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213 A Randomized, Multicenter, Sham-Controlled Trial of Radiofrequency Ablation (RFA) for Subjects with Barrett's Esophagus (Be) Containing Dysplasia: Interim Results of the Aim Dysplasia Trial
chloride/bicarbonate exchanger, and localization studies in parietal cells detected its presence in tubulovesicles. We propose that Slc26a9 plays an essential role in gastric acid secretion by regulating chloride secretion and maintaining the viability of tubulovesicles/secretory canaliculi in parietal cells.
Teduglutide, a Novel GLP-2 Analog, in the Management of Short Bowel Syndrome (SBS) Patients Dependent On Parenteral Nutrition: A Multicenter, Multinational Placebo-Controlled Clinical Trial Stephen J. O'Keefe, Richard Gilroy, Palle B. Jeppesen, Bernard Messing, Johane P. Allard, Douglas L. Seidner, Marek Pertkiewicz, Roxanne Kapikian, Nancy McGraw, John Caminis
210
Home parenteral IV fluid and nutrition (PN) allows patients with intestinal failure SBS to survive, but outcome is impaired by potential life-threatening complications and poor quality of life. We investigate the potential for a new recombinant analog of glucagon-like peptide2, teduglutide (TG), to reduce PN dependence with the hope of reducing complication risks. Methods: A double-blind, placebo-controlled, parallel-group trial was conducted in adults with SBS resulting from major intestinal resection needing PN =>3x/week for 12 months. Following a 4-wk PN optimization period, patients were randomized to placebo or one of 2 dose levels of TG (0.05 or 0.1 mg/kg/d sc) for 24 wks. Endpoints were the effects on weekly PN requirements between weeks 20-24, lean body mass (LBM) by DEXA scan and fasting plasma citrulline concentrations measured by HPLC as an index of enterocyte mass and function. A clinically significant PN response was defined as a reduction of >20% of the weekly (optimal) PN requirements. Results were evaluated as intention to treat by ANOVA, expressed as mean(SD). Results: 139 patients were screened and 83 were randomized: 46 women; age 48.8(14.2)years, BMI 21.5(2.8)Kg/m2, PN 10.0(5.6)L/wk. 86% completed the study. The estimated length of residual intestine was 66(45)cm; 2/3 had additional colon. All groups showed a reduction in weekly PN volumes (p=0.03), the achievement of a >20% reduction was significantly greater than placebo in the low-dose(45.7% vs 6.3%, respectively, p=0.007) but not the high-dose group (25.0% vs 6.3%, p=0.161). Two patients from the low-dose and 1 from the high dose group discontinued PN by week 24. Trunk LBM increased (p<0.05) by 632(244) in low and 969(217)g in high dose groups, and total LBM by 1527(439)g in high dose group. Plasma citrulline concs increased in both drug groups by +10.9(11.5) and +15.8(12.2)umol/l compared to placebo (p=0.06). Serious adverse events (AEs) were recorded in 31.3% of placebo, 37.1% of low-dose and 34.4% of high dose TG groups (NS). The most common AEs associated with therapy were nausea, abdominal pain, headache and nasopharyngitis. Conclusions: In this population of SBS patients, teduglutide at both dose levels was more clinically effective in reducing PN requirements, though only the lower dose group showed statistical significance vs than placebo. The additional findings of increased LBM and plasma citrulline concentrations are consistent with the conclusions of earlier human studies that GLP-2 administration can enhance physiological adaptation to SBS by amplifying trophism and absorption. This effect was not associated with an increase in serious AEs.
