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Salloom RJ, Sahtout DZ, Ahmad IM, Abdalla MY. Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment. Transl Oncol 2025; 54:102339. [PMID: 40037158 PMCID: PMC11925535 DOI: 10.1016/j.tranon.2025.102339] [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: 09/09/2024] [Revised: 01/24/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025] Open
Abstract
Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.
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Affiliation(s)
| | | | - Iman M Ahmad
- Department of Clinical, Diagnostics, and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, NE, USA
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Dallang B, Ezike KN, Emmanuel I, Mandong BM, Dauda AM, Akpa PO, Oguntebi EE. Prognostic Significance of Ki67 Expression in Prostate Cancer in Nigerians: A Single-Center Study. Cureus 2025; 17:e80997. [PMID: 40260342 PMCID: PMC12011347 DOI: 10.7759/cureus.80997] [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] [Accepted: 03/21/2025] [Indexed: 04/23/2025] Open
Abstract
Introduction Prostate cancer is one of the most common cancers occurring in men and one of the leading causes of cancer deaths globally. Associated risk factors include age, race, and positive family history. Older patients have an increased risk for more aggressive forms. Its incidence is particularly high in Black men. The Gleason grading and scoring system is an established prognostic factor for prostate cancer. Ki67, a nuclear protein, coded for by the MKi67 gene located on chromosome 10q26.2 and detected in all phases of the cell cycle, provides information on the proliferation index of cancer cells, including prostate cancer. This study is purposed to establish the significance of Ki67 expression as a prognostic marker of prostate cancer by correlating it with patients' age and Gleason scores, respectively, with the aim of understanding the molecular characteristics of prostate cancers in our environment, in order to assist in categorizing patients for treatment. Materials and methods This was a retrospective study carried out in Jos University Teaching Hospital (JUTH), Jos, Nigeria, involving histologically diagnosed prostate cancers over a five-year period. The surgical pathology reports and information on patients' biodata and clinical features were retrieved from departmental records and the hospital's electronic records. The appropriate archival hematoxylin and eosin (H&E)-stained slides and their respective formalin-fixed paraffin-embedded (FFPE) tissue blocks were retrieved and reviewed, with new sections made when necessary. Immunohistochemical analysis to assess the Ki67 proliferative index was carried out on sections made from representative blocks of each case using Ki67 monoclonal antibodies, according to the established protocol prescribed by the manufacturers. The Ki67 proliferative index was categorized as negative, low, and high. Data obtained were analyzed, and results were presented as percentages/frequencies and displayed as tables and charts. Results One hundred forty-two cases met the inclusion criteria. The age range was 30-90 years. The peak age group was 70-79 years with 38% (54/142). Majority, 81.7% (117/142), of cases occurred in patients above 60 years old. An overwhelming majority, 71.8% (102/142), of cases were poorly differentiated adenocarcinomas (Gleason scores 8-10), 21.1% (30/142) were moderately differentiated (Gleason score 7), and 7.0% (10/142) were well-differentiated (Gleason score 6). Among high Ki67 proliferative index cases, 81.4% (57/70) were aged above 60 years. Similarly, 85.1% (40/47) of low proliferative index cases were also aged above 60 years. Additionally, 92.5% (37/40) of well- and moderately differentiated cancers (Gleason scores 6 and 7) had negative or low Ki67 proliferative indices, while 65.7% (67/102) of the poorly differentiated (Gleason scores 8-10) had high indices. Conclusion Our study demonstrated a direct correlation of the Ki67 proliferative index with both histologic grade and aggressiveness of prostate carcinoma in a Nigerian population thereby confirming high Ki67 proliferative index as an adverse prognostic factor in prostate cancer. It, however, showed no direct relationship between age and Ki67 proliferative index. Determination of the Ki67 proliferative index is recommended for routine assessment of prostate cancer patients to help in risk stratification and instituting treatment plans.
