Neoplastic Progression In Patients Research Articles

Validation of an Epigenetic Prognostic Assay to Accurately Risk-Stratify Patients with Barrett's Esophagus.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is the second-most lethal cancer in the United States, with Barrett esophagus (BE) being the strongest risk factor. Assessing the future risk of neoplastic progression in patients with BE is difficult; however, high-grade dysplasia (HGD) and early EAC are treatable by endoscopic eradication therapy (EET), with survival rates of 90%. Thus, it would be beneficial to develop a molecular assay to identify high-risk patients, who merit more frequent endoscopic surveillance or EET, as well as low-risk patients, who can avoid EET and undergo less frequent surveillance. METHODS: Deidentified endoscopic biopsies were acquired from 240 patients with BE at 6 centers and confirmed as future progressors or nonprogressors. Tissues were analyzed by a set of methylation-specific biomarker assays. Test performance was assessed in an independent validation set using 4 stratification levels: low risks, low-moderate risks, high-moderate risks, and high risks. RESULTS: Relative to patients in the low-risk group, high-risk patients were 15.2 times more likely to progress within 5 years to HGD or EAC. For patients in the high-risk category, the average risk of progressing to HGD or EAC within 5 years was 21.5%, 4-fold the BE population prevalence within 5 years, whereas low-risk patients had a progression risk of only 1.85%. DISCUSSION: This clinical assay, Esopredict, stratifies future neoplastic progression risk to identify higher-risk patients with BE who can benefit from EET or more frequent surveillance and lower-risk patients who can benefit from reduced surveillance.

The Tissue Systems Pathology Test Outperforms Pathology Review in Risk Stratifying Patients With Low-Grade Dysplasia

Low-grade dysplasia (LGD) is associated with an increased risk of progression in Barrett's esophagus (BE); however, the diagnosis of LGD is limited by substantial interobserver variability. Multiple studies have shown that an objective tissue systems pathology test (TissueCypher Barrett's Esophagus Test, TSP-9), can effectively predict neoplastic progression in patients with BE. This study aimed to compare the risk stratification performance of the TSP-9 test vs benchmarks of generalist and expert pathology. A blinded cohort study was conducted in the screening cohort of a randomized controlled trial of patients with BE with community-based LGD. Biopsies from the first endoscopy with LGD were assessed by the TSP-9 test and independently reviewed by 30 pathologists from 5 countries per standard practice. The accuracy of the test and the diagnoses in predicting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) were compared. A total of 154 patients with BE (122 men), mean age 60.9 ± 9.8 years were studied. Twenty-four patients progressed to HGD/EAC within 5 years (median time of 1.7 years) and 130 did not progress to HGD/EAC within 5 years (median 7.8 years follow-up). The TSP-9 test demonstrated higher sensitivity (71% vs mean 63%, range 33%-88% across 30 pathologists), than the pathology review in detecting patients who progressed (P=.01186). The TSP-9 test outperformed the pathologists in risk stratifying patients with BE with LGD. Care guided by the test can provide an effective solution to variable pathology review of LGD, improving health outcomes by upstaging care to therapeutic intervention for patients at high risk for progression, while reducing unnecessary interventions in low-risk patients.

Improving the Endoscopic Detection and Management of Gastric Intestinal Metaplasia Through Training: A Practical Guide

Improving the Endoscopic Detection and Management of Gastric Intestinal Metaplasia Through Training: A Practical Guide

The risk of neoplasia in patients with Barrett's esophagus indefinite for dysplasia: a multicenter cohort study