Math1 Directs Intestinal Secretory Cell Specification and Is a Novel Regulator of Epithelium-Mesenchyme Signaling Kelli L. VanDussen, Linda C. Samuelson INTRODUCTION: The Notch-regulated basic helix-loop-helix transcription factor mammalian atonal homologue 1 (Math1) is required for the development of intestinal secretory cells, including goblet, endocrine and Paneth cells. This study was designed to test whether Math1 expression is sufficient to trigger secretory cell development from multipotential progenitors. METHODS: The intestine-specific villin promoter was used to over-express Math1 throughout the developing intestinal epithelium of transgenic mice. The resulting phenotype was analyzed in day 18.5 embryos by immunohistochemistry and quantitative RT-PCR to follow changes in cell fate and proliferation. RESULTS: Vil-Math1 transgenic founders exhibited a dramatic increase in secretory cell number and secretory marker expression along with a profound, unexpected expansion of the mesenchyme. Much of the epithelium in transgenics was transformed to goblet cells with goblet cell number increased as much as 11-fold. Endocrine cell number was also found to be increased along with increased expression of Neurogenin3, a marker of endocrine precursor cells. Although mature Paneth cells are normally not formed until after birth, Paneth cell marker expression was increased dramatically in Vil-Math1 transgenics. Thus, Math1 induced an increase in all secretory cell types. In contrast, there was an almost complete loss of enterocytes and their markers Ifabp and lactase. The intestinal epithelium of the most severely affected transgenic founders appeared hypocellular. Accordingly, Ki67 immunostaining revealed that epithelial cell proliferation was decreased in the intervillus zone, the normal location of intestinal epithelium proliferation. Surprisingly, there were Ki67-positive cells observed in villus tips suggesting that the proliferative Wnt signaling pathway was displaced in the Vil-Math1 transgenics. In concordance, nuclear β-catenin was mostly absent in the intervillus zone, but was observed in villus tip regions of transgenics. Although transgene expression was limited to the epithelium, an unexpected increase in mesenchyme proliferation was observed along with massive smooth muscle differentiation, suggesting that signaling between the epithelium and mesenchyme was altered by the cellular changes induced by Math1. CONCLUSIONS: These data demonstrate that Math1 is the key cell lineage determinant in the intestinal epithelium and can redirect multipotential progenitors to secretory cells to the detriment of absorptive cells. Moreover, this study revealed a novel function of Math1 as a regulator of Wnt signaling and cross-talk between the intestinal epithelium and mesenchyme.
213 A Randomized, Multicenter, Sham-Controlled Trial of Radiofrequency Ablation (RFA) for Subjects with Barrett's Esophagus (Be) Containing Dysplasia: Interim Results of the Aim Dysplasia Trial Nicholas J. Shaheen, Prateek Sharma, Bergein F. Overholt, Charles J. Lightdale, Herbert C. Wolfsen, Richard E. Sampliner, Kenneth K. Wang, Mary P. Bronner, John R. Goldblum, Blair A. Jobe, Glenn M. Eisen, David E. Fleischer, Virender K. Sharma, Brenda Hoffman, Richard I. Rothstein, Hiroshi Mashimo, Kenneth J. Chang, V. Raman Muthusamy, Steven A. Edmundowicz, Stuart J. Spechler, Ali Siddiqui, Anthony Infantolino, Gary W. Falk, Michael B. Kimmey, Amitabh Chak
211 Does the First Colonoscopy of the Day Yield More Polyps Than Cases Performed Later? Michael Y. Chan, Hartley Cohen, Brennan M. Spiegel Introduction: Data indicate that morning colonoscopies are associated with higher cecal intubation rates vs afternoon colonoscopies, largely due to differences in bowel prep quality. However, the relationship between timing of colonoscopy and polyp yield has not been described, and it remains unclear if timing impacts polyp detection independent of bowel prep quality and other confounders. If earlier cases improved yield after adjusting for confounders, then it might suggest that provider-level factors could contribute to diminished yield as the day progresses. We sought to measure the adjusted polyp yield for colonoscopies performed as the first case (FC) of the day vs later cases (LC). Methods: We performed a