- Email: [email protected]
879 Resolution of Esophageal Remodeling Following Oral Viscous Budesonide (OVB) Therapy for Eosinophilic Esophagitis (EoE)
881
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.
879 Resolution of Esophageal Remodeling Following Oral Viscous Budesonide (OVB) Therapy for Eosinophilic Esophagitis (EoE) Seema Aceves, Robert O. Newbury, Diana Chen, David Broide, John F. Bastian, Ranjan Dohil Background: Pediatric eosinophilic esophagitis is accompanied by lamina propria (LP) fibrosis and increased levels of the pro-fibrotic factor TGFβ1 and its signaling molecule pSmad2/3. The effects of topical corticosteroids on LP fibrosis have not been determined in a prospective placebo controlled trial. Methods: Esophageal biopsies with adequate LP for evaluation (n= 11 biopsies from 8 children) from patients in a randomized placebo controlled trial of OVB were analyzed for fibrosis using: (1) a graded fibrosis score (maximum score=3); (2) a total LP score accounting for fibroblasts, collagen bundles, and eosinophilic inflammation (maximum score=6); (3) quantitative immunohistochemistry for TGFβ1and pSmad2/3-positive cells. Results: 8 patients (5 OVB, 3 placebo) had adequate LP for evaluation pre- (7 biopsies: 4 placebo, 3 OVB) and/or post- (4 biopsies: 2 placebo, 2 OVB) treatment. 3 patients (1 OVB, 2 placebo) had adequate LP for analysis both before and after OVB therapy. OVB and placebo groups had similar fibrosis scores, total LP scores, TGFβ1, and pSmad2/3positive cell counts prior to therapy. Following therapy, OVB patients had lower fibrosis scores (0 vs 2.5), lower total LP scores (0 vs 4), fewer TGFβ1 (29 vs 131), and pSmad2/3 positive cells (58 vs 108) than placebo patients. The numbers of TGFβ1 and pSmad2/3 positive cells correlated well with the degree of fibrosis (r=0.89 and 0.65, respectively, p<0.05). Conclusions: In this small group of pediatric patients, subjects treated with OVB had reduced levels of fibrosis as well as TGFb1 and pSmad2/3 positive cells compared to placebo treated patients. The levels of TGFβ1 and pSmad2/3 correlate well with the severity of fibrosis implicating this pathway in the pathogenesis of pediatric esophageal remodeling in EoE.
882 880
Selective Activation of PPARδ by Helicobacter pylori cag Island Substrates Regulates Epithelial Cell Hyperproliferation Toni Nagy, Dingzhi Wang, Lydia E. Wroblewski, Seth R. Ogden, Shannon S. Allen, Dawn Israel, Richard M. Peek
Recumbent Impedance-pH Detected Swallows Predict Awakenings in GERD Patients Lubin F. Arevalo, Donald O. Castell, Janice Freeman, Daniel Pohl
Introduction: Helicobacter pylori is the strongest identified risk factor for the development of gastric cancer and the cag secretion system, which translocates CagA and components of peptidoglycan (PGN) into host cells, further augments cancer risk. p120-catenin and βcatenin are host signaling molecules that orchestrate carcinogenic epithelial responses by regulating transcription of genes implicated in tumor initiation. Peroxisome proliferatoractivated receptor δ (PPARδ) is a ligand-activated transcription factor that is targeted by p120 and β-catenin, and PPARδ signaling promotes tumor growth in models of gastrointestinal carcinogenesis. Therefore, we defined the role of H. pylori virulence constituents and activation of PPARδ in regulation of epithelial hyperproliferation, a host response that lowers the threshold for oncogenic transformation. Methods: PPARδ expression in control, p120specific, or β-catenin-specific siRNA-treated gastric epithelial cells (MKN28) was quantified via real-time RT-PCR and Western blot. To assess functional activation of PPARδ, MKN28 cells transfected with a PPARδ reporter construct were co-cultured with the H. pylori wildtype cag+ carcinogenic strain 7.13, isogenic cagA- or cagE- mutants, a mutant lacking the soluble lytic transglycosylase (slt-) that is deficient in PGN