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      An Analysis of Immunoreactive Signatures in Early Stage Hepatocellular Carcinoma

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          Abstract

          Background

          Hepatocellular carcinoma (HCC) is prevalent worldwide and early diagnosis of HCC is critical for effective treatment and optimal prognosis.

          Methods

          Serum was screened first by immunoproteomic analysis for HCC-related tumor associated antigens (TAAs). Selected TAAs were clinically evaluated retrospectively in patients with HCC, liver cirrhosis, chronic hepatitis and healthy controls. Levels of autoantibody to the selected TAAs were measured by protein microarrays containing protein antigens of the candidate TAAs. Analyses were done by using receiver operating characteristics (ROC) to calculate diagnostic accuracy.

          Findings

          Twenty-two candidate TAAs were assessed by protein microarray analysis in 914 participants with serum α-fetoprotein (AFP) available. Twelve candidate TAAs were statistically different in signal intensity between HCC and controls. Among them, CENPF, HSP60 and IMP-2 showed AUC (area under the curve) values of 0.826, 0.764 and 0.796 respectively for early HCC. The highest prevalence of autoantibody positivity was observed in HCC cases with BCLC tumor stage A, well-differentiated histology and Child-Pugh grade C. Specifically, 73.6% or 79.3% cases of early HCC with negative AFP were positive for autoantibody to CENPF or HSP60.

          Interpretation

          Tumor-associated autoimmune reactions may be triggered by early stage HCCs. Measurement of serum autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC.

          Highlights

          • Tumor-associated autoimmune reaction may be triggered by early stage HCCs, and TAAs may be potential marker for early HCC.

          • Measurement of autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC.

          • Generation of autoantibody to CENPF may result from autoimmune reaction in response to overexpression of CENPF in tumor cell.

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          Most cited references25

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          Management of hepatocellular carcinoma.

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            Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study.

            Hepatocellular carcinoma (HCC) is prevalent worldwide and improvements in timely and effective diagnosis are needed. We assessed whether measurement of Dickkopf-1 (DKK1) in serum could improve diagnostic accuracy for HCC. We analysed data for patients with HCC, chronic hepatitis B virus (HBV) infection, liver cirrhosis, and healthy controls, recruited from two Chinese centres between December, 2008, and July, 2009. A validation cohort matched for age and sex was recruited from another centre in China between July, 2010, and June, 2011. DKK1 was measured in serum by ELISA by independent researchers who had no access to patients' clinical information. We used receiver operating characteristics (ROC) to calculate diagnostic accuracy. We assessed serum DKK1 in 831 participants: 424 with HCC, 98 with chronic HBV infection, 96 with cirrhosis, and 213 healthy controls. The validation cohort comprised 453 participants: 209 with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy controls. Levels of DKK1 in serum were significantly higher in patients with HCC than in all controls. ROC curves showed the optimum diagnostic cutoff was 2·153 ng/mL (area under curve [AUC] 0·848 [95% CI 0·820-0·875], sensitivity 69·1%, and specificity 90·6% in the test cohort; 0·862 [0·825-0·899], 71·3%, and 87·2% in the validation cohort). Similar results were noted for early-stage HCC (0·865 [0·835-0·895], 70·9%, and 90·5% in the test cohort; 0·896 [0·846-0·947], 73·8%, and 87·2% in the validation cohort). Furthermore, DKK1 maintained diagnostic accuracy for patients with HCC who were α-fetoprotein (AFP) negative (0·841 [0·801-0·882], 70·4%, and 90·0% in the test cohort; 0·869 [0·815-0·923], 66·7%, and 87·2% in the validation cohort), including for patients with early-stage HCC (0·870 [0·829-0·911], 73·1%, and 90·0% in the test cohort; 0·893 [0·804-0·983], 72·2%, and 87·2% in the validation cohort), compared with all controls. Raised concentrations of DKK1 in serum could differentiate HCC from chronic HBV infection and cirrhosis (0·834 [0·798-0·871], 69·1%, and 84·7% in the test cohort; 0·873 [0·832-0·913], 71·3%, and 90·6% in the validation cohort). Moreover, measurement of DKK1 and AFP together improved diagnostic accuracy for HCC versus all controls compared with either test alone (0·889 [0·866-0·913], 73·3%, and 93·4% in the test cohort; 0·888 [0·856-0·920], 78·5%, and 87·2% in the validation cohort). DKK1 could complement measurement of AFP in the diagnosis of HCC and improve identification of patients with AFP-negative HCC and distinguish HCC from non-malignant chronic liver diseases. National Key Basic Research Programme of China, National Key Sci-Tech Special Projects of Infectious Diseases, National Natural Science Foundation of China, Research Fund for the Doctoral Programme of Higher Education of China. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?

