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Dizman N, Necchi A. Promises and Challenges of Dietary Intervention in Patients With Prostate Cancer: Lessons Learned From the CAPFISH-3 Trial. J Clin Oncol 2025; 43:767-770. [PMID: 39671546 DOI: 10.1200/jco-24-02444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 12/15/2024] Open
Affiliation(s)
- Nazli Dizman
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Andrea Necchi
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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Pan X, Wei C, Su J, Fang M, Lin Q, Qin Y, Gao J, Zhao J, Zhao H, Liu F. A comprehensive analysis of the prognostic value, expression characteristics and immune correlation of MKI67 in cancers. Front Immunol 2025; 16:1531708. [PMID: 40070823 PMCID: PMC11894575 DOI: 10.3389/fimmu.2025.1531708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Background nuclear-associated antigen Ki67 (Ki67) emerges as a clinically practical biomarker for proliferation assessment among many cancer types. However, the definite prognostic value of Ki67 against a specific cancer type has remained vague. This study aims to perform a comprehensive pan-cancer analysis of the prognosis value of Ki67 across various cancer types. Methods This study explored the expression, prognostic value, and tumor-infiltrating immune of MKI67 in the TCGA database by pan-cancer, and then performed immunohistochemical, correlation analysis and prognostic analysis using 10028 patients of the top 10 cancer patients in China we collected. The correlation between MKI67 expression and survival outcome, clinical features, MSI, TMB, and tumor-infiltrating immune cells by TCGA database, xCell, and TIMER algorithms. Results MKI67 expression was significantly upregulated across varied cancer types verified by datasets. We found MKI67 expression was significantly associated with poor prognosis in LUADLUSC, LIHC, and BRCA patients, but good prognosis in COADREAD and READ patients via Kaplan-Meier survival analysis using 10028 patients collected. These results of our validation were generally consistent with TCGA database except BRCA, COADREAD and READ. Meanwhile, upregulation of MKI67 elevates the degree of immune infiltration of several immune cell subtypes, such as functional T cells, CD4+ T cells, and CD8+ T cells, as well as, MKI67 was related to Cell cycle, Oocyte meiosis, p53 and other pathways. Conclusion Our comprehensive analysis may supply useful guidance on MKI67 applicability across various cancer types. These observed results contribute to the promise of MKI67 in a realistic clinical setting and improve the outcomes of cancer patients.
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Affiliation(s)
- Xiaolan Pan
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Caibiao Wei
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jingyu Su
- Genetic Metabolism Center laboratory, Guangxi Zhuang Autonomous Region Maternal and Child Health Care Hospital, Nanning, China
| | - Min Fang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiumei Lin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yuling Qin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jie Gao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jie Zhao
- Department of Medical Records, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Huiliu Zhao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Fengfei Liu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
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Jones LW, Moskowitz CS, Lee CP, Fickera GA, Chun SS, Michalski MG, Stoeckel K, Underwood WP, Lavery JA, Bhanot U, Linkov I, Dang CT, Ehdaie B, Laudone VP, Eastham JA, Collins A, Sheerin PT, Liu LY, Eng SE, Boutros PC. Neoadjuvant Exercise Therapy in Prostate Cancer: A Phase 1, Decentralized Nonrandomized ControlledTrial. JAMA Oncol 2024; 10:1187-1194. [PMID: 39023900 PMCID: PMC11258635 DOI: 10.1001/jamaoncol.2024.2156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/22/2024] [Indexed: 07/20/2024]
Abstract
Importance Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known. Objective To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer. Design, Setting, and Participants This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024. Intervention Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring. Main Outcomes and Measures Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed. Results A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (-4.3% to 14.0%) for 90 minutes per week, 2.4% (-1.3% to 6.2%) for 150 minutes per week, -1.3% (-5.8% to 3.3%) for 225 minutes per week, -0.2% (-4.0% to 3.7%) for 300 minutes per week, -2.6% (-9.2% to 4.1%) for 375 minutes per week, and 2.2% (-0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (-1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (-1.1 to 1.5) for 150 minutes per week, -0.5 ng/mL (-1.2 to 0.3) for 225 minutes per week, -0.2 (-1.7 to 1.3) for 300 minutes per week, -0.7 ng/mL (-1.7 to 0.4) for 375 minutes per week, and -0.9 ng/mL (-2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 45 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer. Trial Registration ClinicalTrials.gov Identifier: NCT03813615.
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Affiliation(s)
- Lee W. Jones
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | | | | | | | - Su S. Chun
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | | | | | | | - Umeshkumar Bhanot
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Irina Linkov
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chau T. Dang
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Behfar Ehdaie
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Vincent P. Laudone
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - James A. Eastham
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Anne Collins
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Lydia Y. Liu
- Institute for Precision Health, University of California, Los Angeles
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles
- Department of Urology, University of California, Los Angeles
| | - Stefan E. Eng
- Institute for Precision Health, University of California, Los Angeles
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles
- Department of Urology, University of California, Los Angeles
| | - Paul C. Boutros
- Institute for Precision Health, University of California, Los Angeles
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles
- Department of Urology, University of California, Los Angeles
- Department of Human Genetics, University of California, Los Angeles
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Kildal W, Cyll K, Kalsnes J, Islam R, Julbø FM, Pradhan M, Ersvær E, Shepherd N, Vlatkovic L, Tekpli X, Garred Ø, Kristensen GB, Askautrud HA, Hveem TS, Danielsen HE. Deep learning for automated scoring of immunohistochemically stained tumour tissue sections - Validation across tumour types based on patient outcomes. Heliyon 2024; 10:e32529. [PMID: 39040241 PMCID: PMC11261074 DOI: 10.1016/j.heliyon.2024.e32529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 06/05/2024] [Indexed: 07/24/2024] Open
Abstract
We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9-98.5 %) for the nuclear model, 85.6 % (73.3-96.6 %) for the cytoplasmic model, and 78.4 % (75.5-84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.
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Affiliation(s)
- Wanja Kildal
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Karolina Cyll
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Joakim Kalsnes
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Rakibul Islam
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Frida M. Julbø
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Manohar Pradhan
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Elin Ersvær
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Neil Shepherd
- Gloucestershire Cellular Pathology Laboratory, Gloucester, GL53 7AN, UK
| | - Ljiljana Vlatkovic
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - OSBREAC
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
- Gloucestershire Cellular Pathology Laboratory, Gloucester, GL53 7AN, UK
- Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, NO-0450, Oslo, Norway
- Department of Pathology, Oslo University Hospital, NO-0424, Oslo, Norway
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, OX3 9DU, UK
| | - Xavier Tekpli
- Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, NO-0450, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Gunnar B. Kristensen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Hanne A. Askautrud
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Tarjei S. Hveem
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
| | - Håvard E. Danielsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, NO-0424, Oslo, Norway
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, OX3 9DU, UK
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Poalelungi DG, Neagu AI, Fulga A, Neagu M, Tutunaru D, Nechita A, Fulga I. Revolutionizing Pathology with Artificial Intelligence: Innovations in Immunohistochemistry. J Pers Med 2024; 14:693. [PMID: 39063947 PMCID: PMC11278211 DOI: 10.3390/jpm14070693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Artificial intelligence (AI) is a reality of our times, and it has been successfully implemented in all fields, including medicine. As a relatively new domain, all efforts are directed towards creating algorithms applicable in most medical specialties. Pathology, as one of the most important areas of interest for precision medicine, has received significant attention in the development and implementation of AI algorithms. This focus is especially important for achieving accurate diagnoses. Moreover, immunohistochemistry (IHC) serves as a complementary diagnostic tool in pathology. It can be further augmented through the application of deep learning (DL) and machine learning (ML) algorithms for assessing and analyzing immunohistochemical markers. Such advancements can aid in delineating targeted therapeutic approaches and prognostic stratification. This article explores the applications and integration of various AI software programs and platforms used in immunohistochemical analysis. It concludes by highlighting the application of these technologies to pathologies such as breast, prostate, lung, melanocytic proliferations, and hematologic conditions. Additionally, it underscores the necessity for further innovative diagnostic algorithms to assist physicians in the diagnostic process.
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Affiliation(s)
- Diana Gina Poalelungi
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Anca Iulia Neagu
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint John Clinical Emergency Hospital for Children, 800487 Galati, Romania
| | - Ana Fulga
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Marius Neagu
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Dana Tutunaru
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
| | - Aurel Nechita
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint John Clinical Emergency Hospital for Children, 800487 Galati, Romania
| | - Iuliu Fulga
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania; (D.G.P.); (M.N.); (D.T.); (A.N.); (I.F.)
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania
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Jha N, Phulware RH, Kumar A, Singh A, Durgapal P, Chowdhury N, Mittal A, Kishore S. A Study of Ki-67 Immunostaining in Prostate Carcinomas and Its Correlation with Gleason's Score and Prognosis: An Experience at a Tertiary Centre in the Himalayan Foothills. Indian J Surg Oncol 2024; 15:341-348. [PMID: 38741642 PMCID: PMC11088575 DOI: 10.1007/s13193-024-01902-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 02/14/2024] [Indexed: 05/16/2024] Open
Abstract
Prostate cancer is a significant cause of cancer-related mortality among men worldwide, necessitating the exploration of prognostic biomarkers to aid in accurate risk assessment and treatment decision-making. This cross-sectional study aimed to comprehensively evaluate the role of Ki-67 as a prognostic marker in prostate cancer by examining its association with clinicopathological parameters. A total of 102 archived cases of prostate core biopsy specimens, histopathologically reported as prostate carcinoma, were included in this study. Histopathological grading was conducted using Gleason's scoring and grading system based on morphology. The statistical software "R" was utilized for data analysis. Kruskal-Wallis test and Fisher's exact test were employed to analyze the association between Ki-67 expression and clinicopathological parameters. The study revealed significant correlations between Ki-67 expression and various clinicopathological parameters in prostate cancer cases. High Ki-67 expression levels were associated with higher Gleason scores, increased incidence of perineural invasion, advanced T stages, lymph node metastasis, presence of distant metastasis, and higher prognostic stage groups. The findings of this cross-sectional study support the potential of Ki-67 as a prognostic marker in prostate cancer. The significant associations observed between Ki-67 expression and clinicopathological parameters indicate its usefulness in risk stratification and treatment decision-making. The incorporation of histopathological grading, including Gleason scoring, and analysis of perineural invasion strengthens the validity of the study. Ki-67, in combination with morphological assessments, provides valuable prognostic information for prostate cancer patients.