prospective study of consecutive patients receiving screening, surveillance, or diagnostic colonoscopies at a University-based VA medical center from 2006-2007. Prior to data collection, we delineated a conceptual model to specify patient & procedure-level variables that predict polyp detection during colonoscopy. Patient variables: age, gender, race, BMI, prior surgery, personal or family h/o CRC or polyp, h/o previous colon or flexsig. Procedure variables: indication, bowel prep quality, withdrawal time & cecal intubation. The primary outcome was number of polyps reported by the endoscopist. We performed bivariate analysis to compare polyp yield by colonoscopy start time (FC vs. LC). We performed multivariate Poisson regression adjusting for key covariates to isolate the independent effect of colonoscopy start time on diagnostic yield. Results: 500 patients met inclusion criteria (121=FC; 379= LC; mean age=63+9; 97% men). At least 1 polyp was found in 71% (mean # polyps=1.8+2). In bivariate analysis, more polyps were found in the FC (mean=2.1; median=2) than LC (mean=1.6; median=1) groups (p<0.01). In multivariate analysis adjusting for significant factors, FC remained an independent predictor of higher polyp yield (p=0.033). Conclusion: We found that patients undergoing colonoscopy as the first case of the day are more likely to have polyps detected vs patients undergoing colonoscopy later in the day. The effect of procedure timing on diagnostic yield is independent of a wide range of key variables, including demographics, patient history, prep quality, withdrawal time, and cecal intubation. This suggests that provider-level factors may explain the observed relationship, and that providers may be most adept at detecting polyps at the beginning of an endoscopic work shift. Further research should measure whether schedule-related factors, such as provider fatigue or distraction, could diminish polyp yield as the work shift progresses.
Background: The optimal management strategy for BE with dysplasia is not known. In cohort studies, RFA is effective in inducing reversion of dysplastic BE to squamous. Aim: To assess the efficacy of RFA for the treatment of BE containing dysplasia. Methods: We performed a randomized sham-controlled trial of RFA for subjects with BE containing dysplasia at 19 U.S. centers. The baseline diagnosis was confirmed by Cleveland Clinic (CC) pathology laboratory. Subjects were then randomized to RFA or sham (2:1), stratified by dysplasia grade (HGD,LGD) and BE length (<4 vs. 4-8 cm). Step-wise circumferential and focal ablation was performed using the HALO System (max 4 sessions). Every 3 mos (HGD) or 6 mos (LGD) after randomization, biopsies were obtained throughout the original BE length (four quadrant, q1cm), and processed by CC. Primary outcomes included: 1) complete histological clearance of dysplasia in HGD and LGD cohorts at 12 mos, and, 2) complete histological clearance of intestinal metaplasia (IM) at 12 mos, comparing RFA vs. sham. Secondary outcomes included: 1) progression/regression of dysplasia, and 2) adverse events. Intent-to-treat (ITT) and per protocol (PP) analyses are reported. Results: Randomization is complete. Of 127 subjects (63 HGD/64 LGD), 58 have reached the primary endpoint with results reported below (male 84%, mean age 65, mean BE length (cm): LGD 4.6, HGD 5.2.) Randomization resulted in similar demographics and BE length in RFA vs. sham. Mean # of treatment sessions was 3.5. Higher proportions of RFA subjects had clearance of dysplasia and IM (table). By ITT, 74% of RFA subjects achieved complete clearance of IM (83% PP), compared to 0% of sham (p<0.0001, NNT for ITT=1.35). There were no perforations or deaths related to RFA. In 39 RFA subjects (ITT) at 12 mos, there was 1 stricture (2.6%) which resolved with 1 dilation. No RFA subject had progression of dysplasia, while 3 sham subjects had progression (2 LGD→HGD; 1 HGD→CA). Conclusions: Interim results of the AIM Dysplasia Trial suggest that RFA is superior to sham for clearance of dysplasia and IM in BE containing dysplasia. In subjects randomized to RFA, 74% (ITT) have no evidence of IM at 12 mo follow-up (83% PP), and 85% are free of dysplasia (94% PP). The procedure is associated with a favorable side-effect profile. This trial will be completed June 2008.