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Affiliation(s)
- Bamnan Dallang
- Anatomic Pathology and Forensic Medicine, Nile University of Nigeria, Abuja, NGA
| | - Kevin N Ezike
- Anatomic Pathology and Forensic Medicine, Nile University of Nigeria, Abuja, NGA
| | - Innocent Emmanuel
- Anatomic Pathology and Forensic Medicine, Jos University Teaching Hospital, Jos, NGA
| | - Barnabas M Mandong
- Anatomic Pathology and Forensic Medicine, Jos University Teaching Hospital, Jos, NGA
| | - Ayuba M Dauda
- Anatomic Pathology and Forensic Medicine, Jos University Teaching Hospital, Jos, NGA
| | - Philip O Akpa
- Pathology, University of Jos, Jos, NGA
- Anatomic Pathology and Forensic Medicine, Jos University Teaching Hospital, Jos, NGA
| | - Emmanuel E Oguntebi
- Anatomic Pathology and Forensic Medicine, Asokoro District Hospital, Abuja, NGA
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Radi S, Al‐Maghrabi M, Binmahfooz S, Franco M, Payne R, Tamilia M. Characteristics and Prognostic Markers of Aggressive Subtypes of Thyroid Cancer: A Retrospective Study. Cancer Rep (Hoboken) 2025; 8:e70131. [PMID: 40085528 PMCID: PMC11908615 DOI: 10.1002/cnr2.70131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/06/2025] [Accepted: 01/24/2025] [Indexed: 03/16/2025] Open
Abstract
OBJECTIVE The prevalence of thyroid cancer has increased significantly. Aggressive subtypes of papillary thyroid cancer (AG-PTC) and high-grade follicular cell-derived malignancies (HGFM) are malignancies that lie between well-differentiated and undifferentiated cancers, and their management needs to be clarified. The aim of our study is to describe the clinicopathological characteristics of AG-PTC and HGFM and to assess their prognostic value. METHODS This was a retrospective chart review study at single center of patients with AG-PTC or HGFM. HGFM comprised of patients with poorly differentiated thyroid cancer (PDTC) and differentiated high-grade thyroid carcinoma. The clinical presentation, pathological characteristics, molecular markers, specific treatments, and clinical outcomes were compared between the groups. RESULTS Of the 3244 thyroid cancer charts reviewed, 136 met the criteria for AG-PTC and HGFM. The mean age at diagnosis was 49 years, with a predominance of women. The median follow-up duration was 3 years. The rate of persistent or recurrent disease was 40.3% in the AG-PTC group and 29.3% in the HGFM group, 4.5% died in the AG-PTC group, and 1.8% died in the HGFM group. The presence of vascular, lymphovascular invasion and extrathyroidal extension were associated with a higher incidence of persistent or recurrent disease (Hazard ratio: 2.5, 3.8, and 4.2, respectively; p < 0.05). When the Ki-67 index was divided into five groups, the recurrence rate was higher in the ≥ 20% Ki-67 group. CONCLUSIONS Possible prognostic markers for predicting worse prognosis include vascular/lymphovascular invasion, extrathyroidal extension, and the proliferative index Ki-67.
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Affiliation(s)
- Suhaib Radi
- College of MedicineKing Saud Bin Abdulaziz University for Health SciencesJeddahSaudi Arabia
- King Abdullah International Medical Research CentreJeddahSaudi Arabia
- Department of Internal Medicine, Division of EndocrinologyMinistry of the National Guard‐Health AffairsJeddahSaudi Arabia
| | - Mazin Al‐Maghrabi
- Division of Endocrinology and MetabolismJewish General Hospital, McGill UniversityMontrealQuebecCanada
| | | | - Miguel Franco
- Academic Unit of MedicineAutonomous University of NayaritTepicNayaritMexico
| | - Richard Payne
- Department of OtolaryngologyRoyal Victoria Hospital, McGill UniversityMontrealQuebecCanada
| | - Michael Tamilia
- Division of Endocrinology and MetabolismJewish General Hospital, McGill UniversityMontrealQuebecCanada
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Masui T, Yane K, Ota I, Kakudo K, Wakasa T, Koike S, Kinugawa H, Yasumatsu R, Kitahara T. Low Ki-67 labeling index is a clinically useful predictive factor for recurrence-free survival in patients with papillary thyroid carcinoma. J Pathol Transl Med 2025; 59:115-124. [PMID: 39962924 PMCID: PMC12010870 DOI: 10.4132/jptm.2024.11.08] [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: 09/28/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND We report a new risk stratification of invasive stage papillary thyroid carcinomas (PTCs) by combining invasive status, using extrathyroid invasion (Ex) status, and tumor growth speed using the Ki-67 labeling index (LI). METHODS We examined tumor recurrence in 167 patients with PTC who were surgically treated at the Kindai University Nara Hospital between 2010 and 2022. The patients were classified according to the degree of invasion [negative (Ex0) or positive (Ex1, Ex2, and Ex3)] and tumor growth speed expressed with Ki-67 LI, as low (<5%) or high (>5%). This study confirmed previous findings that the disease-free survival (DFS) rate in PTCs significantly differed between patients with a high and low Ki-67 index. RESULTS When combining Ex status (negative or positive) and Ki-67 proliferation status (low or high), the DFS rate of invasion in the negative, low Ki-67 LI group was only 1.1%, while that of invasion in the positive, high Ki-67 LI was 44.1%. This study reports for the first time that recurrence risks can be stratified accurately when combining carcinoma's essential two features of extrathyroid invasion status and tumor growth speed. CONCLUSIONS We believe the evidence for low tumor recurrence risk may contribute to use of more conservative treatment options for invasive-stage PTCs and help alleviate patient anxiety about tumor recurrence and death.