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Affiliation(s)
- Nishi Jha
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Ravi Hari Phulware
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Arvind Kumar
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Ashok Singh
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Prashant Durgapal
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Nilotpal Chowdhury
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Ankur Mittal
- Department of Urology, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
| | - Sanjeev Kishore
- Department of Pathology & Laboratory Medicine, Level-3, Medical Block, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand India
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Siddiqui S. Assessment of Ki-67 expression in cases of prostatic carcinoma and its correlation with clinical outcomes. INDIAN J PATHOL MICR 2024; 67:362-366. [PMID: 38391304 DOI: 10.4103/ijpm.ijpm_171_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/28/2022] [Indexed: 02/24/2024] Open
Abstract
BACKGROUND Treatment decisions after diagnosis of clinically localized prostate cancer are difficult due to variability in tumor behavior. As there is a high prevalence of low-grade prostate cancer with an indolent course, we need improved markers of prostate cancer lethality in order to reduce the overtreatment. In the current study, we assessed Ki-67 expression in cases of prostate carcinoma and correlated its expression with clinical outcomes. MATERIALS AND METHODS It was a single-center retrospective descriptive type of study. A total of 50 cases were included. Diagnosed cases of adenocarcinoma on Transurethral Resection of the Prostate (TURP) chips and Trucut prostatic biopsies (Archival biopsy specimens) for whom five years follow-up was available from record files and/or telephonic interviews were included. The clinical outcomes (rate of distant metastases, disease specific survival, and overall survival) over a period of five years were recorded. RESULTS In the current study, 78% of the cases of carcinoma prostate were positive for Ki-67 expression. The mean Ki-67 staining index was 15.22% among the cases. The cases with High Ki-67 Staining index had a significantly higher rate of distant metastasis, poor disease-specific survival, and overall survival compared to cases with low Ki-67 staining index. CONCLUSION Ki-67 can be used along with the other established prognostic parameters to assess the lethality of prostate cancer.
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Affiliation(s)
- Sumaira Siddiqui
- Department of Pathology, Regency Hospital, Kanpur, Uttar Pradesh, India
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Kumar NB. Contemporary Strategies for Clinical Chemoprevention of Localized Prostate Cancer. Cancer Control 2024; 31:10732748241302863. [PMID: 39573923 PMCID: PMC11583501 DOI: 10.1177/10732748241302863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2024] Open
Abstract
Prostate cancer (PCa) is the most common cancer among men in the United States and the second leading cause of cancer-related deaths. Metastatic castration-resistant PCa is still a fatal disease. On the other hand, between 2016 and 2020, about 70% of PCa cases were diagnosed at a localized stage. Evolving data demonstrates that men with low-grade cancers treated with definitive therapies may now be exposed to morbidities of overtreatment and poor quality of life, with little or no benefit in terms of cancer specific mortality. Active surveillance (AS) is thus the recommended management strategy for men with low-grade disease. Although this subgroup of men have reported anxiety during the AS period, they account to be highly motivated to make positive lifestyle changes to further reduce their risk of PCa progression, underscoring the urgent need to identify novel strategies for preventing progression of localized PCa to metastatic disease through pharmacologic means, an approach termed chemoprevention. Although several promising agents and approaches have been examined over the past 2 decades, currently, there are several limitations in the approach used to systematically examine agents for chemoprevention targeting men on AS. The goal of this review is to summarize the current agents and approaches evaluated, targeting men on AS, recognize the gaps, and identify a contemporary and comprehensive path forward. Results of these studies may inform the development of phase III clinical trials and ultimately provide a strategy for clinical chemoprevention in men on AS, for whom, currently, there are no options for reducing the risk of progression to metastatic disease.
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Affiliation(s)
- Nagi B Kumar
- Cancer Epidemiology Program, Population Sciences Division, Genitourinary Oncology and Breast Oncology Departments, Department of Oncologic Sciences, Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL, USA
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Qiao X, Gu X, Liu Y, Shu X, Ai G, Qian S, Liu L, He X, Zhang J. MRI Radiomics-Based Machine Learning Models for Ki67 Expression and Gleason Grade Group Prediction in Prostate Cancer. Cancers (Basel) 2023; 15:4536. [PMID: 37760505 PMCID: PMC10526397 DOI: 10.3390/cancers15184536] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/02/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
PURPOSE The Ki67 index and the Gleason grade group (GGG) are vital prognostic indicators of prostate cancer (PCa). This study investigated the value of biparametric magnetic resonance imaging (bpMRI) radiomics feature-based machine learning (ML) models in predicting the Ki67 index and GGG of PCa. METHODS A total of 122 patients with pathologically proven PCa who had undergone preoperative MRI were retrospectively included. Radiomics features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. Then, recursive feature elimination (RFE) was applied to remove redundant features. ML models for predicting Ki67 expression and GGG were constructed based on bpMRI and different algorithms, including logistic regression (LR), support vector machine (SVM), random forest (RF), and K-nearest neighbor (KNN). The performances of different models were evaluated with receiver operating characteristic (ROC) analysis. In addition, a joint analysis of Ki67 expression and GGG was performed by assessing their Spearman correlation and calculating the diagnostic accuracy for both indices. RESULTS The ML model based on LR and ADC + T2 (LR_ADC + T2, AUC = 0.8882) performed best in predicting Ki67 expression, and ADC_wavelet-LHH_firstorder_Maximum had the highest feature weighting. The SVM_DWI + T2 (AUC = 0.9248) performed best in predicting GGG, and DWI_wavelet HLL_glcm_SumAverage had the highest feature weighting. The Ki67 and GGG exhibited a weak positive correlation (r = 0.382, p < 0.001), and LR_ADC + DWI had the highest diagnostic accuracy in predicting both (0.6230). CONCLUSION The proposed ML models are suitable for predicting both Ki67 expression and GGG in PCa. This algorithm could be used to identify indolent or invasive PCa with a noninvasive, repeatable, and accurate diagnostic method.
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Affiliation(s)
- Xiaofeng Qiao
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Xiling Gu
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Yunfan Liu
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Xin Shu
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Guangyong Ai
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Shuang Qian
- Big Data and Software Engineering College, Chongqing University, Chongqing 400000, China; (S.Q.); (L.L.)
| | - Li Liu
- Big Data and Software Engineering College, Chongqing University, Chongqing 400000, China; (S.Q.); (L.L.)
| | - Xiaojing He
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; (X.Q.); (X.G.); (Y.L.); (X.S.); (G.A.)
| | - Jingjing Zhang
- Departments of Diagnostic Radiology, National University of Singapore, Singapore 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, National University of Singapore, Singapore 117599, Singapore
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Milligan K, Deng X, Ali-Adeeb R, Shreeves P, Punch S, Costie N, Crook JM, Brolo AG, Lum JJ, Andrews JL, Jirasek A. Prediction of disease progression indicators in prostate cancer patients receiving HDR-brachytherapy using Raman spectroscopy and semi-supervised learning: a pilot study. Sci Rep 2022; 12:15104. [PMID: 36068275 PMCID: PMC9448740 DOI: 10.1038/s41598-022-19446-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/29/2022] [Indexed: 11/09/2022] Open
Abstract
This work combines Raman spectroscopy (RS) with supervised learning methods-group and basis restricted non-negative matrix factorisation (GBR-NMF) and linear discriminant analysis (LDA)-to aid in the prediction of clinical indicators of disease progression in a cohort of 9 patients receiving high dose rate brachytherapy (HDR-BT) as the primary treatment for intermediate risk (D'Amico) prostate adenocarcinoma. The combination of Raman spectroscopy and GBR-NMF-sparseLDA modelling allowed for the prediction of the following clinical information; Gleason score, cancer of the prostate risk assessment (CAPRA) score of pre-treatment biopsies and a Ki67 score of < 3.5% or > 3.5% in post treatment biopsies. The three clinical indicators of disease progression investigated in this study were predicted using a single set of Raman spectral data acquired from each individual biopsy, obtained pre HDR-BT treatment. This work highlights the potential of RS, combined with supervised learning, as a tool for the prediction of multiple types of clinically relevant information to be acquired simultaneously using pre-treatment biopsies, therefore opening up the potential for avoiding the need for multiple immunohistochemistry (IHC) staining procedures (H&E, Ki67) and blood sample analysis (PSA) to aid in CAPRA scoring.
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Affiliation(s)
- Kirsty Milligan
- Department of Physics, University of British Columbia, Kelowna, BC, Canada
| | - Xinchen Deng
- Department of Physics, University of British Columbia, Kelowna, BC, Canada
| | - Ramie Ali-Adeeb
- Department of Physics, University of British Columbia, Kelowna, BC, Canada
| | - Phillip Shreeves
- Department of Statistics, University of British Columbia, Kelowna, Canada
| | - Samantha Punch
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada
| | - Nathalie Costie
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada
| | - Juanita M Crook
- Department of Radiation Oncology, University of British Columbia, Kelowna, BC, Canada
| | - Alexandre G Brolo
- Department of Chemistry, University of Victoria, British Columbia, Canada
| | - Julian J Lum
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada.,Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada
| | - Jeffrey L Andrews
- Department of Statistics, University of British Columbia, Kelowna, Canada
| | - Andrew Jirasek
- Department of Physics, University of British Columbia, Kelowna, BC, Canada.
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11
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Kurozumi A, Lupold SE. Alternative polyadenylation: An untapped source for prostate cancer biomarkers and therapeutic targets? Asian J Urol 2021; 8:407-415. [PMID: 34765448 PMCID: PMC8566364 DOI: 10.1016/j.ajur.2021.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/20/2021] [Accepted: 05/05/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE To review alternative polyadenylation (APA) as a mechanism of gene regulation and consider potential roles for APA in prostate cancer (PCa) biology and treatment. METHODS An extensive review of mRNA polyadenylation, APA, and PCa literature was performed. This review article introduces APA and its association with human disease, outlines the mechanisms and components of APA, reviews APA in cancer biology, and considers whether APA may contribute to PCa progression and/or produce novel biomarkers and therapeutic targets for PCa. RESULTS Eukaryotic mRNA 3'-end cleavage and polyadenylation play a critical role in gene expression. Most human genes encode more than one polyadenylation signal, and produce more than one transcript isoform, through APA. Polyadenylation can occur throughout the gene body to generate transcripts with differing 3'-termini and coding sequence. Differences in 3'-untranslated regions length can modify post-transcriptional gene regulation by microRNAs and RNA binding proteins, and alter mRNA stability, translation efficiency, and subcellular localization. Distinctive APA patterns are associated with human diseases, tissue origins, and changes in cellular proliferation rate and differentiation state. APA events may therefore generate unique mRNA biomarkers or therapeutic targets in certain cancer types or phenotypic states. CONCLUSIONS The full extent of cancer-associated and tissue-specific APA events have yet to be defined, and the mechanisms and functional consequences of APA in cancer remain incompletely understood. There is evidence that APA is active in PCa, and that it may be an untapped resource for PCa biomarkers or therapeutic targets.
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Affiliation(s)
- Akira Kurozumi
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Shawn E. Lupold
- The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- The Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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12
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Prognostic role of Ki-67 in glioblastomas excluding contribution from non-neoplastic cells. Sci Rep 2021; 11:17918. [PMID: 34504133 PMCID: PMC8429554 DOI: 10.1038/s41598-021-95958-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/14/2021] [Indexed: 01/01/2023] Open
Abstract
Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas (p = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate (p = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas (p = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.
