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Sa1987 AMACR Immunohistochemistry for Prediction of Neoplastic Progression in Patients With Barrett's Esophagus: Results From a Large Multicentre Prospective Cohort
Sa1984
BMI group, while tumor stage was equivalent in the normal and high BMI groups. Diseasefree survival of the low and high BMI groups was significantly worse than that of the normal BMI group (P,0.0001 between the low and normal BMI groups; P=0.0076 between the normal and high BMI groups). Multivariate analysis revealed that high BMI was an independent risk factor for recurrence in patients who underwent curative esophagectomy (HR 2.227, 95% confidence interval, 1.104 to 4.189). Disease-free survival of the high BMI group was significantly worse than that of the normal BMI group in the propensity score-matched cohort (P=0.0020). Multivariate analysis in this cohort demonstrated that high BMI was an independent prognostic factor (HR 2.949, 95% confidence interval, 1.132-7.683). Conclusions: Both low and high BMI are associated with poor prognosis for ESCC, through different mechanisms. Advanced tumors are the reason for poor prognosis in patients with a low BMI, while biological aggressiveness of tumors is possibly the determining factor in patients with a high BMI. Although further analysis is required to clarify the influence of overweight on the biological features of ESCC, glucose metabolism may be a therapeutic target for ESCC.
AGA Abstracts
Lewis Biomarkers for Detection of Dysplasia in Barrett's Esophagus Elizabeth L. Bird-Lieberman, Maria O'Donovan, Pierre Lao-Sirieix, Laurence Lovat, Rebecca Fitzgerald Background: Biomarkers are required to improve the problems associated with poor inter and intra-observer agreement in the diagnosis of dysplasia in endoscopic biopsies of Barrett's esophagus (BE). Glycosylation changes associated with the development of cancer have been used clinically as tissue biomarkers in other contexts. Hypothesis: Glycosylation changes that take place as dysplasia develops within BE may act as biomarkers to more accurately predict propensity for cancer. Aims: (i) Empirically identify, using gene expression data, the glycan groups with greatest alteration of expression in progression from BE to AC. (ii) Validate findings in an Early Detection Research Network (EDRN) Phase 2 biomarker study. Methods: Gene set enrichment analysis and unsupervised clustering of gene expression profiles was used to identify glycan genes with altered expression in the development of oesophageal cancer. Automated validation immunohistochemistry was undertaken in an independent cohort (n=86) of patients from University College Hospital. Variance between groups and multivariable logistic regression was undertaken using SPSS. ANOVA analysis was performed using the Bonferroni correction. Results: A list of glycan genes which had altered expression in progression to cancer were identified. 5 of the 6 genes at the top of this list are involved in the synthesis of Lewis (Le) antigens. E-selectin gene expression also increased in the progression towards cancer (P ,0.05) Histochemistry confirmed that sialyl Lea expression did increase in progression to cancer within multiple epithelial compartments (apical epithelial membrane P,0.00001, pan-membranous P,0.0001, diffusely within the cytoplasm P=0.001). Lex similarly validated (apical epithelial membrane P ,0.00001, diffusely within the cytoplasm P,0.0001) and in a pan-membranous distribution P ,0.00001. The sialylated form of the Lex antigen failed to validate. Multivariable logistic regression confirmed that the following were independent predictors of dysplasia: sLea diffuse cytoplasmic staining (P=0.028, 95%CI 1.030-1.681), Lex pan membranous staining (P=0.044, 95%CI 1.008-1.886), Lex apical membrane staining (P=0.008 95%CI 1.095-1.806) and Lex diffuse cytoplasmic staining (P=0.018, 95%CI 0.499-0.938). Conclusions: This phase 2 biomarker study has shown that sLea and Lex are able to act as biomarkers for the detection of dysplasia and staining for this could be performed in an automated manner in the clinical setting. A Phase 3 study is warranted.