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Affiliation(s)
- Takashi Masui
- Department of Otolaryngology-Head and Neck Surgery, Kindai University Nara Hospital, Ikoma, Japan
| | - Katsunari Yane
- Department of Otolaryngology-Head and Neck Surgery, Kindai University Nara Hospital, Ikoma, Japan
| | - Ichiro Ota
- Department of Otolaryngology-Head and Neck Surgery, Kindai University Nara Hospital, Ikoma, Japan
| | - Kennichi Kakudo
- Department of Diagnostic Pathology, Kindai University Nara Hospital, Ikoma, Japan
- Department of Pathology and Thyroid Disease Center, Izumi City General Hospital, Izumi, Japan
| | - Tomoko Wakasa
- Department of Diagnostic Pathology, Kindai University Nara Hospital, Ikoma, Japan
| | - Satoru Koike
- Department of Otolaryngology-Head and Neck Surgery, Kindai University Nara Hospital, Ikoma, Japan
| | - Hirotaka Kinugawa
- Department of Otolaryngology-Head and Neck Surgery, Kindai University Nara Hospital, Ikoma, Japan
| | - Ryuji Yasumatsu
- Department of Otolaryngology-Head and Neck Surgery, Kindai University, Osakasayama, Japan
| | - Tadashi Kitahara
- Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara, Japan
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Haffner MC, Morris MJ, Ding CKC, Sayar E, Mehra R, Robinson B, True LD, Gleave M, Lotan TL, Aggarwal R, Huang J, Loda M, Nelson PS, Rubin MA, Beltran H. Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies. Clin Cancer Res 2025; 31:466-478. [PMID: 39589343 PMCID: PMC11790385 DOI: 10.1158/1078-0432.ccr-24-2061] [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] [Received: 07/01/2024] [Revised: 09/18/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024]
Abstract
Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine (NE) prostate cancer (NEPC) occur in up to 15% to 20% of patients with castration-resistant prostate cancer (CRPC) as a mechanism of treatment resistance and are associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of NE lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions, making clinical trial design challenging. In this manuscript, we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and IHC markers with a priority for AR, NK3 homeobox 1, insulinoma-associated protein 1, synaptophysin, and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.
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Affiliation(s)
- Michael C. Haffner
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Michael J. Morris
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chien-Kuang C. Ding
- Department of Anatomic Pathology, University of California San Francisco, San Francisco, CA, USA
| | - Erolcan Sayar
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Rohit Mehra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, Ann Arbor, MI, USA
- Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA
| | - Brian Robinson
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Lawrence D. True
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Martin Gleave
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Tamara L. Lotan
- Departments of Pathology, Urology, Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Rahul Aggarwal
- Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA, USA
| | - Jiaoti Huang
- Department of Pathology and Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Peter S. Nelson
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Mark A. Rubin
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Bern Center for Precision Medicine, University of Bern and Inselspital, Bern, Switzerland
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Falkenbach F, Budäus L. Neoadjuvant Exercise Therapy in Patients With Prostate Cancer. JAMA Oncol 2025; 11:183-184. [PMID: 39636632 DOI: 10.1001/jamaoncol.2024.5566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Affiliation(s)
- Fabian Falkenbach
- Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
| | - Lars Budäus
- Martini-Klinik Prostate Cancer Center and Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Rajendran R, Beck RC, Waskasi MM, Kelly BD, Bauer DR. Digital analysis of the prostate tumor microenvironment with high-order chromogenic multiplexing. J Pathol Inform 2024; 15:100352. [PMID: 38186745 PMCID: PMC10770522 DOI: 10.1016/j.jpi.2023.100352] [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: 07/18/2023] [Revised: 09/30/2023] [Accepted: 11/16/2023] [Indexed: 01/09/2024] Open
Abstract
