Working Group #07 Presentation for June 2007 Meeting.ppt

Working Group: Oropharynx and Esophagus

PJ Pasricha

June 18-19, 2007 NCDD Meeting

Working Group Members

Chair: PJ PasrichaVice-Chair: D Lieberman

Members: P Biancani

A ChakG FurataP KahrilasJ Hunter

R OrlandoN ShaheenR Shaker

S Spechler

Research Goals: Oropharynx and Aerodigestive Tract

Research Goal #1:

• To understand the neurobiology of central swallowing mechanisms in health and disease and mechanisms of recovery– Development of useful animal models of

central swallowing disorders– Clinical studies of recovery and plasticity with

creative use of functional imaging

Research Goals: Oropharynx and Aerodigestive Tract

Research Goal #2:• To study physiological and pathological

communication between the different functional components of the aerodigestive tract.– Effects of gastroesophageal reflux on the airways

including the larynx and bronchi – Effects of sleep abnormalities on upper GI tract

physiologyResearch Goal #3:• To identify novel molecular, physiological and

anatomical targets for the development of more effective treatment and/or functional rehabilitation

Research Goals: Gastroesophageal Reflux

Research Goal # 1:• To investigate pathobiological mechanisms

of events leading to and/or associated with GERD– TLESRs- mechanisms, acidification,

prevention/attenuation– Biomechanical factors in the pathogenesis of

GERD including the role of longitudinal muscle– Pathogenesis of hiatal hernia– Pathogenesis of motility abnormalities in

GERD- low LES pressure, IEP


Research Goal # 2:• To validate and develop more effective and less

invasive long-term approaches to GERD– Identification of patients that most likely will benefit e.g those with

predominant regurgitation– Long-term outcomes of anatomical approaches e.g. antireflux

surgery– Identification of the precise anatomical and/or functional

targets/end-points that correlate with good long-term outcome– Identify patients with medically refractory GERD who would

benefit from an antireflux procedure.– Determine the efficacy of new endoscopic antireflux procedures.– Identify the impact of esophageal motility disorders associated

with GERD on the response to antireflux surgery.


Research Goal # 3:• To understand the clinical spectrum, outcomes and

natural history of childhood reflux and its relationship/evolution into adult patterns of disease

Research Goal # 4:• To identify novel molecular, physiological and anatomical

targets for the development of more effective and rational treatment of gastroesophageal reflux

Research Goal # 5:• To develop reliable, simple and inexpensive

methodologies that will provide more accurate and clinically relevant information about reflux events

Research Goals: Esophageal Injury, Inflammation and Repair

Research Goal # 1:• To understand the mechanisms responsible for

esophageal injury and repair with particular emphasis on the interactions between the various components of the esophageal wall (epithelial, neuromuscular and neurohormonal, interstitial, and immunological) as they relate to health and disease– Mechanisms of increased permeability in esophageal

epithelium.– Effects and mechanisms of GERD induced changes in

esophageal nerve and muscle– Conversely, modulation or enhancement of

esophageal injury by neural and muscular elements


Research Goal # 1 (continued):– Determine the role of food/aero-/environmental

allergens in promoting eosinophilic esophagitis.– Identification of the route (inhalation/ingestion) and

proteins that trigger infiltration of the esophageal mucosa with eosinophils and mast cells.

– Characterization of the acute and chronic allergen-induced inflammatory products in esophagus and their cell of origin.

– Define basic pathogenic mechanisms that eosinophils mediate esophageal dysfunction- eosinophil homing, esophageal contraction, and fibrosis

– Characterization of the acute and chronic mechanisms responsible for esophageal epithelial squamous cell repair.


Research Goal # 2:

• To understand host factors and genetic profiles determining susceptibility to injury as well as resultant symptomatic phenotype– Determine genetics of eosinophilic esophagitis


Research Goal #3:• To better understand the epidemiology, natural

history and outcomes of eosinophilic esophagitis– Define and validate diagnostic guidelines for

eosinophilic esophagitis.– Identify novel non-invasive biomarkers/imaging for

eosinophilic esophagitis that will eliminate need for repeated endoscopy and biospy.

– Determine quality of life for patients with eosinophilic esophagitis.

– Determine the natural history of eosinophilic esophagitis in children and adults.

– Determine risk factors associated with eosinophilic esophagitis


Research Goal #4:• To identify novel targets for more effective and

rational therapeutic approaches to inflammatory disorders of the esophagus– Demonstrate efficacy, safety, and benefits of

medications utilized for other GI inflammatory/allergic diseases in adults and children with eosinophilic esophagitis.

– Demonstrate efficacy, safety, and benefits of novel biologicals such as anti-IL-5, anti-Il-13, or anti-CCR3 antibody in adults and children with eosinophilic esophagitis,

– Develop an effective treatment and long-term follow up strategy for adults and children with eosinophilic esophagitis based on molecular analysis.

