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Proton Pump Inhibitors and the Risk of Neoplastic Progression in Barrett's Esophagus: Results of a Large Multicenter Prospective Cohort Study
AGA Abstracts
lesion does not appear to impact the frequency of change in diagnosis. Based on the potential to make an accurate histological diagnosis and thus allowing for better patient selection, EMR should be considered as the first step in the management of BE-associated early neoplasia irrespective of presence or absence of endoscopically visible lesions. Table 1: Frequency of change in diagnosis by EMR in patients with HGD on biopsy
or EAC (p=0.028). Conclusion: Long duration of PPI use is associated with a reduced risk of neoplastic progression in patients with Barrett's esophagus. This observation supports the premise that patients with Barrett's esophagus should be encouraged to continue long term PPI use. Sa1073 The Relationship Between the Distal Margin of the Esophageal Palisade Vessels and the Distal Margin of the Lower Esophageal Sphincter Katsuhiko Iwakiri, Yoshio Hoshihara, Noriyuki Kawami, Hirohito Sano, Yuriko Tanaka, Mariko Umezawa, Seiji Futagami, Choitsu Sakamoto Background: The esophagogastric junction (EGJ), according to the endoscopic diagnostic criteria, is defined differently in Japan to that of Western countries. Although in Western countries, the upper limit of the gastric fold is considered to be the landmark of the EGJ, in Japan, the distal margin of the esophageal palisade vessels is used as the endoscopic landmark of the EGJ. The relationship between the distal margin of the palisade vessels and the distal margin of the LES was investigated because, in esophageal manometry, the distal margin of the LES is considered to be the EGJ. Methods: The subjects were 11 healthy volunteers without hiatus hernia. Esophageal manometry was carried out using the highresolution manometry system, where firstly, the tip of a manometric catheter was inserted into the proximal stomach, after which the catheter was fixed to the mouthpiece at the point where the LES was to be evaluated. The distance from the tip of the mouthpiece to the distal margin of the LES was then continuously measured and an ultra thin endoscope, with a 7mm long translucent silicon hood attached to the tip, was inserted orally into the proximal stomach without being inflated. A measuring device with 1mm gradations was attached to the surface of the endoscope, after which the hood was slightly pressed onto the mucosa near the EGJ, the endoscope was then gradually pulled out and the distance between the tip of the mouthpiece and the distal margin of the palisade vessels was evaluated at 1mm intervals. Measurement of the distance was carried out at the end of an expiration and after practicing several times, the true measurement was carried out 5 times. Maximum and minimum values were excluded and the mean value for each subject was calculated. Results: The distance between the distal margin of the palisade vessels and the distal margin of the LES was 6 mm (2.3-8.8) (median (interquartile range)). In cases where the distal margin of the palisade vessels was regarded as the EGJ, the distal margin of the LES in 6 (54.5%) of 11 subjects was located on the gastric side and the range was 7.5 mm (3-10) below the distal margin of the palisade vessels. In the remaining 5 subjects, the distal margin of the LES was located on the esophageal side and the range was 6 mm (1.8-8) above the distal margin of the palisade vessels. Conclusions: The difference between the distal margin of the palisade vessels and the distal margin of the LES was 6mm (median), therefore, it is considered that the concept of the distal margin of the palisade vessels being the EGJ, is reasonable.