As our understanding of the tumor microenvironment grows, the pathology field is increasingly utilizing multianalyte diagnostic assays to understand important characteristics of tumor growth. In clinical settings, brightfield chromogenic assays represent the gold-standard and have developed significant trust as the first-line diagnostic method. However, conventional brightfield tests have been limited to low-order assays that are visually interrogated. We have developed a hybrid method of brightfield chromogenic multiplexing that overcomes these limitations and enables high-order multiplex assays. However, how compatible high-order brightfield multiplexed images are with advanced analytical algorithms has not been extensively evaluated. In the present study, we address this gap by developing a novel 6-marker prostate cancer assay that targets diverse aspects of the tumor microenvironment such as prostate-specific biomarkers (PSMA and p504s), immune biomarkers (CD8 and PD-L1), a prognostic biomarker (Ki-67), as well as an adjunctive diagnostic biomarker (basal cell cocktail) and apply the assay to 143 differentially graded adenocarcinoma prostate tissues. The tissues were then imaged on our spectroscopic multiplexing imaging platform and mined for proteomic and spatial features that were correlated with cancer presence and disease grade. Extracted features were used to train a UMAP model that differentiated healthy from cancerous tissue with an accuracy of 89% and identified clusters of cells based on cancer grade. For spatial analysis, cell-to-cell distances were calculated for all biomarkers and differences between healthy and adenocarcinoma tissues were studied. We report that p504s positive cells were at least 2× closer to cells expressing PD-L1, CD8, Ki-67, and basal cell in adenocarcinoma tissues relative to the healthy control tissues. These findings offer a powerful insight to understand the fingerprint of the prostate tumor microenvironment and indicate that high-order chromogenic multiplexing is compatible with digital analysis. Thus, the presented chromogenic multiplexing system combines the clinical applicability of brightfield assays with the emerging diagnostic power of high-order multiplexing in a digital pathology friendly format that is well-suited for translational studies to better understand mechanisms of tumor development and growth.
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Affiliation(s)
- Rahul Rajendran
- Roche Diagnostics Solutions, (Ventana Medical Systems, Inc.), Tucson, AZ, USA
| | - Rachel C. Beck
- Roche Diagnostics Solutions, (Ventana Medical Systems, Inc.), Tucson, AZ, USA
| | - Morteza M. Waskasi
- Roche Diagnostics Solutions, (Ventana Medical Systems, Inc.), Tucson, AZ, USA
| | - Brian D. Kelly
- Roche Diagnostics Solutions, (Ventana Medical Systems, Inc.), Tucson, AZ, USA
| | - Daniel R. Bauer
- Roche Diagnostics Solutions, (Ventana Medical Systems, Inc.), Tucson, AZ, USA
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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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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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10
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Song Z, Zhou Q, Zhang JL, Ouyang J, Zhang ZY. Marker Ki-67 is a potential biomarker for the diagnosis and prognosis of prostate cancer based on two cohorts. World J Clin Cases 2024; 12:32-41. [PMID: 38292624 PMCID: PMC10824173 DOI: 10.12998/wjcc.v12.i1.32] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/30/2023] [Accepted: 12/15/2023] [Indexed: 01/02/2024] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a widespread malignancy, predominantly affecting elderly males, and current methods for diagnosis and treatment of this disease continue to fall short. The marker Ki-67 (MKI67) has been previously demonstrated to correlate with the proliferation and metastasis of various cancer cells, including those of PCa. Hence, verifying the association between MKI67 and the diagnosis and prognosis of PCa, using bioinformatics databases and clinical data analysis, carries significant clinical implications. AIM To explore the diagnostic and prognostic efficacy of antigens identified by MKI67 expression in PCa. METHODS For cohort 1, the efficacy of MKI67 diagnosis was evaluated using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. For cohort 2, the diagnostic and prognostic power of MKI67 expression was further validated using data from 271 patients with clinical PCa. RESULTS In cohort 1, MKI67 expression was correlated with prostate-specific antigen (PSA), Gleason Score, T stage, and N stage. The receiver operating characteristic (ROC) curve showed a strong diagnostic ability, and the Kaplan-Meier method demonstrated that MKI67 expression was negatively associated with the progression-free interval (PFI). The time-ROC curve displayed a weak prognostic capability for MKI67 expression in PCa. In cohort 2, MKI67 expression was significantly related to the Gleason Score, T stage, and N stage; however, it was negatively associated with the PFI. The time-ROC curve revealed the stronger prognostic capability of MKI67 in patients with PCa. Multivariate COX regression analysis was performed to select risk factors, including PSA level, N stage, and MKI67 expression. A nomogram was established to predict the 3-year PFI. CONCLUSION MKI67 expression was positively associated with the Gleason Score, T stage, and N stage and showed a strong diagnostic and prognostic ability in PCa.
