 32, 33 It seems likely that subsequent iterations of ReQuest will prove to be of value in clinical practice.

Most patients with abnormal acid reflux on pH-metry have normal-appearing oesophageal mucosa at endoscopy and in those with visible damage, the grade bears only modest correlation with symptom severity. Should NERD be considered at the milder end of the spectrum of GERD? Though there have been recent reports of increased release of interleukin (IL)-8 in the oesophageal mucosa in NERD (suggesting immune activation)34 and the presence of dilated intracellular spaces on electron microscopy,35, 36 the fact that NERD behaves therapeutically differently to erosive oesophagitis suggests that the underlying pathophysiology may be different in patients with and without erosions.

Both oesophageal and gastric pH-metry appear to be severely limited as diagnostic tools in reflux disease. The correlations between both the severity of oesophageal damage and abnormalities on pH-metry37 and between symptom occurrence and reflux episodes38 are both very poor. Thus, the main indications currently for 24-h pH recording are in the evaluation of patients with GERD prior to antireflux surgery and in the evaluation of atypical presentations of GERD such as non-cardiac chest pain (but even in this context the PPI test may be as accurate).39 There is considerable interest currently in developing improved methods of evaluating oesophageal reflux events. The Bravo capsule attaches to the oesophageal mucosa and interferes less directly with daily activities than a naso-oesophageal device. The option of monitoring for 48 h and perhaps recording pH at sites other than 5 cm above the GE junction may provide more reliable results – especially with the recognition of short segment reflux,40 this remains to be established. Indeed, recent direct comparisons of conventional vs. capsule pH measurement revealed that the capsule records significantly fewer reflux episodes and less oesophageal acid exposure than conventional catheter-based devices.41, 42 The ability to simultaneously record non-acidic reflux using probes that detect either bilirubin (by bilitec probe) or volume reflux (by impedance) may also be helpful in the diagnosis and management of GERD. However, the benefit of this technology for clinical practice remains unproven.

The development of H2-receptor antagonists was a revolution in the pharmacological management of acid. Subsequently PPI therapy has been a major advance in the management of GERD. While research into prokinetic agents continues, the history of developing drugs focused on the lower oesophageal sphincter and oesophago-gastric contractility does not engender much enthusiasm in their eventual widespread use. In the continued absence of therapies other than for inhibiting acid secretion, debate revolves around the optimal dose and timing of PPIs, how to manage PPI ‘non-responders’ and whether intermittent use of prescription or over-the-counter PPIs is to be encouraged. PPIs are remarkably effective at healing oesophageal erosions, but in clinical trials about a quarter of patients with erosive GERD continue to experience heartburn after a month of treatment.43 Double dosing and prolonged therapy appear to increase efficacy, especially in patients with extra-oesophageal symptoms. The consistent lack of response in some patients reported in clinical trials of erosive GERD probably reflects the fact that the symptoms initially targeted were never, or not exclusively, acid-related. Indeed, failure to inhibit oesophageal acid exposure is rarely the explanation for such ‘non-responders’.44 How much of their persistent symptoms are due to excessive volume reflux and what proportion is totally unrelated to GERD? Another important issue to consider in the era of intermittent PPI use is acid rebound following PPI withdrawal. Does this phenomenon promote long-term reliance on these medications? How should we attempt to wean our patients off therapy? Finally, what is the role of surgery and endoscopic therapy in GERD patients? Laparoscopic fundoplication is performed relatively frequently, although the results in practice may be far from ideal.45 There continues to be evolution and proliferation in the methods to tamper with the GE junction endoscopically, reflecting technology in its infancy. Fortunately, novel endoscopic therapies are currently being evaluated with increasing rigor. To date, however, no particular device or injection can be recommended as either safer or more effective than the use of PPIs or laparoscopic fundoplication.

The mechanisms of oesophageal carcinogenesis associated with prolonged acid reflux remain obscure. Recent attention has focused on the role of nitrosating species and nitric oxide at the GE junction.46 While the benefit to the host of these species may be to kill ingested microbes, this could have deleterious effects on the lower oesophagus, including mutagenesis (via nitrosation) and the promotion of further reflux through altering the physiology of the GE junction. The difficulties in the diagnosis and management of Barrett's oesophagus and the dearth of current markers on which to usefully prognosticate in this condition remain a major and, as yet, little resolved challenge. While we continue to perform surveillance in this condition, enthusiasm for doing so is tempered by a lack of efficacy data and, regrettably, it is unlikely that the large trials necessary to evaluate the effectiveness of screening programmes will ever be performed. The concept of surveillance for an entity that has proved difficult to accurately define may well however, be an exercise resembling ‘The Hunting of the Snark’, so aptly described by Lewis Carroll.47

As low-grade dysplasia is a poorly defined entity,48 high-grade dysplasia (HGD) is the most useful end point for surveillance. Because the risk of cancer following a diagnosis of HGD is approximately 10–30% over 5 years.49 Due to the attendant morbidity and mortality of oesophagectomy, there is now growing enthusiasm for the evaluation of ablative treatments – either photodynamic therapy or endoscopic mucosal resection. It is still too early to tell whether endoscopic mucosal resection will be widely adopted. Experience of mucosal resection from some specialized centres is very encouraging.50