*p<0.05, #p<0.001 vs. sham
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AGA Abstracts
AGA Abstracts
212
Teduglutide, a Novel GLP-2 Analog, in the Management of Short Bowel Syndrome (SBS) Patients Dependent On Parenteral Nutrition: A Multicenter, Multinational Placebo-Controlled Clinical Trial Stephen J. O'Keefe, Richard Gilroy, Palle B. Jeppesen, Bernard Messing, Johane P. Allard, Douglas L. Seidner, Marek Pertkiewicz, Roxanne Kapikian, Nancy McGraw, John Caminis
210
Home parenteral IV fluid and nutrition (PN) allows patients with intestinal failure SBS to survive, but outcome is impaired by potential life-threatening complications and poor quality of life. We investigate the potential for a new recombinant analog of glucagon-like peptide2, teduglutide (TG), to reduce PN dependence with the hope of reducing complication risks. Methods: A double-blind, placebo-controlled, parallel-group trial was conducted in adults with SBS resulting from major intestinal resection needing PN =>3x/week for 12 months. Following a 4-wk PN optimization period, patients were randomized to placebo or one of 2 dose levels of TG (0.05 or 0.1 mg/kg/d sc) for 24 wks. Endpoints were the effects on weekly PN requirements between weeks 20-24, lean body mass (LBM) by DEXA scan and fasting plasma citrulline concentrations measured by HPLC as an index of enterocyte mass and function. A clinically significant PN response was defined as a reduction of >20% of the weekly (optimal) PN requirements. Results were evaluated as intention to treat by ANOVA, expressed as mean(SD). Results: 139 patients were screened and 83 were randomized: 46 women; age 48.8(14.2)years, BMI 21.5(2.8)Kg/m2, PN 10.0(5.6)L/wk. 86% completed the study. The estimated length of residual intestine was 66(45)cm; 2/3 had additional colon. All groups showed a reduction in weekly PN volumes (p=0.03), the achievement of a >20% reduction was significantly greater than placebo in the low-dose(45.7% vs 6.3%, respectively, p=0.007) but not the high-dose group (25.0% vs 6.3%, p=0.161). Two patients from the low-dose and 1 from the high dose group discontinued PN by week 24. Trunk LBM increased (p<0.05) by 632(244) in low and 969(217)g in high dose groups, and total LBM by 1527(439)g in high dose group. Plasma citrulline concs increased in both drug groups by +10.9(11.5) and +15.8(12.2)umol/l compared to placebo (p=0.06). Serious adverse events (AEs) were recorded in 31.3% of placebo, 37.1% of low-dose and 34.4% of high dose TG groups (NS). The most common AEs associated with therapy were nausea, abdominal pain, headache and nasopharyngitis. Conclusions: In this population of SBS patients, teduglutide at both dose levels was more clinically effective in reducing PN requirements, though only the lower dose group showed statistical significance vs than placebo. The additional findings of increased LBM and plasma citrulline concentrations are consistent with the conclusions of earlier human studies that GLP-2 administration can enhance physiological adaptation to SBS by amplifying trophism and absorption. This effect was not associated with an increase in serious AEs.