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13
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Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes. Cancers (Basel) 2021; 13:cancers13174425. [PMID: 34503235 PMCID: PMC8430998 DOI: 10.3390/cancers13174425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary NRDP1 is an E3 ubiquitin ligase that has been shown by our group and others to target ErbB3 for proteasomal degradation in prostate and breast cancer cells and thereby decrease the likelihood cancer progression. Our group has found that NRDP1 can be located in the nucleus as well as the cytoplasm of prostate cancer (CaP) cells, which is unexpected as NRDP1 lacks a nuclear localization signal. Here we elucidate the mechanism by which nuclear translocation of NRDP1 can occur and demonstrate that nuclear NRDP1 retains its ubiquitin ligase activity. Our patient data and cell line studies indicate that increased levels of nuclear NRDP1 contributes CaP progression, thereby underscoring the clinical relevance of our findings and supporting continued investigation and elucidation of the specific role(s) played by NRDP1 in the nucleus of CaP cells. Abstract To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.
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14
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Prostate Cancer Biomarkers: From diagnosis to prognosis and precision-guided therapeutics. Pharmacol Ther 2021; 228:107932. [PMID: 34174272 DOI: 10.1016/j.pharmthera.2021.107932] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/23/2022]
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and among the leading causes of cancer-related death worldwide. It is a highly heterogeneous disease, ranging from remarkably slow progression or inertia to highly aggressive and fatal disease. As therapeutic decision-making, clinical trial design and outcome highly depend on the appropriate stratification of patients to risk groups, it is imperative to differentiate between benign versus more aggressive states. The incorporation of clinically valuable prognostic and predictive biomarkers is also potentially amenable in this process, in the timely prevention of metastatic disease and in the decision for therapy selection. This review summarizes the progress that has so far been made in the identification of the genomic events that can be used for the classification, prediction and prognostication of PCa, and as major targets for clinical intervention. We include an extensive list of emerging biomarkers for which there is enough preclinical evidence to suggest that they may constitute crucial targets for achieving significant advances in the management of the disease. Finally, we highlight the main challenges that are associated with the identification of clinically significant PCa biomarkers and recommend possible ways to overcome such limitations.
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15
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Epstein JI, Amin MB, Fine SW, Algaba F, Aron M, Baydar DE, Beltran AL, Brimo F, Cheville JC, Colecchia M, Comperat E, da Cunha IW, Delprado W, DeMarzo AM, Giannico GA, Gordetsky JB, Guo CC, Hansel DE, Hirsch MS, Huang J, Humphrey PA, Jimenez RE, Khani F, Kong Q, Kryvenko ON, Kunju LP, Lal P, Latour M, Lotan T, Maclean F, Magi-Galluzzi C, Mehra R, Menon S, Miyamoto H, Montironi R, Netto GJ, Nguyen JK, Osunkoya AO, Parwani A, Robinson BD, Rubin MA, Shah RB, So JS, Takahashi H, Tavora F, Tretiakova MS, True L, Wobker SE, Yang XJ, Zhou M, Zynger DL, Trpkov K. The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer. Arch Pathol Lab Med 2021; 145:461-493. [PMID: 32589068 DOI: 10.5858/arpa.2020-0015-ra] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Controversies and uncertainty persist in prostate cancer grading. OBJECTIVE.— To update grading recommendations. DATA SOURCES.— Critical review of the literature along with pathology and clinician surveys. CONCLUSIONS.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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Affiliation(s)
- Jonathan I Epstein
- From the Departments of Pathology (Epstein, DeMarzo, Lotan), McGill University Health Center, Montréal, Quebec, Canada.,Urology (Epstein), David Geffen School of Medicine at UCLA, Los Angeles, California (Huang).,and Oncology (Epstein), The Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Mahul B Amin
- Department of Pathology and Laboratory Medicine and Urology, University of Tennessee Health Science, Memphis (Amin)
| | - Samson W Fine
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Fine)
| | - Ferran Algaba
- Department of Pathology, Fundacio Puigvert, Barcelona, Spain (Algaba)
| | - Manju Aron
- Department of Pathology, University of Southern California, Los Angeles (Aron)
| | - Dilek E Baydar
- Department of Pathology, Faculty of Medicine, Koç University, İstanbul, Turkey (Baydar)
| | - Antonio Lopez Beltran
- Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal (Beltran)
| | - Fadi Brimo
- Department of Pathology, McGill University Health Center, Montréal, Quebec, Canada (Brimo)
| | - John C Cheville
- Department of Pathology, Mayo Clinic, Rochester, Minnesota (Cheville, Jimenez)
| | - Maurizio Colecchia
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (Colecchia)
| | - Eva Comperat
- Department of Pathology, Hôpital Tenon, Sorbonne University, Paris, France (Comperat)
| | | | | | - Angelo M DeMarzo
- From the Departments of Pathology (Epstein, DeMarzo, Lotan), McGill University Health Center, Montréal, Quebec, Canada
| | - Giovanna A Giannico
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Giannico, Gordetsky)
| | - Jennifer B Gordetsky
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Giannico, Gordetsky)
| | - Charles C Guo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Guo)
| | - Donna E Hansel
- Department of Pathology, Oregon Health and Science University, Portland (Hansel)
| | - Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Hirsch)
| | - Jiaoti Huang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Huang)
| | - Peter A Humphrey
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Humphrey)
| | - Rafael E Jimenez
- Department of Pathology, Mayo Clinic, Rochester, Minnesota (Cheville, Jimenez)
| | - Francesca Khani
- Department of Pathology and Laboratory Medicine and Urology, Weill Cornell Medicine, New York, New York (Khani, Robinson)
| | - Qingnuan Kong
- Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China (Kong).,Kong is currently located at Kaiser Permanente Sacramento Medical Center, Sacramento, California
| | - Oleksandr N Kryvenko
- Departments of Pathology and Laboratory Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (Kryvenko)
| | - L Priya Kunju
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (Kunju, Mehra)
| | - Priti Lal
- Perelman School of Medicine, University of Pennsylvania, Philadelphia (Lal)
| | - Mathieu Latour
- Department of Pathology, CHUM, Université de Montréal, Montréal, Quebec, Canada (Latour)
| | - Tamara Lotan
- From the Departments of Pathology (Epstein, DeMarzo, Lotan), McGill University Health Center, Montréal, Quebec, Canada
| | - Fiona Maclean
- Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Maclean)
| | - Cristina Magi-Galluzzi
- Department of Pathology, The University of Alabama at Birmingham, Birmingham (Magi-Galluzzi, Netto)
| | - Rohit Mehra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (Kunju, Mehra)
| | - Santosh Menon
- Department of Surgical Pathology, Tata Memorial Hospital, Parel, Mumbai, India (Menon)
| | - Hiroshi Miyamoto
- Departments of Pathology and Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, New York (Miyamoto)
| | - Rodolfo Montironi
- Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region, United Hospitals, Ancona, Italy (Montironi)
| | - George J Netto
- Department of Pathology, The University of Alabama at Birmingham, Birmingham (Magi-Galluzzi, Netto)
| | - Jane K Nguyen
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Nguyen)
| | - Adeboye O Osunkoya
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Osunkoya)
| | - Anil Parwani
- Department of Pathology, Ohio State University, Columbus (Parwani, Zynger)
| | - Brian D Robinson
- Department of Pathology and Laboratory Medicine and Urology, Weill Cornell Medicine, New York, New York (Khani, Robinson)
| | - Mark A Rubin
- Department for BioMedical Research, University of Bern, Bern, Switzerland (Rubin)
| | - Rajal B Shah
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas (Shah)
| | - Jeffrey S So
- Institute of Pathology, St Luke's Medical Center, Quezon City and Global City, Philippines (So)
| | - Hiroyuki Takahashi
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan (Takahashi)
| | - Fabio Tavora
- Argos Laboratory, Federal University of Ceara, Fortaleza, Brazil (Tavora)
| | - Maria S Tretiakova
- Department of Pathology, University of Washington School of Medicine, Seattle (Tretiakova, True)
| | - Lawrence True
- Department of Pathology, University of Washington School of Medicine, Seattle (Tretiakova, True)
| | - Sara E Wobker
- Departments of Pathology and Laboratory Medicine and Urology, University of North Carolina, Chapel Hill (Wobker)
| | - Ximing J Yang
- Department of Pathology, Northwestern University, Chicago, Illinois (Yang)
| | - Ming Zhou
- Department of Pathology, Tufts Medical Center, Boston, Massachusetts (Zhou)
| | - Debra L Zynger
- Department of Pathology, Ohio State University, Columbus (Parwani, Zynger)
| | - Kiril Trpkov
- and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada (Trpkov)
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16
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Sopyllo K, Erickson AM, Mirtti T. Grading Evolution and Contemporary Prognostic Biomarkers of Clinically Significant Prostate Cancer. Cancers (Basel) 2021; 13:cancers13040628. [PMID: 33562508 PMCID: PMC7914622 DOI: 10.3390/cancers13040628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Prostate cancer treatment decisions are based on clinical stage and histological diagnosis, including Gleason grading assessed by a pathologist, in biopsies. Prior to staging and grading, serum or blood prostate-specific antigen (PSA) levels are measured and often trigger diagnostic examinations. However, PSA is best suited as a marker of cancer relapse after initial treatment. In this review, we first narratively describe the evolution of histological grading, the current status of Gleason pattern-based diagnostics and glance into future methodology of risk assessment by histological examination. In the second part, we systematically review the biomarkers that have been shown, independent from clinical characteristics, to correlate with clinically relevant end-points, i.e., occurrence of metastases, disease-specific mortality and overall survival after initial treatment of localized prostate cancer. Abstract Gleason grading remains the strongest prognostic parameter in localized prostate adenocarcinoma. We have here outlined the evolution and contemporary practices in pathological evaluation of prostate tissue samples for Gleason score and Grade group. The state of more observer-independent grading methods with the aid of artificial intelligence is also reviewed. Additionally, we conducted a systematic review of biomarkers that hold promise in adding independent prognostic or predictive value on top of clinical parameters, Grade group and PSA. We especially focused on hard end points during the follow-up, i.e., occurrence of metastasis, disease-specific mortality and overall mortality. In peripheral blood, biopsy-detected prostate cancer or in surgical specimens, we can conclude that there are more than sixty biomarkers that have been shown to have independent prognostic significance when adjusted to conventional risk assessment or grouping. Our search brought up some known putative markers and panels, as expected. Also, the synthesis in the systematic review indicated markers that ought to be further studied as part of prospective trials and in well characterized patient cohorts in order to increase the resolution of the current clinico-pathological prognostic factors.
