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2.  Radiofrequency Ablation is Associated with Decreased Neoplastic Progression in Patients with Barrett’s Esophagus and Confirmed Low-Grade Dysplasia 
Gastroenterology  2015;149(3):567-576.e3.
Background & Aims
Barrett’s esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD following RFA to that with endoscopic surveillance alone in routine clinical practice.
Methods
We performed a retrospective study of patients who either underwent RFA (n=45) or surveillance endoscopy (n=125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the US. Cox regression analysis was used to assess the association between progression and RFA.
Results
Data were collected over median follow-up periods of 889 days (inter-quartile range, 264–1623 days) after RFA and 848 days (inter-quartile range, 322–2355 days) after surveillance endoscopy (P=.32). The annual rates of progression to HGD or EAC was 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio, 0.06; 95% confidence interval, 0.008–0.48).
Conclusions
Among patients with BE and confirmed LGD, rates of progression to a combined endpoint of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.
doi:10.1053/j.gastro.2015.04.013
PMCID: PMC4550488  PMID: 25917785
eradication; clinical setting; prevention; esophageal cancer
4.  Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett’s Esophagus 
Article Synopsis
The prevalence of esophageal adenocarcinoma is increasing dramatically. Barrett’s esophagus remains the most well established risk factor for the development of esophageal adenocarcinoma. There are multiple clinical, endoscopic, and pathologic factors that increase the risk of neoplastic progression to high-grade dysplasia or esophageal adenocarcinoma in Barrett’s esophagus. This article will review both risk and protective factors for neoplastic progression in patients with Barrett’s esophagus.
doi:10.1016/j.gtc.2015.02.005
PMCID: PMC4449455  PMID: 26021196
Barrett’s esophagus; esophageal adenocarcinoma; dysplasia; risk factors; neoplastic progression
5.  BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett’s Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia 
OBJECTIVES
Barrett’s esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).
METHODS
We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.
RESULTS
In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.
CONCLUSIONS
In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.
doi:10.1038/ajg.2015.55
PMCID: PMC4436697  PMID: 25869390
6.  Quality Indicators for the Management of Barrett’s Esophagus, Dysplasia, and Esophageal Adenocarcinoma: International Consensus Recommendations from the American Gastroenterological Association Symposium 
Gastroenterology  2015;149(6):1599-1606.
The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barrett’s esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barrett’s esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barrett’s esophagus.
doi:10.1053/j.gastro.2015.08.007
PMCID: PMC4820399  PMID: 26296479
Barrett’s Esophagus; Consensus Statements; Quality Indicators; Gastroesophageal Reflux Disease; Low-Grade Dysplasia; High-Grade Dysplasia; Esophageal Adenocarcinoma; Endoscopic Mucosal Resection; Radiofrequency Ablation; Barrett’s Surveillance; Prague Criteria; Metastatic Esophageal Adenocarcinoma; Proton Pump Inhibitors
7.  Metformin Does not Reduce Markers of Cell Proliferation in Esophageal Tissues of Patients with Barrett's Esophagus 
Background & Aims
Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's Esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1) -- a biomarker of insulin pathway activation.
Methods
Seventy-four subjects with BE (mean age 58.7 years; 58 men [78%0; 52 with BE>2 cm [70%] were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4; n=38) or placebo (n=36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary endpoint.
Results
The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs – 14.7% among subjects given placebo; 1-sided P=.80). Metformin was associated with an almost significant reduction in serum levels of insulin (median −4.7% among subjects given metformin vs 23.6% increase among those given placebo, P=.08) as well as in homeostatic model assessments of insulin resistance (median −7.2% among subjects given metformin vs 38% increase among those given placebo, P=.06). Metformin had no effects on cell proliferation (based on assays for KI67) or apoptosis (based on levels of caspase 3).
Conclusions
In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis.
doi:10.1016/j.cgh.2014.08.040
PMCID: PMC4362887  PMID: 25218668
HOMA-IR; diabetes drug; cancer development; tumorigenesis
8.  Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas 
Abstract
Background
Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).
Methods
We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families.
Results
Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported.
