Incidence Of Esophageal Adenocarcinoma Research Articles

In Western populations, the incidence of oesophageal squamous cell carcinoma (OSCC) has been declining, whereas the incidence of oesophageal adenocarcinoma (OAC) has been increasing. Our study examines temporal trends in the incidence of oesophageal cancer in the Netherlands between 1989 and 2016, in addition to predicting future trends through 2041. Data from the Netherlands Cancer Registry and Statistics Netherlands were collected to obtain incidence trends of OSCC and OAC for the period 1989 to 2016. Age‐period‐cohort (APC) modelling was used to estimate the contribution of age, calendar period and birth cohort on the observed incidence trends. To predict the future numbers of new cases of both OSCC and OAC from 2017 to 2041, log‐linear APC models were fitted to the trends of 1989 to 2016. The age‐standardised incidence rates of OSCC have decreased slightly for men and increased slightly for women. In contrast, a marked increase in the incidence of OAC was observed, ranging from 2.8 per 100 000 persons in 1989 to 10.1 in 2016. This increase in OAC incidence was more prominent in men, and it will result in an increased risk of OAC for successive generations. Future projections indicate that the incidence of OAC will further increase to 13.1 per 100 000 persons in 2037 to 2041, meaning that there will be 13 259 cases of OAC in 2037 to 2041, as compared to 9386 diagnoses in 2017 to 2021. The changing epidemiologic trends in oesophageal cancer in the Netherlands should be reflected in the development of prevention, early detection and treatment strategies.

Esophageal adenocarcinoma (EAC) is a lethal disease with rapidly rising incidence. Screening for EAC and its metaplastic precursor, Barrett's esophagus (BE), followed by endoscopic surveillance and endoscopic treatment of dysplasia or early EAC are promising approaches to decreasing EAC incidence and EAC mortality. Historically, screening for EAC has been completed with a traditional per-oral esophagogastroduodenoscopy (EGD); however, this method has limitations including cost, tolerability, and accessibility. For this reason, much effort has been put forward to develop more effective, minimally invasive, and accessible BE and EAC screening tools. The purpose of this review is to describe recent developments of these novel tools. While endoscopic alternatives such as transnasal endoscopy are cheaper and well tolerated, they have not gained acceptance. Non-endoscopic modalities namely, swallowable cell collection devices coupled with biomarker analysis have been found to have excellent performance characteristics, tolerability, and cost effectiveness. In this article, we provide an update on innovative developments in EAC/BE screening modalities including transnasal endoscopy, capsule endomicroscopy, swallowable cell collection devices, and exhaled volatile organic compound analyses.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

One of the most notable changes in the epidemiology of esophageal cancer (EC) is the rising incidence and prevalence of esophageal adenocarcinoma (EAC) in developed countries. The aim of this systematic review was to collect and summarize all the available evidence regarding lifestyle, diet, and EAC risk. We searched the PubMed and Scopus databases in January 2021 for studies providing information about lifestyle, diet, WCRF/AICR recommendations, and EAC risk; published in English; without a time filter. The Newcastle–Ottawa Scale was used to assess risk of bias. The results are stratified by risk factor. A total of 106 publications were included. Half of the case-control studies were judged as high quality, whilst practically all cohort studies were judged as high quality. Body mass index and waist circumference were associated with increased EAC risk. Physical activity did not appear to have a significant direct role in EAC risk. A diet rich in fruit, vegetables, and whole grains appeared to be more protective than a Western diet. Alcohol does not seem to be related to EAC, whereas smokers, particularly heavy smokers, have an increased risk of EAC. Prevention remains the best option to avert EAC. Comprehensible and easy to follow recommendations should be provided to all subjects. Protocol ID number: CRD-42021228762, no funds received.

