- Email: [email protected]
244 Evidence for Involvement of the Cysteinyl Leukotriene Receptor Type 2 (cysLTR2) in the Regulation of Food Intake and Body Weight and Possible Role for Vagal Afferents
AGA Abstracts
agreed that colon cancer screening is part of good overall health care) and 90% thought that colonoscopy was the most effective CRC screening test. Only 47%, however, were compliant with colonoscopy screening recommendations at baseline (every 1-2 years for HNPCC; every 5 years for HR). The most commonly reported barriers to colonoscopy screening were lack of symptoms (34%), being too busy (26%) and concern about the preparation (25%). Of the 632 subjects randomized, 570 (90%) completed the 24 month follow-up. Colonoscopy compliance increased from 43% to 59% in the intensive intervention group but only from 52% to 55% in the minimal intervention group (OR 1.6: 95% CI 0.91.8). The intervention was comparably effective in the HNPCC and HR groups. Conclusions: Compliance with colonoscopy screening is surprisingly low in unaffected members of HNPCC and HR families and a telephone-based intervention may be able to improve colonoscopy screening in this group.
celecoxib is also associated with a lower risk of all clinically significant GI events throughout the entire GI tract compared to patients treated with nsNSAIDs. 244 Evidence for Involvement of the Cysteinyl Leukotriene Receptor Type 2 (cysLTR2) in the Regulation of Food Intake and Body Weight and Possible Role for Vagal Afferents Ala'a Al-Helaili, Sung Jin Park, Donna M. Daly, Michael Beyak A variety of lipid mediators are known to be involved in satiety signaling and body weight. For example endocannabinoids and related compounds have profound effects on food intake, via vagal afferent pathways. More recently evidence has emerged for eicosanoids such as prostaglandins and leukotrienes in the regulation of body weight. For example, 5-lipoxygenase deficient mice are obese and glucose intolerant, and mice deficient in the EP3 prostanoid receptor are obese and have increased food intake. The aim of the present study was to examine the role of cysLTR2 receptors in regulation of food intake and body weight. Methods: cysLTR2-/- lacZ transgenic mice (-/-) and wild type controls (+/+) on a C57Bl6j background were used for this study. Mice were housed and fed identically from the time of weaning to the end of the study. Food intake was measured using specialized cages equipped with a continuously weighed food reservoir, connected to a computer interface. Food and body weight were measured from 7 to 25 weeks of age. X-Gal staining was used to visualize sites of cysLTR2 expression in nodose ganglion and vagus nerve. For calcium imaging, nodose ganglia were isolated, and neurons dissociated and plated on glass coverslips for 18-24h prior to experimentation. Fluorescent calcium imaging experiments were performed on fura2-AM loaded dissociated nodose ganglion cells. Results: Body weight increased more over time in -/- mice compared to +/+ (maximal at 25 weeks, 50.3±1.2g vs. 47.0±0.49 g p<0.05), as did food intake (maximal at 25 weeks 4.8±0.14g/d vs. 3.9±0.29g/d, p<0.05 n= 4 mice each group). Meal frequency was no different between groups, suggesting an overall increase in meal size. X-Gal staining of nodose ganglia from -/- mice revealed widespread staining in the nodose ganglion and vagus nerve. Calcium imaging experiments were performed on isolated nodose ganglion neurons, and responses to the cysLTR2 agonists LTC4 and LTD4 (100nM) were assessed. In +/+ mice, LTC4 caused an increase in intracellular calcium in 37% of cells tested, 48.5±14.9% (n=11) of the response to high potassium (80mM), and LTD4 in 25% of cells tested, with a magnitude of 61.4±22% (n=7) of the high potassium response. Conclusions: cysLTR2-/- mice gain more weight and have higher food intake compared to wildtype controls. This appears to be due to an increase in meal size rather than frequency. The cysLTR2 receptor is expressed in vagal afferents, and these afferents can be activated by LTC4 and LTD4, suggesting a possible role for vagal satiety signals. The endogenous source and stimulus for release of leukotrienes as it relates to food intake remains to be determined.