Conclusion
Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC.
doi:10.1002/mgg3.211
PMCID: PMC4947860  PMID: 27468417
Barrett's esophagus; esophageal adenocarcinoma; familial; genetics; linkage
9.  Barrett’s Esophagus: Frequency and Prediction of Dysplasia and Cancer 
The incidence of esophageal adenocarcinoma is continuing to increase at an alarming rate in the Western world today. Barrett’s esophagus is a clearly recognized risk factor for the development of esophageal adenocarcinoma, but the overwhelming majority of patients with Barrett’s esophagus will never develop esophageal cancer. A number of endoscopic, histologic and epidemiologic risk factors identify Barrett’s esophagus patients at increased risk for progression to high-grade dysplasia and esophageal adenocarcinoma. Endoscopic factors include segment length, mucosal abnormalities as seemingly trivial as esophagitis and the 12 to 6 o’clock hemisphere of the esophagus. Both intestinal metaplasia and low grade dysplasia, the latter only if confirmed by a pathologist with expertise in Barrett’s esophagus pathologic interpretation are the histologic risk factors for progression. Epidemiologic risk factors include aging, male gender, obesity, and smoking. Factors that may protect against the development of adenocarcinoma include a diet rich in fruits and vegetables, and the use of proton pump inhibitors, aspirin/NSAIDs and statins.
doi:10.1016/j.bpg.2015.01.001
PMCID: PMC4352690  PMID: 25743461
Barrett’s esophagus; esophageal adenocarcinoma; dysplasia; cancer risk factors
10.  In vivo endomicroscopy improves detection of Barrett’s esophagus–related neoplasia: a multicenter international randomized controlled trial 
Gastrointestinal endoscopy  2013;79(2):211-221.
BACKGROUND
Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the gastrointestinal tract mucosa. However, there are limited data on endoscope-based eCLE for imaging Barrett’s esophagus (BE).
OBJECTIVE
To compare high definition white light endoscopy alone (HDWLE) with random biopsy (RB) and HDWLE+eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia.
DESIGN
Multicenter randomized controlled trial.
SETTING
Academic medical centers.
PATIENTS
Adult BE patients undergoing routine surveillance or referred for early neoplasia.
INTERVENTIONS
Patients were randomized to HDWLE+RB (Group 1) or HDWLE+eCLE+TB (Group 2). Real time diagnoses and management plans were recorded after HDWLE in both groups, and after eCLE in Group 2. Blinded expert pathologic diagnosis was the reference standard.
MAIN OUTCOME MEASUREMENTS
Diagnostic yield, performance characteristics, clinical impact.
RESULTS
192 BE patients were studied. HDWLE+eCLE+TB led to a lower number of mucosal biopsies, higher diagnostic yield for neoplasia (34% vs. 7%, p<.0001) compared to HDWLE+RB but with comparable accuracy. HDWLE+eCLE+TB tripled the diagnostic yield for neoplasia (22% vs. 6%, p=.002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% (p<.0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients.
LIMITATIONS
Tertiary referral centers and expert endoscopists limiting generalizability.
CONCLUSIONS
Real time eCLE and targeted biopsy after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision-making by altering the diagnosis and guiding therapy.
doi:10.1016/j.gie.2013.09.020
PMCID: PMC4668117  PMID: 24219822
11.  Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia 
Oncotarget  2015;6(32):32980-33005.
Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1β transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1β double transgenic mice had half as many metaplastic nodules as control L2-IL-1β mice. This effect was not due to a reduction in esophageal IL-1β mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2::L2-IL-1β mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1β mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2::L2-IL-1β mice is CD8+ T cell dependent, which CD11b+Gr-1+ cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+ cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2::L2-IL-1β double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+ cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+ immature myeloid cells.
PMCID: PMC4741744  PMID: 26460825
Barrett's esophagus; myeloid-derived suppressor cells (MDSC); IL-17; S100A9; IL-1β
12.  Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems 
Gastrointestinal (GI) illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammation are a common element of many GI diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett’s esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible.
doi:10.1177/1535370214529388
PMCID: PMC4156523  PMID: 24781339
inflammation; oxidative stress; autophagy; gastrointestinal (GI) disease; gastroesophageal reflux disease (GERD); Barrett’s esophagus (BE); esophageal adenocarcinoma (EAC); graft-versus-host disease (GvHD); inflammatory bowel disease (IBD); human 3D organotypic model systems (OTC)
13.  Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition 
Experimental cell research  2014;330(1):102-110.