Introduction: Helicobacter pylori (HP) is the most common cause of peptic ulcers in the gastrointestinal tract (GIT) and has been linked to various GIT malignancies, especially gastric cancer. There is little data on the association between HP infection and esophageal cancer incidence (EC). Therefore, we aimed to conduct this meta-analysis to investigate the effect of HP infection on the risk of developing esophageal cancer. Methods: We searched PubMed and the CINHAL databases for studies reporting the association between H. pylori infection and esophageal cancer from inception to September 2020. We assessed the relationship between H. Pylori infection and the incidence of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) using odds ratio (OR) and relative 95% confidence intervals (CI). Two investigators extracted the data independently, and discrepancies were resolved by discussion with a third investigator. We used RevMan Software to perform the analysis and assessed the heterogeneity using the I2 statistic. Results: This meta-analysis included 45 studies. Total HP positive cases were 311,974 and 38,188 in the ESCC and EAC group, respectively. No statistically significant difference was found between HP and ESCC (OR = 1.10, 95% CI [0.80-1.52], P = 0.55). However, according to region, the subgroup analysis revealed a significantly higher incidence of ESCC with HP (OR = 1.83, 95% CI [1.17-2.87]) for North America. There was a statistically significant reduction in EAC with HP in the overall study population (OR = 0.54, 95% CI [0.34-0.87], P = 0.01). Subgroup analysis showed that western countries were associated with statistically reduced EAC incidence (OR = 0.51, 95% CI [0.32-0.83]). On the other hand, subgroup analysis of eastern countries reported non-significant results (OR = 0.81, 95% CI [0.15-4.30]). Conclusion: Overall, no significant association was found between H. pylori infection and the risk of ESCC. There was a statistically significant reduction in EAC with HP in the overall study population. In subgroup analysis a significantly increased incidence of ESCC is seen in North America and a significantly reduced risk of EAC in western countries. Further randomized controlled trials are need to investigate the protective effect of helicobacter pylori infection for risk of esophageal adenocarcinoma.

Introduction: Incidence of Esophageal adenocarcinoma (EAC) in the US has increased at a greater rate than any other cancer. EAC arises from pre-malignant metaplastic tissue - Barrett’s Esophagus (BE). Periodic histological assessment of an endoscopic biopsy is used to assess progression along dysplasia-carcinoma sequence. Current surveillance protocols have clinical limitations as 80% of EAC patients present in advanced cancer stages. The aim of this study is to compare 8 proteomic expression patterns to distinguish stable BE patients from those who developed EAC using the STLA101 assay. Methods: After Institutional Review Board approval (Mayo Clinic and KUMC) patients with BE were identified. 2 cohorts were selected: progressors (progressed to EAC at subsequent interval of 0.5-3 years) and non–progressors (who had 10 yrs of f/u surveillance without progression along dysplasia/carcinoma path). 11 normal esophageal mucosa samples were also retrieved for analysis. Serial tissue sections were microdissected to reduce proteomic noise from surrounding stromal cells. Isolated cells underwent a multi-step process where cross-links were reversed, and proteins were digested and reduced into a mass spec-compatible lysate. Isotopically labeled control peptides of the STLA101 panel were spiked in with digested tissue samples to quantify all of the markers simultaneously using a Q-Exactive HFX mass spectrometer in a CAP/CLIA setting. Results: A total of 42 tissues were analyzed. Cohort tissue descriptions can be found in Table 1. 13 BEs progressed to EAC within a mean of 334 days while the remaining 18 BEs did not progress over a 10-yr period. All 8 biomarkers were expressed at a higher level when comparing dysplastic BE tissue that progressed to cancer to BE tissue that remained stable over 10 yrs and normal esophageal mucosa. There was not a significant difference in age, sex and length of BE between the groups. The assay had a 100% technical success rate as no samples yielded “non-detectable” data points. Conclusion: The overexpression of the STLA101 panel in dysplastic BE tissue that progressed to cancer demonstrates the potential predictability of the assay when assessing molecular hallmarks of carcinogenesis. The expression quantities of the non-progressive BE tissues were closer to normal mucosa and may warrant patients with this profile type to be screened less. Patients with high expression quantities of the STLA101 panel may be candidates for a more frequent screening cadence or therapeutic intervention.Figure 1.: Mass spectrometry-based expression patterns of 2 markers in the STLA101 panel demonstrating clear overexpression of proteins involved in the malignant transformation of Barrett’s precancerous tissue into esophageal adenocarcinoma. The expression mean of non-diseased esophageal squamous mucosa, labeled as “normal”, are represented by blue bars. The green bars represent non-progressive BE tissue that remained stable for over 10-years according to collaborating institutional databases. The red bars represent progressive BE tissue retrieved at a mean of 334 days before adenocarcinoma diagnosis.Table 1.: Specimen types analyzed in this study