230 Long Term Outcome of Early Colorectal Cancer Treated With Local Excision or Radical Resection Monique E. van Leerdam, Thomas C. Smyrk, Felicity Enders, Sara Holton, Petrus C. de Groen BACKGROUND: Treatment of early stage colorectal cancer (CRC) with minimally invasive techniques decreases morbidity but carries the risk of incomplete local excision. AIM: To compare long term outcome in a large cohort of patients with non-invasive intramucosal (NIIM) or T1 CRC treated with local excision (LE) or radical surgical resection (RSR). METHODS: Mayo Clinic databases were used to select patients with NIIM and T1 CRC who were diagnosed between 1/1994 and 1/2004 to ensure at least 5 years of follow up (FU). Patients with prior or synchronous CRC, IBD, FAP or incomplete data were excluded. Tumor characteristics (stage, grade, depth submucosal invasion, angiolymphatic invasion, tumor budding) were reviewed. Overall and disease free survival were determined only in patients without metastatic disease at the time of diagnosis. Breslow statistics and Cox proportional Hazard Ratios (HR) were used to compare overall and disease free survival and to determine risk factors for recurrent disease (local recurrence, lymph node or distant metastases). RESULTS: A total of 569 eligible patients were included in the study. NIIM CRC cases (N=52): 54% were treated with LE and 46% with RSR. No recurrent disease occurred during mean FU of 127 ± 8.5 months. Overall survival was equal for both treatment groups. T1 CRC cases (N=517): 25% were treated with LE and 75% with RSR. LE was more often performed for rectal lesions and RSR more often for proximal lesions (p<0.001). 50 patients had metastatic disease at the time of diagnosis and 9 patients developed metachronous CRC during FU. CRC recurrence during mean FU of 134 ± 3.1 months was more often seen in the LE group (13% vs 3% in RSR, p<0.001). Recurrence occurred more often in rectal than in non-rectal CRC (81% vs 19% p<0.001). After adjusting for age, gender and co-morbidity, overall survival was better in the RSR group than in the LE group (HR 1.42, 95% CI 1.0-2.0, p=0.05). Disease free survival was also better in the RSR group (HR 1.62, 95% CI 1.15-2.28). After adjusting for age and gender, rectal location (HR 4.3, 95%CI 1.413.7), tumor budding (HR 3.5, 95%CI 1.4-8.9) and LE (HR 4.2, 95%CI 1.5-11.6) were significantly associated with recurrent disease, whereas angiolymphatic invasion, submucosal invasion and tumor grade were not. CONCLUSIONS: Disease free survival among NIIM patients is 100% and among T1 CRC patients is significantly better in those who were treated with surgical resection rather than local excision. Rectal location of cancer, tumor budding and LE were associated with recurrent disease. Better criteria are needed to identify those T1 CRC patients who can safely be treated with local excision.
245 Does the Preload of a Non-Caloric Carbonated Beverage, During a Standardized Solid and Liquid Meal, Affect Gastric Volume and Energy Intake in Healthy Subjects? Maria Flavia Savarese, Emanuele Nicolai, Adriana Aragri, Giovanni Sarnelli, Elisabetta Atteo, Ivana Giusy Savino, Maxime E. Buyckx, Rosario Cuomo Background and Aim: Carbon dioxide (CO2), contained in carbonated beverages, could increase gastric volume inducing epigastric discomfort and reducing meal intake. We aimed to verify effect of a sugar-free carbonated beverage (CB) preload compared to a CB without CO2 (DCB) and water (W) during a standardized solid (SM) and liquid (LM) meal on gastric volume, gastrointestinal symptoms and eating perceptions. Subjects & Methods: After 300 ml of CB, DCB and W a standardized SM or LM was administered at constant rate (100 kcal/5 min) to ten healthy subjects (4 females, aged 22-30 years; BMI 21-24) on six days in a random order (D1: CB+SM; D2: DCB+SM; D3: W+SM; D4: CB+LM; D5: DCB+LM; D6: W+LM). Gastrointestinal symptoms (bloating and epigastric pain), eating perceptions (desire to eat, hunger, prospective of food consumption) and maximum satiety (MS) as total kcals intake were measured. Total gastric (TGV) and gas volumes by MRI after the beverages and at MS were also evaluated. All data are expressed as mean±SD. Results: Epigastric pain was absent in all experiment. A slight presence of epigastric bloating was found during the SM and LM without differences among beverages. Desire to eat, hunger and prospective of food consumption were not different among beverages and meals. TGV and gas volumes after beverages were significantly higher with CB than DCB and W (TGV: 715±194 ml, 521±83, 478±63, p<0.01; gas: 306±107, 101±29, 107±40, p<0.01). TGV at MS were not different during SM (665±129; 670±147; 664±167; ) and LM (702±252; 674±206; 709±264) respectively. Gas volumes at MS markedly decrease (p<0.01) respect to evalution after beverage and were not different among beverages during SM (20±8, 13±7, 12±5) and LM (15±12, 22±19, 17±17) respectively. Total kcal intakes at MS were not different among beverages during SM (D1: 774±209; D2:837±208; D3: 783±244) and LM (D4: 585±299; D5:585±280; D6: 630±353) respectively. However kcal intakes were higher with SM than LM (p<0.01) independently of beverage preload. Conclusions: A preload of 300 ml of non caloric carbonated beverage does not determine gastrointestinal symptoms and does not affect satiety ratings and eating perceptions in healthy subjects. Other factors as time of administration, volume and carbon dioxide concentration of carbonated beverage must be explored to exclude interference with gastric function.