Background and AimsCurrent understanding of the risk of neoplastic progression in patients with Barrett's esophagus with indefinite dysplasia (BE-IND) stems from small retrospective and pathology registry studies. In this multicenter cohort study, we aimed to determine the incidence and prevalence of neoplasia in BE-IND.MethodsPatients with confirmed BE-IND from 2 academic centers were included if they had no previous evidence of dysplasia and underwent endoscopic follow-up (FU) of ≥1 year. The rate of progression to neoplasia was calculated and categorized as prevalent (progression within 1 year of FU) and incident (progression after 1 year of FU). Multivariable regression adjusted for relevant clinical features was performed to identify risk factors for progression.ResultsFour hundred sixty-five patients diagnosed with BE-IND were identified between 1997 and 2017, of which 223 (48.0%) were excluded. Of the remaining 242 patients, 184 (76.0%) had no evidence of dysplasia during FU. In 23 patients (9.5%), prevalent neoplasia occurred (20 low-grade dysplasia [LGD], 2 high-grade dysplasia [HGD], 1 intramucosal cancer [IMC]), whereas 35 patients (14.5%) developed incident neoplasia (27 LGD, 5 HGD, 3 IMC), after a median 1.5 years (interquartile range, 0.6-3.2 years). The incidence rates of any neoplasia and HGD/IMC were 3.2 and 0.6 cases/100 patient-years, respectively. BE length correlated with an increased risk of prevalent (odds ratio, 1.18 per 1 cm; 95% confidence interval, 1.02-1.38; P = .033) and incident neoplasia (odds ratio, 1.02; 95% confidence interval, 1.00-1.03; P = .016).ConclusionPatients with BE-IND should be closely monitored, because nearly a quarter harbor or will shortly develop dysplasia. BE length is a clinical predictor of neoplastic progression; however, more-accurate molecular biomarkers for risk stratification are warranted.

Predictive Factors for Pancreatic Cancer and Its Early Detection Using Special Pancreatic Ultrasonography in High-Risk Individuals.

Simple SummaryThe early detection of pancreatic cancer is required to improve prognosis. We aimed to analyze the predictive factors of neoplastic progression in patients at high risk for pancreatic cancer and examined the efficiency of surveillance using transabdominal special ultrasonography focusing on the pancreas (special pancreatic US). On long-term surveillance with special pancreatic US of 498 patients who had main pancreatic duct (MPD) dilatation (≥2.5 mm) and/or pancreatic cysts (≥5 mm), neoplastic progression developed in 11 patients (2.2%). Findings of both MPD dilatation and pancreatic cysts, MPD growth (≥0.2 mm/year) and cyst growth (≥2 mm/year) during surveillance were risk factors for neoplastic progression. Periodic surveillance using special pancreatic US allowed the early diagnosis of neoplastic progression (stage 0/I: 72.7%), leading to a favorable prognosis (overall survival: 8.8 years). This study clarified the efficiency of surveillance with special pancreatic US for high-risk individuals and key changes during surveillance to watch for.Because pancreatic cancer has a dismal prognosis, a strategy for early diagnosis is required. This study aimed to identify predictive factors of neoplastic progression in patients at high risk for pancreatic cancer and examined the efficiency of surveillance using transabdominal special ultrasonography focusing on the pancreas (special pancreatic US). Patients with slight main pancreatic duct (MPD) dilatation (≥2.5 mm) and/or pancreatic cysts (≥5 mm) were enrolled in a prospective surveillance study with special pancreatic US in a Japanese cancer referral center. A total of 498 patients undergoing surveillance for ≥3 years were included. During the median follow-up of 5.9 years, neoplastic progression developed in 11 patients (2.2%), including 9 patients who underwent pancreatectomy. Eight patients (72.7%) were diagnosed with stage 0/I disease, with an overall survival duration of 8.8 years. Findings of both MPD dilatation and pancreatic cysts at initial surveillance, MPD growth (≥0.2 mm/year) and cyst growth (≥2 mm/year) during surveillance were identified as independent risk factors for neoplastic progression. In summary, surveillance with special pancreatic US for high-risk individuals contributed to earlier detection of neoplastic progression, leading to a favorable prognosis. During surveillance, attention should be paid to MPD growth as well as to cyst growth.

Neutrophil to lymphocyte ratio and risk of neoplastic progression in patients with Barrett's esophagus.