Abstract There is an unexplained male predominance in the incidence of esophageal (EAC) and non-cardia gastric adenocarcinoma (GAC) which cannot be explained by known risk factors. Differences in the exposures to sex hormones may play a part in the observed sex difference. This study aimed to test the hypothesis that androgens increase the risk of EAC, cardia GAC, and non-cardia GAC. We analysed a matched cohort based on a national Swedish database of prostate cancer patients. Methods Prostate cancer patients receiving androgen deprivation therapy (ADT) were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios and 95% confidence intervals were adjusted for confounders. Results There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24–0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60–2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40–2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31–3.13]). Conclusion This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Simple SummaryEsophageal adenocarcinoma (EAC) is a highly lethal cancer with rising incidence in Western countries. Despite diagnostic and therapeutic advances, average 5-year EAC survival remains poor (~20%), with tumor stage and treatment the strongest prognostic factors. The role of lifestyle-related exposures remains uncertain. To address this gap, we analyzed survival associations among EAC patients treated at a tertiary cancer center. Importantly, this study is among the first to assess survival relationships by disease stage for several key lifestyle-related exposures (e.g., physical activity, medications, and diet), enabling us to identify associations which may have been obscured in past analyses. Our findings suggest that lifestyle interventions such as smoking cessation, exercise regimens, and use of cholesterol-lowering (statin) or anti-inflammatory (NSAID) medications may represent promising avenues to improve outcomes in this deadly cancer.Purpose: The incidence of esophageal adenocarcinoma (EAC) has risen substantially in recent decades, while the average 5-year survival remains only ~20%. Disease stage and treatment are the strongest prognostic factors. The role of lifestyle factors in relation to survival remains uncertain, with a handful of studies to date investigating associations with obesity, smoking, physical activity, diet, or medications. Methods: This study included patients diagnosed with primary adenocarcinoma of the esophagus, gastroesophageal junction, or cardia (N = 371) at Roswell Park Comprehensive Cancer Center between 2003 and 2019. Leveraging extensive data abstracted from electronic medical records, epidemiologic questionnaires, and a tumor registry, we analyzed clinical, behavioral, and environmental exposures and evaluated stage-specific associations with survival. Survival distributions were visualized using Kaplan–Meier curves. Cox proportional hazards regression models adjusted for age, sex, stage, treatment, and comorbidities were used to estimate the association between each exposure and all-cause or cancer-specific mortality. Results: Among patients presenting with localized/regional tumors (stages I–III), current smoking was associated with increased overall mortality risk (HR = 2.5 [1.42–4.53], p = 0.002), while current physical activity was linked to reduced risk (HR = 0.58 [0.35–0.96], p = 0.035). Among patients with stage IV disease, individuals reporting pre-diagnostic use of statins (HR = 0.62 [0.42–0.92], p = 0.018) or NSAIDs (HR = 0.61 [0.42–0.91], p = 0.016) had improved overall survival. Exploratory analyses suggested that high pre-diagnostic dietary consumption of broccoli, carrots, and fiber correlated with prolonged overall survival in patients with localized/regional disease. Conclusion: Our data suggest that lifestyle exposures may be differentially associated with EAC survival based on disease stage. Future investigation of larger, diverse patient cohorts is essential to validate these findings. Our results may help inform the development of lifestyle-based interventions to improve EAC prognosis and quality of life.

Ultrashort-segment Barrett's esophagus (USSBE; length of <1 cm) is very frequently diagnosed in Japan, but the cancer risk of USSBE is unknown. In this study, by retrieving endoscopic images, we retrospectively investigated the incidence of esophageal adenocarcinoma (EAC) by the grade of Barrett's esophagus (BE) and compared the findings with those of gastric cancer by the degree of endoscopic gastric atrophy in the same population. Among consecutive participants who had undergone endoscopy for an annual health checkup in 2014, the 9121 who had received at least one follow-up endoscopy by December 2020 were enrolled in this study. Using the retrieved endoscopic images, we retrospectively evaluated BE and gastric atrophy. Information on the subsequent occurrence of EAC and gastric cancer as of December 2020 was also collected. The incidence of cancer by the extent of BE and gastric atrophy was calculated and expressed as the percentage per year. On reviewing the endoscopic image in 2014, 4190 (45.9%) were found to have been diagnosed with BE, of whom 3318 (36.4%) were judged to have USSBE. During an observation period of 54.1 (17.9) months, 89 gastric cancers and only two EACs were identified. The incidence of EAC in USSBE was 0.0068%/year, which was nearly as low as the incidence of gastric cancer in atrophy-free patients (0.0068% vs. 0.0059%/year). Although the prevalence of USSBE is quite high (36.4%), the incidence of EAC in USSBE is very low (0.0068%/year). Accordingly, USSBE can be excluded from targets for endoscopic surveillance in Japan.

