Low (A) and high (B) power microscopic views of the esophageal epithelium in , showing distinctive features of this condition, such as increased numbers of immune cells called .

Image courtesy of Dr. Glenn Furuta. Reprinted from , 133, Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, Bonis P, Hassall E, Straumann A, Rothenberg ME. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment, pp. 1342-1363, Copyright 2007, with permission from Elsevier.

 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Diseases of the Oropharynx and

SUMMARY OF RESEARCH GOALS

Because normal functioning of the oropharynx and esophagus can be compromised by a wide spectrum of diseases, the Commission suggests a number of research goals that address the diverse etiologies and potential treatments for these disorders. Research to understand the neuromuscular biology of the oropharynx and esophagus is critical to developing therapies for conditions like swallowing disorders brought on by stroke, premature birth, non-erosive reflux disease (NERD), and other motility disorders that affect this portion of the gastrointestinal (GI) tract. Similarly, more studies are needed to identify better therapeutic targets for gastroesophageal reflux disease (GERD), among the most common diagnoses for a digestive disorder in the U.S. GERD is also associated with increased risk for Barrett’s esophagus and esophageal cancer. Thus, research is needed to uncover the risk factors and mechanisms of disease progression in order to develop more effective prevention and treatment strategies. The emergence of eosinophilic esophagitis and other inflammatory diseases of theesophagus over the last decade highlights the need for research to define the clinical course of these poorly understood diseases and design rational therapies to reverse them. Progress toward these research goals will help to reduce the significant economic toll that these diseases, particularlyGERD, take on individuals and the U.S. healthcare system.

Diseases of the Oropharynx and Esophagus 117 INTRODUCTION AND BACKGROUND The oropharyngeal musculature is striated, signifying its close control by cranial nerves. The oropharynx and the esophagus can be This pattern continues for the proximal one- considered the gateways to the GI tract and, third of the esophagus, after which it is replaced as such, are critical for the digestive processes by , which is more characteristic that follow. Although the two components of of the rest of the GI tract and indicative of the the oropharynx (i.e., mouth and ) are greater influence of the intrinsic nerve cells relatively distinct anatomically, the oropharynx found in the wall itself (i.e., the enteric nervous is usually considered as a unitary functional system). Despite its deceptively simple tubular entity from a gastroenterological perspective, form, the esophagus is in fact a complex organ. with its overarching purpose being to facilitate Like much of the GI tract, it is organized safe passage of the ingested bolus of food cross-sectionally into several concentric layers: across the opening to the airways and into the epithelium (which is squamous in nature, the esophagus proper. In accordance with this similar to the skin), the , and two function, this region is under tight control of principal muscle layers, with the myenteric the central nervous system (CNS); its nerves plexus sandwiched in between. In addition, it and muscles are, therefore, its most critical receives extensive innervation from the vagal components, with even subtle dysfunction (cranial) and spinal nerves. Any one of these resulting in considerable morbidity. It is not components or layers can be the primary or surprising, therefore, that cerebrovascular secondary site of a variety of diseases. accidents (strokes) and subsequent uncoordinated nerve activity account for the The heterogeneous nature of these organs vast majority of functional disturbances in this makes them vulnerable to a considerable region, with only a minority related to other variety of pathologic processes and a structural lesions. This is a huge problem: correspondingly broad clinical spectrum nearly 700,000 strokes per year occur in the that affects patients across all demographic U.S. alone, with the incidence of post-stroke categories. This chapter focuses on some (difficulty inswallowing) ranging of the diseases in these organs that have from 37-45 percent, even with cursory screening large impacts, as defined either by their techniques, and as high as 64-78 percent with socioeconomic effects or by the burden of formal instrumental testing. Dysphagia not only suffering they impose on individual patients. leads to impairment in food intake, but also Perhaps the most well-known and most puts these patients at a 3-fold or higher risk common of these syndromes is GERD, for pneumonia. Disturbances in oropharyngeal commonly referred to as “.” GERD function are also common in the elderly, is common worldwide, but is particularly perhaps independently of overt lesions in the prevalent in developed countries. The CNS. Swallowing disorders have been reported prevalence of heartburn (with or without acid in 30-40 percent of nursing home residents and regurgitation) at least once a week ranged 6.9 percent of the surveyed general population. from 14-29 percent in the U.S. population The importance of an abnormal swallowing and did not differ between Blacks and Whites mechanism in the elderly is reflected by the in a survey from Houston. In a 2004 report, high incidence of aspiration pneumonia in GERD was the leading physician diagnosis autopsy studies. A majority of patients with for GI disorders, accounting for almost 7 swallowing dysfunction will, therefore, require million outpatient clinic visits. This imposes rehabilitation therapy. a severe economic cost, estimated to be over $11 billion in 2004. Much of this cost is related