Background and Aims
Eosinophilic esophagitis (EoE) is an allergic inflammatory disease that leads to esophageal fibrosis and stricture. We have recently shown that in EoE, esophageal epithelial cells undergo an epithelial to mesenchymal transition (EMT), characterized by gain of mesenchymal markers and loss of epithelial gene expression. Whether epithelial cells exposed to profibrotic cytokines can also acquire the functional characteristics of activated myofibroblasts, including migration, contraction, and extracellular matrix deposition, is relevant to our understanding and treatment of EoE-associated fibrogenesis. In the current study, we characterize cell migration, contraction, and collagen production by esophageal epithelial cells that have undergone cytokine-induced EMT in vitro.
Methods and Results
Stimulation of human non-transformed immortalized esophageal epithelial cells (EPC2-hTERT) with profibrotic cytokines TNFα, TGFβ, and IL1β for three weeks led to acquisition of mesenchymal αSMA and vimentin, and loss of epithelial E-cadherin expression. Upon removal of the profibrotic stimulus, epithelial characteristics were partially rescued. TGFβ stimulation had a robust effect upon epithelial collagen production. Surprisingly, TNFα stimulation had the most potent effect upon cell migration and contraction, exceeding the effects of the prototypical profibrotic cytokine TGFβ. IL1β stimulation alone had minimal effect upon esophageal epithelial migration, contraction, and collagen production.
Conclusions
Esophageal epithelial cells that have undergone EMT acquire functional characteristics of activated myofibroblasts in vitro. Profibrotic cytokines exert differential effects upon esophageal epithelial cells, underscoring complexities of fibrogenesis in EoE, and implicating esophageal epithelial cells as effector cells in EoE-associated fibrogenesis.
doi:10.1016/j.yexcr.2014.08.026
PMCID: PMC4489692  PMID: 25183431
14.  BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis 
The Journal of Clinical Investigation  2015;125(4):1557-1568.
Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett’s intestinal differentiation; however, in mice, basal progenitor cell–specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE.
doi:10.1172/JCI78850
PMCID: PMC4396468  PMID: 25774506
Gastroenterology; Stem cells
15.  T-helper 2 Cytokines, Transforming Growth Factor β1, and Eosinophil Products Induce Fibrogenesis and Alter Muscle Motility in Patients with Eosinophilic Esophagitis 
Gastroenterology  2014;146(5):1266-1277.e9.
BACKGROUND & AIMS
Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEF), muscle cells (HEMC), and esophageal muscle strips to eosinophil-derived products.
METHODS
Biopsies were collected via endoscopy from the upper, middle and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured expression of ICAM1 and VCAM1 by, and adhesion of human eosinophils to, HEF and HEMC. Eosinophil products were tested in an esophageal muscle contraction assay.
RESULTS
Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were spontaneously secreted in mucosal biopsies from patients with EoE than controls. Exposure of HEF and HEMC to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEF and HEMC to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor (TGF)β1 and p38 mitogen-activated protein kinase (MAKP) signaling. Eosinophil binding to HEF and HEMC increased following incubation of mesenchymal cells with eosinophil-derived products, and decreased following blockade of TGFβ1 and p38MAPK blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction.
CONCLUSION
In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.
doi:10.1053/j.gastro.2014.01.051
PMCID: PMC3992171  PMID: 24486052
Primary human cells; transmural disease; swallowing; immune regulation
16.  Positive correlation between endoscopist radiofrequency ablation volume and response rates in Barrett’s esophagus 
Gastrointestinal endoscopy  2014;80(1):71-77.
Background
Radiofrequency ablation (RFA) has become an accepted form of endoscopic treatment for Barrett’s esophagus (BE), yet reported response rates are variable. There are no accepted quality measures for performing RFA, and provider-level characteristics may influence RFA outcomes.
Objective
To determine whether endoscopist RFA volume is associated with rates of complete remission of intestinal metaplasia (CRIM) after RFA in patients with BE.
Design
Retrospective analysis of longitudinal data.
Setting
Three tertiary-care medical centers.
Patients
Patients with BE treated with RFA.
Intervention
RFA.
Main Outcome Measurements
For each endoscopist, we recorded RFA volume, defined as the number of unique patients treated as well as corresponding CRIM rates. We calculated a Spearman correlation coefficient relating these 2 measures.
Results
We identified 417 patients with BE treated with RFA who had at least 1 post-RFA endoscopy with biopsies. A total of 73% of the cases had pretreatment histology of high-grade dysplasia or adenocarcinoma. The procedures were performed by 7 endoscopists, who had a median RFA volume of 62 patients (range 20–188). The overall CRIM rate was 75.3% (provider range 62%–88%). The correlation between endoscopist RFA volume and CRIM rate was strong and significant (rho = 0.85; P = .014). In multivariable analysis, higher RFA volume was significantly associated with CRIM (P for trend .04).