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix

Edkins’ discovery of gastrin was followed by substantial changes in the understanding of the regulation of gastric acid secretion and led, as a consequence, to the development of acid secretion inhibitors. Thus, to clinicians of the 20th century acid became the ‘agent’. The subsequent rediscovery of the relevance of gastric bacteria and the advantages of their elimination led to vastly improved management of peptic ulcer disease and with a consequent dramatic decline in their impact on public health. One hundred years after Edkins’ discovery of gastrin, the ‘decline and fall’ of ulcer disease per se has led to GERD becoming the dominant upper GI disease in developed countries. This has occurred in the context of the current epidemic of obesity. Issues that demand clarification include the need to better understand the aetiology of GERD and its transformation from a damage responsive process to a potentially neoplastic disease. What are required are improved tools for the diagnosis and follow-up of GERD, better definitions of subgroups of GERD patients and a more global approach to symptom management in reflux disease. It seems likely that understanding the multiple dimensions of GERD symptomatology, rather than focusing on one or two such as heartburn or regurgitation alone, may be the key to restoration of the patients’ quality of life. Critical to successful therapy will be the development of improved acid suppression by drugs that provide faster symptom relief and longer lasting healing. The introduction of agents targeting the underlying pathophysiology of GERD sadly remain over the horizon as we struggle to define the precise cause of a disease characterized by little more than its own symptomatology.

Edkins’ fall from grace and the subsequent posthumous vindication of his gastrin theory is a sobering reminder that it may be worthwhile considering new directions as well as re-evaluating unfashionable old theories in advancing the management of the many patients with GERD. Who knows – while gastrin was once thought to be ‘humbug’, it may well be the ‘hambug’ that we eat that is the actual enemy of the junction.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix
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Appendix

  1. Top of page
  2. Summary
  3. Introduction
  4. A century of progress in the biology and pathobiology of gastrin
  5. Acid suppression and other therapeutic strategies in ulcer management
  6. The rise of GERD and current management dilemmas
  7. Conclusions
  8. Acknowledgement
  9. References
  10. Appendix
List of participants (alphabetical)

K. D. Bardhan, Rotherham District General Hospital, Rotherham, UK; A. N. G. Barkun, McGill University, Montreal, Canada; H. Barr, Gloucestershire Royal Hospital, Gloucester, UK; C. Beglinger, Kantonsspital Basel, Basel, Switzerland; R. Benamouzig, Hô pital Avicennes, Bobigny, France; J. Black, James Black Foundation, London, UK; M. Caplin, Royal Free Hospital, London, UK; K. DeVault, Mayo Clinic Jacksonville, Jacksonville, FL, USA; F. Di Mario, Universita’ degli Studi di Parma, Parma, Italy; G. Dockray, University of Liverpool, Liverpool, UK; E. Elias, Queen Elisabeth University Hospital, Edgbaston, UK; R. Fass, University of Arizona, Tucson, AZ, USA; K.-L. Goh, University of Malaya, Kuala Lumpur, Malaysia; K. Hine, The Princess Royal Hospital, West Sussex, UK; G. J. Holtmann, Royal Adelaide Hospital, Adelaide, Australia; P. Katelaris, Concord Hospital, Sydney, Australia; J. R. Malagelada, Hospital Vall D'Hebrón, Barcelona, Spain; P. Malfertheiner, Otto von Guericke University, Magdeburg, Germany; D. M. McCarthy, University of Albuquerque, Albuquerque, NM, USA; K. McColl, Western Infirmary, Glasgow, UK; J. McGuigan, University of Florida, Gainesville, FL, USA; I. Modlin, Yale University, New Haven, CT, USA; S. F. Moss, Rhode Island Hospital and Brown University, Providence, RI, USA; S. Peikin, Cooper University Hospital, Camden, NJ, USA; W. Peterson, UT Southwestern Medical Center at Dallas, Dallas, TX, USA; R. Pounder, Royal Free & University College, London, UK; J. Prado Pinto des Moraes-Filho, Sao Paulo, Brazil; E. M. M. Quigley, National University of Ireland Cork, Cork, Ireland; J. Regula, Centrum Onkologii – Instytut Sklodowskiej-Curie, Warszawa, Poland; R. D. Rosin, St Mary's Hospital, Surgical Oncology, London, UK; R. I. Rothstein, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; G. Rubin, University of Sunderland School of Health, Sunderland, UK; G. Sachs, Wadsworth VA Hospital, Los Angeles, CA, USA; R Shaker, Medical College of Wisconsin, Milwaukee, WI, USA; S. Spechler, UT Southwestern Medical Center at Dallas, Dallas, TX, USA; V Stanghellini, Policlinico S. Orsola, Bologna, Italy; J Sung, Prince of Wales Hospital, Hong Kong, China; J. Tack, University of Leuven, Leuven, Belgium; N. J. Talley, Mayo Clinic, Rochester, MN, USA; G. Tytgat, Academic Medical Center, Amsterdam, the Netherlands; H. L. Waldum, Trondheim University Hospital, Trondheim, Norway; N. A. Wright, Barts. and the London and Queen Mary's School of Medicine and Dentistry, London, UK.