118 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases to medications, particularly proton pump conditions, such as achalasia with an incidence inhibitors (PPIs), for which nearly 8 million of approximately 1 in 100,000 per year, which prescriptions were written per month in are nevertheless important because of their 2004—a number that represents more than chronic and lifelong nature. Other disorders a doubling compared to the previous 5 years. may perhaps be more common, but are less Beyond economic considerations, the most well defined clinically and pathophysiologically. sinister health threat represented by GERD In addition, severe GERD is often associated is the elevated risk for adenocarcinoma of with significant motility abnormalities of the the esophagus. The incidence of esophageal esophagus, either as a cause or effect, and adenocarcinoma has grown dramatically in these may lead to symptoms by themselves in recent years, and many experts link it to the some patients. Abnormal esophageal motility rise in GERD in the general population. This is a consequence of some systemic disorders, is based on the current paradigm that chronic notably diabetes and scleroderma or related GERD leads to Barrett’s esophagus, a change connective tissue syndromes. Particularly in the epithelial lining of the esophagus from in the latter, an incompetent sphincter and a squamous to an intestinal type. In some impaired esophageal acid clearance can lead to patients, such a change is associated with devastating reflux with serious consequences, dysplasia, an abnormality in the appearance of such as stricture formation. the lining cells that indicates their instability and tendency to progress to cancer, which Neural changes can not only produce motility occurs in about 0.5 percent of cases per year. disturbances in the esophagus, but can also lead Disorders affecting other parts of the body to sensory abnormalities and a hypersensitive have also been ascribed to GERD, including esophagus that may account for a significant asthma, dental problems, and ear, nose, and number of patients with non-cardiac chest throat disturbances (e.g., erosions, laryngitis, pain. This syndrome probably results from hoarseness, and even laryngeal cancer), but in multiple etiologies with prominent psychosocial many cases actual causality has been difficult components, akin to what has been described to establish. for other painful functional GI disorders, such as functional dyspepsia and irritable bowel Another common form of esophageal cancer syndrome. “, not otherwise specified” is squamous cell cancer, which arises at a is the most common inpatient GI diagnosis, location higher up in the esophagus and with over 320,000 hospital discharges in a is strongly associated with smoking and recent year. alcohol intake. GERD does not appear to be a risk factor for this cancer. Unlike Barrett’s Esophageal diseases affect children as well esophagus, which is predominantly a disease as adults. “Reflux” is extremely common of white males, squamous cell cancer affects in neonates and can assume pathologic African Americans disproportionately, with proportions requiring treatment in a subset of an incidence that is several times greater, infants. Such children are more likely to have although the incidence appears to be declining. GERD when they grow up. However, there is a paucity of good data on effective treatment Another major class of disorders that affects in this age group. Swallowing dysfunction the esophagus arises from disturbances of resulting in oral aversion, dysphagia, and motility—the coordinated action of nerves and regurgitation are also very common problems muscles that produces effective propulsion. in neonatal and pediatric intensive care These disorders include relatively rare units, often associated with prematurity