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Affiliation(s)
- Zhen Song
- Department of Urology, Taixing People’s Hospital, Taizhou 225400, Jiangsu Province, China
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Qi Zhou
- Department of Reproductive Medicine Center, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Jiang-Lei Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Jun Ouyang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
| | - Zhi-Yu Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu Province, China
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11
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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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12
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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: 9] [Impact Index Per Article: 4.5] [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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13
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Harahap WA, Tofrizal T, Oktahermoniza O. Relationship between the Expression of BRAF V600E and Ki-67 with the Recurrence of Well-Differentiated Thyroid Cancer. Asian Pac J Cancer Prev 2022; 23:3617-3622. [PMID: 36444572 PMCID: PMC9930947 DOI: 10.31557/apjcp.2022.23.11.3617] [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: 09/16/2021] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE This study aims to determine the relationship between BRAF V600E and Ki-67 expression with the recurrence of well-differentiated thyroid cancers. METHOD The design of this study is a case-control and survival analysis. The data was taken from the thyroid cancer registry in Padang, Indonesia, where samples were taken from well-differentiated thyroid cancer patients who underwent therapy according to the protocol between 2015 and 2020. During this period, 396 well-differentiated thyroid cancer cases were obtained, of which 24 cases experienced recurrence. Of the cases that recurred, we found as many as 20 cases with complete tissue preservation documents later designated as cases. Calculating the expression of BRAF V600E and Ki-67 was performed semi-quantitatively per 100 tumor cells at random. For statistical tests, chi-square and survival analysis were performed using Kaplan-Meier and Cox regression analysis using a computer program with a determined significance level of p < 0.05. RESULT BRAF V600E expression was found in all cases and controls in which 85% of cases had vigorous intensity and 15% had moderate intensity. Ki-67 expression was found positive in 35% of the recurrent cases, while in control, there was no expression of Ki-67. Patients with positive Ki-67 expression had shorter median survival than patients with negative Ki-67 expression of 40 months (95% CI 35-45 months) to 60 months (95% CI 53-67 months). An association was obtained between Ki-67 expression and thyroid cancer recurrence based on disease-free survival (p<0.05) with HR 1.34 (95% CI 1.13-1.92). CONCLUSION This study confirms the association between Ki-67 expression and thyroid cancer recurrence based on disease-free survival and can be used as alternative to support the significance of Ki-67 as a predictor of thyroid cancer recurrence. In addition, Ki-67 can complement other molecular markers such as the BRAF V600E, to increase its prognostic strength.
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Affiliation(s)
- Wirsma Arif Harahap
- Department of Surgical Oncology, Faculty of Medicine, Andalas University, Padang, Indonesia. ,For Correspondence:
| | - Tofrizal Tofrizal
- Department of Anatomical Pathology, Faculty of Medicine, Andalas University, Padang, Indonesia.
