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Critchley-Thorne R.J.,Cernostics | Davison J.M.,University of Pittsburgh | Prichard J.W.,Geisinger Medical Center | Reese L.M.,Cernostics | And 13 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2017

Background: There is a need for improved tools to detect high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus. In previous work, we demonstrated that a 3-tier classifier predicted risk of incident progression in Barrett's esophagus. Our aim was to determine whether this risk classifier could detect a field effect in nondysplastic (ND), indefinite for dysplasia (IND), or lowgrade dysplasia (LGD) biopsies from Barrett's esophagus patients with prevalent HGD/EAC. Methods: We performed a multi-institutional case-control study to evaluate a previously developed risk classifier that is based upon quantitative image features derived from 9 biomarkers and morphology, and predicts risk for HGD/EAC in Barrett's esophagus patients. The risk classifier was evaluated in ND, IND, and LGD biopsies from Barrett's esophagus patients diagnosed with HGD/EAC on repeat endoscopy (prevalent cases, n = 30, median time to HGD/EAC diagnosis 140.5 days) and nonprogressors (controls, n = 145, median HGD/EAC-free surveillance time 2,015 days). Results: The risk classifier stratified prevalent cases and nonprogressor patients into low-, intermediate-, and high-risk classes [OR, 46.0; 95% confidence interval, 14.86-169 (high-risk vs. lowrisk); P < 0.0001]. The classifier also provided independent prognostic information that outperformed the subspecialist and generalist diagnosis. Conclusions: A tissue systems pathology test better predicts prevalent HGD/EAC in Barrett's esophagus patients than pathologic variables. The results indicate that molecular and cellular changes associated with malignant transformation in Barrett's esophagus may be detectable as a field effect using the test. Impact: A tissue systems pathology test may provide an objective method to facilitate earlier identification of Barrett's esophagus patients requiring therapeutic intervention. © 2016 American Association for Cancer Research.


PubMed | McGowan Institute for Regenerative Medicine, Johns Hopkins University, Esophageal and Lung Institute and Allegheny Health Network
Type: Journal Article | Journal: Oncotarget | Year: 2016

Esophageal adenocarcinoma (EAC) is an aggressive cancer necessitating the development of improved risk stratification tools for personalized care. Previously, microRNAs have been shown to correlate with the progression and prognosis of various cancer types; however, the value in EAC remains largely unexplored. We performed global microRNA profiling on 32 formalin-fixed, paraffin-embedded EAC specimens to identify microRNAs associated with progression. Literature search and pathway analysis further refined output to five significantly deregulated candidate biomarkers. Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR. Survival outcomes were evaluated in testing set of 26 stage II/III EAC patients to determine the prognostic relevance of the selected microRNAs. In the testing set, miR-652-5p and miR-7-2-3p expressions were significantly associated with progression-free survival (p-value = .00771 and p-value = .00293). The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p. Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.


PubMed | Mayo Medical School and Esophageal and Lung Institute
Type: | Journal: BMC cancer | Year: 2016

Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Using a rat model of esophageal adenocarcinoma, and human clinical samples, we investigated genes central to TLR-mediated signal transduction and characterized the esophageal microbiome across the spectrum of esophageal adenocarcinoma carcinogenesis.We surgically induced bile/acid reflux in rats and their esophagi were harvested at 40 weeks post-surgery. Tissue samples from the model were selected for gene expression profiling. Additionally, for rat and human samples microbiome analysis was performed using PCR-ESI-MS-TOF technology with validation by fluorescence in situ hybridization.Gene expression results in the rat model indicated a significant upregulation of TLRs 1-3, 6, 7 and 9 in EAC compared to normal epithelium. PCR-ESI-MS-TOF analysis revealed a prevalence of Escherichia coli in Barretts esophagus (60%) and esophageal adenocarcinoma (100%), which was validated by fluorescence in situ hybridization. In the human clinical samples, Streptococcus pneumonia was detected in high abundance in gastroesophageal reflux disease and Barretts esophagus (50-70%) in comparison to tumor adjacent normal epithelium, dysplasia, and esophageal adenocarcinoma (20-30%). E. coli was detected in the Barretts esophagus and esophageal adenocarcinoma groups but was absent in the tumor adjacent normal epithelium, dysplasia, and the gastroesophageal reflux disease groups.We demonstrated an association between the TLR signaling pathway and E. coli hinting towards possible early molecular changes being mediated by microbes in the rat model of esophageal adenocarcinoma carcinogenesis. Studies on human clinical samples also corroborate results to some extent; however, a study with larger sample size is needed to further explore this association.