Diseases of the Oropharynx and Esophagus 119 and oral/pharyngeal trauma from medical in renewed interest in devising rehabilitative devices such as endotracheal and feeding approaches to swallowing disorders. Such tubes. Currently, inadequate information an approach would benefit an overwhelming is available on the normal development majority of patients with swallowing disorders. of swallowing function, the mechanisms The availability of functional imaging should responsible for its perturbation, and effective provide a powerful tool for manipulation of means to prevent and treat the same. Finally, brain centers involved in swallowing to either a recently described syndrome, eosinophilic induce or speed recovery. esophagitis, has been increasingly recognized in both children and adults. This condition is Gastroesophageal reflux disease characterized by esophageal and infiltration by eosinophils, which are white Considerable insight has been obtained into blood cells that typically are associated with the pathways of acid-induced injury to the and some infections. Symptoms of esophagus. Luminal acid and pepsin initially eosinophilic esophagitis include , damage the esophageal epithelium by attacking , poor growth, difficulty with the apical junctional complex (APJ), a group of swallowing, and food impaction. This condition structures that control the permeability of ions is often misdiagnosed as GERD. Although the and aqueous molecules passing through the underlying etiology of eosinophilic esophagitis intercellular space. The consequence of this is is often unidentified, foodborne and airborne a “leaky” epithelium with dilated intercellular allergens have been frequently implicated. spaces, the latter a clinically identifiable Currently, effective treatments are limited to hallmark of early acid injury to the tissue. In steroids and diet restriction. turn, protons and other noxious factors (e.g., pepsin) gain access to subepithelial structures, Finally, a variety of infections can afflict the such as nerves and muscle, with several esophagus, with the most common being fungal potential consequences. Neural stimulation (e.g., candida) or viral (e.g., may result in initiation and/or amplification or virus); these are typically of inflammation and generate symptoms seen in patients with compromised immune of heartburn and chest pain. An attractive systems, such as those with HIV-AIDS. With candidate for mediating these effects of protons modern therapeutic regimens, such cases are is the vanilloid receptor, TRPV1, which is becoming less common. expressed by nociceptive neurons and responds to noxious stimuli, such as acid and heat. Acute, acid-induced esophagitis is reduced in animals RECENT RESEARCH ADVANCES lacking TRPV1, suggesting that refluxed acid may induce inflammation through TRPV1, Oropharyngeal physiology and possibly via neurogenic mechanisms. Muscle- pathophysiology produced inflammatory products may also cause dysfunction; for example, in esophageal A major advance has been the systematic circular muscle, production of cytokines, evaluation of the biomechanical aspects of hydrogen peroxide, platelet-activating factor, swallowing function. In addition, recent studies and prostaglandin E2 results in inhibition of have addressed the effect of bolus volume, acetylcholine release from cholinergic motor consistency, and temperature on the swallowing neurons without affecting the integrity of the apparatus. A better understanding of the contractile mechanisms. biomechanical aspect of swallowing has resulted

