Oral microbiota analysis of tongue coating in patients with esophageal adenocarcinoma

308 Background: Similarities between esophageal and gastric adenocarcinomas have been identified in terms of genomic characteristics. There is however no consensus on the combined or stratified inclusion of esophageal adenocarcinoma (EAC) within gastric cancer (GC) clinical trials. The aim of our study was to compare patient and tumor characteristics, first-line treatment regimens and overall survival (OS) of patients with EAC and GC. Methods: We selected patients with unresectable advanced and/or synchronous metastatic EAC (n = 1554) or GC (including junction tumors; n = 2095) diagnosed in the period 2015-2017 from the nationwide Netherlands Cancer Registry. Patients with a positive HER2 test result and/or receiving trastuzumab as a first-line treatment were excluded. Data on OS were analyzed using Kaplan-Meier curves with Log-Rank test. Results: The EAC patient population had significantly more male patients (83% vs 66%), lower median age (68 vs 71 years) and higher median BMI (25.4 vs 24.5). Significant differences in location of metastases were identified, with higher percentages in non-regional lymph nodes (48% vs 28%), liver (50% vs 35%), lung (21% vs 9%) and bone (19% vs 7%) and lower in peritoneum (5% vs 42%), in EAC versus GC patients respectively. EAC patients more often received any type (supportive or active systemic) of treatment (76% vs 60%). Median OS was longer in EAC than GC patients (EAC: 4.8 vs GC: 4.1 months; p < 0.01). The percentages of patients receiving first-line systemic treatment were equal in both groups (43%). The number of patients receiving CapOx or FOLFOX was not significantly different (43% vs 47%). Carboplatin+paclitaxel was more frequently given in EAC versus GC (34% vs 3%), while EOX or ECC was given less frequently (12% vs 30%). No significant difference was observed in median OS between EAC and GC patients receiving first-line active systemic treatment (8.0 vs 7.6 months; p = 0.28). Conclusions: Patient characteristics, tumor characteristics, treatment regimens and OS differ between EAC and GC patients. Despite these differences, in patients receiving first-line active systemic treatment no significant differences in OS were found.

336 Background: The high incidence of esophageal adenocarcinoma (EAC) remains a major clinical challenge as majority of these cases are diagnosed at advanced stages, with poor survival outcomes. Emerging evidence indicate intriguing associations between unique microbial profiles and cancer pathogenesis. More recent data also indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers. However, to date, no studies have systematically interrogated circulating metagenome profiling in EAC patients, particularly as non-invasive, early detection, surveillance and prognostic classifiers that may improve the current management paradigms. Methods: Metagenome sequencing was performed on 81 serum specimens collected from 51 EAC, 10 high grade dysplasia (HGD), 10 Barretts’s esophagus (BE), and 10 gastro-esophageal reflux disease (GERD) patients, respectively. Sequencing reads were classified using Bracken and MetaPhlAn3 to determine relative abundance between various classes. The Linear Discriminant Analysis effect size (LEfSe) method was performed to identify potential conserved and discrete microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build a model according to clinical and metagenomic classifiers to examine the diagnostic and prognostic potential of the identified metagenomic signature. Results: A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group – at the phylum, genus, and species level – with Lactobacillus sakei as the most prominent species in GERD vs. other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus ( L.Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris, but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI, 0.78 – 0.95), and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 [95% CI 0.66 – 0.92]) and an accompanying hazard ratio (HR) of 6.23 (95% CI, 2.65 – 14.46, P<0.001). Conclusions: This study describes unique blood-based microbial profiles in patients with GERD, BE, HGD, and EAC, that are further utilized to establish a novel circulating diagnostic and prognostic metagenomic signature in EAC.

Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis

Introduction: The incidence of esophageal adenocarcinoma (EAC) has increased more than any other cancer in our lifetime. Barrett’s esophagus (BE) is the only known precursor to EAC. At present, HER-2 and anti-PD-L1 therapies are FDA-approved for EAC, and off-label use of EGFR-directed therapy has been reported. Our study aims to use liquid chromatography mass spectrometry (LC/MS) to measure the expression of oncoproteins that are currently approved-drug targets in EAC and explore new promising targets for drug development and diagnostic applications for EAC and BE. Methods: EAC patients who underwent esophagectomy without chemo-radiation were identified. BE patients with subsequent progression to EAC and those without progression for >10 years were identified. Normal esophageal mucosa tissues with no history of progression were analyzed for baseline expression. Tissue sections were microdissected to isolate pure EAC, BE and normal mucosal cells from stroma. These biopsies were solubilized for LC/MS-based quantification of 80+ clinically relevant tumor markers including novel markers which are believed to play a role in the disease progression from BE to EAC. The expression trends of these markers were scrutinized by immunofluorescence (IF) in a subset of specimens/biomarkers to confirm mass spec results. Results: A total of 159 tissues were analyzed via LC-MS. In 55 EAC tissues - HER2, PD-L1 and EGFR were overexpressed in 16.3%, 0%, and 0% of patients, respectively. New markers DAD1 and S100P were noted to have high (7,634.0 and 27,222.6 attomoles/ug) and consistent (98.1% and 94.5%) overexpression in EAC samples. Expression of HER2, S100P and DAD1 were significantly higher in EAC compared to 23 normal esophageal mucosa specimens. There was no statistical difference in the expression of PD-L1 and EGFR between EAC and healthy mucosal samples. 45 BE biopsies progressed to EAC within a mean of 380 days, while the remaining 36 BE specimens did not progress over a 10-year period. 8 novel biomarkers were expressed at a higher level in BE tissue that progressed to cancer when compared to esophageal tissue that remained stable over 10 years. The expression trends observed via LC/MS were confirmed via IF in DAD1, S100P and two other novel markers. Discussion: LC-MS revealed low prevalence of target proteins in currently approved EAC therapies and high levels of newly discovered disease drivers that should be explored as possible therapy targets or diagnostic markers. The differential overexpression of the novel markers in progressive and non-progressive BE tissues, as well as the consistent overexpression of these markers in EAC tumors, demonstrates the potential for early detection of esophageal carcinogenesis and/or reveals potential therapeutic programs for an indication that lacks highly efficacious targeted therapy options. Citation Format: Christopher Hartley, Ajay Bansal, Catherine Hagen, Olivia Driscoll, Seyun Oh, Joe Abdo, Sumeet K. Mittal. Mass spectrometry detects lower frequency of routine markers and consistent overexpression of novel disease drivers in Barrett's-related esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2805.

INTRODUCTION: The prevalence of H Pylori (HP) is known to be reduced in patients with GERD and Barrett’s Esophagus (BE) compared to population controls without GERD. However, the prevalence of HP does not differ between GERD patients and BE patients, implying that H Pylori does not influence progression of GERD to BE. We have conducted a systematic review and meta-analysis of the prevalence of HP in population controls compared to patients with Esophageal Adenocarcinoma (EAC). Additionally, we have compared HP prevalence in population controls compared to BE patients to EAC patients. METHODS: The MEDLINE, Ovid and Web of Science databases were searched starting in 1988 to 2019. The literature search was conducted using the terms “helicobacter pylori” or “h pylori” or “HP” and “esophageal neoplasms or adenocarcinoma” or “EAC” or “esophageal adenocarcinoma or cancer” or “esophageal tumour.” RESULTS: Literature search revealed 3045 studies, and 284 abstracts were reviewed based on the title. Based on the abstract review 35 full text articles were reviewed and 14 studies were selected for the analysis of HP in controls vs EAC patients. Eleven studies used serology to classify patients as HP positive or negative. Three studies used biopsy to classify patients as HP positive or negative. The 2 cohort studies which were the largest studies in this meta-analysis, included 10158 patients seronegative for HP and 11342 patients seropositive for HP. Patients in these cohort studies were followed for more than 15 years. The pooled odd ratio for EAC in patients with HP positive infection was 0.559 (95% CI 0.466–0.670, P Value 0.00). Thus, HP positivity decreases the risk of EAC by 45%. Additionally, we identified 5 studies that compared prevalence of HP in controls and BE patients and EAC patients. There was no difference in prevalence of HP between patients with BE and EAC. CONCLUSION: We report a lower prevalence of HP infection in EAC patients compared to population controls, but no difference in HP prevalence between patients with BE and EAC. This implies that HP infection seems to protect against the development of BE or EAC, but does not influence the progression of BE to EAC. Widespread antibiotic use may lead to changes in the bacterial microbiome other than eradication of HP. Further studies are needed to delineate non-HP related changes in the bacterial microbiome contributing to the increasing incidence of EAC.Figure 1Figure 2.: Forrest Plot of Pooled Odds ratio of BE & EAC in H. Pylori Positive with GERD as Control.

BackgroundVisceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Alterations in mitochondrial function and energy metabolism is an emerging hallmark of cancer, however, the potential role that obesity plays in driving these alterations in EAC is currently unknown.MethodsAdipose conditioned media (ACM) was prepared from visceral adipose tissue taken from computed tomography-determined viscerally-obese and non-obese EAC patients. Mitochondrial function in EAC cell lines was assessed using fluorescent probes, mitochondrial gene expression was assessed using qPCR-based gene arrays and intracellular ATP levels were determined using a luminescence-based kit. Glycolysis and oxidative phosphophorylation was measured using Seahorse XF technology and metabolomic analysis was performed using 1H NMR. Expression of metabolic markers was assessed in EAC tumor biopsies by qPCR.ResultsACM from obese EAC patients significantly increased mitochondrial mass and mitochondrial membrane potential in EAC cells, which was significantly associated with visceral fat area, and was coupled with a significant decrease in reactive oxygen species. This mitochondrial dysfunction was accompanied by altered expression of 19 mitochondrial-associated genes and significantly reduced intracellular ATP levels. ACM from obese EAC patients induced a metabolic shift to glycolysis in EAC cells, which was coupled with significantly increased sensitivity to the glycolytic inhibitor 2-deoxyglucose. Metabolomic profiling demonstrated an altered glycolysis and amino acid-related signature in ACM from obese patients. In EAC tumors, expression of the glycolytic marker PKM2 was significantly positively associated with obesity.ConclusionThis study demonstrates for the first time that ACM from viscerally-obese EAC patients elicits an altered metabolic profile and can drive mitochondrial dysfunction and altered energy metabolism in EAC cells in vitro. In vivo, in EAC patient tumors, expression of the glycolytic enzyme PKM2 is positively associated with obesity.

We investigated the potential prognostic association between vitamin D levels (25-Hydroxyvitamin D [25(OH)D]) and vitamin D pathway single nucleotide polymorphisms (SNPs) with overall survival (OS) in esophageal adenocarcinoma (EA) patients. EA patients were recruited from Massachusetts General Hospital near the time of their diagnosis between 1999 and 2016. At the time of recruitment, patients completed a baseline questionnaire and provided blood and serum samples. Serum 25(OH)D levels were measured using radioimmunoassay and adjusted for month of blood draw. Genotypes for 48 tag SNPs from seven candidate genes in the vitamin D pathway (GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR and RXRA) were determined from whole blood DNA. For survival outcomes, we used log-rank test and a multivariable extended Cox model to estimate adjusted hazard ratio (HR) of death. HR models for each SNP were restricted to patients who identified as White and adjusted for age, sex, smoking status, diagnosis year, and treatment, stratifying baseline hazard by clinical stage and modeling surgical resection as a time-dependent covariate. HR models by quartiles 25(OH)D, additionally adjusted for body mass index (BMI), and timing of blood draw. Our analyses included EA patients with complete information on relevant confounders and predictors of OS. The 25(OH)D analysis included 463 EA patients and 337 deaths, with median follow-up of 23.1 months. The mean 25(OH)D level at diagnosis was 20.7 ng/mL. We found no evidence that OS curves differed across quartiles of vitamin D (log rank p=0.83). In the adjusted extended cox model, we found no difference in OS among the highest quartile and quartiles 2-4 (respectively, HR (95% confidence interval), 0.95 (0.70, 1.31), 1.03 (0.76,1.39), 1.01 (0.73, 1.38), global p=0.97). We did not find evidence of interaction between 25(OH)D and clinical stage (p=0.88) or BMI (p=0.43) on OS, and this relationship did not differ by timing of blood draw. Preliminary SNP analysis included 424 EA patients and 305 deaths, with median follow-up of 24.1 months. Two SNPs in CYP24A1 (SNP, HR (95% confidence interval) per minor allele: rs1570669, 1.23 (1.04-1.45); rs927650, 1.22 (1.04-1.44)), two SNPs in GC (rs4588, 1.25(1.04-1.49); rs7041, 0.84(0.71-0.99)), and one SNP in RXRA (rs7039190, 1.57(1.06, 2.31)) were marginally associated with OS in the multivariable survival model. SNPs were not statistically significant after adjusting p-value for multiple testing. Based on the available evidence from our analyses, markers in the vitamin D pathway at the time of diagnosis are not clinically relevant markers of EA survival. Citation Format: Elizabeth Loehrer, Rebecca Betensky, Ruyang Zhang, Li Su, Edward Giovannucci, David Christiani. Molecular markers of the vitamin D pathway and esophageal adenocarcinoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 247.