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Affiliation(s)
- Konrad Sopyllo
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Andrew M. Erickson
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK;
| | - Tuomas Mirtti
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
- Department of Pathology, HUS Diagnostic Centre, Helsinki University Hospital, 00029 Helsinki, Finland
- Correspondence:
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17
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Halin Bergström S, Rudolfsson S, Lundholm M, Josefsson A, Wikström P, Bergh A. High-grade tumours promote growth of other less-malignant tumours in the same prostate. J Pathol 2021; 253:396-403. [PMID: 33330991 PMCID: PMC7986692 DOI: 10.1002/path.5604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Prostate cancer is a multifocal disease, but if and how individual prostate tumours influence each other is largely unknown. We therefore explored signs of direct or indirect tumour–tumour interactions in experimental models and patient samples. Low‐metastatic AT1 and high‐metastatic MatLyLu (MLL) Dunning rat prostate cancer cells were injected into separate lobes of the ventral prostate of immunocompetent rats. AT1 tumours growing in the same prostate as MLL tumours had increased tumour size and proliferation compared to AT1 tumours growing alone. In addition, the vasculature and macrophage density surrounding the AT1 tumours were increased by MLL tumour closeness. In patient prostatectomy samples, selected to contain an index tumour [tumour with the highest grade, International Society of Urological Pathology (ISUP) grade 1, 2, 3 or 4] and a low‐grade satellite tumour (ISUP grade 1), cell proliferation in low‐grade satellite tumours gradually increased with increasing histological grade of the index tumour. The density of blood vessels and CD68+ macrophages also increased around the low‐grade satellite tumour if a high‐grade index tumour was present. This suggests that high‐grade tumours, by changing the prostate microenvironment, may increase the aggressiveness of low‐grade lesions in the organ. Future studies are needed to explore the mechanisms behind tumour–tumour interactions and their clinical importance. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
| | - Stina Rudolfsson
- Department of Surgical and Perioperative Sciences, Urology, Umeå University, Umeå, Sweden
| | - Marie Lundholm
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Andreas Josefsson
- Department of Surgical and Perioperative Sciences, Urology, Umeå University, Umeå, Sweden
| | - Pernilla Wikström
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Anders Bergh
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
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18
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Liu MS, Zhao H, Xu CX, Xie PB, Wang W, Yang YY, Lee WH, Jin Y, Zhou HQ. Clinical significance of EPHX2 deregulation in prostate cancer. Asian J Androl 2021; 23:109-115. [PMID: 32687069 PMCID: PMC7831821 DOI: 10.4103/aja.aja_34_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The arachidonic acid (AA) metabolic pathway participates in various physiological processes as well as in the development of malignancies. We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas (TCGA) prostate cancer (PCa) dataset and found that the gene encoding soluble epoxide hydrolase (EPHX2) is frequently deleted in PCa. EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry. The expression data were analyzed in conjunction with clinicopathological variables. Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time. Furthermore, EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa, respectively. In addition, EPHX2 protein expression correlated negatively with Ki67 expression. In conclusion, EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.
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Affiliation(s)
- Ming-Sheng Liu
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
| | - Hui Zhao
- Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming 650332, China
| | - Chen-Xiang Xu
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
| | - Ping-Bo Xie
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
| | - Wei Wang
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
| | - Ying-Yu Yang
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
| | - Wen-Hui Lee
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Yang Jin
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo 0379, Norway
| | - Hong-Qing Zhou
- The Second Ward of Urology, Qujing Affiliated Hospital of Kunming Medical University, Qujing 655000, China
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19
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Oligometastatic Prostate Adenocarcinoma. Clinical-Pathologic Study of a Histologically Under-Recognized Prostate Cancer. J Pers Med 2020; 10:jpm10040265. [PMID: 33291528 PMCID: PMC7761807 DOI: 10.3390/jpm10040265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/26/2020] [Accepted: 12/02/2020] [Indexed: 12/22/2022] Open
Abstract
The clinical parameters and the histological and immunohistochemical findings of a prospective protocolized series of 27 prostate carcinoma patients with oligometastatic disease followed homogeneously were analyzed. Lymph nodes (81.5%) and bones (18.5%) were the only metastatic sites. Local control after metastatic directed treatment was achieved in 22 (81.5%) patients. A total of 8 (29.6%) patients developed castration-resistant prostate cancer. Seventeen (63%) patients presented with non-organ confined disease. The Gleason index 8-10 was the most frequently observed (12 cases, 44.4%) combined grade. Positive immunostainings were detected with androgen receptor (100%), PGP 9.5 (74%), ERG (40.7%), chromogranin A (29.6%), and synaptophysin (18.5%) antibodies. The Ki-67 index value > 5% was observed in 15% of the cases. L1CAM immunostaining was negative in all cases. Fisher exact test showed that successful local control of metastases was associated to mild inflammation, organ confined disease, Ki-67 index < 5%, and Gleason index 3 + 3. A castration resistant status was associated with severe inflammation, atrophy, a Gleason index higher than 3 + 3, Ki-67 index ≥ 5%, and positive PGP 9.5, chromogranin A, and synaptophysin immunostainings. In conclusion, oligometastatic prostate adenocarcinoma does not have a specific clinical-pathologic profile. However, some histologic and immunohistochemical parameters of routine use may help with making therapeutic decisions.
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20
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Tonry C, Finn S, Armstrong J, Pennington SR. Clinical proteomics for prostate cancer: understanding prostate cancer pathology and protein biomarkers for improved disease management. Clin Proteomics 2020; 17:41. [PMID: 33292167 PMCID: PMC7678104 DOI: 10.1186/s12014-020-09305-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
Following the introduction of routine Prostate Specific Antigen (PSA) screening in the early 1990's, Prostate Cancer (PCa) is often detected at an early stage. There are also a growing number of treatment options available and so the associated mortality rate is generally low. However, PCa is an extremely complex and heterogenous disease and many patients suffer disease recurrence following initial therapy. Disease recurrence commonly results in metastasis and metastatic PCa has an average survival rate of just 3-5 years. A significant problem in the clinical management of PCa is being able to differentiate between patients who will respond to standard therapies and those who may benefit from more aggressive intervention at an earlier stage. It is also acknowledged that for many men the disease is not life threatenting. Hence, there is a growing desire to identify patients who can be spared the significant side effects associated with PCa treatment until such time (if ever) their disease progresses to the point where treatment is required. To these important clinical needs, current biomarkers and clinical methods for patient stratification and personlised treatment are insufficient. This review provides a comprehensive overview of the complexities of PCa pathology and disease management. In this context it is possible to review current biomarkers and proteomic technologies that will support development of biomarker-driven decision tools to meet current important clinical needs. With such an in-depth understanding of disease pathology, the development of novel clinical biomarkers can proceed in an efficient and effective manner, such that they have a better chance of improving patient outcomes.
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Affiliation(s)
- Claire Tonry
- UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Stephen Finn
- Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin 8, Ireland
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21
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Wang YA, Sfakianos J, Tewari AK, Cordon-Cardo C, Kyprianou N. Molecular tracing of prostate cancer lethality. Oncogene 2020; 39:7225-7238. [PMID: 33046797 DOI: 10.1038/s41388-020-01496-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/16/2020] [Accepted: 09/28/2020] [Indexed: 01/14/2023]
Abstract
Prostate cancer is diagnosed mostly in men over the age of 50 years, and has favorable 5-year survival rates due to early cancer detection and availability of curative surgical management. However, progression to metastasis and emergence of therapeutic resistance are responsible for the majority of prostate cancer mortalities. Recent advancement in sequencing technologies and computational capabilities have improved the ability to organize and analyze large data, thus enabling the identification of novel biomarkers for survival, metastatic progression and patient prognosis. Large-scale sequencing studies have also uncovered genetic and epigenetic signatures associated with prostate cancer molecular subtypes, supporting the development of personalized targeted-therapies. However, the current state of mainstream prostate cancer management does not take full advantage of the personalized diagnostic and treatment modalities available. This review focuses on interrogating biomarkers of prostate cancer progression, including gene signatures that correspond to the acquisition of tumor lethality and those of predictive and prognostic value in progression to advanced disease, and suggest how we can use our knowledge of biomarkers and molecular subtypes to improve patient treatment and survival outcomes.
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Affiliation(s)
- Yuanshuo Alice Wang
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John Sfakianos
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ashutosh K Tewari
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Carlos Cordon-Cardo
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.,Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Natasha Kyprianou
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. .,Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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22
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Montes M, MacKenzie L, McAllister MJ, Roseweir A, McCall P, Hatziieremia S, Underwood MA, Boyd M, Paul A, Plevin R, MacKay SP, Edwards J. Determining the prognostic significance of IKKα in prostate cancer. Prostate 2020; 80:1188-1202. [PMID: 33258506 DOI: 10.1002/pros.24045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/02/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways play key roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunit α (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome. METHODS A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth. RESULTS High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC. CONCLUSION The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.
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Affiliation(s)
- Melania Montes
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Lewis MacKenzie
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Milly J McAllister
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Antonia Roseweir
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Pamela McCall
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Sophia Hatziieremia
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
| | - Mark A Underwood
- Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Marie Boyd
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Andrew Paul
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Robin Plevin
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Simon P MacKay
- Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Joanne Edwards
- Unit of Gastrointestinal and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, Institute of Cancer Science, University of Glasgow, Glasgow, UK
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23
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Huh SJ, Oh SY, Lee S, Lee JH, Kim SH, Pak MK, Kim HJ. Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing. Oncol Lett 2020; 20:205. [PMID: 32963611 PMCID: PMC7491050 DOI: 10.3892/ol.2020.12068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 07/06/2020] [Indexed: 12/16/2022] Open
Abstract
Extranodal marginal zone lymphoma is a type of low-grade B-cell lymphoma that can be classified as a mucosal-associated lymphoid tissue (MALT) lymphoma. Recently, second-generation or next-generation sequencing (NGS), which allows simultaneous sequencing of hundreds to billions of DNA strands, has been a focus of attention and is rapidly being adopted in various fields. In the present study, paraffin-embedded tissue samples of gastric MALT lymphoma (n=1) and small intestine MALT lymphoma (n=4) were selected, and DNA was extracted from the tissue samples. After performing quality control, NGS was performed using HemaSCAN™, a custom panel of 426 genes, including essential blood cancer genes. NGS revealed single nucleotide variations (SNVs), short insertions and deletions (InDels) and copy number variations (CNVs). These genomic variants were reported as annotated, known or novel variants. An annotated variant, an erb-b2 receptor tyrosine kinase 2 gene amplification, was observed in one patient. Known and novel variants, including SNVs of SET binding protein 6 (SETBP6), Runt-related transcription factor 1 and Kelch-like ECH-associated protein 1 genes, InDel of the marker of proliferation Ki-67 gene, and CNVs of the zinc finger protein 703 and NOTCH1 genes, were observed in ≥2 patients. Additionally, InDels with frameshift mutations were identified in the B-cell lymphoma/leukemia 10, DEAD-box helicase 3 X-linked, forkhead box O3 and mucin 2, oligomeric mucus/gel-forming genes in one patient. Since few NGS studies have been performed on MALT lymphoma, the current results were unable to determine if the different mutations that were identified are ‘actionable’ (that is, potentially responsive to a targeted therapy) Further studies are required to determine the associations between genetic mutations and the development of MALT lymphoma.