Patient's with Barrett's esophagus (BE) are at risk of progression to esophageal adenocarcinoma (EAC). Neutrophil to lymphocyte ratio (NLR) was found to be a predictor of poor prognosis in patients with EAC; however, its performance in premalignant esophageal lesions is vague. We aimed to evaluate the utility of NLR as a predictor of histologic progression in patients with BE. METHODS : A prospective cohort of patients with proven BE in a tertiary referral center was retrospectively analyzed. All biopsies were reviewed by an expert gastrointestinal pathologist. The discriminatory capacity of NLR was evaluated by area under the receiver operating characteristic (AUC) curve analysis and Cox regression analysis. 324 patients (mean age 62.3 years, 241 [74.4 %] males) were included in the final analysis. Overall, 13 patients demonstrated histologic progression to neoplasia over a mean follow-up of 3.7 years (progression risk 1.0 % per year). The AUC of NLR for progression to high grade dysplasia (HGD) or EAC was 0.88 (95 % confidence interval [CI] 0.83 - 0.96), and baseline NLR was associated with a 3-fold increase of progression to HGD and EAC during follow-up (hazard ratio [HR] 3.2, 95 %CI 1.5 - 5.8; P < 0.001). Notably, in a subgroup analysis of patients with nondysplastic BE (NDBE) at presentation, NLR was also a risk factor for histologic progression (HR 2.4, 95 %CI 1.7 - 3.4; P < 0.001). NLR predicted histologic progression in patients with BE. Patients with NDBE and NLR above 2.4 can be considered for specific surveillance programs with shorter intervals between sessions.

S0025 Patients in Familial Pancreatic Cancer Kindreds Demonstrate Increased High-Risk Radiological Features Compared to Those With Deleterious Germline Variants in a High-Risk Pancreatic Surveillance Program

INTRODUCTION: Recent literature has identified risk factors for neoplastic progression in patients at increased risk of pancreatic ductal adenocarcinoma (PDAC). Solid pancreatic masses, ≥ 3 cysts at baseline, main pancreatic duct dilation ≥ 5 mm at baseline, and the presence of pathogenic germline variants have been described as being associated with neoplastic progression. METHODS: We performed a retrospective study of high-risk individuals (HRIs) who underwent pancreatic surveillance at a tertiary referral center between May 2013 and April 2020. HRIs were included if they 1) had a pathogenic (P) or likely pathogenic (LP) germline variant that has been associated with PDAC, with at least one first- or second-degree relative with PDAC, or 2) were from familial pancreatic cancer (FPC) kindreds, defined as patients without an identifiable germline mutation but with two or more relatives with PDAC, at least one of whom is a first degree relative of the HRI. Initial surveillance imaging results and clinical data were reviewed. Univariable analyses were performed using Fisher’s exact test and multivariable analyses using logistic regression. RESULTS: A total of 117 patients met inclusion criteria: 39 with P/LP germline variants and 78 from FPC kindreds. Seventy-eight (66.7%) study subjects were female and median age was 63.3 ± 12.4. No other differences were noted in demographics. Of the 39 P/LP germline variants, 12 (30.8%) were in BRCA1, BRCA2 20 (51.3%), ATM 2 (5.1%), PALB2 1 (2.6%), and MSH2 4 (10.3%). Worrisome radiologic features included solid masses (n = 2), multifocal cysts (n = 26), or main pancreatic duct dilation ≥ 5 mm (n = 3) at baseline imaging with endoscopic ultrasound or magnetic resonance cholangiopancreatography. On initial surveillance, 27 (34.6%) patients from FPC kindreds exhibited worrisome radiologic findings compared to 4 (10.3%) of those with germline variants (p = 0.007). Multivariate logistic regression demonstrated that FPC (aOR 4.08, 95% CI 1.22–13.68) and age (aOR 1.10, 95% CI 1.04–1.17) were predictors of worrisome radiologic findings on initial surveillance when adjusting for confounders. CONCLUSION: In our study, patients in the FPC cohort exhibited a higher prevalence of worrisome radiologic features compared to patients with germline mutations. Further evaluation is needed to determine whether FPC patients with worrisome features are at increased risk of neoplastic progression compared to patients with P/LP germline variants in a high-risk cohort.Table 1.: Logistic Regression Analysis of Factors Associated with Worrisome Radiologic Features