231 Upper and Lower Gastrointestinal Safety Profile of Celecoxib: Patient-Level Pooled Analysis of 51,048 Patients in Randomized, Double-Blinded, ParallelGroup Clinical Trials Gurkirpal Singh, George Triadafilopoulos, Naurang M. Agrawal, Geoff Makinson, Mark (Chunming) Li, Ha Nguyen Background: While nonsteroidal anti-inflammatory drug (NSAID)-related serious upper and lower gastrointestinal (UGI/LGI) complications are well-recognized, most clinical trials of cyclooxygenase (COX)-2 selective NSAIDs have focused on UGI outcomes as their primary endpoints. By using a novel composite endpoint measuring injury in the entire GI tract— clinically significant upper and lower GI events (CSULGIEs)—we aimed to compare GI outcomes in patients enrolled in celecoxib clinical trials, using individual patient-level data. Methods: 52 randomized, double-blind, parallel group studies were identified from the Celecoxib Clinical Database and included in this patient-level pooled analysis. All studies had a planned duration of continuous treatment with celecoxib and either a nsNSAID (ibuprofen, naproxen, diclofenac, ketoprofen, ioxoprofen), rofecoxib or a placebo comparator arm for ≥ than 4 weeks. All included studies had their final study reports completed by October 1st, 2007. Open-label and cross-over trials, and all healthy volunteer studies were excluded from the analysis. The primary endpoint was the cumulative incidence of CSULGIEs (including perforations, obstructions, clinically significant bleeds, decrease in hemoglobin ≥2g/dL) or symptomatic ulcers as adjudicated by an independent blinded committee. Adjudication was based on predefined criteria and available reported adverse events, laboratory data and narratives. The stratified log rank test was used to compare treatments, adjusting for studies. All doses of celecoxib (from <200 to 800 mg total daily dose) and nsNSAIDS were pooled. Results: 51,048 patients were included: 28,614 patients were randomized to celecoxib (mean age 60.1 years), 15,278 to nsNSAIDs (mean age 59.3 years), 1,329 to rofecoxib (mean age 70.6 years) and 5,827 to placebo (mean age 57.2 years). A total of 803 cases of serious UGI/LGI complications (or decrease in hemoglobin level ≥2g/dL) were reviewed by the adjudication committee who confirmed 511 CSULGIEs. 220 GI events were in the celecoxib group with an incidence rate of 1.8 per 100 person-years; 244 events were in the nsNSAID group with an incidence rate of 5.3 per 100 person-years; the rofecoxib and placebo arms had 2 and 45 events and incidence rates of 1.3 and 1.2 per 100 personyears, respectively.The difference between celecoxib and nsNSAIDs was statistically significant, using a stratified log-rank test (p<0.0001). Conclusion: The known UGI safety of
AGA Abstracts
246 Role of Ghrelin and Ghrelin Receptors in the Effect of Bitter Taste Receptor Agonists on Food Intake and Gastric Emptying Sara Janssen, Pieter-Jan Verhulst, Jorien Laermans, Jan F. Tack, Inge Depoortere Background: Ghrelin is an orexigenic hormone with gastroprokinetic properties, mainly produced by the stomach. Ghrelin secretion depends on the nutritional composition of the meal but the factors involved in chemosensation of the ghrelin cell are not known. Transcripts
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agreed that colon cancer screening is part of good overall health care) and 90% thought that colonoscopy was the most effective CRC screening test. Only 47%, however, were compliant with colonoscopy screening recommendations at baseline (every 1-2 years for HNPCC; every 5 years for HR). The most commonly reported barriers to colonoscopy screening were lack of symptoms (34%), being too busy (26%) and concern about the preparation (25%). Of the 632 subjects randomized, 570 (90%) completed the 24 month follow-up. Colonoscopy compliance increased from 43% to 59% in the intensive intervention group but only from 52% to 55% in the minimal intervention group (OR 1.6: 95% CI 0.91.8). The intervention was comparably effective in the HNPCC and HR groups. Conclusions: Compliance with colonoscopy screening is surprisingly low in unaffected members of HNPCC and HR families and a telephone-based intervention may be able to improve colonoscopy screening in this group.