120 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Thus, in addition to epithelial injury and trials, on the safety and efficacy of emerging symptom generation, acid reflux can alter endoscopic, anti-reflux procedures, as well esophageal neuromuscular function in several as surgical procedures, such as prosthetic ways, perpetuating the process by decreasing reinforcement of the hiatus in the repair of lower esophageal sphincter (LES) tone and giant hiatal . impairing and acid clearance. Further, esophageal longitudinal smooth Barrett’s esophagus muscle function may also be affected and can contribute to both reflux and delayed clearance Barrett’s esophagus can be reversed in some, by creating a spatial separation of the LES but not all, patients with endoscopic treatments and diaphragm. From the perspective of the that either ablate or mucosally resect the mechanics of the esophagogastric junction epithelium. The neosquamous epithelium (EGJ), axial motion attributable to longitudinal may have less malignant potential than the muscle contraction is key to the normal Barrett’s-affected tissue it replaces. The ability opening mechanism, and disordered EGJ to effect reversion in the mucosa suggests mobility and compliance may play a role in the that there is an underlying “stem” cell, which pathogenesis of reflux. Prolonged contraction can either revert to the normal pathway of this may also contribute to of differentiation to a stratified squamous generation of symptoms. epithelium or continue to differentiate down the specialized intestinal metaplastic pathway. Another advance in this area has been Continued development of these treatments the elucidation of the neurophysiology could result in the ability to prevent the and neuropharmacology of transient LES progression of Barrett’s esophagus to cancer relaxations, a major mechanism of reflux. This and may improve healthcare utilization by has raised the prospect of mechanistically decreasing expenditures on surveillance directed therapy using agents such as . the GABAB agonist baclofen in treating symptomatic reflux. Changes in gene expression likely precede the development of histologic Barrett’s esophagus. Progress has also been made in understanding For instance, the expression of a homeobox and managing childhood GERD, symptoms of gene, CDX2, in esophageal epithelium leads which are reported in 8.2 percent of children to metaplasia and may be an early marker for ages 10-17 years. As in adults, a variety of non- Barrett’s esophagus. Also, epigenetic alterations esophageal symptoms have been associated may be instrumental in the development of with childhood GERD, including asthma, malignancy. Hypermethylation of the promoter hoarseness, , sinusitis, and otitis media regions of various tumor suppressor genes are (ear infection). Natural history studies show associated with increasing degrees of dysplasia. that while symptoms improve, histopathology may remain abnormal. Initial studies show The demographic, anthropometric, and an excellent safety profile forPPI use in symptom-based risk factors for Barrett’s children, although infectious esophagus have been better elucidated. and pneumonia may be more common among Despite reports of the association of Barrett’s children using PPIs. esophagus with chronic heartburn symptoms, data suggest that Barrett’s esophagus is Finally, there has been significant clinical relatively common regardless of whether a research, including randomized, controlled patient has a history of heartburn. In fact,

Diseases of the Oropharynx and Esophagus 121 a substantial proportion of patients with with eosinophilic esophagitis. In 2006, a novel adenocarcinoma of the esophagus have no prior translational study identified the key role of symptoms of heartburn. Obesity appears to eotaxin-3 in eosinophilic esophagitis. Utilizing be a risk factor for Barrett’s esophagus and, a combination of microarray techniques, in for any given body mass index, subjects with vivo and in vitro studies, eotaxin-3 was shown visceral adiposity may be at higher risk than to be significantly up-regulated compared to those with higher hip to waist ratios. Multiple controls. Further studies showed mutation trophic hormones are elevated in subjects of this gene in affected patients, and basic with central adiposity, which may explain the analysis confirmed a significant role in this increased risk of metaplasia in this group. inflammatory process. In addition to potential Preliminary data have been reported showing molecular targets for treatment, these data the influence of heritability on the development add to the growing body of knowledge of the of Barrett’s esophagus. central role of the esophageal epithelium in generation of the inflammatory/allergic cascade A number of novel, high-resolution imaging that ultimately translates into the clinical techniques show promise in identifying high- manifestations of the disease. grade dysplasia and early cancers in Barrett’s esophagus patients with moderate sensitivity Esophageal motility and “functional” and specificity. To date, these “optical ” disorders methods do not demonstrate the ability to survey large areas of Barrett’s esophagus. The pathophysiology of achalasia has been reasonably well characterized and appears Eosinophilic esophagitis to result from a relatively selective loss of nitrergic (inhibitory) neurons supplying the Eosinophilic esophagitis is an immune- muscle of the LES. However, the etiology of mediated inflammatory disorder that is often this process remains unknown, although there triggered in atopic individuals by food products is growing evidence for a possible autoimmune or inhaled allergens. It is characterized by process associated with antibodies directed infiltration of the esophageal wall, including against neuronal elements. There have been the epithelium, with mast cells and eosinophils. some advances in the treatment of this Clinically, the inflammatory response by mast disorder. Botulinum toxin injections have been cells and eosinophils within the esophagus shown to be effective in relieving symptoms results in symptoms of chest pain, heartburn, in this condition and, although the benefit and dysphagia—the latter due either to is short-lived, they are valuable alternatives peristaltic dysfunction or to mechanical in patients who are not fit for more invasive narrowing of the lumen by a dense fibrotic forms of therapy. Pneumatic dilation has been reaction within the wall. Notably, infiltration of shown to be of limited efficacy in younger the esophagus by eosinophils has been shown patients, in whom laparoscopic myotomy to result from the release of eotaxin-3 and IL-4, appears to be the best option. This surgical IL-5, and IL-13 by squamous epithelial cells. approach results in less morbidity and earlier This observation provides molecular targets post-operative recovery than traditional, open for potential treatments for the condition. For myotomy. The demonstration that neural stem instance, intravenous antibodies to IL-5 can cells can be injected into the GI tract and reduce both blood and esophageal eosinophilia result in recovery of nitrergic function raises and improve the quality of life in patients hope for a true cure for this condition.