News Article | December 7, 2016
Site: www.prweb.com

Allegheny Health Network (AHN) is one of just nine sites nationwide participating in a clinical trial of EndoStim, an investigational, minimally invasive procedure that may help improve symptoms of Gastroesophageal Reflux Disease (GERD), a chronic condition that affects the lives of millions of Americans. GERD is the chronic backflow (reflux) of stomach contents into the esophagus, causing burning pain in the chest, regurgitation and a variety of other symptoms. It is often caused by a weak valve, or sphincter, between the esophagus and stomach, called the lower esophageal sphincter (LES). “Even with daily use of acid-blocking medications known as proton pump inhibitors (PPIs), nearly 30 percent of GERD patients continue to suffer life-altering symptoms,” said Blair Jobe, MD, principal investigator and director of the Esophageal and Lung Institute at AHN. “People who struggle with GERD but do not get complete relief from daily heartburn medications may be candidates for the EndoStim clinical trial, known as LESS GERD.” With EndoStim, two small electrodes , connected to a neurostimulator, are placed on the lower esophageal sphincter. Throughout the day, the EndoStim delivers mild electrical signals – undetected by the patient – that are designed to restore normal function to the lower esophageal sphincter. The device is implanted below the skin and unlike traditional anti-reflux surgery, it is designed to preserve the body’s natural anatomy in order to reduce or avoid gastro-intestinal side effects. For more information about enrolling in the LESS GERD trial, contact Emily Lloyd at 412.578.1343 or Emily.Lloyd(at)ahn(dot)org , or visit lessgerd.com, or call 1-888-578-8390. About the Allegheny Health Network: Allegheny Health Network (AHN.ORG), part of Highmark Health, is an integrated healthcare delivery system serving the Western Pennsylvania region. The Network is comprised of eight hospitals, including its flagship academic medical center Allegheny General Hospital, Allegheny Valley Hospital, Canonsburg Hospital, Forbes Hospital, Jefferson Hospital, Saint Vincent Hospital, Westfield Memorial Hospital and West Penn Hospital; an employed physician organization, a research institute, health + wellness pavilions, home and community-based health services and a group purchasing organization. The Network employs approximately 17,500 people, and has more than 2,100 physicians on its medical staff. The Network also serves as a clinical campus for Temple University School of Medicine, Drexel University College of Medicine and the Lake Erie College of Osteopathic Medicine.


PubMed | McGowan Institute for Regenerative Medicine, Esophageal and Lung Institute, Allegheny Health Network and University of Pittsburgh
Type: Journal Article | Journal: PloS one | Year: 2015

To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC).The incidence of esophageal adenocarcinoma (EAC) has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies.The modified Levrats surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors.The epithelial origin of distant metastasis was established by IF using villin (VIL1) and mucin 5AC (MUC5AC) antibodies. miRNome analysis identified four down-regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304). Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2.In vivo metastasis was confirmed in the modified Levrats model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized.


Kosovec J.E.,Esophageal and Lung Institute
Annals of Surgery | Year: 2015

OBJECTIVE:: To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo. BACKGROUND:: EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy. METHODS:: In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression. RESULTS:: In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control?=?9.4%), increase in 9.1% (control?=?37.5%), and stable disease in 54.5% (control?=?43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90β, and CDK4, and upregulation of Hsp72. CONCLUSIONS:: AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Jobe B.A.,Esophageal and Lung Institute
Surgical Clinics of North America | Year: 2015

There has been recent interest in minimally invasive esophagectomy (MIE), which has the theoretic advantages of being less traumatic, with a shortened postoperative recovery and fewer cardiopulmonary complications, compared with open approaches. In addition, enhanced visualization afforded by high-definition imaging and magnification may facilitate a safer approach, with a resultant reduction in blood loss and complications. MIE has been adopted in many centers. This article describes the history of MIE in the context of benign disease, the surgical technique, and the outcomes of minimally invasive approaches compared with those of the open approach. © 2015 Elsevier Inc.


Hoppo T.,Esophageal and Lung Institute | Thakkar S.J.,Esophageal and Lung Institute | Schumacher L.Y.,Esophageal and Lung Institute | Komatsu Y.,Esophageal and Lung Institute | And 9 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2016

Background: Peroral endoscopic myotomy (POEM) has been performed as a novel endoscopic procedure to treat achalasia with favorable outcome. The objective of this study was to assess the outcome of POEM in our initial series and to assess the safety and efficacy of POEM in a variety of esophageal motility-related clinical problems. Methods: This is a retrospective cross-sectional study involving all patients with esophageal motility disorders defined by the Chicago classification, who had undergone consideration for POEM at our institution. Validated questionnaires such as gastroesophageal reflux disease health-related quality of life (GERD-HRQL), reflux symptom index (RSI) and achalasia disease-specific health-related quality of life were obtained pre- and postoperatively. Results: From January 2013 to October 2014, a total of 35 POEMs (achalasia n = 25, non-achalasia n = 10) were performed on 33 patients (female n = 20, male n = 13, mean age 56.9 years). There was no mortality. The rate of inadvertent mucosotomy was 17.1 %. The rate of complications requiring interventions was 5.7 %. During a mean follow-up period of 7 months (range 0.5–17), 92 % of patients with achalasia and 75 % of those with non-achalasia motility disorders had a symptomatic improvement in dysphagia. Chest pain was completely resolved in all patients with achalasia (8/8) and 80 % of patients with non-achalasia (4/5). The GERD-HRQL, RSI and dysphagia scores significantly improved after POEM in patients with achalasia. There was a significant improvement in GERD-HRQL and RSI scores, and a trend toward lower dysphagia score in patients with non-achalasia. Conclusions: The outcome of POEM to treat achalasia and non-achalasia motility disorders is consistent with previous studies. Potential benefit of POEM includes not only its flexibility to adjust the length and location of myotomy but also the ability to extend myotomy proximally without thoracoscopy or thoracotomy. POEM can be combined with laparoscopic procedures and used as “salvage” for localized esophageal dysmotility. © 2015, Springer Science+Business Media New York.


PubMed | Esophageal and Lung Institute
Type: Journal Article | Journal: Annals of surgery | Year: 2016

To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo.EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy.In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression.In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control=9.4%), increase in 9.1% (control=37.5%), and stable disease in 54.5% (control=43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90, and CDK4, and upregulation of Hsp72.AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.

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