celecoxib is also associated with a lower risk of all clinically significant GI events throughout the entire GI tract compared to patients treated with nsNSAIDs. 244 Evidence for Involvement of the Cysteinyl Leukotriene Receptor Type 2 (cysLTR2) in the Regulation of Food Intake and Body Weight and Possible Role for Vagal Afferents Ala'a Al-Helaili, Sung Jin Park, Donna M. Daly, Michael Beyak A variety of lipid mediators are known to be involved in satiety signaling and body weight. For example endocannabinoids and related compounds have profound effects on food intake, via vagal afferent pathways. More recently evidence has emerged for eicosanoids such as prostaglandins and leukotrienes in the regulation of body weight. For example, 5-lipoxygenase deficient mice are obese and glucose intolerant, and mice deficient in the EP3 prostanoid receptor are obese and have increased food intake. The aim of the present study was to examine the role of cysLTR2 receptors in regulation of food intake and body weight. Methods: cysLTR2-/- lacZ transgenic mice (-/-) and wild type controls (+/+) on a C57Bl6j background were used for this study. Mice were housed and fed identically from the time of weaning to the end of the study. Food intake was measured using specialized cages equipped with a continuously weighed food reservoir, connected to a computer interface. Food and body weight were measured from 7 to 25 weeks of age. X-Gal staining was used to visualize sites of cysLTR2 expression in nodose ganglion and vagus nerve. For calcium imaging, nodose ganglia were isolated, and neurons dissociated and plated on glass coverslips for 18-24h prior to experimentation. Fluorescent calcium imaging experiments were performed on fura2-AM loaded dissociated nodose ganglion cells. Results: Body weight increased more over time in -/- mice compared to +/+ (maximal at 25 weeks, 50.3±1.2g vs. 47.0±0.49 g p<0.05), as did food intake (maximal at 25 weeks 4.8±0.14g/d vs. 3.9±0.29g/d, p<0.05 n= 4 mice each group). Meal frequency was no different between groups, suggesting an overall increase in meal size. X-Gal staining of nodose ganglia from -/- mice revealed widespread staining in the nodose ganglion and vagus nerve. Calcium imaging experiments were performed on isolated nodose ganglion neurons, and responses to the cysLTR2 agonists LTC4 and LTD4 (100nM) were assessed. In +/+ mice, LTC4 caused an increase in intracellular calcium in 37% of cells tested, 48.5±14.9% (n=11) of the response to high potassium (80mM), and LTD4 in 25% of cells tested, with a magnitude of 61.4±22% (n=7) of the high potassium response. Conclusions: cysLTR2-/- mice gain more weight and have higher food intake compared to wildtype controls. This appears to be due to an increase in meal size rather than frequency. The cysLTR2 receptor is expressed in vagal afferents, and these afferents can be activated by LTC4 and LTD4, suggesting a possible role for vagal satiety signals. The endogenous source and stimulus for release of leukotrienes as it relates to food intake remains to be determined.