Sa1987 AMACR Immunohistochemistry for Prediction of Neoplastic Progression in Patients With Barrett's Esophagus: Results From a Large Multicentre Prospective Cohort Florine Kastelein, Katharina Biermann, Sophie van Olphen, Ewout W. Steyerberg, Leendert Looijenga, Ernst J. Kuipers, Manon C. Spaander, Marco J. Bruno Background and aims: Surveillance is recommended for Barrett's esophagus (BE) to detect esophageal adenocarcinoma (EAC) at an early stage, but is problematic given the overall low incidence of EAC and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is currently the only accepted predictor for progression and therefore crucial for defining surveillance intervals. However, the predictive value of LGD is low due to sample error and interobserver variation. Use of biomarkers may improve risk stratification. The aim of this study was therefore to evaluate the value of alpha-methylacyl-CoA racemase (AMACR) immunohistochemistry for predicting neoplastic progression in BE patients. Methods: We conducted a case-control study within a multicenter prospective cohort of 720 BE patients. Patients were followed according to the ACG guidelines and incident cases of high-grade dysplasia (HGD) and EAC were identified during followup. Patients who developed HGD or EAC were classified as cases and patients without neoplastic progression as controls. AMACR expression was determined by immunohistochemistry in more than 12.000 biopsies from 635 patients and was scored (no expression, mild overexpression, strong overexpression) independently by two expert pathologists who were blinded for long-term outcome. Data were analyzed in loglinear regression models adjusted for age, gender, BE length and esophagitis. Results: 635 BE patients (73% male, median age 60 years (IQR 53-69)) were included in this study and followed during surveillance for a median duration of 6.6 years (IQR 5.1-7.3). Forty-nine (8%) patients developed HGD or EAC during follow-up and were classified as cases. The remaining 586 (92%) patients were classified as controls. AMACR overexpression was more common with higher grades of dysplasia and was seen in 49% of samples without dysplasia, 63% of samples with LGD, 91% of samples with HGD and 77% of samples with EAC (P ,0.001). Mild AMACR overexpression was associated with a trend towards a higher risk of neoplastic progression (RRa 1.6; 95%CI 0.9-3.1), but the risk was especially elevated with strong AMACR overexpression (RRa 4.8; 95%CI 1.9-12.6). The sensitivity of mild AMACR overexpression for predicting progression was 67% with a specificity of 50%. The sensitivity of strong AMACR overexpression for predicting progression was 10% with a specificity of 96%. The positive predictive value increased from 11% with mild AMACR overexpression to 19% with strong AMACR overexpression. Interobserver agreement was moderate ( κ = 0.44; 95%CI 0.410.48). Conclusion: Strong AMACR overexpression is associated with an increased risk of neoplastic progression in BE patients. However, AMACR expression is not sensitive nor specific enough to be used as a single biomarker for prediction of neoplastic progression.
Sa1985 Leukotriene B4 Receptor-1 (Blt-1) and Cysteinyl Leukotriene Receptor-2 (Cyslt-2) Are Deregulated in Both Transformed and Non-Transformed Epithelium of Patients With Esophageal Squamous Cell Carcinoma Marino Venerito, Christoph Helmke, Doerthe Kuester, Thomas Wex, Peter Malfertheiner Background: A role for leukotriene B4 receptors (BLT-1 and BLT-2) and cysteinyl leukotriene receptors (CysLT-1 and CysLT-2) is suggested in malignant cell transformation and proliferation. The expression of these receptors in esophageal squamous cell carcinoma (ESCC) has not been investigated. Aim: To investigate the expression of BLT-1, BLT-2, CysLT-1 and CysLT-2 in ESCC and adjacent non-transformed squamous epithelium of the esophagus (NTSE), as well as in control biopsy samples from esophageal squamous epithelium (CSE) of patients with functional dyspepsia. Methods: Nineteen consecutively diagnosed patients with ESCC were prospectively enrolled between March 