Table 2: Frequency of change in diagnosis by EMR in patients with EAC on biopsy
Sa1071 Sub-Optimal Barrier Function in Neosquamous Epithelium Following Ablative Therapy Biljana Jovov, Nelia Tobey, Nicholas J. Shaheen, Zorka Djukic, Geraldine S. Orlando, Roy C. Orlando Background: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) is an emerging strategy for the prevention of esophageal adenocarcinoma (EAC). The success of RFA is initially assessed by healing of denuded areas on acid suppression therapy with neosquamous epithelium (NSE). Just as vital to the success of RFA, however, is the long term stability of NSE since lack thereof likely accounts for re-emergence of BE and mutagenesis in islands of buried BE. One key to stability of NSE is its barrier function. Methods: Barrier function of NSE was assessed in adults by obtaining endoscopic biopsies (Bx) at varying times following RFA in subjects treated with proton pump inhibitors (PPIs). Bx were fixed for study or mounted in mini-Ussing chambers for recording of electrical resistance (RT) and fluorescein flux and findings compared to that of healthy esophageal epithelium (ESE) and that in gastroesophageal reflux disease (GERD). Results: Mean RT and fluorescein flux of NSE were abnormal, with RT significantly lower and flux significantly higher than for healthy ESE. RT values for NSE recorded 2-22 months post-RFA had no correlation with their duration post-procedure. Further, mean RT and flux values for NSE were similar to those in GERD. Compared to healthy ESE, qRT-PCR, Western blot and immunohistochemistry showed only low expression of claudin 4 at the mRNA and protein level while other claudins were normally expressed. Light microscopy showed dilated intercellular spaces and an increased eosinophils versus ESE. Conclusions: The NSE that emerges post-RFA exhibits barrier function similar to GERD patients. This defect is not related to the time to heal post-RFA and is associated with low claudin-4 in the tight junction. More aggressive acid suppressive measures may be necessary to protect the NSE and decrease the risk of recurrent acid-peptic injury. Support: NIH R37-DK036013
Sa1074 Predictors of Barrett's Esophagus Length Elisabeth B. Cole, Patrick S. Yachimski, Chin Hur Background: Barrett's esophagus (BE) is the greatest known risk factor for the development of esophageal adenocarcinoma. The length of BE, long-segment (length greater than or equal to 3 centimeters) versus short-segment (length less than 3 centimeters), may carry differing risks of progression to cancer. The aim of this study was to analyze variables that predict short-segment versus long-segment BE at index upper endoscopy (EGD). Methods: Study design was a retrospective cross-sectional record review and multivariate logistic regression analysis. Patients who underwent a diagnostic endoscopy at a tertiary referral center over a 12 year time period (1996-2007) were included in the analysis. Results: A total of 311 subjects were included in this analysis. Mean age at diagnosis of BE was 61 ± 14 years; 29% of subjects were female and 92% were Caucasian. Mean height and weight were 68 ± 4 inches and 180 ± 41 pounds, respectively, while mean body mass index (BMI) was 28 ± 5. Half of participants reported some level of alcohol use while 13% were smokers. Over 90% were on proton pump inhibitor (PPI) therapy at the time of BE diagnosis. In terms of BE length, 32% (n=101) were diagnosed with short-segment BE, while 68% (n=210) were found to have a BE segment length of between 3 and 20 centimeters (long-segment BE). Stepwise multivariate regression analysis identified age greater than 70 years (OR=2.6, p= 0.008), male gender (OR=2.1; p=0.01), history of reflux (OR=1.8, p=0.05), and alcohol consumption (OR=1.7, p=0.05) as statistically significant predictors of long-segment BE. No statistically significant associations were observed between co-morbidities (history of heart, lung, liver and stomach conditions, cancer), BMI, weight, tobacco use, current medications (including PPI therapy) or race and BE segment length. Conclusion: Age greater than 70 years, male gender, history of reflux and alcohol consumption were found to be predictive factors in the length of BE among patients diagnosed at their index EGD. Although there are limitations to a cross sectional analysis performed at a single institution, our results may be beneficial in identifying those patients who are more likely to have long-segment BE at endoscopy, a group which may be at higher risk of developing esophageal adenocarcinoma. Future research which confirms and delineates the differences in risk by segment length could allow for personalized risk assessment, including individualized screening and management recommendations.