Research Goals: Barrett;s metaplasia and dysplasia

Research Goal #1:• To understand the initiation of Barrett’s with

particular emphasis on identifying the putative stem cell and studying its biology– Development of more suitable and easier models for

Barrett’s esophagus – Both in vivo and in vitro approaches to define genetic

and epigenetic pathways that lead to the development of Barrett’s esophagus

Research Goal #2:• To understand the contribution and

etiopathogenic role of environmental (e.g. smoking) and genetic/familial factors in the development of Barrett’s


Research Goal #3:• To understand the natural history of Barrett’s

metaplasia and dysplasia and identification of risk factors associated with progression and development of carcinoma

Research Goal #4• To develop and validate reliable, simple and

inexpensive methods for screening and surveillance– New techniques of imaging – Both endoscopic and non-endoscopic approaches


Research Goal #5:• To identify novel targets and/or therapies for chemoprevention

in patients at risk for Barrett’s or its progression to carcinoma – Create plausible American chemoprevention studies in subjects with

BE based on molecular pathways identified through ongoing studies on human tissue and animal models.

Research Goal #6:• To identify novel molecular targets for pharmacological

approaches to restoring a stable epithelial phenotype in patients with Barrett’s esophagus

Research Goal #7:• To promote the development of novel methods for the

physical removal of Barrett’s mucosa and study their efficacy, cost-effectiveness, safety and durability

Research Goals:Motor and Sensorineural Mechanisms

Research Goal #1: • To identify and validate methodologies for studying

esophageal neuromuscular function that better predict underlying pathology and/or symptomatic phenotype– Better physiological tests and imaging– Methods for sampling ENS and muscle in the esophagus

Research Goal #2:• To understand the etiopathogenesis, genetic

predisposition and risk factors for esophageal motility and functional disorders– Role of autoimmunity– Environmental factors (viruses)– Relationship to GERD– Genetic factors and molecular candidates (e.g. ALADIN)


Research Goal #3:• To understand the clinical spectrum, outcomes

and natural history of esophageal motility disorder and, their relationship to each other

Research Goal #4:• To identify novel therapeutic targets for

pharmacological, cellular (e.g. stem cell treatment) and physical (e.g. endoscopic) approaches for more effective and rational treatment for esophageal motility disorders


Research Goal #5:• To understand the neurobiology of normal and

abnormal esophageal sensation– Peripheral mechanisms– Central mechanisms

Research Goal #6:• To identify novel molecular targets for more

effective and rational treatment of esophageal hypersensitivity associated with disorders such as non-cardiac chest pain and non-erosive reflux disease (NERD)

Major Challenges/Steps To Achieve Research Goals

Inadequate understanding of the underlying pathobiology

Lack of convenient and valid experimental models Small number of patients seen by any one center Absence of uniform diagnostic criteria Lack of generally available and reliable methods

for physiological testing Inaccessibility of tissue for histopathological

correlation.


True epidemiological and clinical picture of these disorders has been difficult to obtain

Variations in clinical practice Necessary for planning studies to

elucidate pathogenic mechanisms and improve on current therapeutic strategies.


• Lack of cross-fertilization amongst disciplines– Swallowing disorders secondary to CNS

pathology,• ?neuroscience or ?gastrointestinal

– Eosinophilic esophagitis • ? Allergic/Immunologic or ?gastrointestinal


Challenges peculiar to Barrett’s• Enormous variability in disease definitions and

histologic grading• Novel imaging and therapeutic techniques are

disseminated prior to rigorous, multi-center testing by conflict-free group– Multiple “infant” strategies are being developed– Wasted effort and unnecessary costs– Suboptimal patient outcomes.

• Limiting cancer in the setting of BE have focused on subjects with chronic GERD symptoms.– Such an approach is at best, incomplete and flawed, and at

worse largely ineffective and cost-inefficient.

Recommended General Steps

• Establish multicenter consortia to build large databases and patient registries:– A population-based determination of the incidence of

these disordes, their etiologies and risk factors.– Analysis of the natural history of disease, including

timing of onset, progression, prognosis, quality of life, cost, and healthcare utilization.

– Validation of clinical protocols for the diagnosis and management of these patients


• Multicenter consortia (continued):– Collection of annotated tissue and serum specimens

to study molecular and cellular mechanisms as well as to illuminate genetic and environmental environmental influences

– Run powerful studies of chemopreventive and therapeutic strategies instead of the previous single site studies that have had limited success.

– Bring together experts from a spectrum of relevant disciplines e.g. immunology, oncology, surgery etc.


• Specific initiatives should be taken to bring together investigators across relevant disciplines to tackle problems that require such an approach e.g. swallowing disorders, eosinophilic/allergic esophagitis. – Such an approach can be encouraged through specific RFAs

and is in accordance with the principles of the NIH road map.

• Much progress in this area can be made through technological breakthroughs and such R &D efforts should be actively encourag– Examples include endoscopic access for obtaining tissue

samples from deeper layers of the esophagus, better physiological tests and less invasive and more effective anatomical and physiological approaches to treatment.

Lessons Learned and Anticipated Challenges

• The esophagus, because of its limited length and easy access, can be viewed as a model to test hypotheses of a more generalizable nature– Example would include the phenomenon of visceral

hypersensitivity, the study of which has best been conducted in the esophagus

– Similarly, if a stem cell approach will work at all, it is best tested in the esophagus which offers a relatively easy site for local (endoscopic) delivery.

Lessons Learned and Anticipated Challenges

• It was more accurate and fruitful to search CRISP database myself with keywords

• Also allowed me to have hyperlinked access to summaries

• I think a summit get together at DDW next year should be organized to present the NCDD mission, process, findings and recomendations

Health & Medicine

Working Group #07 Presentation for June 2007 Meeting.ppt