2010 and January 2011. UICC stage was calculated based on the 7th AJCC/UICC edition. Furthermore, 9 sex- and age-matched patients with functional dyspepsia were included as controls. Expression levels of BLT-1, BLT-2, CysLT-1 and CysLT-2 were analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples. Spearman correlation, Friedman test, Wilcoxon rang sum test and Mann-Whitney-U-test (2-sided) were used for statistical analysis. Results: Most patients with ESCC were at AJCC/UICC stage IV (11/19, 58%), whereas only 2, 2 and 4 patients were in stage I, II and III, respectively. In general, BLT-1, BLT-2, CysLT-1 and CysLT-2 were found to be ubiquitously expressed in all biopsy samples. Protein and transcript levels of BLT-1 were significantly increased in both ESCC and NTSE compared to CSE (p , 0.05). ESCC showed a significantly increased BLT-2 protein expression compared to NTSE and CSE (p , 0.05), whereas BLT-2 transcript levels did not differ among the three groups. The protein expression of CysLT-1 and CysLT2 was significantly increased in ESCC compared to NTSE and CSE (p , 0.05). CysLT-1 mRNA expression was significantly decreased (3.2 fold) in ESCC compared to CSE (p , 0.05), but not to NTSE. A significant decrease of CysLT-2 mRNA expression was observed in both ESCC (17 fold) and NTSE (16.1 fold) compared to CSE (p , 0.05). Gene expression levels of BLT-1, BLT-2, CysLT-1 and CysLT-2 were not correlated with AJCC/UICC stage. Conclusions: The expression of LT receptors is deregulated in ESCC. Deregulation of BLT1 and CysLT-2 gene expression occurs already in NTSE of patients with ESCC suggesting a potential role of these receptors in early steps of esophageal carcinogenesis.
Sa1988 Sa1986
Recovery of Gastric Function After Helicobacter pylori Eradication and Acetium Administration: A 6 Years Study in Atrophic Gastritis Subjects Francesco Di Mario, Massimo Rugge, Francesco Ferrara, Nadia Dal Bò, Tiziana Slongo, Roberto Marcello, Helena Heras Salvat, Giovanni Guarnieri, Alessandro Caroli, Roberto Rigoli, Angelo Paolo Dei Tos, Carmelo Scarpignato
Prognostic Impact of Body Mass Index in Patients With Squamous Cell Carcinoma of the Esophagus Masayuki Watanabe, Yoshifumi Baba, Naoya Yoshida, Hideo Baba Objective: Although recent studies have revealed that obesity might influence the prognosis of cancer patients, the prognostic significance of BMI for patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC) remains unknown. Aim of this study is to clarify the prognostic impact of body mass index (BMI) in patients with esophageal squamous cell carcinoma (ESCC). Methods: Two hundred and forty-three patients who underwent esophagectomy for ESCC from April 2005 through December 2010 were eligible. Prognoses of the patients were compared between groups stratified according to BMI. Univariate and multivariate analyses were performed to identify factors affecting disease-free survival. We also analyzed the survival difference using propensity score-matching to adjust differences in staging and treatment. Results: Low, normal, and high BMI groups had 35, 177, and 31 patients, respectively. The low BMI group included more advanced cases than did the normal
AGA Abstracts
INTRODUCTION: The relationship between Helicobacter pylori (H. pylori) eradication and atrophic changes in the gastric mucosa has not yet been fully defined. Athough studies report a partial restoration of serum pepsinogen I (sPGI) levels after eradication, it is not clear if this finding reflects gastric mucosal ealing on a morphological level. Recently a new compound (L-cystein Acetium, Biohit, Finland) has been proposed for prevention of gastric carcinogenesis in patients with atrophic gastritis, by reducing acetaldehyde production after food intake. AIMS: To assess alteration in gastric function after H. pylori eradication on moderate-severe body atrophiv gastritis by determination of sPGI levels and Gastrin 17 (sG 17). METHODS:.74 dyspeptic patients, selected from 738 consecutive H. pylori positive patients, with histological features of moderate-severe body atrophic gastritis and sPGI , 25 microg/L (34 men, mean age 58.4 yrs, range 26-83 yrs), underwent an upper gastrointestinal