3106 Cirrhosis and Barrett's? WATS-3D as a Screening Tool

INTRODUCTION: Barrett's esophagus (BE) is a pre-malignant condition in patients with long-standing GERD. The gold standard for diagnosing BE is taking 4-quadrant esophageal biopsies during endoscopy followed by demonstration of intestinal metaplasia on histopathology. However, in patients with cirrhosis, taking biopsies is rendered difficult due to an increased risk of bleeding due to esophageal varices and coagulopathy. This case series reports three patients with cirrhosis that were successfully diagnosed with BE using WATS3D (Wide angle trans-epithelial sampling with computer assisted 3 dimensional tissue analysis). CASE DESCRIPTION/METHODS: Case 1: 66 year-old female with a history of cirrhosis secondary to autoimmune hepatitis, esophageal varices, GERD and previously diagnosed BE that had liver and kidney transplants 3 years prior to presentation. Case 2: 63 year-old male with a history of BE, Laennec's cirrhosis, esophageal varices and portal hypertensive gastropathy. Case 3: 62 year-old male with a history of cirrhosis due to untreated hepatitis C and alcohol abuse, known carrier for HFE gene, GERD and BE. Case 1 and 2 had WATS3D brushings and mucosal biopsies, while Case 3 had WATS3D brushings alone due to concerns of bleeding. The findings are described in Table 1. There was agreement between the WATS3D analysis and biopsy results in the 2 patients. The patient with WATS3D brushings alone had evidence of goblet cell metaplasia. There were no immediate or post-procedural complications (bleeding, infections) in any of the patients. DISCUSSION: Review of literature suggests that the prevalence of GERD and neoplastic progression in patients with cirrhosis is higher compared to patients without liver disease. However, weighing the benefits and risks of taking biopsies during EGD, many cases of BE go undetected when physicians refrain from taking biopsies and rely solely on endoscopic findings. WATS3D uses a minimally invasive brush biopsy that resects wide area tissue samples, allowing analysis of the full trans-epithelial thickness of the esophagus. It is less invasive than forceps biopsy, has a higher sampling yield, and would be safer in patients at high risk of bleeding complications in patients similar to those presented in this case report.

Predictors of dysplastic and neoplastic progression of Barrett’s esophagus

It is unknown why some cases of Barrett’s esophagus progress to invasive malignant disease rapidly while others do so more slowly or not at all. The aim of this study was to identify demographic and endoscopic factors that predict dysplastic and neoplastic progression in patients with Barrett’s esophagus. Patients with Barrett’s esophagus who were assessed in 2000–2010 were assessed for inclusion in this retrospective study. Demographic and endoscopic variables were collected from an endoscopy database and the medical chart. Dysplastic and neoplastic progression was examined by time-to-event analysis. We used Cox proportional hazard regression modelling and generalized estimating equation methods to identify variables that were most predictive of neoplastic progression. A total of 518 patients had Barrett’s esophagus confirmed by endoscopy and pathology and at least 2 surveillance visits. Longer Barrett’s esophagus segment (≥ 3 cm) (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1–1.3) and increased age (≥ 60 yr) (OR 3.5, 95% CI 1.7–7.4) were independent predictors of progression from nondysplasia to dysplastic or neoplastic grades. Presence of mucosal irregularities (OR 8.6, 95% CI 2.4–30.4) and increased age (OR 5.1, 95% CI 1.6–16.6) were independent predictors of progression from nondysplasia to high-grade dysplasia or adenocarcinoma. Increased age, longer Barrett’s segment and presence of mucosal irregularities were associated with increased risk of dysplastic and neoplastic progression. In addition to dysplasia, these factors may help stratify patients according to risk of neoplastic progression and be used to individualize surveillance. More prospective studies with larger samples are required to validate these results.

Su1053 - Neoplastic Progression in Patients with Short Segment Barrett's Esophagus: Long-Term Follow-up of Over a 1000 Patients in a Multi-Center Consortium

Su1053 - Neoplastic Progression in Patients with Short Segment Barrett's Esophagus: Long-Term Follow-up of Over a 1000 Patients in a Multi-Center Consortium

Lack of incremental effect of histamine receptor antagonists over proton pump inhibitors on the risk of neoplastic progression in patients with Barrett's esophagus: a cohort study.

Long-term acid suppression reduces the risk of progression to esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). Given recent reports about the harmful effects of using chronic proton pump inhibitors (PPI) there is renewed interest in alternative methods of acid suppression. Hence, we studied the effect of H2 receptor antagonists (H2 RA) on the risk of progression to neoplasia in our BE cohort. This is a retrospective analysis of prospectively collected data of patients in our BE registry from 2002 to 2015. Patients' characteristics, endoscopic findings, such as the length of BE, hiatal hernia size and histological findings and patients' use of medications such as PPI, aspirin, H2 RA, metformin and antihyperlipidemic agents were studied. The cohort consisted of 1466 patients with a mean age of 61 ± 13 years. The patients had a predominance of male sex (76.7% [1118/1457]) and Caucasian race (96.6% [1209/1252]). After excluding prevalent high-grade dysplasia (HGD) or EAC, 1025 patients had a median follow up of 43.6 months during which 57 patients progressed to HGD or EAC. PPI use (56% in progressors vs 69% in non-progressors; P = 0.007) but not H2 RA use (12% progressors vs 19% in non-progressors P = 0.162) was associated with lower risk of neoplastic progression. On multivariate analysis, there was no synergistic effect of addition of H2 RA to PPI on risk of neoplastic progression to HGD or EAC (relative risk 0.33; confidence intervals 0.05-2.29, P = 0.262). H2 RA do not seem to have a chemopreventive role in patients with BE.