Limitations
Referral setting may limit generalizability. Limited number of endoscopists analyzed.
Conclusion
Endoscopist RFA volume correlates with rates of successful BE eradication. Further studies are required to confirm these findings and to determine whether RFA volume is a valid predictor of treatment outcomes in BE.
doi:10.1016/j.gie.2014.01.007
PMCID: PMC4317349  PMID: 24565071
17.  Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems 
Stem Cell Research & Therapy  2013;4(Suppl 1):S5.
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), graft-versus-host disease (GVHD), and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are common human gastrointestinal diseases that share inflammation as a key driver for their development. A general outcome resulting from these chronic inflammatory conditions is increased oxidative stress. Oxidative stress is caused by the generation of reactive oxygen and nitrogen species that are part of the normal inflammatory response, but are also capable of damaging cellular DNA, protein, and organelles. Damage to DNA can include DNA strand breaks, point mutations due to DNA adducts, as well as alterations in methylation patterns leading to activation of oncogenes or inactivation of tumor suppressors. There are a number of significant long-term consequences associated with chronic oxidative stress, most notably cancer. Infiltrating immune cells and stromal components of tissue including fibroblasts contribute to dynamic changes occurring in tissue related to disease development. Immune cells can potentiate oxidative stress, and fibroblasts have the capacity to contribute to advanced growth and proliferation of the epithelium and any resultant cancers. Disease models for GERD, BE, GVHD, and ulcerative colitis based on three-dimensional human cell and tissue culture systems that recapitulate in vivo growth and differentiation in inflammatory-associated microphysiological environments would enhance our understanding of disease progression and improve our ability to test for disease-prevention strategies. The development of physiologically relevant, human cell-based culture systems is therefore a major focus of our research. These novel models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders, and will have a translational impact allowing us to more rapidly develop therapeutic and chemopreventive agents. In summary, this work to develop advanced human cell-based models of inflammatory conditions will greatly improve our ability to study, prevent, and treat GERD, BE, GVHD, and inflammatory bowel disease. The work will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.
doi:10.1186/scrt366
PMCID: PMC3983655  PMID: 24564965
inflammation; oxidative stress; DNA damage; gastrointestinal disease; gastroesophageal reflux disease; Barrett's esophagus; graft-versus-host disease; inflammatory bowel disease; human three-dimensional organotypic model systems
19.  Recurrence of Esophageal Intestinal Metaplasia After Endoscopic Mucosal Resection and Radiofrequency Ablation of Barrett’s Esophagus: Results From a US Multicenter Consortium Recurrence of Barrett’s Esophagus after EMR and RFA 
Gastroenterology  2013;145(1):79-86.e1.
BACKGROUND & AIMS
Radiofrequency ablation (RFA) is an established treatment for dysplastic Barrett’s esophagus (BE). Although short-term endpoints of ablation have been ascertained, there have been concerns about recurrence of intestinal metaplasia (IM) after ablation. We aimed to estimate the incidence and identify factors that predicted the recurrence of IM after successful RFA.
METHODS
We analyzed data from 592 patients with BE treated with RFA from 2003 through 2011 at 3 tertiary referral centers. Complete remission of intestinal metaplasia (CRIM) was defined as eradication of IM (in esophageal and gastro esophageal junction biopsies), documented by 2 consecutive endoscopies. Recurrence was defined as presence of IM or dysplasia after CRIM in surveillance biopsies. Two experienced gastrointestinal pathologists confirmed pathology findings.
RESULTS
Based on histology analysis, before RFA, 71% of patients had high-grade dysplasia or esophageal adenocarcinoma, 15% had low-grade dysplasia, and 14% had non-dysplastic BE. Of patients treated, 448 (76%) were assessed following RFA. 55% of patients underwent endoscopic mucosal resection before RFA. The median time to CRIM was 22 months, with 56% of patients in CRIM by 24 months. Increasing age and length of BE segment were associated with a longer times to CRIM. Twenty-four months after CRIM, the incidence of recurrence was 33%; 22% of all recurrences observed were dysplastic BE. There were no demographic or endoscopic factors associated with recurrence. Complications developed in 6.5% of subjects treated with RFA; strictures were the most common complication.