              The clinical usefulness of alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC) management is debatable. To assess, in a large multi-centric survey, diagnostic and prognostic reliability of AFP, predictive factors, and any correlation with the tumor immunophenotype. A total of 1,158 patients with HCC were analyzed with reference to serum AFP levels at diagnosis. We evaluated: HCC grading, histotype, and size; Okuda, tumor-nodes-metastases (TNM), and Child-Pugh scores; liver function, symptoms, presence of metastases or portal thrombosis, etiology, survival, and treatment. In 66 patients with histological diagnosis, the pathologists evaluated p53 overexpression, MIB 1 labeling index, BCL-2 positive cells (index of apoptosis), and CD44 (adhesion molecule) positivity. Patients were divided into three AFP groups: normal ( 400 ng/mL) [18%]. Statistical correlations were significant for: weight loss (p= 0.0056), pain (p= 0.0025), Child-Pugh score (p= 0.001), tumor size, Okuda's and TNM stages, metastases, thrombosis, type of treatment (all p < 0.0001), and female sex (p < 0.004). AFP correlated with survival overall, in patients untreated, transplanted, or undergoing locoregional treatments; but not in those surgically treated. In the discriminant analysis, the related variables were size, female sex, Child-Pugh score, TNM staging (steps 1-4). When using the receiver operating characteristic curve, the prognostic reliability of AFP was limited with area under the curve of 0.59. Finally, patients with low expression of BCL2 had high AFP levels (p < 0.05). AFP positively correlated with Edmonson score (p < 0.0001). The evaluation of this large series of HCC patients allowed us to: confirm the low sensitivity (54%) of AFP in the diagnosis of HCC and its prognostic value, albeit limited, being tumor size, female sex (intriguingly enough), Child-Pugh score, and TNM staging independent predictors.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                13 March 2015
                May 2015
                13 March 2015
                : 2
                : 5
                : 438-446
                Affiliations
                [a ]Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China
                [b ]Biotechnology Center, Beijing Institute of Radiation Medicine, Beijing, China
                [c ]Department of Oncology Minimally Invasive Interventional Radiology, Beijing You-an Hospital, Capital Medical University, Beijing, China
                [d ]Department of Hepatopancreatobiliary and Splenic Medicine, Affiliated Hospital of Medical College of Chinese People's Armed Police Force, Tianjin, China
                [e ]Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
                [f ]Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
                [g ]Department of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
                [h ]National Clinical Research Center of Digestive Diseases, Beijing, China
                Author notes
                [* ]Corresponding authors at: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Beijing 100050, China. youhong30@ 123456sina.com huangj1966@ 123456hotmail.com
                [** ]Correspondence to: S. Wang, Biotechnology Center, Beijing Institute of Radiation Medicine, Beijing, China. sqwang@ 123456bmi.ac.cn
                [1]

                These authors contribute equally to the work.

                Article
                S2352-3964(15)00073-0
                10.1016/j.ebiom.2015.03.010
                4486196
                26137588
                c3358c75-c53e-4f04-bf61-764c225d0824
                © 2015 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 December 2014
                : 10 March 2015
                : 12 March 2015
                Categories
                Original Article

                hepatocellular carcinoma,early diagnosis,serological marker,autoantibody,tumor associated antigen

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