Sa1072 Proton Pump Inhibitors and the Risk of Neoplastic Progression in Barrett's Esophagus: Results of a Large Multicenter Prospective Cohort Study Florine Kastelein, Manon Spaander, Katharina Biermann, Ewout W Steyerberg, Han Geldof, Pieter ter Borg, Wilco Lesterhuis, Elly C. Klinkenberg-Knol, Frank ter Borg, Jeroen J. Kolkman, Gijsbert den Hartog, Antonie J.P. van Tilburg, Gie Tan, Frans T. Peters, Ed Schenk, Leopold G. Engels, Ernst J. Kuipers, Marco J. Bruno Background and aims: Barrett's esophagus (BE) is a premalignant condition predisposing to the development of esophageal adenocarcinoma (EAC). BE usually develops in patients with gastroesophageal reflux disease and therefore it has been suggested that acid exposure plays an import role in the initiation of BE and it's progression toward EAC. For this reason acid suppression with proton pump inhibitors (PPI's) is frequently applied, but it is unclear whether this is truly an effective prevention strategy. Therefore the aim of this study was to evaluate whether acid suppression with proton pump inhibitors is associated with a reduced risk of neoplastic progression in patients with Barrett's esophagus. Methods: In this multicenter, prospective cohort study patients were included with BE of at least 2 cm. Information about medication use was collected from patient interviews and cross-checked with pharmacy records. Multiple pharmacies were contacted for each patient to obtain documentation of all medications that were handed out, including dose and time of prescription. Surveillance was performed according to the ACG guidelines and incident cases of high grade dysplasia (HGD) and EAC were identified during follow-up. Patients, who developed HGD or EAC within 9 months after inclusion, were excluded from this analysis. Cox regression analyses were performed to evaluate the association between PPI use and the risk of neoplastic progression in BE. Results: In this study 570 patients (72% male; mean age 55.1 ± 12.3) were included and followed for a median duration of 7.9 (5.9-11.8) years. Thirty-eight patients developed HGD or EAC during a median follow-up period of 7.6 (4.7-13.0) years. PPI's were prescribed in 562 patients (99%) for a median duration of 9.0 (7.0-12.0) years. Since most patients used a PPI the association between any PPI use and the development of HGD or EAC could not be evaluated. However, after adjustment for age, gender, BE length, baseline histology and use of other medications, longer duration of PPI use was associated with a significantly reduced risk of neoplastic progression (HR 0.86; 95%CI 0.80-0.93; p=<0.001). Prescription of PPI's for more than 10 years was associated with greater reduction in the risk of neoplastic progression (HR 0.09; 95% CI 0.03-0.25; p=<0.001) than prescription of PPI's for 5 to 10 years (HR 0.38; 95%CI 0.15-0.98; p= 0.045). Twenty-six patients (68%) with progression to HGD or EAC used a PPI for at least 90% of the follow-up time, compared to 440 patients (83%) without progression to HGD
AGA Abstracts
Sa1075 Risk Stratification for Barrett's Esophagus: Interim Results of a Logistic Regression Analysis Zehra Omer, Caihua Liang, Kevin J. Nattinger, Patrick S. Yachimski, Chin Hur Purpose: The effectiveness of targeting individuals over age 50 with chronic gastroesophageal reflux disease (GERD) symptoms for Barrett's esophagus (BE) screening is unclear and controversial. Improved risk stratification with comprehensive criteria for determining who
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lesion does not appear to impact the frequency of change in diagnosis. Based on the potential to make an accurate histological diagnosis and thus allowing for better patient selection, EMR should be considered as the first step in the management of BE-associated early neoplasia irrespective of presence or absence of endoscopically visible lesions. Table 1: Frequency of change in diagnosis by EMR in patients with HGD on biopsy
or EAC (p=0.028). Conclusion: Long duration of PPI use is associated with a reduced risk of neoplastic progression in patients with Barrett's esophagus. This observation supports the premise that patients with Barrett's esophagus should be encouraged to continue long term PPI use. Sa1073 The Relationship Between the Distal Margin of the Esophageal Palisade Vessels and the Distal Margin of the Lower Esophageal Sphincter Katsuhiko Iwakiri, Yoshio Hoshihara, Noriyuki Kawami, Hirohito Sano, Yuriko Tanaka, Mariko Umezawa, Seiji Futagami, Choitsu Sakamoto Background: The esophagogastric junction (EGJ), according to the endoscopic diagnostic criteria, is defined differently in Japan to that of Western countries. Although in Western countries, the upper limit of the gastric fold is considered to be the landmark of the EGJ, in Japan, the distal margin of the esophageal palisade vessels is used as the endoscopic landmark of the EGJ. The relationship between the distal margin of the palisade vessels and the distal margin of the LES was investigated because, in esophageal manometry, the distal margin of the LES is considered to be the EGJ. Methods: The subjects were 11 healthy volunteers without hiatus hernia. Esophageal manometry was carried out using the highresolution manometry system, where firstly, the tip of a manometric catheter was inserted into the proximal stomach, after which the catheter was fixed to the mouthpiece at the point where the LES was to be evaluated. The distance from the tip of the mouthpiece to the distal margin of the LES was then continuously measured and an ultra thin endoscope, with a 7mm long translucent silicon hood attached to the tip, was inserted orally into the proximal stomach without being inflated. A measuring device with 1mm gradations was attached to the surface of the endoscope, after which the hood was slightly pressed onto the mucosa near the EGJ, the endoscope was then gradually pulled out and the distance between the tip of the mouthpiece and the distal margin of the palisade vessels was evaluated at 1mm intervals. Measurement of the distance was carried out at the end of an expiration and after practicing several times, the true measurement was carried out 5 times. Maximum and minimum values were excluded and the mean value for each subject was calculated. Results: The distance between the distal margin of the palisade vessels and the distal margin of the LES was 6 mm (2.3-8.8) (median (interquartile range)). In cases where the distal margin of the palisade vessels was regarded as the EGJ, the distal margin of the LES in 6 (54.5%) of 11 subjects was located on the gastric side and the range was 7.5 mm (3-10) below the distal margin of the palisade vessels. In the remaining 5 subjects, the distal margin of the LES was located on the esophageal side and the range was 6 mm (1.8-8) above the distal margin of the palisade vessels. Conclusions: The difference between the distal margin of the palisade vessels and the distal margin of the LES was 6mm (median), therefore, it is considered that the concept of the distal margin of the palisade vessels being the EGJ, is reasonable.