Nonsteroidal Anti-Inflammatory Drug Use is Not Associated With Reduced Risk of Barrett's Esophagus.

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of esophageal adenocarcinoma. Epidemiological studies examining the association between NSAID use and the risk of the precursor lesion, Barrett's esophagus, have been inconclusive. We analyzed pooled individual-level participant data from six case-control studies of Barrett's esophagus in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). We compared medication use from 1,474 patients with Barrett's esophagus separately with two control groups: 2,256 population-based controls and 2,018 gastroesophageal reflux disease (GERD) controls. Study-specific odds ratio (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models and were combined using a random-effects meta-analytic model. Regular (at least once weekly) use of any NSAIDs was not associated with the risk of Barrett's esophagus (vs. population-based controls, adjusted OR=1.00, 95% CI=0.76-1.32, I2=61%; vs. GERD controls, adjusted OR=0.99, 95% CI=0.82-1.19, I2=19%). Similar null findings were observed among individuals who took aspirin or non-aspirin NSAIDs. We also found no association with highest levels of frequency (at least daily use) and duration (≥5 years) of NSAID use. There was evidence of moderate between-study heterogeneity; however, associations with NSAID use remained non-significant in "leave-one-out" sensitivity analyses. Use of NSAIDs was not associated with the risk of Barrett's esophagus. The previously reported inverse association between NSAID use and esophageal adenocarcinoma may be through reducing the risk of neoplastic progression in patients with Barrett's esophagus.

Determination of risk for Barrett's esophagus and esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma and its precursor, Barrett's esophagus, have increased greatly over the past 40 years and continue to rise. This report summarizes the most recent data on the risk factors for Barrett's esophagus and esophageal adenocarcinoma. Other factors, highly correlated with increasing trends for obesity, are the dominant driver of the increase in incidence of esophageal adenocarcinoma, interacting with gastroesophageal reflux disease symptoms. Abdominal obesity, independently of gastroesophageal reflux disease symptoms, is associated with increased risk of Barrett's esophagus and this association is likely mediated by high levels of leptin and insulin. Use of aspirin, nonsteroidal anti-inflammatory drugs, statins, and proton pump inhibitors are associated with a reduced risk of Barrett's esophagus as well as lower risk of neoplastic progression in patients with Barrett's esophagus. An increasing number of genetic loci have been associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Recent advances in identifying risk factors and reporting of more precise estimates of effect for the main risk factors will positively impact clinical risk stratification efforts for Barrett's esophagus and esophageal adenocarcinoma. Large pooling studies are underway to derive and validate reliable clinical risk models.

Sa1250 Improved Prediction of Neoplastic Progression in Patients With Barrett's Oesophagus Using Specific Histological Criteria for Low Grade Dysplasia

Sa1250 Improved Prediction of Neoplastic Progression in Patients With Barrett's Oesophagus Using Specific Histological Criteria for Low Grade Dysplasia

Exam 1: Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

Exam 1: Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

Barrett's esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.

Neoplastic progression in short-segment Barrett's oesophagus is associated with impairment of chemical clearance, but not inadequate acid suppression by proton pump inhibitor therapy.