production, or a cagA-/slt- double mutant. Cell proliferation was measured in a three-dimensional model system using Trypan blue staining and BrdU incorporation. H. pylori-mediated alterations in PPARδ were also examined ex vivo in murine primary gastric cell colonies. Results: H. pylori induced the expression, nuclear localization, and activation of PPARδ in a p120- and β-catenin-dependent manner. Inactivation of cagA or slt alone partially decreased levels of PPARδ; however, the combinatorial loss of CagA and Slt completely abolished PPARδ activation. PPARδ activation by wild-type strain 7.13 stimulated epithelial cell proliferation, which was mediated by the PPARδ target cell cycle regulatory gene cyclin E1. Concordant with these In Vitro findings, H. pylori induced cytoplasmic accumulation and nuclear translocation of PPARδ and increased cyclin E1 expression in ex vivo primary gastric cell colonies. Conclusions: H. pylori enhances PPARδ-dependent, Cyclin E1-mediated epithelial proliferation and these events are dependent upon the cag island substrates CagA and peptidoglycan. Since PPARδ regulates a multitude of host responses, activation of this effector by H. pylori may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated with chronic H. pylori colonization.
Background: Previous studies have shown that patients with GERD swallow more frequently than healthy controls. Combined multichannel intraluminal impedance (MII-pH) detects swallow activity at night. Sleep monitoring using Actigraph detects nocturnal awakenings (AW) by sensing bi-directional acceleration. There is no information comparing these two techniques in patients with GERD as an indicator of sleep fragmentation. Hypothesis: MIIpH detected swallow (SW) activity during sleep can identify nocturnal AW in patients with GERD. Methods: 40 patients were studied; 25 female, 15 male. All were referred for evaluation of GERD. An Actigraph device (ActiGraph, Pensacola, FL) was worn on the wrist during 24 h-MII -pH testing. Sleep monitoring was performed between 10PM to 7AM using the Actilife software. Impedance identified total number of SW per hour for all subjects were correlated with number of AW. Results: For all patients, average recumbent period was 6.6 hours, average sleeping time was 5.4 hours, and average awake time was 1.2 hours (19% of total recumbent period). During recumbent period the total number of SW was 2828. 61% of SW occurred during awake time; 39% occurred during sleeping period. 544 AW were recorded during the study; 96% associated with swallowing activity. In 4% of them, no SW were detected. SW and AW per hour are depicted in the figure (r =0.9; p<0.05). Conclusions: The recumbent swallowing activity detected by MII-pH reliably predicts awakenings shown by Actigraph. The r-square indicates approximately 80% concordance between awakenings and swallows.
883 Helicobacter pylori-Derived HP (2-20) Stimulates Gastric Mucosal Recovery From Stress-Induced Gastric Lesions and Accelerates the Healing of Chronic Gastric Ulcers Tomasz Brzozowski, Marco Romano, Amato de Paulis, Francesca W. Rossi, Nella Prevete, Alexandra Szlachcic, Robert Pajdo, Stanislaw Konturek, Wieslaw W. Pawlik Helicobacter pylori (Hp)-derived peptide RpL1 aa 2-20 (Hp2-20) interacts with formyl peptide receptors (FPRs) and exerts several immunomodulatory effects but its influence on the gastric secretory functions and the mechanism of gastric mucosal integrity remains unknown. We determined the effect of Hp2-20 on the gastric acid secretion in rats equipped with gastric fistula and the mucosal recovery from the water immersion and restraint stress (WRS)
S-123
AGA Abstracts
AGA Abstracts
Long-Term Treatment of Eosinophilic Esophagitis With Budesonide Alex Straumann, Lukas Degen, Christian Bussmann, Christoph Beglinger, Alain Schoepfer, Christina Thalmann, Hans-Uwe Simon
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.
