Romero, Yvonne

97 Background: A diagnosis of EC significantly impairs patient (pt)’s survival and quality of life (QoL). We explored the relationship between pt-assessed QoL and survival. Methods: The Mayo Clinic Romero (formerly Esophageal Adenocarcinoma-Barrett's Esophagus) Registry prospectively collects clinical data during a pt's treatment course. QoL is recorded at enrollment (baseline) and annually using a validated 12-item Linear Analog Self-Assessment (LASA). A 10-pt scale is applied; ≤5 was termed clinically deficient QoL. Initial TNM staging, clinical (age, sex, prior chemotherapy, and esophagectomy), and socioeconomic variables (marital/employment status) were analyzed using Cox proportional hazards regression models. Results: 836 pts were analyzed. Median age was 64 years. 166, 506 and 164 pts had early, locally advanced, and metastatic EC, with 5-year survival rates of 75.1%, 33.6%, and 8.1%, respectively (P≤.0001). Poorer survival rates were seen in clinically QoL deficient pts in the following categories: Overall QoL (Hazard Ratio [H.R.] 0.66; 95% C.I., 0.54-0.80; P≤.0001) and LASA subsets for physical (H.R. 0.68; 95% C.I., 0.57-0.82; P≤.0001), emotional well-being (H.R. 0.69; C.I., 0.57-0.84; P=.0003), and social activity (H.R. 0.76; C.I., 0.63-0.91; P=.0028). No difference in survival was observed for marital or employment status, familial support, and financial/legal concerns. Pts with esophagectomy prior to LASA evaluation had improved survival (H.R. 0.68; 95% C.I., 0.55-0.85; P=.0005). No survival difference was observed whether pts received chemotherapy, before or after their baseline LASA evaluation. Conclusions: A strong association exists between pt’s overall survival and better overall QOL, physical, emotional well-being, and social activities. Using LASA to clinically monitor QoL at specified intervals may afford providers the opportunity to intervene when patients begin to experience QoL decline. The determinants of clinically deficit QoL and its impact on survival warrant further translational and prospective research.

42 Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.

9 Background: We examined patient-reported fatigue scores and overall survival (OS) in patients with esophageal cancer (EC) enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry (EABE). Methods: 1,481 patients enrolled in the EABE between September 2001 and January 2009 returned a baseline quality of life questionnaire including a Linear Analog Self Assessment (LASA) fatigue score which was scored on a 0-10 scale, with 0 as the most extreme fatigue. Patients were categorized as having clinically deficient fatigue (DF) if they reported a score of ≤ 5 and clinically non-deficient fatigue (nDF) if they reported a score of > 5. Kaplan-Meier methodology and Cox models explored OS in relation to fatigue scores in patients with EC. Results: A total of 667 patients with EC were included in the EABE, of which 659 returned a registry questionnaire with a valid LASA fatigue score recorded. Median age at the time of registry entry was 65 years (range 23-92). A total of 392 (59%) and 267 patients (41%) reported DF and nDF, respectively. On univariate analysis, patients with nDF had improved 5-year survival compared to patients with DF. In patients having esophagectomy prior to LASA, those reporting nDF had improved survival compared to patients with DF. Similarly, in patients having no esophagectomy prior to LASA, those with nDF had improved survival compared to those with DF. Among the 368 patients with locally advanced EC (LAEC), those reporting nDF had improved 5-year overall survival compared to patients with DF (28% vs 17%, HR = 0.67, p = 0.003). This remained significant on multivariate analysis (HR = 0.71, p = 0.015). Conclusions: Patient-reported fatigue is associated with overall survival in patients with LAEC. As a result, fatigue scores should be considered as a stratification factor in future clinical trial design. [Table: see text] No significant financial relationships to disclose.

The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic‐epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene‐based approach: versatile gene‐based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body‐mass index, waist‐to‐hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen‐related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

AbstractBackgroundHigh‐resolution manometry using the Chicago classification, which utilizes parameters including integrated relaxation pressure (IRP), distal contractile integral (DCI), and contractile front velocity (CFV), shows better diagnostic ability than previous conventional criteria. However, the current normal cut‐off values for the Chicago classification are based on individuals aged 19–48 years and do not include older people. Here, we aimed to assess the normal values for the Chicago classification in individuals aged 20–67 years and compare the parameters across age groups.MethodsFifty‐four asymptomatic healthy individuals (27 male and 27 female; age range. 20–67 years) were prospectively enrolled. To evaluate the effect of age and sex on manometric profiles, we attempted to enroll equal numbers of male and female subjects for each decade. Manometry was performed in both the supine and sitting positions.Key ResultsThe distal latency (DL) was significantly shorter with increasing age in both measurement positions. Furthermore, IRP was significantly higher with increasing age in both positions. Spearman's ranked correlation coefficient analysis indicated that DCI and IRP in both positions were positively correlated with age.Conclusions & InferencesAge affects the key parameters currently used in the Chicago classification, including IRP, DCI, and DL. Larger prospective studies with older subjects are needed to determine the age‐related normal values for the Chicago classification system.