Pathophysiological mechanisms associated with neoplastic progression in patients with short-segment Barrett's oesophagus (SSBO), who represent the vast majority of the Barrett population, have not been defined. To evaluate pathophysiological characteristics of patients with SSBO and dysplasia detected at 3-year surveillance endoscopy (incident dysplasia). Patients with SSBO underwent impedance-pH monitoring during heartburn-suppressing PPI therapy. Fifteen patients (12 males, median age 62 years) with incident dysplasia and 50 patients (43 males, median age 59 years) without dysplasia were compared. Impedance-pH parameters, including chemical clearance assessed by the post-reflux swallow-induced peristaltic wave (PSPW) index, were evaluated. All patients declared persisting heartburn suppression on maintenance PPI therapy at 3-year follow-up, 58/65 (89%) with standard dosages. The median gastric and oesophageal acid exposure time (GAET and OAET) did not differ between patients with and without incident dysplasia at the time of surveillance (36% and 0.6% vs. 33% and 0.5%) or index endoscopy (33% and 0.3% vs. 41% and 0.5%) (P > 0.05). Contrastingly, the median PSPW index was significantly lower in patients with than in patients without incident dysplasia at the time of surveillance (15%, vs. 32%) and index endoscopy (12% vs. 30%) (P = 0.001). The PSPW index, the GAET and the OAET did not vary over time (P > 0.05). A PSPW index <26% was predictive of incident dysplasia with a 75% accuracy. Neoplastic progression in SSBO is associated with impairment of chemical clearance, but not inadequate acid suppression by PPI therapy. Neoplastic progression in SSBO can be predicted by a low PSPW index.

Mo1854 Risk Factors for Predicting Neoplastic Progression in Patients With Barrett's Esophagus and Low-Grade Dysplasia

Mo1854 Risk Factors for Predicting Neoplastic Progression in Patients With Barrett's Esophagus and Low-Grade Dysplasia

388 IL-1β-STAT3 Mediated Up-Regulation of AKT1 Expression in Barrett's Esophagus: A Potential Link Between Inflammation and Carcinogenesis

BACKGROUND AND AIM: We have recently shown that, in addition to AKT1 activation through its phosphorylation, overall increased expression of AKT1 that is observed during neoplastic progression in patients with Barrett's also plays a direct role in this injury-induced oncogenesis. Since pro-inflammatory cytokine IL-1β promotes esophageal adenocarcinoma and its downstream effector STAT3 could bind to the core promoter region of AKT1, it is plausible that IL-1β-STAT3-AKT1 could link inflammation to carcinogenesis in Barrett's esophagus. The aims of this study were to examine IL-1 β-STAT3 mediated regulation of AKT1 expression and explore the underlying mechanisms in Barrett's epithelium. METHODS and RESULTS: Using Barrett's epithelial cells, we noted that both IL-1 β and constitutively active STAT3c induced AKT1 promoter activity. Moreover, in a dose and time dependent manner IL-1β increased AKT1 mRNA expression. Similarly, constitutively active STAT3c also increased AKT1 mRNA expression. We also noted that IL-1 β increased cellular p300 levels, a histone acetyl transferase that STAT3 recruits on target promoter chromatin to activate them by acetylating histone H3. We found that while constitutively active STAT3c increased AKT1 promoter activity/expression, there was an increased acetylation of AKT1 promoter (ChIP using anti H3 K18 and 27 antibody) during neoplastic progression in Barrett's epithelium. Additionally, both IL-1β and STAT3c partially interfered with repression of AKT1 promoter by anti-inflammatory transcription factor KLF11, a known recruiter of Sin3-HDAC that deacetylates and represses AKT1 promoter. Together, these findings raise a possibility that pro-inflammatory IL-1β, by simultaneously increasing p300 and STAT3 activation could direct p300 onto the AKT1 promoter to hyper acetylate and activate AKT1 promoter. Alternatively, pro-inflammatory IL-1β-pSTAT3 through antagonizing the antiinflammatory KLF11-Sin3-histone deacetylase pathway preserve AKT1 promoter acetylation to activate AKT1 promoter/expression. CONCLUSION: Our observations expose an antagonism between pro-inflammatory IL-1β-STAT3-p300 and anti-inflammatory KLF11-Sin3HDAC pathways in regulating oncogenic AKT1 during neoplastic transformation in Barrett's esophagus, providing a potential link between inflammation and carcinogenesis.

Sa1987 AMACR Immunohistochemistry for Prediction of Neoplastic Progression in Patients With Barrett's Esophagus: Results From a Large Multicentre Prospective Cohort

Sa1987 AMACR Immunohistochemistry for Prediction of Neoplastic Progression in Patients With Barrett's Esophagus: Results From a Large Multicentre Prospective Cohort