879 Resolution of Esophageal Remodeling Following Oral Viscous Budesonide (OVB) Therapy for Eosinophilic Esophagitis (EoE) Seema Aceves, Robert O. Newbury, Diana Chen, David Broide, John F. Bastian, Ranjan Dohil Background: Pediatric eosinophilic esophagitis is accompanied by lamina propria (LP) fibrosis and increased levels of the pro-fibrotic factor TGFβ1 and its signaling molecule pSmad2/3. The effects of topical corticosteroids on LP fibrosis have not been determined in a prospective placebo controlled trial. Methods: Esophageal biopsies with adequate LP for evaluation (n= 11 biopsies from 8 children) from patients in a randomized placebo controlled trial of OVB were analyzed for fibrosis using: (1) a graded fibrosis score (maximum score=3); (2) a total LP score accounting for fibroblasts, collagen bundles, and eosinophilic inflammation (maximum score=6); (3) quantitative immunohistochemistry for TGFβ1and pSmad2/3-positive cells. Results: 8 patients (5 OVB, 3 placebo) had adequate LP for evaluation pre- (7 biopsies: 4 placebo, 3 OVB) and/or post- (4 biopsies: 2 placebo, 2 OVB) treatment. 3 patients (1 OVB, 2 placebo) had adequate LP for analysis both before and after OVB therapy. OVB and placebo groups had similar fibrosis scores, total LP scores, TGFβ1, and pSmad2/3positive cell counts prior to therapy. Following therapy, OVB patients had lower fibrosis scores (0 vs 2.5), lower total LP scores (0 vs 4), fewer TGFβ1 (29 vs 131), and pSmad2/3 positive cells (58 vs 108) than placebo patients. The numbers of TGFβ1 and pSmad2/3 positive cells correlated well with the degree of fibrosis (r=0.89 and 0.65, respectively, p<0.05). Conclusions: In this small group of pediatric patients, subjects treated with OVB had reduced levels of fibrosis as well as TGFb1 and pSmad2/3 positive cells compared to placebo treated patients. The levels of TGFβ1 and pSmad2/3 correlate well with the severity of fibrosis implicating this pathway in the pathogenesis of pediatric esophageal remodeling in EoE.
882 880
Selective Activation of PPARδ by Helicobacter pylori cag Island Substrates Regulates Epithelial Cell Hyperproliferation Toni Nagy, Dingzhi Wang, Lydia E. Wroblewski, Seth R. Ogden, Shannon S. Allen, Dawn Israel, Richard M. Peek
Recumbent Impedance-pH Detected Swallows Predict Awakenings in GERD Patients Lubin F. Arevalo, Donald O. Castell, Janice Freeman, Daniel Pohl
Introduction: Helicobacter pylori is the strongest identified risk factor for the development of gastric cancer and the cag secretion system, which translocates CagA and components of peptidoglycan (PGN) into host cells, further augments cancer risk. p120-catenin and βcatenin are host signaling molecules that orchestrate carcinogenic epithelial responses by regulating transcription of genes implicated in tumor initiation. Peroxisome proliferatoractivated receptor δ (PPARδ) is a ligand-activated transcription factor that is targeted by p120 and β-catenin, and PPARδ signaling promotes tumor growth in models of gastrointestinal carcinogenesis. Therefore, we defined the role of H. pylori virulence constituents and activation of PPARδ in regulation of epithelial hyperproliferation, a host response that lowers the threshold for oncogenic transformation. Methods: PPARδ expression in control, p120specific, or β-catenin-specific siRNA-treated gastric epithelial cells (MKN28) was quantified via real-time RT-PCR and Western blot. To assess functional activation of PPARδ, MKN28 cells transfected with a PPARδ reporter construct were co-cultured with the H. pylori wildtype cag+ carcinogenic strain 7.13, isogenic cagA- or cagE- mutants, a mutant lacking the soluble lytic transglycosylase (slt-) that is deficient in PGN production, or a cagA-/slt- double mutant. Cell proliferation was measured in a