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BMI group, while tumor stage was equivalent in the normal and high BMI groups. Diseasefree survival of the low and high BMI groups was significantly worse than that of the normal BMI group (P,0.0001 between the low and normal BMI groups; P=0.0076 between the normal and high BMI groups). Multivariate analysis revealed that high BMI was an independent risk factor for recurrence in patients who underwent curative esophagectomy (HR 2.227, 95% confidence interval, 1.104 to 4.189). Disease-free survival of the high BMI group was significantly worse than that of the normal BMI group in the propensity score-matched cohort (P=0.0020). Multivariate analysis in this cohort demonstrated that high BMI was an independent prognostic factor (HR 2.949, 95% confidence interval, 1.132-7.683). Conclusions: Both low and high BMI are associated with poor prognosis for ESCC, through different mechanisms. Advanced tumors are the reason for poor prognosis in patients with a low BMI, while biological aggressiveness of tumors is possibly the determining factor in patients with a high BMI. Although further analysis is required to clarify the influence of overweight on the biological features of ESCC, glucose metabolism may be a therapeutic target for ESCC.
AGA Abstracts
Lewis Biomarkers for Detection of Dysplasia in Barrett's Esophagus Elizabeth L. Bird-Lieberman, Maria O'Donovan, Pierre Lao-Sirieix, Laurence Lovat, Rebecca Fitzgerald Background: Biomarkers are required to improve the problems associated with poor inter and intra-observer agreement in the diagnosis of dysplasia in endoscopic biopsies of Barrett's esophagus (BE). Glycosylation changes associated with the development of cancer have been used clinically as tissue biomarkers in other contexts. Hypothesis: Glycosylation changes that take place as dysplasia develops within BE may act as biomarkers to more accurately predict propensity for cancer. Aims: (i) Empirically identify, using gene expression data, the glycan groups with greatest alteration of expression in progression from BE to AC. (ii) Validate findings in an Early Detection Research Network (EDRN) Phase 2 biomarker study. Methods: Gene set enrichment analysis and unsupervised clustering of gene expression profiles was used to identify glycan genes with altered expression in the development of oesophageal cancer. Automated validation immunohistochemistry was undertaken in an independent cohort (n=86) of patients from University College Hospital. Variance between groups and multivariable logistic regression was undertaken using SPSS. ANOVA analysis was performed using the Bonferroni correction. Results: A list of glycan genes which had altered expression in progression to cancer were identified. 5 of the 6 genes at the top of this list are involved in the synthesis of Lewis (Le) antigens. E-selectin gene expression also increased in the progression towards cancer (P ,0.05) Histochemistry confirmed that sialyl Lea expression did increase in progression to cancer within multiple epithelial compartments (apical epithelial membrane P,0.00001, pan-membranous P,0.0001, diffusely within the cytoplasm P=0.001). Lex similarly validated (apical epithelial membrane P ,0.00001, diffusely within the cytoplasm P,0.0001) and in a pan-membranous distribution P ,0.00001. The sialylated form of the Lex antigen failed to validate. Multivariable logistic regression confirmed that the following were independent predictors of dysplasia: sLea diffuse cytoplasmic staining (P=0.028, 95%CI 1.030-1.681), Lex pan membranous staining (P=0.044, 95%CI 1.008-1.886), Lex apical membrane staining (P=0.008 95%CI 1.095-1.806) and Lex diffuse cytoplasmic staining (P=0.018, 95%CI 0.499-0.938). Conclusions: This phase 2 biomarker study has shown that sLea and Lex are able to act as biomarkers for the detection of dysplasia and staining for this could be performed in an automated manner in the clinical setting. A Phase 3 study is warranted.