Objective.Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent anti-neoplastic agent, hence DNA polymorphisms that reduce TNF levels potentially enhance the development of BE and EAC. The aim of the study was to determine the impact of TNF gene variation on the RE–BE–EAC cascade. Methods.DNA from 887 Caucasian participants (197 controls, 305 RE, 257 BE, 128 EAC) was tested for the gene polymorphism TNF-β NcoI, and TNF production was determined by TNF-α specific immunohistochemistry on esophageal biopsies from these BE (n = 31) and EAC (n = 4) patients. Results.As compared with healthy controls, the TNF-β NcoI A/A genotype was significantly more prevalent in BE (p = 0.04) and EAC patients (p = 0.02), but not in RE patients (p = 0.1). While TNF-α protein levels were invariably high in esophageal biopsies from EAC patients, most esophageal BE samples showed low to moderate TNF levels. Conclusions.Chronic inflammation, like in BE, markedly increase the risk of malignant transformation. In this study, the significantly higher frequency of the TNF-β NcoI A/A genotype and the local TNF expression indicate that the pro-inflammatory cytokine TNF plays a role in the development of BE and EAC.

Background: The incidence of esophageal adenocarcinoma in Europe and the United States rapidly increased from the latter half of the 1970s and exceeded that of esophageal squamous cell carcinoma in the latter half of the 1990s, currently accounting for approximately 60% of all esophageal carcinomas. Recently, its incidence has also increased in Japan, raising concerns that it will follow a course similar to that in Europe and the United States. Summary: The incidence of esophageal adenocarcinoma in Japan was about 2% until the 1990s, but in recent years, it has risen to 6.5–7.1%. Causes include the increase in the incidence of obesity due to changes in eating habits with resultant increases in the incidence of hiatal hernia and reflux esophagitis, a decrease in the rate of Helicobacter pylori infection, and the increased interest of physicians in the gastroesophageal junction. The number of gastroesophageal reflux disease patients in Japan rapidly increased from the 1990s, which accordingly increased the number of Barrett’s esophageal adenocarcinoma patients from the latter half of the 1990s. Tabulation and analysis of 1,794 reported cases of Barrett’s esophageal adenocarcinoma in Japan showed that superficial cancers accounted for 77.6%, and that the concomitant rates of hiatal hernia and reflux esophagitis were high at 87 and 70% respectively. Key Message: The future trend in the incidence of Barrett’s esophageal adenocarcinoma in Japan will depend on the increase in the incidence of reflux esophagitis, which is essential for the development of Barrett’s esophagus and Barrett’s esophageal carcinoma. The obesity rate is lower in Japan than that in Europe and the United States, and the incidence and severity of reflux esophagitis are low. We expect that the incidence of Barrett’s esophageal adenocarcinoma in Japan will not rise as high as in Europe and the United States, and will remain below 10%.