Math1 Directs Intestinal Secretory Cell Specification and Is a Novel Regulator of Epithelium-Mesenchyme Signaling Kelli L. VanDussen, Linda C. Samuelson INTRODUCTION: The Notch-regulated basic helix-loop-helix transcription factor mammalian atonal homologue 1 (Math1) is required for the development of intestinal secretory cells, including goblet, endocrine and Paneth cells. This study was designed to test whether Math1 expression is sufficient to trigger secretory cell development from multipotential progenitors. METHODS: The intestine-specific villin promoter was used to over-express Math1 throughout the developing intestinal epithelium of transgenic mice. The resulting phenotype was analyzed in day 18.5 embryos by immunohistochemistry and quantitative RT-PCR to follow changes in cell fate and proliferation. RESULTS: Vil-Math1 transgenic founders exhibited a dramatic increase in secretory cell number and secretory marker expression along with a profound, unexpected expansion of the mesenchyme. Much of the epithelium in transgenics was transformed to goblet cells with goblet cell number increased as much as 11-fold. Endocrine cell number was also found to be increased along with increased expression of Neurogenin3, a marker of endocrine precursor cells. Although mature Paneth cells are normally not formed until after birth, Paneth cell marker expression was increased dramatically in Vil-Math1 transgenics. Thus, Math1 induced an increase in all secretory cell types. In contrast, there was an almost complete loss of enterocytes and their markers Ifabp and lactase. The intestinal epithelium of the most severely affected transgenic founders appeared hypocellular. Accordingly, Ki67 immunostaining revealed that epithelial cell proliferation was decreased in the intervillus zone, the normal location of intestinal epithelium proliferation. Surprisingly, there were Ki67-positive cells observed in villus tips suggesting that the proliferative Wnt signaling pathway was displaced in the Vil-Math1 transgenics. In concordance, nuclear β-catenin was mostly absent in the intervillus zone, but was observed in villus tip regions of transgenics. Although transgene expression was limited to the epithelium, an unexpected increase in mesenchyme proliferation was observed along with massive smooth muscle differentiation, suggesting that signaling between the epithelium and mesenchyme was altered by the cellular changes induced by Math1. CONCLUSIONS: These data demonstrate that Math1 is the key cell lineage determinant in the intestinal epithelium and can redirect multipotential progenitors to secretory cells to the detriment of absorptive cells. Moreover, this study revealed a novel function of Math1 as a regulator of Wnt signaling and cross-talk between the intestinal epithelium and mesenchyme.
213 A Randomized, Multicenter, Sham-Controlled Trial of Radiofrequency Ablation (RFA) for Subjects with Barrett's Esophagus (Be) Containing Dysplasia: Interim Results of the Aim Dysplasia Trial Nicholas J. Shaheen, Prateek Sharma, Bergein F. Overholt, Charles J. Lightdale, Herbert C. Wolfsen, Richard E. Sampliner, Kenneth K. Wang, Mary P. Bronner, John R. Goldblum, Blair A. Jobe, Glenn M. Eisen, David E. Fleischer, Virender K. Sharma, Brenda Hoffman, Richard I. Rothstein, Hiroshi Mashimo, Kenneth J. Chang, V. Raman Muthusamy, Steven A. Edmundowicz, Stuart J. Spechler, Ali Siddiqui, Anthony Infantolino, Gary W. Falk, Michael B. Kimmey, Amitabh Chak
211 Does the First Colonoscopy of the Day Yield More Polyps Than Cases Performed Later? Michael Y. Chan, Hartley Cohen, Brennan M. Spiegel Introduction: Data indicate that morning colonoscopies are associated with higher cecal intubation rates vs afternoon colonoscopies, largely due to differences in bowel prep quality. However, the relationship between timing of colonoscopy and polyp yield has not been described, and it remains unclear if timing impacts polyp detection independent of bowel prep quality and other confounders. If earlier cases improved yield after adjusting for confounders, then it might suggest that provider-level factors could contribute to diminished yield as the day progresses. We sought to measure the adjusted polyp yield for colonoscopies performed as the first case (FC) of the day vs later cases (LC). Methods: We performed a prospective study of consecutive patients receiving screening, surveillance, or