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14
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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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15
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Dovey ZS, Nair SS, Chakravarty D, Tewari AK. Racial disparity in prostate cancer in the African American population with actionable ideas and novel immunotherapies. Cancer Rep (Hoboken) 2021; 4:e1340. [PMID: 33599076 PMCID: PMC8551995 DOI: 10.1002/cnr2.1340] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND African Americans (AAs) in the United States are known to have a higher incidence and mortality for Prostate Cancer (PCa). The drivers of this epidemiological disparity are multifactorial, including socioeconomic factors leading to lifestyle and dietary issues, healthcare access problems, and potentially tumor biology. RECENT FINDINGS Although recent evidence suggests once access is equal, AA men have equal outcomes to Caucasian American (CA) men, differences in PCa incidence remain, and there is much to do to reverse disparities in mortality across the USA. A deeper understanding of these issues, both at the clinical and molecular level, can facilitate improved outcomes in the AA population. This review first discusses PCa oncogenesis in the context of its diverse hallmarks before benchmarking key molecular and genomic differences for PCa in AA men that have emerged in the recent literature. Studies have emphasized the importance of tumor microenvironment that contributes to both the unequal cancer burden and differences in clinical outcome between the races. Management of comorbidities like obesity, hypertension, and diabetes will provide an essential means of reducing prostate cancer incidence in AA men. Although requiring further AA specific research, several new treatment strategies such as immune checkpoint inhibitors used in combination PARP inhibitors and other emerging vaccines, including Sipuleucel-T, have demonstrated some proven efficacy. CONCLUSION Genomic profiling to integrate clinical and genomic data for diagnosis, prognosis, and treatment will allow physicians to plan a "Precision Medicine" approach to AA men. There is a pressing need for further research for risk stratification, which may allow early identification of AA men with higher risk disease based on their unique clinical, genomic, and immunological profiles, which can then be mapped to appropriate clinical trials. Treatment options are outlined, with a concise description of recent work in AA specific populations, detailing several targeted therapies, including immunotherapy. Also, a summary of current clinical trials involving AA men is presented, and it is important that policies are adopted to ensure that AA men are actively recruited. Although it is encouraging that many of these explore the lifestyle and educational initiatives and therapeutic interventions, there is much still work to be done to reduce incidence and mortality in AA men and equalize current racial disparities.
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Affiliation(s)
- Zachary S. Dovey
- The Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Sujit S. Nair
- The Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Dimple Chakravarty
- The Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Ashutosh K. Tewari
- The Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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16
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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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17
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The Clinical Significance of Lymph Node Ratio and Ki-67 Expression in Papillary Thyroid Cancer. World J Surg 2021; 45:2155-2164. [PMID: 33825961 PMCID: PMC8154824 DOI: 10.1007/s00268-021-06070-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND The N stage in papillary thyroid cancer (PTC) is an important prognostic factor based on anatomical localization of cervical lymph nodes (LNs) only and not the extent of lymphatic metastasis. In this retrospective study, the clinical significance of lymph node ratio (LNR) and tumor cell proliferation in relation to the conventional classification of PTC was explored. METHODS Patients diagnosed with PTC at the Karolinska University Hospital in Stockholm, Sweden, during the years 2009-2011 were included. The LNR, defined as the number of metastatic LNs divided by the total number of LNs investigated, and the Ki-67 index were analyzed in relation to clinical data. RESULTS The median number of LN removed was 16 with the following N stage distribution: N0 (26%), N1a (45%), and N1b (29%). A Ki-67 index of ≥3% was significantly correlated with the presence of metastases and tumor recurrence with a sensitivity of 50% and specificity of 80% (p = 0.015). Lymph node ratio ≥21% was related to tumor recurrence with sensitivity of 89% and specificity of 70% (p = 0.006). Patients with LN metastases in the lateral cervical compartment only had significantly lower LNR (14.5%) compared to those with both central and lateral cervical metastases (39.5%) (p = 0.004) and exhibited no tumor recurrence. Increased Ki-67 index was significantly related to LNR ≥21% (p = 0.023) but was not associated with N stage. CONCLUSIONS The Ki-67 proliferation index and LNR may better reflect the malignant behavior of PTC compared to the anatomical classification of LN metastases solely.
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18
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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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19
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Lakshmanan VK, Ojha S, Jung YD. A modern era of personalized medicine in the diagnosis, prognosis, and treatment of prostate cancer. Comput Biol Med 2020; 126:104020. [PMID: 33039808 DOI: 10.1016/j.compbiomed.2020.104020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022]
Abstract
The present era is witnessing rapid advancements in the field of medical informatics and modern healthcare management. The role of translational bioinformatics (TBI), an infant discipline in the field of medical informatics, is pivotal in this revolution. The development of high-throughput technologies [e.g., microarrays, next-generation sequencing (NGS)] has propelled TBI to the next stage in this modern era of medical informatics. In this review, we assess the promising translational outcomes of microarray- and NGS-based discovery of genes, proteins, micro RNAs, and other active biological compounds aiding in the diagnosis, prognosis, and therapy of prostate cancer (PCa) to improve treatment strategies at the localized and/or metastatic stages in patients. Several promising candidate biomarkers in circulating blood (miR-25-3p and miR-18b-5p), urine (miR-95, miR-21, miR-19a, and miR-19b), and prostatic secretions (miR-203) have been identified. AURKA and MYCN, novel candidate biomarkers, were found to be specifically expressed in neuroendocrine PCa. The use of BTNL2 gene mutations and inflammasomes as biomarkers in immune function-mediated, inherited PCa has also been elucidated based on NGS data. Although TBI discoveries can benefit clinical performance metrics, the translational potential and the in vivo performance of TBI outcomes need to be verified. In conclusion, TBI aids in the effective clinical management of PCa; furthermore, the fate of personalized/precision medicine mostly relies on the enhanced diagnostic, prognostic, and therapeutic potential of TBI.