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Affiliation(s)
- Seok Jae Huh
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Sung Yong Oh
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Suee Lee
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Ji Hyun Lee
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Sung Hyun Kim
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Min Kyung Pak
- Department of Pathology, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
| | - Hyo-Jin Kim
- Department of Internal Medicine, Dong-A University College of Medicine, Seo-gu, Busan 49201, Republic of Korea
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24
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Federer-Gsponer JR, Müller DC, Zellweger T, Eggimann M, Marston K, Ruiz C, Seifert HH, Rentsch CA, Bubendorf L, Le Magnen C. Patterns of stemness-associated markers in the development of castration-resistant prostate cancer. Prostate 2020; 80:1108-1117. [PMID: 32628318 DOI: 10.1002/pros.24039] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Putative castration-resistant (CR) stem-like cells (CRSC) have been identified based on their ability to initiate and drive prostate cancer (PCa) recurrence following castration in vivo. Yet the relevance of these CRSC in the course of the human disease and particularly for the transition from hormone-naive (HN) to castration-resistance is unclear. In this study, we aimed at deciphering the significance of CRSC markers in PCa progression. METHODS We constructed a tissue microarray comprising 112 matched HN and CR tissue specimens derived from 55 PCa patients. Expression of eight stemness-associated markers (ALDH1A1, ALDH1A3, ALDH3A1, BMI1, NANOG, NKX3.1, OCT4, SOX2) was assessed by immunohistochemistry and scored as a percentage of positive tumor cells. For each marker, the resulting scores were statistically analyzed and compared to pathological and clinical data associated with the samples. Unsupervised clustering analysis was performed to stratify patients according to the expression of the eight CRSC markers. Publicly-available transcriptional datasets comprising HN and CR PCa samples were interrogated to assess the expression of the factors in silico. RESULTS Immunohistochemical assessment of paired samples revealed atypical patterns of expression and intra- and intertumor heterogeneity for a subset of CRSC markers. While the expression of particular CRSC markers was dynamic over time in some patients, none of the markers showed significant changes in expression upon the development of castration resistance (CR vs HN). Using unsupervised clustering approaches, we identified phenotypic subtypes based on the expression of specific stem-associated markers. In particular, we found (a) patterns of mutual exclusivity for ALDH1A1 and ALDH1A3 expression, which was also observed at the transcriptomic level in publicly-available PCa datasets, and (b) a phenotypic cluster associated with more aggressive features. Finally, by comparing HN and CR matched samples, we identified phenotypic cluster switches (ie, change of phenotypic cluster between the HN and CR state), that may be associated with clinical and predictive relevance. CONCLUSIONS Our findings indicate stemness-associated patterns that are associated with the development of castration-resistance. These results pave the way toward a deeper understanding of the relevance of CRSC markers in PCa progression and resistance to androgen-deprivation therapy.
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Affiliation(s)
| | - David C Müller
- Department of Urology, University Hospital Basel, Basel, Switzerland
| | | | - Maurice Eggimann
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Katharina Marston
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Christian Ruiz
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | | | - Cyrill A Rentsch
- Department of Urology, University Hospital Basel, Basel, Switzerland
| | - Lukas Bubendorf
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Clémentine Le Magnen
- Department of Urology, University Hospital Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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25
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Mohler JL, Antonarakis ES, Armstrong AJ, D'Amico AV, Davis BJ, Dorff T, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz EM, Hurwitz M, Ippolito JE, Kane CJ, Kuettel MR, Lang JM, McKenney J, Netto G, Penson DF, Plimack ER, Pow-Sang JM, Pugh TJ, Richey S, Roach M, Rosenfeld S, Schaeffer E, Shabsigh A, Small EJ, Spratt DE, Srinivas S, Tward J, Shead DA, Freedman-Cass DA. Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020; 17:479-505. [PMID: 31085757 DOI: 10.6004/jnccn.2019.0023] [Citation(s) in RCA: 884] [Impact Index Per Article: 176.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Joseph E Ippolito
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | - Jesse McKenney
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - George Netto
- University of Alabama at Birmingham Comprehensive Cancer Center
| | | | | | | | | | - Sylvia Richey
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | - Mack Roach
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | - Edward Schaeffer
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Ahmad Shabsigh
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Eric J Small
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | - Jonathan Tward
- Huntsman Cancer Institute at the University of Utah; and
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26
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Raspollini MR, Montagnani I, Cirri P, Baroni G, Cimadamore A, Scarpelli M, Cheng L, Lopez-Beltran A, Montironi R, Barnea ER. PreImplantation Factor immunohistochemical expression correlates with prostate cancer aggressiveness. Int J Biol Markers 2020; 35:82-90. [PMID: 32389051 DOI: 10.1177/1724600820919969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The PreImplantation Factor (PIF)-a peptide secreted by viable embryos-exerts autotrophic protective effects, promotes endometrial receptivity and controls trophoblast invasion. Synthetic PIF (sPIF) has both immune-protective and regenerative properties, and reduces oxidative stress and protein misfolding. PIF is detected by immunohistochemistry (IHC) in hyperplastic endometriotic lesions and advanced uterine cancer. sPIF reduces graft-versus-host disease while maintaining a graft-versus-leukemia effect. METHODS PIF detection in prostate cancer was assessed in 50 human prostate samples following radical prostatectomy using tumor-microarray-based IHC correlating PIF immune staining with Gleason score (GS) and cancer aggressiveness. RESULTS PIF was detected in moderate-to-high risk prostate cancer (GS 4+3 and beyond, prognostic groups 3 to 5). In prostate cancer (GS (WHO Grade Group (GG)5), PIF was detected in 50% of cases; in prostate cancer (GS 4+4 GG4), PIF was observed in 62.5% of cases; in prostate cancer (GS 4+3 GG3), PIF immunostaining was observed in 57.1% of cases. In prostate cancer, (GS 3+4 GG2) and (GS 3+3 GG1) cases where PIF staining was negative to weak, membranous staining was observed in 20% of cases (staining pattern considered negative). High-grade prostate intraepithelial neoplasia PIF positive stain in 28.57% of cases (6 of 21) was observed. In contrast, PIF was not detected in normal prostate glands. Importantly, sPIF added to the PC3 cell line alone or combined with prostate cancer fibroblast feeder-cells did not affect proliferation. Only when peripheral blood mononuclear cells were added to the culture, a minor increase in cell proliferation was noted, reflecting local proliferation control. CONCLUSIONS Collectively, PIF assessment could be a valuable, simple-to-use immunohistochemical biomarker to evaluate aggressiveness/prognosis in specimens from prostate cancer patients.
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Affiliation(s)
| | - Ilaria Montagnani
- Histopathology and Molecular Diagnostics, University Hospital Careggi, Florence, Toscana, Italy
| | - Paolo Cirri
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche Sezione di Scienze Biochimiche, Scuola di Scienze della Salute Umana Università degli Studi di Firenze, Florence, Toscana, Italy
| | - Gianna Baroni
- Histopathology and Molecular Diagnostics, University Hospital Careggi, Florence, Toscana, Italy
| | - Alessia Cimadamore
- Institute of Pathological Anatomy and Histopathology Polytechnic University of the Marche Region, Ancona, Torrette, Italy
| | - Marina Scarpelli
- Institute of Pathological Anatomy and Histopathology Polytechnic University of the Marche Region, Ancona, Torrette, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Antonio Lopez-Beltran
- Unit of Anatomical Pathology, Faculty of Medicine, University of Cordoba, Cordoba, Andalucía, Spain
| | - Rodolfo Montironi
- Institute of Pathological Anatomy and Histopathology Polytechnic University of the Marche Region, Ancona, Torrette, Italy
| | - Eytan R Barnea
- BioIncept, LLC & The Society for the Investigation of Early Pregnancy (SIEP), New York, NY, USA
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27
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Saha AK, Contreras-Galindo R, Niknafs YS, Iyer M, Qin T, Padmanabhan K, Siddiqui J, Palande M, Wang C, Qian B, Ward E, Tang T, Tomlins SA, Gitlin SD, Sartor MA, Omenn GS, Chinnaiyan AM, Markovitz DM. The role of the histone H3 variant CENPA in prostate cancer. J Biol Chem 2020; 295:8537-8549. [PMID: 32371391 PMCID: PMC7307189 DOI: 10.1074/jbc.ra119.010080] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 04/14/2020] [Indexed: 01/26/2023] Open
Abstract
Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth.
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Affiliation(s)
- Anjan K Saha
- Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA.,Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Yashar S Niknafs
- Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA.,Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthew Iyer
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Tingting Qin
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Karthik Padmanabhan
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Javed Siddiqui
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Monica Palande
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Claire Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Brian Qian
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Elizabeth Ward
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Tara Tang
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Scott A Tomlins
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Scott D Gitlin
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Maureen A Sartor
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Gilbert S Omenn
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.,Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Arul M Chinnaiyan
- Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA.,Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - David M Markovitz
- Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan, USA .,Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.,Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA
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Byun SS, Lee M, Hong SK, Lee H. 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. PLoS One 2019; 14:e0224671. [PMID: 31697718 PMCID: PMC6837325 DOI: 10.1371/journal.pone.0224671] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 10/18/2019] [Indexed: 01/04/2023] Open
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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Affiliation(s)
- Seok-Soo Byun
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Minseung Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sung Kyu Hong
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hakmin Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
- * E-mail:
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Hu J, Wu X, Yang C, Rashid K, Ma C, Hu M, Ding Q, Jiang H. Anticancer effect of icaritin on prostate cancer via regulating miR-381-3p and its target gene UBE2C. Cancer Med 2019; 8:7833-7845. [PMID: 31646760 PMCID: PMC6912031 DOI: 10.1002/cam4.2630] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 12/14/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common health-related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin-conjugating enzyme E2C (UBE2C) is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR-381-3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR-381-3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR-381-3p/UBE2C pathway.
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Affiliation(s)
- Jimeng Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaobo Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Khalid Rashid
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chenkai Ma
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Vic., Australia
| | - Mengbo Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiang Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
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Prognostic Role of Ki-67 in Adrenocortical Carcinoma After Primary Resection: A Retrospective Mono-Institutional Study. Adv Ther 2019; 36:2756-2768. [PMID: 31471770 DOI: 10.1007/s12325-019-01050-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. It is vitally important to predict prognosis and restrict unnecessary adjuvant treatments for patients with ACC. This study aims to confirm the prognostic value of Ki-67 and provide a prognostic evaluation on ACC after primary surgery. METHODS A total of 66 patients satisfied the inclusion criteria and their complete data were collected and reviewed. The correlation between Ki-67 index and clinicopathologic variables was analyzed using chi-square tests and Pearson's or Spearman's test. Survival curves were generated by Kaplan-Meier analysis and compared with the log-rank test. The Cox regression model was performed to estimate hazard ratios for univariate and multivariate analyses. RESULTS Of the 66 patients, recurrence was observed in 30 patients (45.5%) and 26 patients (39.4%) died of progressive ACC. The evaluated median overall survival (OS) of the entire study population was 16.5 (range 1-104) months and recurrence-free survival (RFS) was 9.0 (range 0-104) months. Increased Ki-67 expression (> 20% and > 3%) was negatively correlated with OS and RFS (chi-square, P = 0.006 and 0.044, respectively). In multivariate analysis, the Ki-67 index with 20% and 3% cutoff as an independent prognostic factor for OS and RFS was validated [hazard ratio (HR) 3.289; 95% CI 1.345-8.042; P = 0.009 and HR 4.471; 95% CI 1.086-18.410; P = 0.038, respectively]. CONCLUSIONS Ki-67 is a reliable, convenient, and independent prognostic marker for ACC. Additionally, as an indicator with a divergent prognostic role at different cutoff values (20% and 3%), Ki-67 could be used for stratifying patients with a high risk of death or rapid recurrence.
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Kammerer-Jacquet SF, Ahmad A, Møller H, Sandu H, Scardino P, Soosay G, Beltran L, Cuzick J, Berney DM. Ki-67 is an independent predictor of prostate cancer death in routine needle biopsy samples: proving utility for routine assessments. Mod Pathol 2019; 32:1303-1309. [PMID: 30976102 PMCID: PMC8647491 DOI: 10.1038/s41379-019-0268-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/06/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022]
Abstract
Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ12 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ12 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ12 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.
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Affiliation(s)
- Solène-Florence Kammerer-Jacquet
- Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1A 7BE, UK. .,Department of Pathology, University Hospital of Rennes, Université de Rennes 1, Université Bretagne Loire, 35000, Rennes, France.
| | - Amar Ahmad
- UK Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, EC1A 7BE London, UK
| | - Henrik Møller
- Cancer Epidemiology and Population Health, King’s College London, SE1 9RT London, UK
| | - Holly Sandu
- UK Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, EC1A 7BE London, UK
| | - Peter Scardino
- Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, 10065 NY, USA
| | - Geraldine Soosay
- Department of Pathology, Queen’s Hospital, Essex, RM7 0AG Romford, UK
| | - Luis Beltran
- Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1A 7BE London, UK
| | - Jack Cuzick
- UK Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, EC1A 7BE London, UK
| | - Daniel M Berney
- Department of Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1A 7BE London, UK
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Zharinov GM, Bogomolov OA, Neklasova NY, Raskin GA, Chepurnaya IV, Bugrov SN, Anisimov VN. Prognostic value of tumor growth kinetic parameters in prostate cancer patients. Oncotarget 2019; 10:5020-5027. [PMID: 31489112 PMCID: PMC6707944 DOI: 10.18632/oncotarget.27088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 06/29/2019] [Indexed: 11/27/2022] Open
Abstract
The goal of this paper was to estimate the predictive value of kinetic parameters of tumor growth in 109 prostatic cancer (PCa) patients with the morphologically verified diagnosis. Results: The cell loss factor, calculated on the basis of Ki-67 values, and the PSA doubling time, proved to be an important prognostic parameter. A cumulative comparative analysis of these criteria, depending on the prevalence of the tumor process, indicates that the level of cell loss significantly decreases with increasing tumor stage (p = 1*10−5), and the growth rate of the tumor significantly increases (p = 1*10−6). In the multivariate prognostic model, the CLF is an independent predictor of tumor-specific survival along with the stage of PCa.
Materials and methods: For each patient of the study group were as follows. The level of Ki-67 expression in biopsies of adenocarcinoma of the prostate gland was estimated. Also, in the selected group of patients, based on the available data on the kinetics of the prostatic specific antigen (PSA), the initial time of doubling of PSA was determined. The obtained values of the actual tumor growth rate and the cell loss factor (CLF) were compared with the parameters characterizing the tumor state (stage, Gleason score, PSA level at diagnosis) and tumor-specific survival rates.
Conclusion: Inclusion of proliferative activity factors in nomograms and prognostic models will increase their prognostic value and practical significance. Further prospective studies are needed to analyze the actual growth rate of PCa and evaluate its proliferative activity.
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Affiliation(s)
- Gennady M Zharinov
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Oleg A Bogomolov
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Natalia Yu Neklasova
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Grigory A Raskin
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Irina V Chepurnaya
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Sergey N Bugrov
- Department of Radiotherapy, The Russian Research Center of Radiology and Surgical Technologies, Ministry of Health of Russian Federation, St. Petersburg, Russia
| | - Vladimir N Anisimov
- Department of Carcinogenesis and Oncogerontology, N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russian Federation, St. Petersburg, Russia
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Barata PC, Magi-Galluzzi C, Gupta R, Dreicer R, Klein EA, Garcia JA. Association of mTOR Pathway Markers and Clinical Outcomes in Patients with Intermediate-/High-risk Prostate Cancer: Long-Term Analysis. Clin Genitourin Cancer 2019; 17:366-372. [PMID: 31262501 DOI: 10.1016/j.clgc.2019.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/19/2019] [Accepted: 05/21/2019] [Indexed: 11/17/2022]
Abstract
INTRODUCTION The mammalian target of rapamycin (mTOR) pathway is up-regulated in prostate cancer (PCa). We evaluated the tumor tissue expression of downstream mTOR targets in patients with intermediate- and high-risk (IR/HR) PCa and their ability to predict outcome after radical prostatectomy (RP). PATIENTS AND METHODS Immunohistochemical (IHC) analysis using antibodies against PTEN, mTOR, p-mTOR, pAKT, pS6, and Ki-67 was performed on a tissue microarray constructed from formalin-fixed paraffin-embedded RP specimens. The marker expression was analyzed to determine their predictability for biochemical recurrence (BCR). RESULTS Tumor tissue from 217 patients (86 IR/131 HR) was analyzed. The most frequent markers were p-mTOR, which was expressed in most cases (85%), whereas PTEN and pS6 were detected in 53% and 40% of the cases, respectively. Overexpression of PTEN (P = .02) and pS6 (P < .001) was associated with HR features. With a median follow up of 13.5 years, 39% (77/196) of patients developed BCR after RP, more frequently (31%) in patients with HR disease (P < .001). Overexpression of pS6 (P = .036), Ki67% (P = .024), and lack of expression of mTOR (P = .021) were associated with BCR. The 5- and 10-year survival rate was 81% and 66%, respectively. CONCLUSIONS Protein expression of downstream mTOR molecules was significantly associated with outcome of patients with IR and HR PCa. Markers of the mTOR pathway could be incorporated in clinical studies evaluating inhibitors of the signaling pathway for treatment selection in men with PCa.
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Affiliation(s)
- Pedro C Barata
- Department of Medicine and Oncology, Tulane University, New Orleans, LA
| | - Cristina Magi-Galluzzi
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Ruby Gupta
- Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Robert Dreicer
- Department of Medicine and Oncology, University of Virginia School of Medicine, Charlottesville, VA
| | - Eric A Klein
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH
| | - Jorge A Garcia
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
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Thysell E, Vidman L, Ylitalo EB, Jernberg E, Crnalic S, Iglesias-Gato D, Flores-Morales A, Stattin P, Egevad L, Widmark A, Rydén P, Bergh A, Wikström P. Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Mol Oncol 2019; 13:1763-1777. [PMID: 31162796 PMCID: PMC6670017 DOI: 10.1002/1878-0261.12526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 06/23/2019] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.
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Affiliation(s)
- Elin Thysell
- Department of Medical Biosciences, Pathology, Umeå University, Sweden
| | - Linda Vidman
- Department of Mathematics and Mathematical Statistics, Umeå University, Sweden
| | | | - Emma Jernberg
- Department of Medical Biosciences, Pathology, Umeå University, Sweden
| | - Sead Crnalic
- Department of Surgical and Perioperative Sciences, Orthopaedics, Umeå University, Sweden
| | - Diego Iglesias-Gato
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Amilcar Flores-Morales
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Pär Stattin
- Department of Surgical Sciences, Uppsala University, Sweden
| | - Lars Egevad
- Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Anders Widmark
- Department of Radiation Sciences, Oncology, Umeå University, Sweden
| | - Patrik Rydén
- Department of Mathematics and Mathematical Statistics, Umeå University, Sweden
| | - Anders Bergh
- Department of Medical Biosciences, Pathology, Umeå University, Sweden
| | - Pernilla Wikström
- Department of Medical Biosciences, Pathology, Umeå University, Sweden
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Oikonomou P, Giatromanolaki A, Tsaroucha AK, Balaska K, Tsalikidis CH, Nikolaou CH, Pitiakoudis M, Simopoulos C. Expression of autophagy-related proteins Beclin-1 and LC3A and proliferation marker Ki-67 in calculous and acalculous human gallbladder epithelium. Hippokratia 2019; 23:64-69. [PMID: 32265586 PMCID: PMC7127918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
BACKGROUND Autophagy is an inducible intracellular process that has been studied mostly in cancer and less in inflammatory diseases. To establish the relation between cholecystitis (calculous and acalculous) and autophagy, we studied the expressions of immunohistochemical markers Beclin-1, LC3A, and Ki-67 in gallbladder epithelium and their significance in the induction of autophagy. METHODS Adult human gallbladder tissues were obtained from 100 patients (45 male, 55 female) who underwent cholecystectomy. According to the findings, the patients were divided into two groups: group A (calculous gallbladder: 24 male, 46 female; mean age 52.6 ± 16.0 years) and group B (acalculous gallbladder: 21 male, nine female; mean age 65.3 ± 12.4 years). The expressions of immunohistochemical markers Beclin-1, LC3A, and Ki-67 in gallbladder epithelium were studied using immunohistochemistry techniques. RESULTS Beclin-1 expression was correlated with LC3A expression in group A with increased Beclin-1 expression promoting LC3A expression (p =0.0001). In group B, the LC3A expression did not follow Beclin-1 expression (p =0.09). The mean percentage of Beclin-1 expression in group A patients was 23.8 % compared to group B patients, where the corresponding percentage was only 17.3 %. Corresponding mean percent expressions of LC3A in groups A and B were 38.9 % and 50.7 %, respectively. The expression of Ki-67 was higher in group A patients compared to group B patients. The mean percentage of Ki-67 expression in group A patients was 3.75 %, whereas, in group B patients, it was only 0.5 % (statistically significantly different; p =0.0003). CONCLUSION In the epithelium of calculous cholecystitis, overexpression of LC3A is related to Beclin-1 overexpression, which reinforces the view that Beclin-1 promotes autophagy in stone cholecystitis. HIPPOKRATIA 2019, 23(2): 64-69.
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Affiliation(s)
- P Oikonomou
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - A Giatromanolaki
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - A K Tsaroucha
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - K Balaska
- Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C H Tsalikidis
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C H Nikolaou
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - M Pitiakoudis
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - C Simopoulos
- 2 Department of Surgery and Laboratory of Experimental Surgery & Surgical Research, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
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Rosenberg A, Nettey OS, Gogana P, Sheikh U, Macias V, Kajdacsy-Balla A, Sharifi R, Kittles RA, Murphy AB. Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients. Cancer Causes Control 2019; 30:207-214. [PMID: 30730018 DOI: 10.1007/s10552-019-1128-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 01/03/2019] [Indexed: 12/20/2022]
Abstract
PURPOSE To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy. METHODS In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis. RESULTS The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman's rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001). Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = - 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (β - 0.46, 95% CI - 0.75, - 0.04, p = 0.04). CONCLUSION The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.