Table 2: Frequency of change in diagnosis by EMR in patients with EAC on biopsy
Sa1071 Sub-Optimal Barrier Function in Neosquamous Epithelium Following Ablative Therapy Biljana Jovov, Nelia Tobey, Nicholas J. Shaheen, Zorka Djukic, Geraldine S. Orlando, Roy C. Orlando Background: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) is an emerging strategy for the prevention of esophageal adenocarcinoma (EAC). The success of RFA is initially assessed by healing of denuded areas on acid suppression therapy with neosquamous epithelium (NSE). Just as vital to the success of RFA, however, is the long term stability of NSE since lack thereof likely accounts for re-emergence of BE and mutagenesis in islands of buried BE. One key to stability of NSE is its barrier function. Methods: Barrier function of NSE was assessed in adults by obtaining endoscopic biopsies (Bx) at varying times following RFA in subjects treated with proton pump inhibitors (PPIs). Bx were fixed for study or mounted in mini-Ussing chambers for recording of electrical resistance (RT) and fluorescein flux and findings compared to that of healthy esophageal epithelium (ESE) and that in gastroesophageal reflux disease (GERD). Results: Mean RT and fluorescein flux of NSE were abnormal, with RT significantly lower and flux significantly higher than for healthy ESE. RT values for NSE recorded 2-22 months post-RFA had no correlation with their duration post-procedure. Further, mean RT and flux values for NSE were similar to those in GERD. Compared to healthy ESE, qRT-PCR, Western blot and immunohistochemistry showed only low expression of claudin 4 at the mRNA and protein level while other claudins were normally expressed. Light microscopy showed dilated intercellular spaces and an increased eosinophils versus ESE. Conclusions: The NSE that emerges post-RFA exhibits barrier function similar to GERD patients. This defect is not related to the time to heal post-RFA and is associated with low claudin-4 in the tight junction. More aggressive acid suppressive measures may be necessary to protect the NSE and decrease the risk of recurrent acid-peptic injury. Support: NIH R37-DK036013
Sa1074 Predictors of Barrett's Esophagus Length Elisabeth B. Cole, Patrick S. Yachimski, Chin Hur Background: Barrett's esophagus (BE) is the greatest known risk factor for the development of esophageal adenocarcinoma. The length of BE, long-segment (length greater than or equal to 3 centimeters) versus short-segment (length less than 3 centimeters), may carry differing risks of progression to cancer. The aim of this study was to analyze variables that predict short-segment versus long-segment BE at index upper endoscopy (EGD). Methods: Study design was a retrospective cross-sectional record review and multivariate logistic regression analysis. Patients who underwent a diagnostic endoscopy at a tertiary referral center over a 12 year time period (1996-2007) were included in the analysis. Results: A total of 311 subjects were included in this analysis. Mean age at diagnosis of BE was 61 ± 14 years; 29% of subjects were female and 92% were Caucasian. Mean height and weight were 68 ± 4 inches and 180 ± 41 pounds, respectively, while mean body mass index (BMI) was 28 ± 5. Half of participants reported some level of alcohol use while 13% were smokers. Over 90% were on proton pump inhibitor (PPI) therapy at the time of BE diagnosis. In terms of BE length, 32% (n=101) were diagnosed with short-segment BE, while 68% (n=210) were found to have a BE segment length of between 3 and 20 centimeters (long-segment BE). Stepwise multivariate regression analysis identified age greater than 70 years (OR=2.6, p= 0.008), male gender (OR=2.1; p=0.01), history of reflux (OR=1.8, p=0.05), and alcohol consumption (OR=1.7, p=0.05) as statistically significant predictors of long-segment BE. No statistically significant associations were observed between co-morbidities (history of heart, lung, liver and stomach conditions, cancer), BMI, weight, tobacco use, current medications (including PPI therapy) or race and BE segment length. Conclusion: Age greater than 70 years, male gender, history of reflux and alcohol consumption were found to be predictive factors in the length of BE among patients diagnosed at their index EGD. Although there are limitations to a cross sectional analysis performed at a single institution, our results may be beneficial in identifying those patients who are more likely to have long-segment BE at endoscopy, a group which may be at higher risk of developing esophageal adenocarcinoma. Future research which confirms and delineates the differences in risk by segment length could allow for personalized risk assessment, including individualized screening and management recommendations.