122 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases The recognition of esophageal hypersensitivity pathophysiologic events that lead to esophageal and, in particular, emerging concepts of post- symptom generation in patients. This includes inflammatory neuronal sensitization have been non-cardiac chest pain and “emerging” important in understanding the spectrum of syndromes, such as NERD.

14 Goals for Research 14

Research Goal 7.1: Understand the ß Conduct clinical studies of recovery and neurobiology of oropharyngeal structure and plasticity with creative use of functional imaging function in health and disease. and novel interventional techniques. ß Understand physiologic and pathologic Identifying novel molecular, physiologic, and communication between the functional anatomic targets within the oropharynx will components of the aerodigestive tract. accelerate the development of more effective ß Understand the effects of gastroesophageal reflux treatments and/or functional rehabilitation of on the airways, including the larynx and bronchi. stroke-induced swallowing dysfunction, a major ß Define the effects of sleep abnormalities on cause of morbidity, particularly in the elderly. upper GI tract physiology. Similarly, understanding the processes involved in the development of swallowing function and the mechanisms by which these processes Research Goal 7.2: Understand the clinico- are disturbed in the neonate is very important. pathologic mechanisms leading to and/or Currently, our approach to these problems is associated with GERD and identify novel empirical and palliative at best, with little ability to molecular, physiologic, and anatomic targets for prevent permanent disability. more effective and rational treatment.

In addition, this region is vulnerable to the effects Although effective in the majority of patients, acid of gastroesophageal reflux with consequences suppression is an indirect method for the treatment that potentially affect the airways in the form of of GERD and its complications. Further, treatment laryngitis and asthma. Much needs to be learned is indefinite in duration because of the chronic about the pathogenesis and treatment of these nature of the disorder. Developing more effective problems. treatments, whether they are pharmacological, endoscopic, or surgical in nature, requires a better Objectives: understanding of the underlying mechanisms. ß Develop useful animal models of oropharyngeal swallowing disorders to facilitate neuropathologic Objectives: studies of central and peripheral components and ß Understand the clinical spectrum, outcomes, evaluate the effects of interventions directed at and natural history of childhood reflux and its specific molecular and/or cellular targets. relationship/evolution into adult patterns of disease.

14 Research Goals are numbered for ease of reference only; the numbers do not indicate prioritization of scientific topics.