diagnostic colonoscopies at a University-based VA medical center from 2006-2007. Prior to data collection, we delineated a conceptual model to specify patient & procedure-level variables that predict polyp detection during colonoscopy. Patient variables: age, gender, race, BMI, prior surgery, personal or family h/o CRC or polyp, h/o previous colon or flexsig. Procedure variables: indication, bowel prep quality, withdrawal time & cecal intubation. The primary outcome was number of polyps reported by the endoscopist. We performed bivariate analysis to compare polyp yield by colonoscopy start time (FC vs. LC). We performed multivariate Poisson regression adjusting for key covariates to isolate the independent effect of colonoscopy start time on diagnostic yield. Results: 500 patients met inclusion criteria (121=FC; 379= LC; mean age=63+9; 97% men). At least 1 polyp was found in 71% (mean # polyps=1.8+2). In bivariate analysis, more polyps were found in the FC (mean=2.1; median=2) than LC (mean=1.6; median=1) groups (p<0.01). In multivariate analysis adjusting for significant factors, FC remained an independent predictor of higher polyp yield (p=0.033). Conclusion: We found that patients undergoing colonoscopy as the first case of the day are more likely to have polyps detected vs patients undergoing colonoscopy later in the day. The effect of procedure timing on diagnostic yield is independent of a wide range of key variables, including demographics, patient history, prep quality, withdrawal time, and cecal intubation. This suggests that provider-level factors may explain the observed relationship, and that providers may be most adept at detecting polyps at the beginning of an endoscopic work shift. Further research should measure whether schedule-related factors, such as provider fatigue or distraction, could diminish polyp yield as the work shift progresses.
Background: The optimal management strategy for BE with dysplasia is not known. In cohort studies, RFA is effective in inducing reversion of dysplastic BE to squamous. Aim: To assess the efficacy of RFA for the treatment of BE containing dysplasia. Methods: We performed a randomized sham-controlled trial of RFA for subjects with BE containing dysplasia at 19 U.S. centers. The baseline diagnosis was confirmed by Cleveland Clinic (CC) pathology laboratory. Subjects were then randomized to RFA or sham (2:1), stratified by dysplasia grade (HGD,LGD) and BE length (<4 vs. 4-8 cm). Step-wise circumferential and focal ablation was performed using the HALO System (max 4 sessions). Every 3 mos (HGD) or 6 mos (LGD) after randomization, biopsies were obtained throughout the original BE length (four quadrant, q1cm), and processed by CC. Primary outcomes included: 1) complete histological clearance of dysplasia in HGD and LGD cohorts at 12 mos, and, 2) complete histological clearance of intestinal metaplasia (IM) at 12 mos, comparing RFA vs. sham. Secondary outcomes included: 1) progression/regression of dysplasia, and 2) adverse events. Intent-to-treat (ITT) and per protocol (PP) analyses are reported. Results: Randomization is complete. Of 127 subjects (63 HGD/64 LGD), 58 have reached the primary endpoint with results reported below (male 84%, mean age 65, mean BE length (cm): LGD 4.6, HGD 5.2.) Randomization resulted in similar demographics and BE length in RFA vs. sham. Mean # of treatment sessions was 3.5. Higher proportions of RFA subjects had clearance of dysplasia and IM (table). By ITT, 74% of RFA subjects achieved complete clearance of IM (83% PP), compared to 0% of sham (p<0.0001, NNT for ITT=1.35). There were no perforations or deaths related to RFA. In 39 RFA subjects (ITT) at 12 mos, there was 1 stricture (2.6%) which resolved with 1 dilation. No RFA subject had progression of dysplasia, while 3 sham subjects had progression (2 LGD→HGD; 1 HGD→CA). Conclusions: Interim results of the AIM Dysplasia Trial suggest that RFA is superior to sham for clearance of dysplasia and IM in BE containing dysplasia. In subjects randomized to RFA, 74% (ITT) have no evidence of IM at 12 mo follow-up (83% PP), and 85% are free of dysplasia (94% PP). The procedure is associated with a favorable side-effect profile. This trial will be completed June 2008.
*p<0.05, #p<0.001 vs. sham
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AGA Abstracts
AGA Abstracts
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