Sa1072 Proton Pump Inhibitors and the Risk of Neoplastic Progression in Barrett's Esophagus: Results of a Large Multicenter Prospective Cohort Study Florine Kastelein, Manon Spaander, Katharina Biermann, Ewout W Steyerberg, Han Geldof, Pieter ter Borg, Wilco Lesterhuis, Elly C. Klinkenberg-Knol, Frank ter Borg, Jeroen J. Kolkman, Gijsbert den Hartog, Antonie J.P. van Tilburg, Gie Tan, Frans T. Peters, Ed Schenk, Leopold G. Engels, Ernst J. Kuipers, Marco J. Bruno Background and aims: Barrett's esophagus (BE) is a premalignant condition predisposing to the development of esophageal adenocarcinoma (EAC). BE usually develops in patients with gastroesophageal reflux disease and therefore it has been suggested that acid exposure plays an import role in the initiation of BE and it's progression toward EAC. For this reason acid suppression with proton pump inhibitors (PPI's) is frequently applied, but it is unclear whether this is truly an effective prevention strategy. Therefore the aim of this study was to evaluate whether acid suppression with proton pump inhibitors is associated with a reduced risk of neoplastic progression in patients with Barrett's esophagus. Methods: In this multicenter, prospective cohort study patients were included with BE of at least 2 cm. Information about medication use was collected from patient interviews and cross-checked with pharmacy records. Multiple pharmacies were contacted for each patient to obtain documentation of all medications that were handed out, including dose and time of prescription. Surveillance was performed according to the ACG guidelines and incident cases of high grade dysplasia (HGD) and EAC were identified during follow-up. Patients, who developed HGD or EAC within 9 months after inclusion, were excluded from this analysis. Cox regression analyses were performed to evaluate the association between PPI use and the risk of neoplastic progression in BE. Results: In this study 570 patients (72% male; mean age 55.1 ± 12.3) were included and followed for a median duration of 7.9 (5.9-11.8) years. Thirty-eight patients developed HGD or EAC during a median follow-up period of 7.6 (4.7-13.0) years. PPI's were prescribed in 562 patients (99%) for a median duration of 9.0 (7.0-12.0) years. Since most patients used a PPI the association between any PPI use and the development of HGD or EAC could not be evaluated. However, after adjustment for age, gender, BE length, baseline histology and use of other medications, longer duration of PPI use was associated with a significantly reduced risk of neoplastic progression (HR 0.86; 95%CI 0.80-0.93; p=<0.001). Prescription of PPI's for more than 10 years was associated with greater reduction in the risk of neoplastic progression (HR 0.09; 95% CI 0.03-0.25; p=<0.001) than prescription of PPI's for 5 to 10 years (HR 0.38; 95%CI 0.15-0.98; p= 0.045). Twenty-six patients (68%) with progression to HGD or EAC used a PPI for at least 90% of the follow-up time, compared to 440 patients (83%) without progression to HGD
AGA Abstracts
Sa1075 Risk Stratification for Barrett's Esophagus: Interim Results of a Logistic Regression Analysis Zehra Omer, Caihua Liang, Kevin J. Nattinger, Patrick S. Yachimski, Chin Hur Purpose: The effectiveness of targeting individuals over age 50 with chronic gastroesophageal reflux disease (GERD) symptoms for Barrett's esophagus (BE) screening is unclear and controversial. Improved risk stratification with comprehensive criteria for determining who
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