Diseases of the Oropharynx and Esophagus 123 Goaloalss for for Rese Rarcesearchh

ß Validate and develop more effective and/or less Research Goal 7.4: Understand the invasive long-term approaches to GERD and epidemiology, natural history, and outcomes of identify more precisely the clinical, anatomic, eosinophilic esophagitis and identify targets for and/or functional predictors of response. more rational and effective therapy. ß Understand the biologic basis of gastroesophageal reflux, hiatalhernia, and Eosinophilic esophagitis is rapidly emerging as a GERD-associated esophageal dysmotility, significant health problem in children and adults. including the role of biomechanical factors and Since it has only been formally recognized in the longitudinal muscle. last decade or so, very little is known about this disease, and much research is needed to answer fundamental questions relating to clinical course Research Goal 7.3: Define the mechanisms and treatment. responsible for esophageal injury and repair, with particular emphasis on the interactions among Objectives: components of the esophageal wall. ß Determine risk factors, natural history, and outcomes of patients with eosinophilic Acute and chronic inflammation of theesophagus esophagitis and identify biomarkers for disease can lead to serious complications, such as strictures, activity and progression. dysmotility, and pre-malignant or malignant ß Identify novel targets and interventions for more transformation. Esophagitis results from a complex effective and rational therapeutic approaches to interaction between the inciting factor and the eosinophilic esophagitis and other inflammatory tissue response, which involves many diverse disorders of the esophagus. cell types, some of which are harmful and others perhaps beneficial. A full understanding of these pathways will pave the way for more effective Research Goal 7.5: Understand the methods for treatment and prevention of many etiopathogenesis of Barrett’s esophagus, determine esophageal disorders. risk factors associated with its progression, and identify novel targets and/or therapies for Objectives: chemoprevention and treatment. ß Elucidate mechanisms of increased permeability in the esophageal epithelium. Despite several decades of research on Barrett’s ß Understand the role of neural and muscular esophagus, this disorder continues to be a major elements in modulation or enhancement of clinical challenge. Although it is strongly associated esophageal injury. with GERD, little is known about the biologic ß Characterize acute and chronic mechanisms mechanisms by which chronic reflux leads to responsible for esophageal epithelial squamous transformation of the esophageal lining or the cell repair. particular genetic or acquired factors that predispose ß Determine the role of foodborne, airborne, and a given patient with reflux to this complication. other environmental allergens in promoting eosinophilic esophagitis and the underlying Objectives: mechanisms. ß Understand the initiation of Barrett’s esophagus, ß Define basic pathogenic mechanisms by which with particular emphasis on identifying the eosinophils mediate esophageal dysfunction. putative stem cell involved and studying its biology.

124 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases GOALS FOR RESEARCH

ß Define the contribution and etiopathogenic role of esophageal dysfunction remain largely unknown, environmental (e.g., smoking) and genetic/familial leading to therapies that are generally ineffective factors in the development of Barrett’s esophagus. and palliative at best. Similarly, although chest ß Develop biomarkers that reliably predict dysplastic pain or discomfort of putative esophageal origin and neoplastic progression. is a major drain on healthcare resources, little ß Identify novel molecular targets for is known about its underlying neurobiology or pharmacological approaches to restoring a potential targets for treatment. stable epithelial phenotype in patients with Barrett’s esophagus. Objectives: ß Conduct chemoprevention studies in subjects with ß Understand the neurobiology of normal Barrett’s based on molecular pathways identified and abnormal esophageal sensation and through ongoing studies on human tissue and identify novel molecular targets for more animal models. effective and rational treatment of esophageal ß Develop better and more cost-effective tools for hypersensitivity associated with disorders such screening and surveillance. as non-cardiac chest pain and NERD. ß Understand the etiopathogenesis, genetic predisposition, and risk factors for esophageal Research Goal 7.6: Understand the etiology motility and functional disorders, including the and biology of esophageal neuromuscular function roles of autoimmunity, environmental factors (e.g., in health and disease and develop more effective viruses), relationship to GERD, genetic factors, and treatments. molecular candidates (e.g., ALADIN). ß Identify novel therapeutic targets for Esophageal dysmotility can be primary in origin pharmacological, cellular (e.g., stem cell or result from several systemic diseases, such as treatment), and physical (e.g., endoscopic) diabetes or connective tissue disorders. In most approaches for more effective and rational cases, the pathologic mechanisms responsible for treatment for esophageal motility disorders.