CONCLUSION
Of patients with BE treated by RFA, 56% are in complete remission after 24 months. However, 33% of these patients have disease recurrence within the next 2 years. Most recurrences were non-dysplastic and endoscopically manageable, but continued surveillance after RFA is essential.
doi:10.1053/j.gastro.2013.03.008
PMCID: PMC3696438  PMID: 23499759
esophageal cancer; prevention; endoscopic therapy; EAC
20.  TSLP-elicited basophil responses can mediate the pathogenesis of eosinophilic esophagitis 
Nature medicine  2013;19(8):1005-1013.
Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis remains unknown. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE but was dependent on TSLP-elicited basophils. Therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. Critically, in human subjects with EoE, we observed elevated TSLP levels and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses. Together, these data suggest that the TSLP-basophil axis could be therapeutically targeted to treat EoE.
doi:10.1038/nm.3281
PMCID: PMC3951204  PMID: 23872715
21.  Esomeprazole and 325 mg/d Aspirin Reduce Tissue Concentrations of Prostaglandin E2 in Patients with Barrett’s Esophagus 
Gastroenterology  2012;143(4):917-926.e1.
Background & Aims
Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett’s esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled phase II trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin E2 (PGE2) in patients with BE with no dysplasia or low-grade dysplasia.
Methods
Participants were recruited through the multi-center Cancer Prevention Network and randomly assigned to groups that were given esomeprazole (40 mg, twice daily) in combination with an aspirin placebo (once daily) (Arm A; n=42), with 81 mg aspirin (once daily) (Arm B; n=63), or with 325 mg aspirin (once daily) (Arm C; n=63) for 28 days. We collected esophageal biopsies before and after the intervention period, to determine the absolute change in mean concentrations of PGE2 (the primary endpoint).
Results
Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentrations of PGE2 was reduced by 67.6±229.68 pg/mL in Arm A, was reduced by 123.9±284.0 pg/mL in Arm B (P=.10 vs Arm A), and was reduced by 174.9 ±263.62 pg/mL in Arm C (P=.02 vs Arm A).
Conclusions
In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE2 patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients.
doi:10.1053/j.gastro.2012.06.044
PMCID: PMC3458136  PMID: 22796132
esophageal cancer; NSAIDs; inflammation; esophagus
23.  Association of insulin and insulin-like growth factors with Barrett’s oesophagus 
Gut  2011;61(5):665-672.
Background
It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett’s oesophagus (BO) has not been well examined.
Methods
Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n = 135), GORD (n = 135) and screening colonoscopy (n = 932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO.
Results
Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79).
Conclusions
These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.
doi:10.1136/gutjnl-2011-300641
PMCID: PMC3669672  PMID: 21930730
24.  Variation In Age At Cancer Diagnosis In Familial Versus Non-Familial Barrett’s Esophagus 
BACKGROUND
Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study we determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC).
METHODS
Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between non-familial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.
RESULTS
The study included 830 non-familial, 274 duplex and 41 multiplex FBE kindreds with 274, 133 and 43 EAC and 566, 288 and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (p = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared to duplex and non-familial kindreds (57 vs. 62 vs. 63 yrs, respectively, p = 0.0448). Mean body mass index (BMI) was significantly lower in multiplex kindreds (p = 0.0033) as was smoking (p < 0.0001), and reported regurgitation (p = 0.0014).
CONCLUSIONS
Members of multiplex FBE kindreds develop EAC at an earlier age compared to non-familial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor.
IMPACT
These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.
doi:10.1158/1055-9965.EPI-11-0927
PMCID: PMC3275661  PMID: 22178570
Esophageal adenocarcinoma; Barrett’s esophagus; genetics; family history
25.  Durability of Radiofrequency Ablation in Barrett’s Esophagus with Dysplasia 
Gastroenterology  2011;141(2):460-468.
Background & Aims
Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett’s esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE.
Methods
We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events.
Results
After 2 years, 101/106 patients had complete eradication of all dysplasia (95%) and 99/106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51/52 (98%) and intestinal metaplasia was eradicated in 51/52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50/54 (93%) and intestinal metaplasia was eradicated in 48/54 (89%). After 3 years, dysplasia was eradicated in 55/56 of subjects (98%) and intestinal metaplasia was eradicated in 51/56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4/119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1/181 pt-yrs (0.55%/pt-yr); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1/73 pt-yrs (1.37%/pt-yr).
Conclusion
In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.
doi:10.1053/j.gastro.2011.04.061
PMCID: PMC3152658  PMID: 21679712
esophagus; cancer; prevention; endoscopic therapy

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