Objective Recent years, there has been a rapid increase in the incidence of esophageal adenocarcinoma (EAC), while the prognosis for patients diagnosed remains poor and has slightly improved. Methods We extracted 6,466 cases with detailed demographical characteristics including age at diagnosis, sex, ethnicity, marital status, and clinical features, involving tumor grade and stage at diagnosis and treatment modalities (radiation therapy, chemotherapy, and surgery) from the Surveillance, Epidemiology, and End Results (SEER) (1975–2017) dataset. They were further randomly divided into the training and validating cohorts. Univariate and multivariate Cox analyses were conducted to determine significant variables for construction of nomogram. The predictive power of the model was then assessed by Harrell concordance index (C-index) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Results Multivariate analysis revealed that age, marital status, insurance, tumor grade, TNM stage, surgery, and chemotherapy all showed a significant association with overall survival (OS) and cancer-specific survival (CSS). These characteristics were employed to build a nomogram. Particularly, the discrimination of nomogram for OS and CSS prediction in the training set were excellent (C-index = 0.762, 95% CI: 0.754–0.770 and C-index = 0.774, 95% CI: 0.766–0.782). The AUC of the nomogram for predicting 2- and 5-year OS was 0.834 and 0.853 and CSS was 0.844 and 0.866. Similar results were observed in the internal validation set. Conclusion We have successfully established a novel nomogram for predicting OS and CSS in EAC patients with good accuracy, which can help clinicians predict the survival of individual patient survival and provide optimal treatment strategies.

Hybrid argon plasma coagulation for Barrett's esophagus.

e16095 Background: There has been a definite histopathological shift in esophageal cancer in the West over the past few decades, with adenocarcinoma overtaking squamous cell carcinoma as the commonest type. Asian countries with a high human development index like China have also reported an increased incidence of esophageal adenocarcinoma. Data on the epidemiology of esophageal cancer in India are limited. Methods: We retrospectively evaluated the data of all patients with histologically proven esophageal cancer at Tata Memorial Hospital, from 2003 to 2018. We excluded non-squamous and non-adenocarcinoma histologies. Results: Of a total of 7,874 patients with esophageal cancer, 5,092 (64.7%) were men, for a male to female ratio of 2.5:1. The median age was 57 years (IQR, 50-65); 4,465 (56.7%) were below 60 years old. Of the 4912 patients in whom a history of tobacco or alcohol use had been elicited, there were 1,360 (27.7%) patients with no history of substance use. The site of the primary was the upper third in 906 (12.8%), middle third esophagus in 2,942 (41.5%), lower third in 2,331 (32.8%) and gastroesophageal junction in 917 (12.9%) patients. The predominant histology was squamous cell carcinoma in 6,413 (81.4%) patients and adenocarcinoma in 1461 (18.6%). There was no change in the histologic pattern over the period of the study; squamous cell carcinoma constituted 78.5% of the cases in 2003, and 85.5% in 2018; Chi square test for the year wise trend in histologic patterns was not significant, p=0.143. Evaluation of the histologic subtype according to sex revealed that in the male patients, there were 3890 (76.4%) squamous and 1202 (23.6%) adenocarcinoma cases, while in female patients, there were 2523 (90.7%) squamous and 259 (9.3%) adenocarcinoma cases. On a uni variate analysis, male sex (p&lt;0.001), a history of tobacco or alcohol use (p&lt;0.001), and the presence of comorbidity (p&lt;0.007) were associated with an increased risk of squamous cell carcinoma. Multivariate analysis by logistic regression model revealed that female sex and use of tobacco or alcohol were positively associated with squamous cell carcinoma, while the presence of comorbities and primary in lower esophagus/GEJ were positively associated with adenocarcinoma. Conclusions: Squamous cell carcinoma continues to be the commonest esophageal cancer histologic subtype in over 80% Indian patients. The mid esophagus is the most common site (42%). There is no evidence of an epidemiological shift or an increase in the occurrence of adenocarcinoma or of lower esophageal/GEJ malignancy over the past two decades.

Barrett's esophagus (BE) is the main known precursor condition of esophageal adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is probably mediated by chronic esophageal inflammation, secondary to gastroesophageal reflux disease in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high-fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, whereas both NSAIDs were effective chemoprevention agents in the accelerated HFD-fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.