MAJOR CHALLENGES AND STEPS diagnostic criteria, the lack of generally TO ACHIEVE the RESEARCH GOALS available and reliable methods for physiologic testing, and the inaccessibility of tissue for Animal models: Many, if not most, disorders histopathologic correlation. Further, because of the oropharynx and esophagus lack complete of variations in practice management, a true understanding in terms of the underlying patho- epidemiological and clinical picture of these biology. This is true even of common problems, disorders has been difficult to obtain. Such such as GERD, and is due in part to a lack of information is necessary for planning studies convenient and valid experimental models. to elucidate pathogenic mechanisms and improve on current therapeutic strategies. Standards for diagnosis: Challenges in less common or emerging disorders, such as Interdisciplinary research: A major challenge esophageal dysmotility syndromes, eosinophilic affecting some disorders in this group is the lack esophagitis, and even Barrett’s esophagus, of cross-fertilization among disciplines. This include the small number of patients seen issue is best exemplified byswallowing disorders by any one center, the absence of uniform secondary to CNS pathology, an area that seems

Diseases of the Oropharynx and Esophagus 125 to have “fallen through the cracks” between the National research resources: The neuroscience and GI specialties. In contrast to establishment of multicenter consortia with other areas of CNS, research progress in the the ability to build large databases and patient neurobiology and pathology of the “swallowing registries would promote progress in several center” and related structures has lagged. ways. Such resources would enable researchers Similarly, although emerging disorders, such to make a population-based determination of as eosinophilic esophagitis, initially present the incidence of these disorders, their etiologies, to gastroenterologists, research progress in and risk factors. Researchers could also analyze understanding these conditions may require the the natural history of disease, including timing scientific input of specialists in immunology of onset, progression, prognosis, quality of life, and . cost, and healthcare utilization, and collect annotated tissue and serum specimens to study Disease definitions: In diseases like Barrett’s molecular and cellular mechanisms, as well esophagus, enormous variability in disease as to illuminate genetic and environmental definitions and histologic grading can be found influences. Collaborative trial groups that bring in the literature. Even among expert centers, together experts from relevant disciplines (e.g., one group’s low-grade dysplasia is another’s immunology, oncology, and surgery) would non-dysplastic disease. A multinational be able to validate clinical protocols for the consensus conference to arrive at standardized diagnosis and management of these patients disease definitions would strengthen the field. and conduct trials of chemopreventive and therapeutic strategies. Multicenter studies Validation of novel interventions: Another could be more effective than single-site trials, barrier to the advancement of knowledge in which are often restricted by insufficient this area is that novel imaging and therapeutic patient numbers. techniques are disseminated prior to rigorous, multicenter testing by conflict-free groups. Advanced technology: Much progress in The result is that multiple “infant” strategies this area could be made through technological are being developed, with no effort to grade breakthroughs, and such research and the relative value of the interventions, leading development efforts should be actively to wasted effort and unnecessary costs, as encouraged. Examples include endoscopic access well as suboptimal patient outcomes. Direct for obtaining tissue samples from deeper layers marketing to community gastroenterologists of the esophagus, better physiologic tests, and and surgeons is occurring before rigorous less invasive and more effective anatomic and testing. Emphasizing rigorous testing of physiologic approaches to treatment. Although this technology as part of a Request for there is significant overlap between esophageal Applications may improve this situation. motility disorders and their counterparts in Finally, in this context, it is important to point the rest of the GI tract, the esophagus, because out that past attempts at limiting cancer in of its limited length and easy access, can be the setting of Barrett’s esophagus have focused viewed as a model to test hypotheses of a more on subjects with chronic GERD symptoms. general nature. An example would include the Increasing evidence suggests that such an phenomenon of visceral hypersensitivity, the approach is, at best, incomplete and flawed study of which has best been conducted in the and, at worst, largely ineffective and esophagus. Similarly, if a stem cell approach will cost-inefficient. work at all, it is best tested in the esophagus, which offers a relatively easy site for local (endoscopic) delivery.

126 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases