Dataset Information

The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis.

ABSTRACT: PURPOSE:The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9. EXPERIMENTAL DESIGN:We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set. RESULTS:The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement (P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker. CONCLUSIONS:sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.

SUBMITTER: Staal B

PROVIDER: S-EPMC7246054 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis.

Staal Ben B Liu Ying Y Barnett Daniel D Hsueh Peter P He Zonglin Z Gao ChongFeng C Partyka Katie K Hurd Mark W MW Singhi Aatur D AD Drake Richard R RR Huang Ying Y Maitra Anirban A Brand Randall E RE Haab Brian B BB

Clinical cancer research : an official journal of the American Association for Cancer Research 20190107 9

<h4>Purpose</h4>The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9.<h4>Experimental design</h4>We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed ...[more]

PMID: 30617132

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Project description:OBJECTIVESPancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets.METHODSThe expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321).RESULTSTissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2?ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7?ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ?0.0001) benign controls (BC) (7.2?ng/ml, IQR: 0.4-26.5) and (P-value ?0.0001) chronic pancreatitis (CP) controls (8.4?ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls.CONCLUSIONSMUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

Project description:BackgroundAn estimated 87% of torture survivors experience chronic pain such as brachial plexopathy from upper extremity suspension or lumbosacral plexus injury from leg hyperextension. However, a vast majority of pain is undetected by evaluators due to a lack of diagnostic tools and confounding psychiatric illness. This diagnostic gap results in exclusive psychological treatment rather than multimodal therapies, substantially limiting rehabilitation. We hypothesized that the United Nations Istanbul Protocol (UNIP) would have a sensitivity of approximately 15% for pain detection, and that the use of a validated pain screen would improve its sensitivity by at least 29%, as compared to the reference standard (pain specialist evaluation).Methods and findingsThis prospective blind-comparison-to-gold-standard study of survivors of torture, as defined by the World Medical Association, took place at Weill Cornell Medicine between February 1, 2017, and June 21, 2019. 11 women and 9 men, for a total of 20 participants, were included in the analysis. Five participants received 2 UNIP evaluations, for a total of 25 unique evaluations included in the analysis. Participants were representative of a global population, with home countries in Africa, Central America, South Asia, the Caribbean, and the Middle East. Methods of torture experienced were homogeneous, following the predictable pattern of systematic torture. Participants first received the standard evaluation protocol for torture survivors (UNIP) by a trained evaluator, and subsequently received a validated pain screen (Brief Pain Inventory-Short Form [BPISF]) followed by a noninvasive examination by a pain specialist physician (reference standard). The primary outcome was the diagnostic and treatment capability of the standard protocol (index test) versus the validated pain screen (BPISF), as compared to the reference standard. Trained evaluators performing the initial assessment with the UNIP (index test) were blinded to the study, and the pain specialist physician (reference standard) was blinded to the outcome of the initial UNIP evaluation and the BPISF; data from the initial UNIP assessment were not gathered by the principal investigator until all other study procedures were completed. Providers using only the UNIP captured pain in a maximum of 16% of evaluations, as compared to 85% of participants being diagnosed with pain by the reference standard. When employed, the validated pain screen had a sensitivity of 100% (95% CI 72%-100%) and a negative predictive value of 100%, as compared to a sensitivity of 24% (95% CI 8%-50%) and a negative predictive value of 19% (95% CI 5%-46%) for the index test. The difference in the sensitivity of the UNIP as compared to the BPISF was significant, with p < 0.001. No adverse events owing to participation in the study were reported by participants. Limitations of the study include small sample size, its single-site nature, and the exclusion of individuals who did not speak 1 of the 5 study languages.ConclusionsThese data indicate that a validated pain screen can supplement the current global standard assessment of torture survivors, the UNIP, to increase the accuracy of pain diagnosis.Trial registrationClinicalTrials.gov NCT03018782.

Project description:CA19-9 values are regularly measured in patients with pancreatic cancer. Certainly, its potential as a biomarker has been compromised by false negative results in CA19-9 negative patients and false positive results in benign pancreatico-biliary diseases. For detection of PDAC recurrence, however, CA19-9 might play an important role. The aim of this study is to analyze the accuracy of CA19-9 for detecting recurrence of pancreatic cancer. All included patients were treated either at the University Medical Center Goettingen, or at the Department of Interdisciplinary Oncology and Pneumonology, DRK-Kliniken Nordhessen, Kassel. We analyzed data of 93 patients with pancreatic cancer in the training set and 41 in the validation set, both retrospectively. Pre- and postoperative CA19-9 values and results of imaging techniques were compared. We performed ROC-analysis. The association between longitudinally measured CA19-9 values and relapse was studied with a joint model between a random effects model for the longitudinal CA19-9 measurements and a Cox proportional hazards models for the survival data. In the test set (n = 93 patients) the median follow-up time was 644 days (22 months). Overall, 71 patients (76.3%) developed recurrence during follow-up. Patients with CA19-9 values of <10kU/l were considered as CA19-9 negative patients (n = 11) and excluded from further analysis. Among the rest, approximately 60% of the patients showed significantly elevated CA19-9 prior to detection of recurrence by imaging techniques. Recurrence was shown by 2.45 times elevated CA19-9 values with 90% positive predictive value. In the validation set, 2.45 times elevated CA19-9 values showed recurrence with 90% sensitivity and 83,33% specificity, with an area under the curve of 95%. Based on measured CA19-9 values during follow-up care, the joint model estimates in recurrence-free patients the probability of recurrence-free survival. CA19-9 elevation is an early and reliable sign for PDAC recurrence. On the strength of a very high accuracy in CA19-9 positive patients, it should be considered to use CA19-9 for therapy decision even without a correlate of imaging technics. Using the joint model, follow-up care of PDAC patients after curative therapy can be stratified.

Dataset Information

The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis.

Publications

The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis.

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