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      Elevated Ki-67 (MIB-1) expression as an independent predictor for unfavorable pathologic outcomes and biochemical recurrence after radical prostatectomy in patients with localized prostate cancer: A propensity score matched study

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          Abstract

          Background

          Ki-67 is known to be useful in estimating the fraction of proliferation tumor cells in various malignancies. We tried to investigate clinical association of Ki-67 (MIB-1) expression with the oncological outcomes in patients with localized prostate cancer (PCa) after the radical prostatectomy (RP).

          Materials and Methods

          We retrospectively analyzed the data of 1,561 patients who underwent RP for localized PCa. According to the propensity score having Ki-67 expression, 183 patients with positive Ki-67 expression were matched to 549 patients without Ki-67 expression. By using multivariate Cox-proportional hazards models and logistic regression tests, the prognostic value of each variable was tested.

          Results

          After propensity score matching, positive Ki-67 group showed significant worse clinical characteristics and pathologic outcomes than negative Ki-67 group. The multivariate analysis showed that the Ki-67 expression was significantly associated with several adverse pathologic outcomes including higher pathologic stage (p = 0.006), higher grade group (p = 0.005), seminal vesicle invasion (p = 0.036), and positive surgical margin (p = 0.025). The group with Ki-67 expression showed significant worse biochemical recurrence-free survival (p<0.001) than negative Ki-67 group. Subsequent multivariate Cox analyses showed that Ki-67 was independent predictor for BCR after RP (HR 1.549, 95% CI 1.187–2.021, p = 0.001).

          Conclusion

          In our study, high Ki-67 expression was significantly related with adverse pathological and finally with worse biochemical recurrence-free survival. Further studies are needed to validate the prognostic value of Ki-67 more exactly in PCa patients.

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          Most cited references17

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          The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

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            Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry

            The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, who had been diagnosed between 2005 and 2011, in 3,658 cases Ki-67 was routinely determined. Thus, a total of 3,658 patients with invasive breast cancer were included in the present study and used for statistical analysis. Ki-67 expression was associated with the common histopathological parameters. The strongest correlation was found between grading and Ki-67 (P   45 %, HR = 1.96, P = 0.001) as well as for OS (Ki-67: 26–35 %, HR = 1.71, P = 0.017; Ki-67: 36–45 %, HR = 2.05, P = 0.011; Ki-67 > 45 %, HR = 2.06, P = 0.002) independent of common clinical and histopathological factors. The 5-year DFS (OS) rate was 86.7 % (89.3 %) in patients with a Ki-67 value ≤15 % compared to 75.8 % (82.8 %) in patients with a Ki-67 value >45 %. Based on the data from a large cohort of a clinical cancer registry, it was demonstrated that Ki-67 is frequently determined in routine clinical work. Ki-67 expression is associated with common histopathological parameters, but is an additional independent prognostic parameter for DFS and OS in breast cancer patients. Future work should focus on standardization of Ki-67 assessment and specification of its role in treatment decisions.
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              Novel diagnostic biomarkers for prostate cancer

              Prostate cancer is the most frequently diagnosed malignancy in American men, and a more aggressive form of the disease is particularly prevalent among African Americans. The therapeutic success rate for prostate cancer can be tremendously improved if the disease is diagnosed early. Thus, a successful therapy for this disease depends heavily on the clinical indicators (biomarkers) for early detection of the presence and progression of the disease, as well as the prediction after the clinical intervention. However, the current clinical biomarkers for prostate cancer are not ideal as there remains a lack of reliable biomarkers that can specifically distinguish between those patients who should be treated adequately to stop the aggressive form of the disease and those who should avoid overtreatment of the indolent form. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker reveals further information to presently existing clinical and pathological analysis. It facilitates screening and detecting the cancer, monitoring the progression of the disease, and predicting the prognosis and survival after clinical intervention. A biomarker can also be used to evaluate the process of drug development, and, optimally, to improve the efficacy and safety of cancer treatment by enabling physicians to tailor treatment for individual patients. The form of the prostate cancer biomarkers can vary from metabolites and chemical products present in body fluid to genes and proteins in the prostate tissues. Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for prostate cancer. These emerging biomarkers will be beneficial and critical in developing new and clinically reliable indicators that will have a high specificity for the diagnosis and prognosis of prostate cancer. The purpose of this review is to examine the current status of prostate cancer biomarkers, with special emphasis on emerging markers, by evaluating their diagnostic and prognostic potentials. Both genes and proteins that reveal loss, mutation, or variation in expression between normal prostate and cancerous prostate tissues will be covered in this article. Along with the discovery of prostate cancer biomarkers, we will describe the criteria used when selecting potential biomarkers for further development towards clinical use. In addition, we will address how to appraise and validate candidate markers for prostate cancer and some relevant issues involved in these processes. We will also discuss the new concept of the biomarkers, existing challenges, and perspectives of biomarker development.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Project administrationRole: ResourcesRole: Validation
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Project administration
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 November 2019
                2019
                : 14
                : 11
                : e0224671
                Affiliations
                [001]Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
                The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1247-9958
                Article
                PONE-D-19-06983
                10.1371/journal.pone.0224671
                6837325
                31697718
                88e2a667-2aa1-4b0f-bd68-dd8ea65a75f2
                © 2019 Byun 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
                : 10 March 2019
                : 18 October 2019
                Page count
                Figures: 1, Tables: 3, Pages: 9
                Funding
                Funded by: National Research Foundation of Korea
                Award ID: NRF-2017R1C1B1009252
                Award Recipient :
                This study was supported in part by National Research Foundation of Korea (NRF) grant NRF-2017R1C1B1009252 (grant receiver: Hakmin Lee), funded by the Korean government (MSIP; Ministry of Science, ICT, and Future Planning). However, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Genitourinary Tract Tumors
                Prostate Cancer
                Medicine and Health Sciences
                Urology
                Prostate Diseases
                Prostate Cancer
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Reproductive System Procedures
                Prostatectomy
                Radical Prostatectomy
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Surgical Excision
                Prostatectomy
                Radical Prostatectomy
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Clinical Pathology
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and Life Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Anatomy
                Exocrine Glands
                Prostate Gland
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Anatomical Pathology
                Surgical Pathology
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Multivariate Analysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Multivariate Analysis
                Medicine and Health Sciences
                Diagnostic Medicine
                Prognosis
                Custom metadata
                All relevant data are within the manuscript.

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