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      Serum APN/CD13 as a novel diagnostic and prognostic biomarker of pancreatic cancer

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          Abstract

          Aminopeptidase N, also known as CD13, has been reported to be overexpressed in several cancers and may contribute to tumor metastasis and angiogenesis. The aim of this study was to evaluate whether serum APN/CD13 could be a potential biomarker for the diagnosis and prognosis of pancreatic cancer (PC). Serum APN/CD13 and carbohydrate antigen 19-9 (CA19-9) levels were measured from 382 participants, which comprised of 204 participants with PC, 48 participants with benign pancreatic tumors (BPT), 43 participants with chronic pancreatitis (CP) and 87 healthy controls (HC). We used receiver operating characteristic (ROC) analysis to calculate diagnostic accuracy. The association of serum APN/CD13 levels with the clinicopathological characteristics of PC patients and their survival was investigated. Serum APN/CD13 levels were substantially higher in PC patients than in controls. ROC analysis revealed that APN/CD13 was significantly better than CA19-9 in differentiating patients with PC from controls. Similar results were noted for early-stage PC. Moreover, the combined use of APN/CD13 and CA19-9 data improved the diagnostic accuracy for PC vs. controls, compared with either test alone. High serum APN/CD13 levels were associated with tumor size, lymph nodes, and metastasis (TNM) stage. Multivariate and ROC curve analyses revealed that high serum APN/CD13 level is an independent factor for predicting mortality and overall survival (OS). Moreover, Kaplan–Meier analysis demonstrated an inverse correlation between increased serum APN/CD13 level and OS. Our study established that serum APN/CD13 may be a novel diagnostic and prognostic biomarker for PC.

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          Most cited references27

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          Youden Index and optimal cut-point estimated from observations affected by a lower limit of detection.

          The receiver operating characteristic (ROC) curve is used to evaluate a biomarker's ability for classifying disease status. The Youden Index (J), the maximum potential effectiveness of a biomarker, is a common summary measure of the ROC curve. In biomarker development, levels may be unquantifiable below a limit of detection (LOD) and missing from the overall dataset. Disregarding these observations may negatively bias the ROC curve and thus J. Several correction methods have been suggested for mean estimation and testing; however, little has been written about the ROC curve or its summary measures. We adapt non-parametric (empirical) and semi-parametric (ROC-GLM [generalized linear model]) methods and propose parametric methods (maximum likelihood (ML)) to estimate J and the optimal cut-point (c *) for a biomarker affected by a LOD. We develop unbiased estimators of J and c * via ML for normally and gamma distributed biomarkers. Alpha level confidence intervals are proposed using delta and bootstrap methods for the ML, semi-parametric, and non-parametric approaches respectively. Simulation studies are conducted over a range of distributional scenarios and sample sizes evaluating estimators' bias, root-mean square error, and coverage probability; the average bias was less than one percent for ML and GLM methods across scenarios and decreases with increased sample size. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. We address the limitations and usefulness of each method in order to give researchers guidance in constructing appropriate estimates of biomarkers' true discriminating capabilities. Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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            Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report.

            Pancreatic ductal adenocarcinoma is one of the most difficult malignancies to diagnose and treat. The aim of this article is to review how tumor markers can aid the diagnosis and management of patients with this malignancy. The most widely used and best validated marker for pancreatic cancer is CA 19-9. Inadequate sensitivity and specificity limit the use of CA 19-9 in the early diagnosis of pancreatic cancer. In non-jaundiced patients, however, CA 19-9 may complement other diagnostic procedures. In patients with resectable pancreatic cancer, presurgical and postresection CA 19-9 levels correlate with overall survival. In advanced disease, elevated pretreatment levels of CA 19-9 are associated with adverse patient outcome and thus may be combined with other factors for risk stratification. Most, but not all, reports indicate that serial levels of CA 19-9 correlate with response to systemic therapy. Use of CA 19-9 kinetics in conjunction with imaging is therefore recommended in monitoring therapy. Although several potential serum and tissue markers for pancreatic cancer are currently undergoing evaluation, none are sufficiently validated for routine clinical use. CA 19-9 thus remains the serum pancreatic cancer marker against which new markers for this malignancy should be judged.
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              CD13/APN is activated by angiogenic signals and is essential for capillary tube formation.

              In the hematopoietic compartment, the CD13/APN metalloprotease is one of the earliest markers of cells committed to the myeloid lineage where it is expressed exclusively on the surface of myeloid progenitors and their differentiated progeny. CD13/APN is also found in nonhematopoietic tissues, and its novel expression on the endothelial cells of angiogenic, but not normal, vasculature was recently described. Treatment of animals with CD13/APN inhibitors significantly impaired retinal neovascularization, chorioallantoic membrane angiogenesis, and xenograft tumor growth, indicating that CD13/APN plays an important functional role in vasculogenesis and identifying it as a critical regulator of angiogenesis. To investigate the mechanisms of CD13/APN induction in tumor vasculature, the regulation of CD13/APN by factors contributing to angiogenic progression was studied. In this report, it is shown that endogenous CD13/APN levels in primary cells and cell lines are up-regulated in response to hypoxia, angiogenic growth factors, and signals regulating capillary tube formation during angiogenesis. Transcription of reporter plasmids containing CD13/APN proximal promoter sequences is significantly increased in response to the same angiogenic signals that regulate the expression of the endogenous gene and in human tumor xenografts, indicating that this fragment contains elements essential for the angiogenic induction of CD13/APN expression. Finally, functional antagonists of CD13/APN interfere with tube formation but not proliferation of primary vascular endothelial cells, suggesting that CD13/APN functions in the control of endothelial cell morphogenesis. These studies clearly establish the CD13/APN metalloprotease as an important regulator of endothelial morphogenesis during angiogenesis.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                22 November 2016
                24 October 2016
                : 7
                : 47
                : 77854-77864
                Affiliations
                1 Department of Emergency, The First Hospital of Jilin University, Changchun 130021, China
                2 Department of Gastroenterology, The First Hospital of Jilin University, Changchun 130021, China
                3 Basic Medical College of Jilin University, Changchun 130021, China
                Author notes
                Correspondence to: Xiangwei Meng, xiangweimeng2003@ 123456163.com
                Article
                12835
                10.18632/oncotarget.12835
                5363626
                27788483
                0ac510f4-4a71-4b11-af6d-740967e152fd
                Copyright: © 2016 Pang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 June 2016
                : 14 October 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                aminopeptidase n/cd13,pancreatic cancer,diagnosis,prognosis,biomarker
                Oncology & Radiotherapy
                aminopeptidase n/cd13, pancreatic cancer, diagnosis, prognosis, biomarker

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