Sa1987 AMACR Immunohistochemistry for Prediction of Neoplastic Progression in Patients With Barrett's Esophagus: Results From a Large Multicentre Prospective Cohort Florine Kastelein, Katharina Biermann, Sophie van Olphen, Ewout W. Steyerberg, Leendert Looijenga, Ernst J. Kuipers, Manon C. Spaander, Marco J. Bruno Background and aims: Surveillance is recommended for Barrett's esophagus (BE) to detect esophageal adenocarcinoma (EAC) at an early stage, but is problematic given the overall low incidence of EAC and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is currently the only accepted predictor for progression and therefore crucial for defining surveillance intervals. However, the predictive value of LGD is low due to sample error and interobserver variation. Use of biomarkers may improve risk stratification. The aim of this study was therefore to evaluate the value of alpha-methylacyl-CoA racemase (AMACR) immunohistochemistry for predicting neoplastic progression in BE patients. Methods: We conducted a case-control study within a multicenter prospective cohort of 720 BE patients. Patients were followed according to the ACG guidelines and incident cases of high-grade dysplasia (HGD) and EAC were identified during followup. Patients who developed HGD or EAC were classified as cases and patients without neoplastic progression as controls. AMACR expression was determined by immunohistochemistry in more than 12.000 biopsies from 635 patients and was scored (no expression, mild overexpression, strong overexpression) independently by two expert pathologists who were blinded for long-term outcome. Data were analyzed in loglinear regression models adjusted for age, gender, BE length and esophagitis. Results: 635 BE patients (73% male, median age 60 years (IQR 53-69)) were included in this study and followed during surveillance for a median duration of 6.6 years (IQR 5.1-7.3). Forty-nine (8%) patients developed HGD or EAC during follow-up and were classified as cases. The remaining 586 (92%) patients were classified as controls. AMACR overexpression was more common with higher grades of dysplasia and was seen in 49% of samples without dysplasia, 63% of samples with LGD, 91% of samples with HGD and 77% of samples with EAC (P ,0.001). Mild AMACR overexpression was associated with a trend towards a higher risk of neoplastic progression (RRa 1.6; 95%CI 0.9-3.1), but the risk was especially elevated with strong AMACR overexpression (RRa 4.8; 95%CI 1.9-12.6). The sensitivity of mild AMACR overexpression for predicting progression was 67% with a specificity of 50%. The sensitivity of strong AMACR overexpression for predicting progression was 10% with a specificity of 96%. The positive predictive value increased from 11% with mild AMACR overexpression to 19% with strong AMACR overexpression. Interobserver agreement was moderate ( κ = 0.44; 95%CI 0.410.48). Conclusion: Strong AMACR overexpression is associated with an increased risk of neoplastic progression in BE patients. However, AMACR expression is not sensitive nor specific enough to be used as a single biomarker for prediction of neoplastic progression.
Sa1985 Leukotriene B4 Receptor-1 (Blt-1) and Cysteinyl Leukotriene Receptor-2 (Cyslt-2) Are Deregulated in Both Transformed and Non-Transformed Epithelium of Patients With Esophageal Squamous Cell Carcinoma Marino Venerito, Christoph Helmke, Doerthe Kuester, Thomas Wex, Peter Malfertheiner Background: A role for leukotriene B4 receptors (BLT-1 and BLT-2) and cysteinyl leukotriene receptors (CysLT-1 and CysLT-2) is suggested in malignant cell transformation and proliferation. The expression of these receptors in esophageal squamous cell carcinoma (ESCC) has not been investigated. Aim: To investigate the expression of BLT-1, BLT-2, CysLT-1 and CysLT-2 in ESCC and adjacent non-transformed squamous epithelium of the esophagus (NTSE), as well as in control biopsy samples from esophageal squamous epithelium (CSE) of patients with functional dyspepsia. Methods: Nineteen consecutively diagnosed patients with ESCC were prospectively enrolled between March 2010 and January 2011. UICC stage was calculated based on the 7th AJCC/UICC