It is important to note that although the current treatment for advanced esophageal cancer (EC) has made great technological advances, patients' 5-year survival rates do not appear to be encouraging. Therefore, understanding the clinicopathological features and metastasis patterns of the patients with stage IV EC, combined with the prognosis of these patients, can aid in choosing the optimal treatment plan. It is well known that esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common pathological types. The aim of this study is to examine and compare the clinicopathological features and metastatic modes of stage IV ESCC and EAC, as well as their prognosis and survival. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the characteristics of ESCCs and EACs associated with prognosis using the Kaplan-Meier survival analysis, and the Cox regression model. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. A total of 3,707 cases treated between 2010 and 2016 were included. The incidence of EAC in the United States is much higher than that of ESCC. Common metastasis patterns were lungs only, liver only, bones only, and lung & liver. The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the overall survival (OS) time of patients (stage IV ESCC & EAC). EAC patients with only lung metastases may have a longer survival if chose treatment options that included surgery. In the external cohort, a total of 217 cases were included. The prevalence of ESCC is much higher than that of EAC, and the common metastasis patterns are liver only, lung only, and liver & lung. The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS time of patients (stage IV ESCC & EAC). EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. In general, the prognosis of patients with stage IV ESCC and EAC are poor. However, surgery was found to significantly improve the OS time of patients with stage IV EAC in this study.

Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048-61. ©2017 AACR.

<div>Abstract<p><b>Purpose:</b> Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.</p><p><b>Experimental Design:</b> Here we utilized an <i>IL1β</i> transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.</p><p><b>Results:</b> IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4<sup>+</sup>) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4<sup>+</sup> columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in <i>ex vivo</i> fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.</p><p><b>Conclusion:</b> In conclusion, the recruitment of CXCR4<sup>+</sup> immune cells and expansion of CXCR4<sup>+</sup> epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. <i>Clin Cancer Res; 24(5); 1048–61. ©2017 AACR</i>.</p></div>

<div>Abstract<p><b>Purpose:</b> Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.</p><p><b>Experimental Design:</b> Here we utilized an <i>IL1β</i> transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.</p><p><b>Results:</b> IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4<sup>+</sup>) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4<sup>+</sup> columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in <i>ex vivo</i> fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.</p><p><b>Conclusion:</b> In conclusion, the recruitment of CXCR4<sup>+</sup> immune cells and expansion of CXCR4<sup>+</sup> epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. <i>Clin Cancer Res; 24(5); 1048–61. ©2017 AACR</i>.</p></div>

BackgroundThe association of the gut microbiome with obesity and metabolic diseases as type 2 diabetes (T2D) as well as the influence of environmental factors like nutrition on its composition is...

BackgroundBarrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) incidence has been increasing in the United States for greater than 30 years. For the majority of EAC patients, treatment is limited and prognosis poor. Doublecortin like kinase-1 (DCLK1) is a cancer stem cell marker with elevated expression in BE patients with high grade dysplasia and/or EAC. This prospective cohort study was designed to compare serum DCLK1 levels before and after EAC treatment with endoscopic mucosal resection (EMR) and/or radio-frequency ablation (RFA).MethodsBarrett’s esophagus patients with low or high-grade dysplasia (n = 9) and EAC patients (Stage I/II) eligible for treatment were enrolled (n = 14). Serum was obtained at enrollment and at end of treatment (EoT) where possible (n = 6). Normal control samples (n = 5) were obtained from patients with normal upper endoscopies. Serum was analyzed for DCLK1 protein content by ELISA. Kruskal-Wallis, Mann Whitney U, Pearson correlation, and Receiver Operating Characteristic tests were used to analyze the data.ResultsSerum DCLK1 levels were increased by > 50% in Barrett’s Esophagus (n = 9) and EAC patients (n = 14) vs controls (n = 5, p = 0.0007). These levels were reduced > 50% at EoT compared to EAC (p = 0.033). Although age was significantly lower in controls, this factor was not statistically related to DCLK1 serum levels (p = 0.66).ConclusionsEAC treatment results in significantly decreased serum DCLK1 levels, suggesting that DCLK1 may be useful as a non-invasive disease regression biomarker following treatment.ImpactBiomarkers for EAC therapeutic response have been poorly studied and no reliable marker has been discovered thus far. These results demonstrate that DCLK1 may have potential as a circulating biomarker of the response to therapy in EAC, which could be used to improve patient outcomes.