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      Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer

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          Abstract

          Background

          Esophageal cancer often appears as postoperative metastasis or recurrence after radical surgery. Although we had previously reported that serum programmed cell death ligand 1 (PD-L1) level correlated with the prognosis of esophageal cancer, further novel biomarkers are required for more precise prediction of the prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with the cholesterol metabolism. But there was no report of relationship between serum PCSK9 antibody and cancer. Therefore, we investigated whether anti-PCSK9 antibodies could be a novel biomarker for solid cancer.

          Methods

          Serum levels of anti-PCSK9 antibodies and antigens in patients with solid cancer were analyzed using amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA). The reactivity of serum antibodies against recombinant PCSK9 protein was investigated by Western blotting, and the expression of PCSK9 antigens in esophageal cancer tissues was examined by immunohistochemical staining.

          Results

          AlphaLISA showed that serum anti-PCSK9 antibody (s-PCSK9-Ab) levels were significantly higher in patients with esophageal cancer, gastric cancer, colorectal cancer, lung cancer, and breast cancer than in healthy donors, and patients with esophageal cancer had the highest levels. The presence of serum antibody in patients was confirmed by Western blotting. There was no apparent correlation between s-PCSK9-Ab and PCSK9 antigen levels. Immunohistochemical staining demonstrated the expression of PCSK9 antigen in both the cytoplasm and nuclear compartments of esophageal squamous cell carcinoma tissue but not in normal tissue. Compared with patients with low s-PCSK9-Ab levels, those with high s-PCSK9-Ab levels had a favorable postoperative prognosis after radical surgery for esophageal cancer. In the multivariate analysis, tumor depth and s-PCSK9-Ab level were identified as independent prognostic factors. In the univariate analysis of clinicopathological features, high PCSK9 antibody levels were not associated with sex, age, location, tumor depth, lymph node status, squamous cell carcinoma antigen, or p53-Ab, whereas they correlated significantly with PD-L1 levels, which were associated with unfavorable prognosis. Correlation between s-PCSK9-Ab and PD-L1 levels was also confirmed in the logistic regression analysis; therefore, low s-PCSK9-Ab levels could discriminate another poor prognosis group other than high-PD-L1 group.

          Conclusions

          Patients with solid cancer had higher s-PCSK9-Ab levels than healthy donors. High s-PCSK9-Ab levels indicated better prognosis for overall survival after surgery in patients with esophageal cancer.

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          Most cited references48

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          Investigation of the freely available easy-to-use software ‘EZR' for medical statistics

          Y Kanda (2012)
          Although there are many commercially available statistical software packages, only a few implement a competing risk analysis or a proportional hazards regression model with time-dependent covariates, which are necessary in studies on hematopoietic SCT. In addition, most packages are not clinician friendly, as they require that commands be written based on statistical languages. This report describes the statistical software ‘EZR' (Easy R), which is based on R and R commander. EZR enables the application of statistical functions that are frequently used in clinical studies, such as survival analyses, including competing risk analyses and the use of time-dependent covariates, receiver operating characteristics analyses, meta-analyses, sample size calculation and so on, by point-and-click access. EZR is freely available on our website (http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html) and runs on both Windows (Microsoft Corporation, USA) and Mac OS X (Apple, USA). This report provides instructions for the installation and operation of EZR.
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            Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

            Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
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              Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

              Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                24 August 2021
                2021
                : 11
                : 708039
                Affiliations
                [1] 1Department of Clinical Oncology, Toho University Graduate School of Medicine , Tokyo, Japan
                [2] 2Department of Neurological Surgery, Chiba University Graduate School of Medicine , Chiba, Japan
                [3] 3Department of Gastroenterological Surgery, Toho University School of Medicine , Tokyo, Japan
                [4] 4Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare , Chiba, Japan
                [5] 5Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University , Chiba, Japan
                [6] 6Port Square Kashiwado Clinic, Kashiwado Memorial Foundation , Chiba, Japan
                Author notes

                Edited by: Zsolt Kovács, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureş, Romania

                Reviewed by: Qingyuan Yang, Massachusetts General Hospital and Harvard Medical School, United States; Nicola Tartaglia, University of Foggia, Italy

                *Correspondence: Hideaki Shimada, hideaki.shimada@ 123456med.toho-u.ac.jp

                This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2021.708039
                8421770
                34504788
                c720d464-b4c1-4574-8342-5bcbe475e912
                Copyright © 2021 Ito, Hiwasa, Oshima, Yajima, Suzuki, Nanami, Sumazaki, Shiratori, Funahashi, Li, Iwadate, Yamagata, Jambaljav, Takemoto, Yokote, Takizawa and Shimada

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 11 May 2021
                : 03 August 2021
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 48, Pages: 12, Words: 4944
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                proprotein convertase subtilisin/kexin type 9,programmed cell death ligand 1,esophageal cancer,antibody biomarker,overall survival,hyperlipidemia

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