three-dimensional model system using Trypan blue staining and BrdU incorporation. H. pylori-mediated alterations in PPARδ were also examined ex vivo in murine primary gastric cell colonies. Results: H. pylori induced the expression, nuclear localization, and activation of PPARδ in a p120- and β-catenin-dependent manner. Inactivation of cagA or slt alone partially decreased levels of PPARδ; however, the combinatorial loss of CagA and Slt completely abolished PPARδ activation. PPARδ activation by wild-type strain 7.13 stimulated epithelial cell proliferation, which was mediated by the PPARδ target cell cycle regulatory gene cyclin E1. Concordant with these In Vitro findings, H. pylori induced cytoplasmic accumulation and nuclear translocation of PPARδ and increased cyclin E1 expression in ex vivo primary gastric cell colonies. Conclusions: H. pylori enhances PPARδ-dependent, Cyclin E1-mediated epithelial proliferation and these events are dependent upon the cag island substrates CagA and peptidoglycan. Since PPARδ regulates a multitude of host responses, activation of this effector by H. pylori may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated with chronic H. pylori colonization.
Background: Previous studies have shown that patients with GERD swallow more frequently than healthy controls. Combined multichannel intraluminal impedance (MII-pH) detects swallow activity at night. Sleep monitoring using Actigraph detects nocturnal awakenings (AW) by sensing bi-directional acceleration. There is no information comparing these two techniques in patients with GERD as an indicator of sleep fragmentation. Hypothesis: MIIpH detected swallow (SW) activity during sleep can identify nocturnal AW in patients with GERD. Methods: 40 patients were studied; 25 female, 15 male. All were referred for evaluation of GERD. An Actigraph device (ActiGraph, Pensacola, FL) was worn on the wrist during 24 h-MII -pH testing. Sleep monitoring was performed between 10PM to 7AM using the Actilife software. Impedance identified total number of SW per hour for all subjects were correlated with number of AW. Results: For all patients, average recumbent period was 6.6 hours, average sleeping time was 5.4 hours, and average awake time was 1.2 hours (19% of total recumbent period). During recumbent period the total number of SW was 2828. 61% of SW occurred during awake time; 39% occurred during sleeping period. 544 AW were recorded during the study; 96% associated with swallowing activity. In 4% of them, no SW were detected. SW and AW per hour are depicted in the figure (r =0.9; p<0.05). Conclusions: The recumbent swallowing activity detected by MII-pH reliably predicts awakenings shown by Actigraph. The r-square indicates approximately 80% concordance between awakenings and swallows.
883 Helicobacter pylori-Derived HP (2-20) Stimulates Gastric Mucosal Recovery From Stress-Induced Gastric Lesions and Accelerates the Healing of Chronic Gastric Ulcers Tomasz Brzozowski, Marco Romano, Amato de Paulis, Francesca W. Rossi, Nella Prevete, Alexandra Szlachcic, Robert Pajdo, Stanislaw Konturek, Wieslaw W. Pawlik Helicobacter pylori (Hp)-derived peptide RpL1 aa 2-20 (Hp2-20) interacts with formyl peptide receptors (FPRs) and exerts several immunomodulatory effects but its influence on the gastric secretory functions and the mechanism of gastric mucosal integrity remains unknown. We determined the effect of Hp2-20 on the gastric acid secretion in rats equipped with gastric fistula and the mucosal recovery from the water immersion and restraint stress (WRS)
S-123
AGA Abstracts
AGA Abstracts
Long-Term Treatment of Eosinophilic Esophagitis With Budesonide Alex Straumann, Lukas Degen, Christian Bussmann, Christoph Beglinger, Alain Schoepfer, Christina Thalmann, Hans-Uwe Simon