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Affiliation(s)
- Adrian Rosenberg
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Oluwarotimi S Nettey
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Pooja Gogana
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ujalla Sheikh
- Department of Pathology, University of Illinois at Chicago School of Medicine, Chicago, IL, USA
| | - Virgilia Macias
- Department of Pathology, University of Illinois at Chicago School of Medicine, Chicago, IL, USA
| | - Andre Kajdacsy-Balla
- Department of Pathology, University of Illinois at Chicago School of Medicine, Chicago, IL, USA
| | - Roohollah Sharifi
- Section of Urology, Jesse Brown VA Medical Center, Chicago, IL, USA
- Department of Urology, University of Illinois at Chicago School of Medicine, Chicago, IL, USA
| | - Rick A Kittles
- Division of Health Equities, Department of Population Sciences, City of Hope Cancer Center, Duarte, CA, USA
| | - Adam B Murphy
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Section of Urology, Jesse Brown VA Medical Center, Chicago, IL, USA.
- , 303 E Chicago Avenue, Tarry Building 16-729, 60611, Chicago, IL, USA.
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Hammarsten P, Josefsson A, Thysell E, Lundholm M, Hägglöf C, Iglesias-Gato D, Flores-Morales A, Stattin P, Egevad L, Granfors T, Wikström P, Bergh A. Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome. Mod Pathol 2019; 32:1310-1319. [PMID: 30980038 PMCID: PMC6760646 DOI: 10.1038/s41379-019-0260-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 02/23/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023]
Abstract
Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.
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Affiliation(s)
- Peter Hammarsten
- 0000 0001 1034 3451grid.12650.30Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Andreas Josefsson
- 0000 0000 9919 9582grid.8761.8Department of Urology, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Elin Thysell
- 0000 0001 1034 3451grid.12650.30Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Marie Lundholm
- 0000 0001 1034 3451grid.12650.30Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Christina Hägglöf
- 0000 0001 1034 3451grid.12650.30Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Diego Iglesias-Gato
- 0000 0001 0674 042Xgrid.5254.6Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Amilcar Flores-Morales
- 0000 0001 0674 042Xgrid.5254.6Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pär Stattin
- 0000 0004 1936 9457grid.8993.bDepartment of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Lars Egevad
- 0000 0000 9241 5705grid.24381.3cDepartment of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Torvald Granfors
- 0000 0004 0584 1036grid.413653.6Department of Urology, Central Hospital, Västerås, Sweden
| | - Pernilla Wikström
- 0000 0001 1034 3451grid.12650.30Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Anders Bergh
- Departments of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
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38
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Zhang AY, Chiam K, Haupt Y, Fox S, Birch S, Tilley W, Butler LM, Knudsen K, Comstock C, Rasiah K, Grogan J, Mahon KL, Bianco-Miotto T, Ricciardelli C, Böhm M, Henshall S, Delprado W, Stricker P, Horvath LG, Kench JG. An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy. Int J Cancer 2018; 144:1151-1159. [PMID: 30288742 DOI: 10.1002/ijc.31906] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 08/22/2018] [Indexed: 12/23/2022]
Abstract
A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.
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Affiliation(s)
- Alison Y Zhang
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia
| | - Karen Chiam
- Cancer Research Division, Cancer Council New South Wales, Woolloomooloo, NSW, Australia
| | - Ygal Haupt
- Peter MacCallum Cancer Centre, Parkville, VIC, Australia
| | - Stephen Fox
- Peter MacCallum Cancer Centre, Parkville, VIC, Australia.,University of Melbourne, Parkville, VIC, Australia
| | - Simone Birch
- Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Wayne Tilley
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Lisa M Butler
- Freemason's Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Karen Knudsen
- Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, US
| | - Clay Comstock
- Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, US
| | | | - Judith Grogan
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Kate L Mahon
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Tina Bianco-Miotto
- School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA, Australia
| | - Carmela Ricciardelli
- Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
| | - Maret Böhm
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Susan Henshall
- Union for International Cancer Control, Geneva, Switzerland
| | - Warick Delprado
- Douglass Hanly Moir Pathology, Macquarie Park, NSW, Australia
| | - Phillip Stricker
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Department of Urology, St Vincent's Clinic, Darlinghurst, NSW, Australia
| | - Lisa G Horvath
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,Chris O'Brien Lifehouse, Camperdown, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - James G Kench
- Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,University of Sydney, Camperdown, NSW, Australia.,Royal Prince Alfred Hospital, Camperdown, NSW, Australia
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Centenera MM, Hickey TE, Jindal S, Ryan NK, Ravindranathan P, Mohammed H, Robinson JL, Schiewer MJ, Ma S, Kapur P, Sutherland PD, Hoffmann CE, Roehrborn CG, Gomella LG, Carroll JS, Birrell SN, Knudsen KE, Raj GV, Butler LM, Tilley WD. A patient-derived explant (PDE) model of hormone-dependent cancer. Mol Oncol 2018; 12:1608-1622. [PMID: 30117261 PMCID: PMC6120230 DOI: 10.1002/1878-0261.12354] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 11/24/2022] Open
Abstract
Breast and prostate cancer research to date has largely been predicated on the use of cell lines in vitro or in vivo. These limitations have led to the development of more clinically relevant models, such as organoids or murine xenografts that utilize patient-derived material; however, issues related to low take rate, long duration of establishment, and the associated costs constrain use of these models. This study demonstrates that ex vivo culture of freshly resected breast and prostate tumor specimens obtained from surgery, termed patient-derived explants (PDEs), provides a high-throughput and cost-effective model that retains the native tissue architecture, microenvironment, cell viability, and key oncogenic drivers. The PDE model provides a unique approach for direct evaluation of drug responses on an individual patient's tumor, which is amenable to analysis using contemporary genomic technologies. The ability to rapidly evaluate drug efficacy in patient-derived material has high potential to facilitate implementation of personalized medicine approaches.
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Affiliation(s)
- Margaret M. Centenera
- Freemasons Foundation Centre for Men's HealthAdelaide Medical SchoolUniversity of AdelaideSAAustralia
- South Australian Health and Medical Research InstituteAdelaideSAAustralia
| | - Theresa E. Hickey
- Dame Roma Mitchell Cancer Research LaboratoriesAdelaide Medical SchoolUniversity of AdelaideSAAustralia
| | - Shalini Jindal
- Dame Roma Mitchell Cancer Research LaboratoriesAdelaide Medical SchoolUniversity of AdelaideSAAustralia
| | - Natalie K. Ryan
- Freemasons Foundation Centre for Men's HealthAdelaide Medical SchoolUniversity of AdelaideSAAustralia
- South Australian Health and Medical Research InstituteAdelaideSAAustralia
| | | | - Hisham Mohammed
- Knight Cancer Early Detection Advanced Research CenterOregon Health and Science UniversityPortlandORUSA
| | - Jessica L. Robinson
- Transcription Factor LaboratoryCancer Research UKCambridge InstituteCambridge UniversityUK
| | | | - Shihong Ma
- Department of UrologyUT Southwestern Medical Center at DallasTXUSA
| | - Payal Kapur
- Department of UrologyUT Southwestern Medical Center at DallasTXUSA
| | | | - Clive E. Hoffmann
- Breast ClinicBurnside War Memorial HospitalToorak GardensSAAustralia
| | | | | | - Jason S. Carroll
- Transcription Factor LaboratoryCancer Research UKCambridge InstituteCambridge UniversityUK
| | | | - Karen E. Knudsen
- Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Ganesh V. Raj
- Department of UrologyUT Southwestern Medical Center at DallasTXUSA
| | - Lisa M. Butler
- Freemasons Foundation Centre for Men's HealthAdelaide Medical SchoolUniversity of AdelaideSAAustralia
- South Australian Health and Medical Research InstituteAdelaideSAAustralia
| | - Wayne D. Tilley
- Freemasons Foundation Centre for Men's HealthAdelaide Medical SchoolUniversity of AdelaideSAAustralia
- Dame Roma Mitchell Cancer Research LaboratoriesAdelaide Medical SchoolUniversity of AdelaideSAAustralia
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Fantony JJ, Howard LE, Csizmadi I, Armstrong AJ, Lark AL, Galet C, Aronson WJ, Freedland SJ. Is Ki67 prognostic for aggressive prostate cancer? A multicenter real-world study. Biomark Med 2018; 12:727-736. [PMID: 29902938 DOI: 10.2217/bmm-2017-0322] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM To test if Ki67 expression is prognostic for biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS Ki67 immunohistochemistry was performed on tissue microarrays constructed from specimens obtained from 464 men undergoing RP at the Durham and West LA Veterans Affairs Hospitals. Hazard ratios (HR) for Ki67 expression and time to BCR were estimated using Cox regression. RESULTS Ki67 was associated with more recent surgery year (p < 0.001), positive margins (p = 0.001) and extracapsular extension (p < 0.001). In center-stratified analyses, the adjusted HR for Ki67 expression and BCR approached statistical significance for west LA (HR: 1.54; p = 0.06), but not Durham (HR: 1.10; p = 0.74). CONCLUSION This multi-institutional 'real-world' study provides limited evidence for the prognostic role of Ki67 in predicting outcome after RP.
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Affiliation(s)
- Joseph J Fantony
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Lauren E Howard
- Urology Section, Durham Veterans Affairs Medical Center, Durham, NC 27705, USA.,Department of Biostatistics and Bioinformatics, Duke School of Medicine, Durham, NC 27705, USA
| | - Ilona Csizmadi
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Andrew J Armstrong
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Amy L Lark
- Department of Pathology, Duke University Hospital, Durham, NC 27710, USA.,Department of Pathology, Durham Veterans Affairs Medical Center, Durham, NC 27710, USA
| | - Colette Galet
- Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.,Division of Acute Care Surgery, Department of Surgery, Carver College of Medicine, University of Iowa, IA 52242, USA
| | - William J Aronson
- Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.,Urology Section, Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System, CA 90073, USA
| | - Stephen J Freedland
- Urology Section, Durham Veterans Affairs Medical Center, Durham, NC 27705, USA.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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41
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Fernández-Pomares C, Juárez-Aguilar E, Domínguez-Ortiz MÁ, Gallegos-Estudillo J, Herrera-Covarrubias D, Sánchez-Medina A, Aranda-Abreu GE, Manzo J, Hernández ME. Hydroalcoholic extract of the widely used Mexican plant Justicia spicigera Schltdl. exerts a cytostatic effect on LNCaP prostate cancer cells. J Herb Med 2018. [DOI: 10.1016/j.hermed.2017.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Investigating Various Thresholds as Immunohistochemistry Cutoffs for Observer Agreement. Appl Immunohistochem Mol Morphol 2018; 25:599-608. [PMID: 27093449 DOI: 10.1097/pai.0000000000000357] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. MATERIALS AND METHODS A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa (κ) statistic was used to assess the strength of agreement for each cutoff. RESULTS The interobserver agreement between all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.64, 0.59, and 0.62, respectively, for 10%, 20%, and +2/+3 cutoffs. A good agreement was observed for experienced pathologists using the 10% cutoff, and their agreement was statistically higher than for junior pathologists (P=0.02). In addition, the mean intraobserver agreement for all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.71, 0.60, and 0.73, respectively, for 10%, 20%, and +2/+3 cutoffs. For all 3 cutoffs, a positive correlation was observed with perceived ease of interpretation (P<0.003). Finally, cytoplasmic-only staining achieved higher agreement using all 3 cutoffs than mixed staining patterns. CONCLUSIONS All 3 cutoffs investigated achieve reasonable strength of agreement, modestly decreasing interobserver and intraobserver variability in IHC interpretation. These cutoffs have previously been used in cancer pathology, and this study provides evidence that these cutoffs can be reproducible between practicing pathologists.