230 Long Term Outcome of Early Colorectal Cancer Treated With Local Excision or Radical Resection Monique E. van Leerdam, Thomas C. Smyrk, Felicity Enders, Sara Holton, Petrus C. de Groen BACKGROUND: Treatment of early stage colorectal cancer (CRC) with minimally invasive techniques decreases morbidity but carries the risk of incomplete local excision. AIM: To compare long term outcome in a large cohort of patients with non-invasive intramucosal (NIIM) or T1 CRC treated with local excision (LE) or radical surgical resection (RSR). METHODS: Mayo Clinic databases were used to select patients with NIIM and T1 CRC who were diagnosed between 1/1994 and 1/2004 to ensure at least 5 years of follow up (FU). Patients with prior or synchronous CRC, IBD, FAP or incomplete data were excluded. Tumor characteristics (stage, grade, depth submucosal invasion, angiolymphatic invasion, tumor budding) were reviewed. Overall and disease free survival were determined only in patients without metastatic disease at the time of diagnosis. Breslow statistics and Cox proportional Hazard Ratios (HR) were used to compare overall and disease free survival and to determine risk factors for recurrent disease (local recurrence, lymph node or distant metastases). RESULTS: A total of 569 eligible patients were included in the study. NIIM CRC cases (N=52): 54% were treated with LE and 46% with RSR. No recurrent disease occurred during mean FU of 127 ± 8.5 months. Overall survival was equal for both treatment groups. T1 CRC cases (N=517): 25% were treated with LE and 75% with RSR. LE was more often performed for rectal lesions and RSR more often for proximal lesions (p<0.001). 50 patients had metastatic disease at the time of diagnosis and 9 patients developed metachronous CRC during FU. CRC recurrence during mean FU of 134 ± 3.1 months was more often seen in the LE group (13% vs 3% in RSR, p<0.001). Recurrence occurred more often in rectal than in non-rectal CRC (81% vs 19% p<0.001). After adjusting for age, gender and co-morbidity, overall survival was better in the RSR group than in the LE group (HR 1.42, 95% CI 1.0-2.0, p=0.05). Disease free survival was also better in the RSR group (HR 1.62, 95% CI 1.15-2.28). After adjusting for age and gender, rectal location (HR 4.3, 95%CI 1.413.7), tumor budding (HR 3.5, 95%CI 1.4-8.9) and LE (HR 4.2, 95%CI 1.5-11.6) were significantly associated with recurrent disease, whereas angiolymphatic invasion, submucosal invasion and tumor grade were not. CONCLUSIONS: Disease free survival among NIIM patients is 100% and among T1 CRC patients is significantly better in those who were treated with surgical resection rather than local excision. Rectal location of cancer, tumor budding and LE were associated with recurrent disease. Better criteria are needed to identify those T1 CRC patients who can safely be treated with local excision.
245 Does the Preload of a Non-Caloric Carbonated Beverage, During a Standardized Solid and Liquid Meal, Affect Gastric Volume and Energy Intake in Healthy Subjects? Maria Flavia Savarese, Emanuele Nicolai, Adriana Aragri, Giovanni Sarnelli, Elisabetta Atteo, Ivana Giusy Savino, Maxime E. Buyckx, Rosario Cuomo Background and Aim: Carbon dioxide (CO2), contained in carbonated beverages, could increase gastric volume inducing epigastric discomfort and reducing meal intake. We aimed to verify effect of a sugar-free carbonated beverage (CB) preload compared to a CB without CO2 (DCB) and water (W) during a standardized solid (SM) and liquid (LM) meal on gastric volume, gastrointestinal symptoms and eating perceptions. Subjects & Methods: After 300 ml of CB, DCB and W a standardized SM or LM was administered at constant rate (100 kcal/5 min) to ten healthy subjects (4 females, aged 22-30 years; BMI 21-24) on six days in a random order (D1: CB+SM; D2: DCB+SM; D3: W+SM; D4: CB+LM; D5: DCB+LM; D6: W+LM). Gastrointestinal symptoms (bloating and epigastric pain), eating perceptions (desire to eat, hunger, prospective of food consumption) and maximum satiety (MS) as total kcals intake were measured. Total gastric (TGV) and gas volumes by MRI after the beverages and at MS were also evaluated. All data are expressed as mean±SD. Results: Epigastric pain was absent in all experiment. A slight presence of epigastric bloating was found during the SM and LM without differences among beverages. Desire to eat, hunger and prospective of food consumption were not different among beverages and meals. TGV and gas volumes after beverages were significantly higher with CB than DCB and W (TGV: 715±194 ml, 521±83, 478±63, p<0.01; gas: 306±107, 101±29, 107±40, p<0.01). TGV at MS were not different during SM (665±129; 670±147; 664±167; ) and LM (702±252; 674±206; 709±264) respectively. Gas volumes at MS markedly decrease (p<0.01) respect to evalution after beverage and were not different among beverages during SM (20±8, 13±7, 12±5) and LM (15±12, 22±19, 17±17) respectively. Total kcal intakes at MS were not different among beverages during SM (D1: 774±209; D2:837±208; D3: 783±244) and LM (D4: 585±299; D5:585±280; D6: 630±353) respectively. However kcal intakes were higher with SM than LM (p<0.01) independently of beverage preload. Conclusions: A preload of 300 ml of non caloric carbonated beverage does not determine gastrointestinal symptoms and does not affect satiety ratings and eating perceptions in healthy subjects. Other factors as time of administration, volume and carbon dioxide concentration of carbonated beverage must be explored to exclude interference with gastric function.
