A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

Esophageal adenocarcinoma risk in Barrett’s esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of 8 BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors (NPs) and 50 progressors (Ps) using real-time quantitative methylation-specific PCR. Ps were significantly older than NPs (70.6 vs. 62.5 years, p < 0.001). We evaluated a linear combination of the 8 markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUCs) were high in the 2-, 4-year and combined data models (0.843, 0.829 and 0.840; p<0.001, p<0.001 and p<0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age vs. age alone were substantial (Δ-AUC = 0.152, 0.114 and 0.118, respectively) in all three models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia

Use of endoscopic ultrasound for diagnosis of cholangiocarcinoma in auto-immune hepatitis

In this report, a patient was exposed to an herbal remedy for hypercholesterolemia. She became acutely jaundiced while taking the remedy and presented for medical care. Endoscopic ultrasound was utilized, and found a distal common bile duct mass. Endoscopic retrograde cholangiopancreatography guided bile duct biopsies revealed that the mass was cholangiocarcinoma (CCA). This case highlights a unique association between autoimmune hepatitis and CCA. It also highlights that EUS can be safely used in patients with cirrhosis to spare invasive evaluation such as exploratory laporotomy for diagnosis and staging of cholangiocarcinoma

Task-based optimization of flip angle for fibrosis detection in T1-weighted MRI of liver

Chronic liver disease is a worldwide health problem, and hepatic fibrosis (HF) is one of the hallmarks of the disease. The current reference standard for diagnosing HF is biopsy followed by pathologist examination; however, this is limited by sampling error and carries a risk of complications. Pathology diagnosis of HF is based on textural change in the liver as a lobular collagen network that develops within portal triads. The scale of collagen lobules is characteristically in the order of 1 to 5 mm, which approximates the resolution limit of in vivo gadolinium-enhanced magnetic resonance imaging in the delayed phase. We use MRI of formalin-fixed human ex vivo liver samples as phantoms that mimic the textural contrast of in vivo Gd-MRI. We have developed a local texture analysis that is applied to phantom images, and the results are used to train model observers to detect HF. The performance of the observer is assessed with the area-under-the-receiver-operator-characteristic curve (AUROC) as the figure-of-merit. To optimize the MRI pulse sequence, phantoms were scanned with multiple times at a range of flip angles. The flip angle that was associated with the highest AUROC was chosen as optimal for the task of detecting HF. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.NIBIB NIH HHS [T32 EB000809]SPIE grants to authors of papers published in an SPIE Journal or Proceedings the right to post an author-prepared version or an official version (preferred version) of the published paper on an internal or external server controlled exclusively by the author/employer, provided that (a) such posting is noncommercial in nature and the paper is made available to users without charge; (b) an appropriate copyright notice and full citation appear with the paper, and (c) a link to SPIE's official online version of the abstract is provided using the DOI (Document Object Identifier) link.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Subspecialty surgical pathologist′s performances as triage pathologists on a telepathology-enabled quality assurance surgical pathology service: A human factors study

Background: The case triage practice workflow model was used to manage incoming cases on a telepathology-enabled surgical pathology quality assurance (QA) service. Maximizing efficiency of workflow and the use of pathologist time requires detailed information on factors that influence telepathologists′ decision-making on a surgical pathology QA service, which was gathered and analyzed in this study. Materials and Methods: Surgical pathology report reviews and telepathology service logs were audited, for 1862 consecutive telepathology QA cases accrued from a single Arizona rural hospital over a 51 month period. Ten university faculty telepathologists served as the case readers. Each telepathologist had an area of subspecialty surgical pathology expertise (i.e. gastrointestinal pathology, dermatopathology, etc.) but functioned largely as a general surgical pathologist while on this telepathology-enabled QA service. They handled all incoming cases during their individual 1-h telepathology sessions, regardless of the nature of the organ systems represented in the real-time incoming stream of outside surgical pathology cases. Results: The 10 participating telepathologists′ postAmerican Board of pathology examination experience ranged from 3 to 36 years. This is a surrogate for age. About 91% of incoming cases were immediately signed out regardless of the subspecialty surgical pathologists′ area of surgical pathology expertise. One hundred and seventy cases (9.13%) were deferred. Case concurrence rates with the provisional surgical pathology diagnosis of the referring pathologist, for incoming cases, averaged 94.3%, but ranged from 88.46% to 100% for individual telepathologists. Telepathology case deferral rates, for second opinions or immunohistochemistry, ranged from 4.79% to 21.26%. Differences in concordance rates and deferral rates among telepathologists, for incoming cases, were significant but did not correlate with years of experience as a practicing pathologist. Coincidental overlaps of the area of subspecialty surgical pathology expertise with organ-related incoming cases did not influence decisions by the telepathologists to either defer those cases or to agree or disagree with the referring pathologist′s provisional diagnoses. Conclusions: Subspecialty surgical pathologists effectively served as general surgical pathologists on a telepathology-based surgical pathology QA service. Concurrence rates with incoming surgical pathology report diagnoses, and case deferral rates, varied significantly among the 10 on-service telepathologists. We found no evidence that the higher deferral rates correlated with improving the accuracy or quality of the surgical pathology reports

Endoscopic ultrasound with biopsy of omental mass for cholangiocarcinoma diagnosis in cirrhosis

In this report, a patient had a previous diagnosis of cholangiocarcinoma with an extended cholecystectomy. Three years later, he was evaluated for recurrent ascites. The patient had several large volume paracentesis, without evidence of malignant cells. Subsequently, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) of both lymph and omental nodules was utilized. While the lymph nodes were negative for malignancy, the omental nodule was interrogated with multiple antibodies and was found to be positive for neoplasia. EUS with FNA can safely be used in patients with cirrhosis to spare the patient invasive evaluation such as exploratory laparotomy (ex-lap) for diagnosis and staging of cholangiocarcinoma

Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma

Given the poor survival rate and efficacy of current therapy for esophageal adenocarcinoma (EAC), there is a need to identify and develop new therapeutic targets for treatment. Microarray analysis (Affymetrix U133A GeneChips, Robust Multi-Chip Analysis) was used to expression profile 11 normal squamous and 18 Barrett's esophagus biopsies, 7 surgically resected EACs and 3 EAC cell lines. Two hundred transcripts representing potential therapeutic targets were identified using the following criteria: significant overexpression in EAC by analysis of variance (p = 0.05, Benjamini Hochberg false discovery rate); 3-fold increase in EAC relative to normal and Barrett's esophagus and expression in at least 2 of the 3 EAC cell lines. From the list of potential targets we selected TNFRSF12A/Fn14/TWEAK receptor, a tumor necrosis factor super-family receptor, for further validation based on its reported role in tumor cell survival and potential as a target for therapy. Fn14 protein expression was confirmed in SEG-1 and BIC-1 cell lines, but Fn14 was not found to affect tumor cell survival after exposure to chemotherapeutics as expected. Instead, a novel role in EAC was discovered in transwell assays, in which modulating Fn14 expression affected tumor cell invasion. Fn14's potential as a therapeutic target was further supported by immunohistochemistry on a tissue microarray of patient samples that showed that Fn14 protein expression increased with disease progression in EAC