edition. Furthermore, 9 sex- and age-matched patients with functional dyspepsia were included as controls. Expression levels of BLT-1, BLT-2, CysLT-1 and CysLT-2 were analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples. Spearman correlation, Friedman test, Wilcoxon rang sum test and Mann-Whitney-U-test (2-sided) were used for statistical analysis. Results: Most patients with ESCC were at AJCC/UICC stage IV (11/19, 58%), whereas only 2, 2 and 4 patients were in stage I, II and III, respectively. In general, BLT-1, BLT-2, CysLT-1 and CysLT-2 were found to be ubiquitously expressed in all biopsy samples. Protein and transcript levels of BLT-1 were significantly increased in both ESCC and NTSE compared to CSE (p , 0.05). ESCC showed a significantly increased BLT-2 protein expression compared to NTSE and CSE (p , 0.05), whereas BLT-2 transcript levels did not differ among the three groups. The protein expression of CysLT-1 and CysLT2 was significantly increased in ESCC compared to NTSE and CSE (p , 0.05). CysLT-1 mRNA expression was significantly decreased (3.2 fold) in ESCC compared to CSE (p , 0.05), but not to NTSE. A significant decrease of CysLT-2 mRNA expression was observed in both ESCC (17 fold) and NTSE (16.1 fold) compared to CSE (p , 0.05). Gene expression levels of BLT-1, BLT-2, CysLT-1 and CysLT-2 were not correlated with AJCC/UICC stage. Conclusions: The expression of LT receptors is deregulated in ESCC. Deregulation of BLT1 and CysLT-2 gene expression occurs already in NTSE of patients with ESCC suggesting a potential role of these receptors in early steps of esophageal carcinogenesis.
Sa1988 Sa1986
Recovery of Gastric Function After Helicobacter pylori Eradication and Acetium Administration: A 6 Years Study in Atrophic Gastritis Subjects Francesco Di Mario, Massimo Rugge, Francesco Ferrara, Nadia Dal Bò, Tiziana Slongo, Roberto Marcello, Helena Heras Salvat, Giovanni Guarnieri, Alessandro Caroli, Roberto Rigoli, Angelo Paolo Dei Tos, Carmelo Scarpignato
Prognostic Impact of Body Mass Index in Patients With Squamous Cell Carcinoma of the Esophagus Masayuki Watanabe, Yoshifumi Baba, Naoya Yoshida, Hideo Baba Objective: Although recent studies have revealed that obesity might influence the prognosis of cancer patients, the prognostic significance of BMI for patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC) remains unknown. Aim of this study is to clarify the prognostic impact of body mass index (BMI) in patients with esophageal squamous cell carcinoma (ESCC). Methods: Two hundred and forty-three patients who underwent esophagectomy for ESCC from April 2005 through December 2010 were eligible. Prognoses of the patients were compared between groups stratified according to BMI. Univariate and multivariate analyses were performed to identify factors affecting disease-free survival. We also analyzed the survival difference using propensity score-matching to adjust differences in staging and treatment. Results: Low, normal, and high BMI groups had 35, 177, and 31 patients, respectively. The low BMI group included more advanced cases than did the normal
AGA Abstracts
INTRODUCTION: The relationship between Helicobacter pylori (H. pylori) eradication and atrophic changes in the gastric mucosa has not yet been fully defined. Athough studies report a partial restoration of serum pepsinogen I (sPGI) levels after eradication, it is not clear if this finding reflects gastric mucosal ealing on a morphological level. Recently a new compound (L-cystein Acetium, Biohit, Finland) has been proposed for prevention of gastric carcinogenesis in patients with atrophic gastritis, by reducing acetaldehyde production after food intake. AIMS: To assess alteration in gastric function after H. pylori eradication on moderate-severe body atrophiv gastritis by determination of sPGI levels and Gastrin 17 (sG 17). METHODS:.74 dyspeptic patients, selected from 738 consecutive H. pylori positive patients, with histological features of moderate-severe body atrophic gastritis and sPGI , 25 microg/L (34 men, mean age 58.4 yrs, range 26-83 yrs), underwent an upper gastrointestinal
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