231 Upper and Lower Gastrointestinal Safety Profile of Celecoxib: Patient-Level Pooled Analysis of 51,048 Patients in Randomized, Double-Blinded, ParallelGroup Clinical Trials Gurkirpal Singh, George Triadafilopoulos, Naurang M. Agrawal, Geoff Makinson, Mark (Chunming) Li, Ha Nguyen Background: While nonsteroidal anti-inflammatory drug (NSAID)-related serious upper and lower gastrointestinal (UGI/LGI) complications are well-recognized, most clinical trials of cyclooxygenase (COX)-2 selective NSAIDs have focused on UGI outcomes as their primary endpoints. By using a novel composite endpoint measuring injury in the entire GI tract— clinically significant upper and lower GI events (CSULGIEs)—we aimed to compare GI outcomes in patients enrolled in celecoxib clinical trials, using individual patient-level data. Methods: 52 randomized, double-blind, parallel group studies were identified from the Celecoxib Clinical Database and included in this patient-level pooled analysis. All studies had a planned duration of continuous treatment with celecoxib and either a nsNSAID (ibuprofen, naproxen, diclofenac, ketoprofen, ioxoprofen), rofecoxib or a placebo comparator arm for ≥ than 4 weeks. All included studies had their final study reports completed by October 1st, 2007. Open-label and cross-over trials, and all healthy volunteer studies were excluded from the analysis. The primary endpoint was the cumulative incidence of CSULGIEs (including perforations, obstructions, clinically significant bleeds, decrease in hemoglobin ≥2g/dL) or symptomatic ulcers as adjudicated by an independent blinded committee. Adjudication was based on predefined criteria and available reported adverse events, laboratory data and narratives. The stratified log rank test was used to compare treatments, adjusting for studies. All doses of celecoxib (from <200 to 800 mg total daily dose) and nsNSAIDS were pooled. Results: 51,048 patients were included: 28,614 patients were randomized to celecoxib (mean age 60.1 years), 15,278 to nsNSAIDs (mean age 59.3 years), 1,329 to rofecoxib (mean age 70.6 years) and 5,827 to placebo (mean age 57.2 years). A total of 803 cases of serious UGI/LGI complications (or decrease in hemoglobin level ≥2g/dL) were reviewed by the adjudication committee who confirmed 511 CSULGIEs. 220 GI events were in the celecoxib group with an incidence rate of 1.8 per 100 person-years; 244 events were in the nsNSAID group with an incidence rate of 5.3 per 100 person-years; the rofecoxib and placebo arms had 2 and 45 events and incidence rates of 1.3 and 1.2 per 100 personyears, respectively.The difference between celecoxib and nsNSAIDs was statistically significant, using a stratified log-rank test (p<0.0001). Conclusion: The known UGI safety of
AGA Abstracts
246 Role of Ghrelin and Ghrelin Receptors in the Effect of Bitter Taste Receptor Agonists on Food Intake and Gastric Emptying Sara Janssen, Pieter-Jan Verhulst, Jorien Laermans, Jan F. Tack, Inge Depoortere Background: Ghrelin is an orexigenic hormone with gastroprokinetic properties, mainly produced by the stomach. Ghrelin secretion depends on the nutritional composition of the meal but the factors involved in chemosensation of the ghrelin cell are not known. Transcripts
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