Abstract Background Long‐lasting food impactions requiring endoscopic bolus removal occur frequently in patients with eosinophilic esophagitis ( E o E ) and harbor a risk for severe esophageal injuries. We evaluated whether treatment with swallowed topical corticosteroids is able to reduce the risk of occurrence of this complication. Methods We analyzed data from the S wiss E o E C ohort Study. Patients with yearly clinic visits, during which standardized assessment of symptoms, endoscopic, histologic, and laboratory findings was carried out, were included. Results A total of 206 patients (157 males) were analyzed. The median follow‐up time was 5 years with a total of 703 visits (mean 3.41 visits/patient). During the follow‐up period, 33 patients (16 % of the cohort) experienced 42 impactions requiring endoscopic bolus removal. We evaluated the following factors regarding the outcome ‘bolus impaction’ by univariate logistic regression modeling: swallowed topical corticosteroid therapy ( OR 0.503, 95%‐ CI 0.255–0.993, P = 0.048), presence of EoE symptoms ( OR 1.150, 95%‐ CI 0.4668–2.835, P = 0.761), esophageal stricture ( OR 2.832, 95%‐ CI 1.508–5.321, P = 0.001), peak eosinophil count >10 eosinophils/ HPF ( OR 0.724, 95%‐ CI 0.324–1.621, P = 0.433), blood eosinophilia ( OR 1.532, 95%‐ CI 0.569–4.118, P = 0.398), and esophageal dilation ( OR 1.852, 95%‐ CI 1.034–3.755, P = 0.017). In the multivariate model, the following factors were significantly associated with bolus impaction: swallowed topical corticosteroid therapy ( OR 0.411, 95%‐ CI 0.203–0.835, P = 0.014) and esophageal stricture ( OR 2.666, 95%‐ CI 1.259–5.645, P = 0.01). Increasing frequency of use of swallowed topical steroids was associated with a lower risk for bolus impactions. Conclusions Treatment of E o E with swallowed topical corticosteroids significantly reduces the risk for long‐lasting bolus impactions.

Abstract Background: In patients with Barrett's esophagus, chronic reflux injury and inflammation are associated with esophageal adenocarcinoma, one of the most rapidly increasing lethal cancers. Epidemiological and preclinical studies support decreased risk of esophageal adenocarcinoma with NSAID use. Gastroesophageal refluxate contents can promote carcinogenesis in Barrett's metaplasia by activating AKT, which up regulates COX-2 expression and prostaglandin biosynthesis. We recently noted that neoplastic transformation in Barrett's esophagus is associated with increased AKT expression, particularly isoform AKT1. The AIM of this study is to investigate the effect of NSAID (Aspirin) use in patients with Barrett's esophagus on AKT1 expression using frozen tissue from the randomized, phase II trial of aspirin and esomeprazole for esophageal cancer chemoprevention in Barrett's esophagus patients and to assess the functional consequences of AKT1 expression in-vitro. Methods and Results: In a subset of patients (12 of 120 patients) with Barrett's esophagus who were randomized to placebo, lower dose (81 mg) or higher dose (325 mg) Aspirin for 4 weeks, both PCR and Western blot revealed marked reduction in AKT1 expression in patients who received 325 mg of Aspirin daily compared to patients who received placebo. Our in-vitro experiments support that AKT1 expression is functionally relevant to the process of carcinogenesis in Barrett's epithelial cells. Using adenovirus to induce AKT1 expression, we show that increased AKT1 expression increases Barrett's epithelial cell growth, facilitates RAS-mediated transformation of pre-neoplastic epithelial cells and promotes colony formation. Since AKT1 is known as Warburg kinase and regulates cellular glucose uptake to support aerobic glycolysis during growth de-regulation and neoplasia, we examined the uptake of fluorescent deoxyglucose analog (2-NBDG) in Barrett's epithelial cells transduced with AKT1 adenovirus. At 48 hrs, compared to control, AKT1 overexpression resulted in increased glucose uptake both by metaplastic and neoplastic Barrett's epithelial cells. Transcriptional repression of AKT1 abrogated the 2-NBDG uptake by these cells. Finally, we did pathway specific qPCRs and noted that use of Aspirin is associated with altered expression of chromatin remodelers that could down-regulate AKT1 expression. Conclusion: Collectively, our results demonstrate that Aspirin mediated down-regulation of Warburg kinase AKT1 in patients with Barrett?s esophagus is a novel mechanism for the regulation of Barrett?s epithelial cell growth. The in-depth characterization of molecular mechanisms is currently underway. This abstract is also presented as Poster A82. Citation Format: Navtej S. Buttar, Gary W. Falk, Cathrine J. DeMars, Sonia Chowdhury, Ahmed Elebiary, Anamay Sharma, Sidhartha Chaudhry, Nathan R. Foster, Katie L. Allen Ziegler, Yvonne Romero, Norman E. Marcon, Thomas Schnell, Douglas A. Corley, Prateek Sharma, Marcia R. Cruz-Correa, Chin Hur, David E. Fleischer, Amitabh Chak, Kenneth R. DeVault, David S. Weinberg, Gary Della’Zanna, Ellen Richmond, Thomas C. Smyrk, Sumithra Mandrekar, Paul J. Limburg. Aspirin mediated downregulation of Warburg kinase AKT1 in patients with Barrett's esophagus: Implications in neoplastic transformation. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PR-03.