Guidelines suggest screening of individuals who are at increased risk of esophageal adenocarcinoma (EAC). Tools for identifying patients at risk of Barrett's esophagus have been validated. Here, we aimed to compare and validate the tools for the primary outcomes of interest: EAC and esophagogastric junction adenocarcinoma (EGJAC). Retrospective longitudinal analysis of the Kaiser Permanente Northern California Multiphasic Health Checkup Cohort, a community-based cohort including 206,974 patients enrolled between 1964 and 1973 followed through 2016. Baseline questionnaires and anthropometrics classified predictor variables for each tool and were linked to cancer registry outcomes. Analyses used logistic regression, Cox proportional hazards regression, and Kaplan-Meier survival curves. We identified 168 incident EAC cases and 151 EGJAC cases at a mean of 32 years after enrollment (mean follow-up among controls 26 years). Gastroesophageal reflux disease (GERD) symptoms predicted incident EAC (hazard ratio 2.66; 95% confidence interval 1.01, 7.00), but not EGJAC. The Nord-Trøndelag Health Study tool, Kunzmann tool, and Michigan Barrett's Esophagus pREdiction Tool were more accurate than GERD for predicting EAC, with individuals in the fourth quartile of Kunzmann having 17-fold the risk of those in the 1st quartile (hazard ratio = 16.7, 95% confidence interval = 4.72, 58.8). Each tool also predicted incident EGJAC with smaller magnitudes of effect. The study independently validated 4 tools for predicting incident EAC and EGJAC in a large community-based population. The Kunzmann tool appears best calibrated; all appear preferable to using GERD alone for risk stratification. Future studies should determine how best to implement such tools into clinical practice.

BackgroundProton pump inhibitors (PPIs) have been used to treat Barrett’s esophagus (BE), but there seems to be insufficient evidence that PPIs can prevent esophageal adenocarcinoma (EAC) and high grade dysplasia (HGD). This study aimed to evaluate the effects of PPIs in BE patients.MethodsPubMed and EMBASE were systematically searched. Stata13 and trial sequential analysis (TSA) software were used to carry out related statistics. Pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.ResultsUsing PPIs to reduce the incidence of EAC and HGD has not been confirmed (OR, 0.61; 95% CI, 0.29–1.26). The pooled results of three cohort studies reported that PPIs use was protective (OR 0.48; 95% CI, 0.33–0.70). But the pooled results of five case-control study indicating PPIs use does not prove this protective effect (OR 0.73; 95% CI, 0.21–2.48). On pooled analysis of 4 US studies 2 Netherlands, protective effect on development of EAC and HGD was noted (OR, 0.59; 95% CI, 0.43–0.80) and (OR, 0.16; 95% CI, 0.03–0.75).ConclusionsAccording to the Meta analysis and TSA of existing studies, the protective effect of PPIs on the progression of BE patients to EAC and/or HGD has not been confirmed. TSA shows that more patients are needed before a clear conclusion can be reached.

In the past few decades, the incidence of esophageal adenocarcinoma has increased by six-fold in western countries, as the proton pump inhibitor targeting the gastric acid reflux has failed to control the disease. It is currently suggested that deoxycholic acid reflux leads to esophageal adenocarcinoma. As an inflammation-related cancer, the formation and progression of esophageal adenocarcinoma are closely related to the concentration of reactive oxygen species (ROS). Meanwhile, the critical developmental stage of esophageal adenocarcinoma involves characteristic pathological changes in which the distal esophageal squamous epithelial cells are replaced by intestinal columnar epithelial cells, suggesting the involvement of cancer stem cells. Thus, esophageal adenocarcinoma is a good model to study the interplay between ROS and stem cells in cancer. Until now, some important questions related to ROS in esophageal adenocarcinoma remain unanswered. For example, the molecular mechanism by which deoxycholic acid induces malignant transformation in esophageal adenocarcinoma remains unclear. In addition, whether ROS are involved in the induction of cancer stem cell formation by chemotherapeutic drugs and deoxycholic acid stimulation in esophageal adenocarcinoma remains to be further explored. This review summarizes current research progress on ROS and stemness activity, regulation of ROS by stanniocalcin-1 (STC1)/uncoupling protein 2 (UCP2), and inspiration for ROS in esophageal adenocarcinoma to guide further research and provide insight into the clinical treatment of esophageal adenocarcinoma.