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20(S)-protopanaxadiol regio-selectively targets androgen receptor: anticancer effects in castration-resistant prostate tumors. Oncotarget 2018; 9:20965-20978. [PMID: 29765513 PMCID: PMC5940378 DOI: 10.18632/oncotarget.24695] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 02/24/2018] [Indexed: 01/21/2023] Open
Abstract
We have explored the effects of 20(S)-protopanaxadiol (aPPD), a naturally derived ginsenoside, against androgen receptor (AR) positive castration resistant prostate cancer (CRPC) xenograft tumors and have examined its interactions with AR. In silico docking studies for aPPD binding to AR, alongside transactivation bioassays and in vivo efficacy studies were carried out in the castration-resistant C4-2 xenograft model. Immunohistochemical (IHC) and Western blot analyses followed by evaluation of AR, apoptotic, cell cycle and proliferative markers in excised tumors was performed. The growth of established CRPC tumors was inhibited by 53% with aPPD and a corresponding decrease in serum PSA was seen compared to controls. The IHC data revealed that Ki-67 was significantly lower for aPPD treated tumors and was associated with elevated p21 and cleaved caspase-3 expression, compared to vehicle treatment. Furthermore, aPPD decreased AR protein expression in xenograft tumors, while significantly upregulating p27 and Bax protein levels. In vitro data supporting this suggests that aPPD binds to and significantly inhibits the N-terminal or the DNA binding domains of AR. The AR androgen binding site docking score for androgen (dihydrotestosterone) was −11.1, while that of aPPD was −7.1. The novel findings described herein indicate aPPD potently inhibits PCa in vivo partly via inhibition of a site on the AR N-terminal domain. This manifested as cell cycle arrest and concurrent induction of apoptosis via an increase in Bax, cleaved-caspase-3, p27 and p21 expression.
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Graham N, Qian BZ. Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis. Int J Mol Sci 2018; 19:E1121. [PMID: 29642534 PMCID: PMC5979535 DOI: 10.3390/ijms19041121] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/25/2018] [Accepted: 03/29/2018] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis.
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Affiliation(s)
- Nicola Graham
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
| | - Bin-Zhi Qian
- Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
- Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh EH4 2XR, UK.
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45
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Ma T, Yang S, Jing H, Cong L, Cao Z, Liu Z, Huang Z. Apparent diffusion coefficients in prostate cancer: correlation with molecular markers Ki-67, HIF-1α and VEGF. NMR IN BIOMEDICINE 2018; 31:e3884. [PMID: 29315957 DOI: 10.1002/nbm.3884] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 11/20/2017] [Accepted: 11/22/2017] [Indexed: 06/07/2023]
Abstract
Prostate cancer (PCa) is the second most common cancer in men. The Gleason score (GS) and biomarkers play important roles in the diagnosis and treatment of patients with PCa. The purpose of this study was to investigate the relationship between the apparent diffusion coefficient (ADC) and the molecular markers Ki-67, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in PCa. Thirty-nine patients with 39 lesions, who had been diagnosed with PCa, were enrolled in this study. All patients underwent diffusion-weighted magnetic resonance imaging (DW-MRI) (b = 800 s/mm2 ). The expression of Ki-67, HIF-1α and VEGF was assessed by immunohistochemistry. Statistical analysis was applied to analyze the association between ADC and prostate-specific antigen (PSA), GS and the expression of Ki-67, HIF-1α and VEGF. The group differences in ADC among different grades of Ki-67, HIF-1α and VEGF were also analyzed. The mean ± standard deviation of ADC was (0.76 ± 0.27) × 10-3 mm2 /s. ADC correlated negatively with PSA and GS (p < 0.05). The Ki-67 staining index (SI), HIF-1α expression and VEGF expression in PCa were correlated inversely with ADC, controlling for age (r = -0.332, p < 0.05; r = -0.662, p < 0.0005; and r = -0.714, p < 0.0005, respectively). ADC showed a significant difference among different grades of Ki-67 (F = 9.164, p = 0.005), HIF-1α (F = 40.333, p < 0.0005) and VEGF (F = 22.048, p < 0.0005). In conclusion, ADC was correlated with PSA, GS, and Ki-67, HIF-1α and VEGF expression in patients with PCa. ADC may be used to evaluate tumor proliferation, hypoxia and angiogenesis in PCa.
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Affiliation(s)
- Teng Ma
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province, China
| | - Shaolin Yang
- Departments of Psychiatry, Radiology and Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Haiyan Jing
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province, China
| | - Lin Cong
- Department of Interventional Ultrasound, Shandong Medical Imaging Research Institute, Jinan City, Shandong Province, China
| | - Zhixin Cao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province, China
| | - Zhiling Liu
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province, China
| | - Zhaoqin Huang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, Shandong Province, China
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Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma. Am J Clin Oncol 2017; 41:18-23. [PMID: 26270441 DOI: 10.1097/coc.0000000000000224] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. MATERIALS AND METHODS The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). RESULTS The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P<0.001). However, PORT (n=29) did not affect LC (P=0.412) for patients with Ki-67 LI≤13% (n=33). CONCLUSIONS Ki-67 LI can be a useful prognostic factor for LC in WHO grade II meningioma. In patients with Ki-67 LI>13%, PORT should be recommended to improve LC.
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Fu L, Hwang M, Adeniran AJ, Humphrey PA. Proliferation index of different Gleason pattern 4 histomorphologies and associated pattern 3 adenocarcinoma of the prostate. Hum Pathol 2017; 70:1-5. [DOI: 10.1016/j.humpath.2017.06.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 06/02/2017] [Accepted: 06/14/2017] [Indexed: 01/31/2023]
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High immunoexpression of Ki67, EZH2, and SMYD3 in diagnostic prostate biopsies independently predicts outcome in patients with prostate cancer. Urol Oncol 2017; 36:161.e7-161.e17. [PMID: 29174711 DOI: 10.1016/j.urolonc.2017.10.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 10/05/2017] [Accepted: 10/31/2017] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Overtreatment is a major concern in patients with prostate cancer (PCa). Prognostic biomarkers discriminating indolent from aggressive disease in prostate biopsy are urgently needed. We aimed to evaluate the prognostic value of Ki67, EZH2, LSD1, and SMYD3 immunoexpression in diagnostic biopsies from a cohort of PCa patients with long term follow-up. MATERIALS AND METHODS A series of 189 consecutive prostate biopsies diagnosed with PCa (1997-2001) in a cancer center was included in the study, with follow-up last updated in November 2016. Biopsies were reviewed and graded according to 2016 WHO criteria. Immunohistochemistry was performed in the most representative block. Nuclear staining was assessed using digital image analysis. Study outcomes included disease-specific, disease-free, and progression-free survival. Statistical analysis was tabulated using SPSS version 22.0. Survival curves and hazard ratios (HRs) were estimated using Kaplan-Meyer and Cox-regression models, respectively. Statistical significance was set at P<0.05. RESULTS The proportion of patients who completed the study was 177/189 (94%). In univariable analysis, high Ki67, EZH2, and SMYD3 immunoexpression associated with significantly worse disease-specific survival (HR = 1.86, 95% CI: 1.05-3.29; HR = 1.87, 95% CI: 1.10-3.27; HR = 2.68, 95% CI: 1.02-7.92). In multivariable analysis, the 3 biomarkers displayed significantly worse DSS adjusted for CAPRA score (HR = 1.78, 95% CI: 1.01-3.16; HR = 1.93, 95% CI: 1.12-3.32; HR = 2.71, 95% CI: 1.04-7.10). Among patients with low/intermediate risk CAPRA score, high Ki67 immunoexpression identified those more prone to experience disease recurrence (HR = 9.20, 95% CI: 1.27-66.44) and progression (HR = 2.97, 95% CI: 1.05-8.43). CONCLUSIONS High Ki67, EZH2, and SMYD3 immunoexpression, adjusted for standard clinicopathological parameters, independently predicts outcome in patients with PCa, at diagnosis. This might assist in discriminating indolent from aggressive PCa, improving treatment selection.
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Evaluation of the proliferation marker Ki-67 in a large prostatectomy cohort. PLoS One 2017; 12:e0186852. [PMID: 29141018 PMCID: PMC5687762 DOI: 10.1371/journal.pone.0186852] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 10/09/2017] [Indexed: 12/01/2022] Open
Abstract
The tumor proliferation index marker Ki-67 is strongly associated with tumor cell proliferation, growth and progression, and is widely used in routine clinicopathological investigation. Prostate cancer is a complex multifaceted and biologically heterogeneous disease, and overtreatment of localized, low volume indolent tumors, is evident. Here, we aimed to assess Ki-67 expression and related outcomes of 535 patients treated with radical prostatectomy. The percentage of tumor epithelial cells expressing Ki-67 was determined by immunohistochemical assay, both digital image analysis and visual scoring by light microscope were used for quantification. The association of Ki-67 and prostate cancer was evaluated, as well as its prognostic value. There was a positive correlation between high expression of Ki-67 and Gleason score > 7 (p < 0.001) as well as tumor size (≥ 20 mm, p = 0.03). In univariate analyses, a high expression of Ki-67 in tumor epithelium was significantly associated with biochemical failure (BF) (digital scoring, p = 0.014) and (visual scoring, p = 0.004). In the multivariate analyses, a high level of Ki-67 was an independent poor prognostic factor for biochemical failure-free survival (BFFS) (Visual scoring, Ki67, p = 0.012, HR:1.50, CI95% 1.10–2.06). In conclusion, high Ki-67 expression is an independent negative prognostic marker for biochemical failure. Our findings support the role of Ki-67 as a significant, poor prognostic factor for in prostate cancer outcome.
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MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:3269379. [PMID: 29104726 PMCID: PMC5632457 DOI: 10.1155/2017/3269379] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 08/07/2017] [Accepted: 08/20/2017] [Indexed: 02/07/2023]
Abstract
Renal cell carcinoma (RCC) incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA); cell proliferation (E2F3); and cell differentiation (SOX2 and TGFB3) as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854), MET (AUC = 0.765), and E2F3 (AUC = 0.761). The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression.
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