During the past several decades, while the incidence of esophageal adenocarcinoma (EAC) has risen dramatically, our primary EAC-prevention strategies have been endoscopic screening of individuals with GERD symptoms for Barrett’s esophagus (BE), and endoscopic surveillance for those found to have BE. Unfortunately, current screening practices have failed to identify most patients who develop EAC, and the efficacy of surveillance remains highly questionable. We review potential reasons for failure of these practices including recent evidence that most EACs develop through a rapid genomic doubling pathway, and recent data suggesting that many EACs develop from segments of esophageal intestinal metaplasia too short to be recognized as BE. We highlight need for a biomarker to identify BE patients at high risk for neoplasia (who would benefit from early therapeutic intervention), and BE patients at low risk (who would not benefit from surveillance). Promising recent efforts to identify such a biomarker are reviewed herein.

Esophageal cancer is a lethal malignancy with a poor prognosis. The incidence of esophageal adenocarcinoma, which develops from Barrett's esophagus (BE), has recently been increasing. In a previous study, we found that PDZK1 expression is higher in long segment BE compared to that in short-segment BE. However, the function of PDZK1 in the mucosa of BE is unclear. Clarify the role of PDZK1 in BE mucosa using PDZK1 overexpressed cells. Human adenocarcinoma-derived OE33 cells were used as a parental cell line and transfected to generate PDZK1 overexpressed OE33 cells (PC cells) or transfected with empty vector as control cells (NC cells). Cell growth of NC and PC cells in 10% fetal bovine serum was evaluated by cell counting. The effect of PDZK1 on proteasome inhibitor (PSI)-induced apoptosis was qualified by fluorescence microscopy and quantified by flow cytometry. Expression of apoptosis-related proteins was evaluated by western blotting. There were no significant differences in cell growth between NC and PC cells. PSI significantly increased apoptosis in NC cells, but not in PC cells. In response to PSI, increased levels of cleaved-caspase3 and decreased pro-caspase3 levels were found in NC cells, but not in PC cells. In NC cells, PSI significantly decreased Bcl-2 expression without affecting Bax levels. In contrast, high expression of both Bcl-2 and Bax was observed in PC cells. Overexpression of PDZK1 protein induces an apoptosis-resistant phenotype in BE cells, which may be a potential therapeutic target.

Obesity is a risk factor for Barrett’s oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett’s cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett’s oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users.

Barrett's esophagus (BE), a premalignant condition for the development of esophageal adenocarcinoma (EAC), is a consequence of chronic gastroesophageal reflux disease (GERD). Although the incidence of EAC is increasing, a similar trend for BE is not clear. We aimed to evaluate the prevalence of newly diagnosed BE over time in a cohort of patients presenting with GERD symptoms. Information was prospectively collected between 1998 and 2015 for patients presenting to the endoscopy unit at a tertiary referral center for their index upper endoscopy for evaluation of GERD symptoms. Patients were asked to complete a validated GERD questionnaire that documents the onset of GERD symptoms (heartburn and acid regurgitation) and grades the frequency and severity of symptoms experienced. Demographic information, body mass index (BMI), and use of aspirin, nonsteroidal anti-inflammatory drugs, acid suppression therapy if any, smoking, family history, and endoscopic findings: erosive esophagitis, BE, and hiatal hernia were recorded. Patients evaluated during 1998-2003 (control) were compared with those presented in subsequent years (3-year cohorts) using chi-square test, and a multivariable logistic regression model was used to evaluate independent predictors. A total of 1109 patients were included in the analysis: mean age 56.9years (standard deviation [SD] 12.8), 83% Caucasian, 93% male, and mean BMI 29.8 (SD 5.5). Overall, 226 (20.3%) patients were diagnosed with BE, with a mean BE length of 2.1cm (SD 2.6). There was a significant decrease in the prevalence of BE over time from 24.3% in 1998-2003 to 13.5% in 2013-2015 (P = 0.002). During the same time period, a significant increasing trend in proton pump inhibitor (PPI) (41.7%; 1998-2003 vs. 80.2%; 2013-2015) (P < 0.001) and aspirin (ASA) use (23.7%; 1998-2003 vs. 25.9%; 2013-2015) (P = 0.034) was noted. There was also a significant reduction in cigarette smoking. In a multivariable logistic regression model for predicting the presence of newly diagnosed BE, there was a significant effect of timeframe even after adjusting for confounding variables. The results of our study indicate that there has been a steady and significant decline in the prevalence of BE in GERD patients over the last 2 decades. During this same time period, there has been an accompanying increase in the use of PPI, aspirin therapy, and a reduction in smoking, all modifiable risk factors potentially contributing to the decreasing prevalence of BE. Whether this decreasing prevalence of BE will lead to a reduction in EAC remains to be seen.