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Affiliation(s)
- Vinoth-Kumar Lakshmanan
- Centre for Preclinical and Translational Medical Research (CPTMR), Central Research Facility (CRF), Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600 116, Tamil Nadu, India; Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, 4184, United Arab Emirates.
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, 160 Baeksuh-Roh, Dong Gu, Gwangju, 61469, Republic of Korea
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20
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Besalú E, De Julián-Ortiz JV. Ranking Series of Cancer-Related Gene Expression Data by Means of the Superposing Significant Interaction Rules Method. Biomolecules 2020; 10:E1293. [PMID: 32911598 PMCID: PMC7564041 DOI: 10.3390/biom10091293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 11/17/2022] Open
Abstract
The Superposing Significant Interaction Rules (SSIR) method is a combinatorial procedure that deals with symbolic descriptors of samples. It is able to rank the series of samples when those items are classified into two classes. The method selects preferential descriptors and, with them, generates rules that make up the rank by means of a simple voting procedure. Here, two application examples are provided. In both cases, binary or multilevel strings encoding gene expressions are considered as descriptors. It is shown how the SSIR procedure is useful for ranking the series of patient transcription data to diagnose two types of cancer (leukemia and prostate cancer) obtaining Area Under Receiver Operating Characteristic (AU-ROC) values of 0.95 (leukemia prediction) and 0.80-0.90 (prostate). The preferential selected descriptors here are specific gene expressions, and this is potentially useful to point to possible key genes.
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Affiliation(s)
- Emili Besalú
- Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, 17003 Girona, Spain
| | - Jesus Vicente De Julián-Ortiz
- Molecular Topology and Drug Design Research Unit, Departament de Química Física, Facultat de Farmàcia, Universitat de València, 46100 Burjassot, Spain;
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Basatac C, Sağlam S, Aktepe F, Akpinar H. Primary large cell prostate neuroendocrine carcinoma with central and nephrogenic diabetes insipidus. Int Braz J Urol 2020; 46:859-863. [PMID: 32648432 PMCID: PMC7822364 DOI: 10.1590/s1677-5538.ibju.2019.0180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 05/06/2019] [Indexed: 02/08/2023] Open
Affiliation(s)
- Cem Basatac
- Istanbul Bilim UniversityDepartment of UrologyIstanbulTurkeyDepartment of Urology, Istanbul Bilim University, Istanbul, Turkey
| | - Sezer Sağlam
- Istanbul Bilim UniversityDepartment of Medical OncologyIstanbulTurkeyDepartment of Medical Oncology, Istanbul Bilim University, Istanbul, Turkey
| | - Fatima Aktepe
- Group Florence Nightingale HospitalsDepartment of PathologyIstanbulTurkeyDepartment of Pathology, Group Florence Nightingale Hospitals, Istanbul, Turkey
| | - Haluk Akpinar
- Istanbul Bilim UniversityDepartment of UrologyIstanbulTurkeyDepartment of Urology, Istanbul Bilim University, Istanbul, Turkey
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22
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Serag A, Ion-Margineanu A, Qureshi H, McMillan R, Saint Martin MJ, Diamond J, O'Reilly P, Hamilton P. Translational AI and Deep Learning in Diagnostic Pathology. Front Med (Lausanne) 2019; 6:185. [PMID: 31632973 PMCID: PMC6779702 DOI: 10.3389/fmed.2019.00185] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/30/2019] [Indexed: 12/15/2022] Open
Abstract
There has been an exponential growth in the application of AI in health and in pathology. This is resulting in the innovation of deep learning technologies that are specifically aimed at cellular imaging and practical applications that could transform diagnostic pathology. This paper reviews the different approaches to deep learning in pathology, the public grand challenges that have driven this innovation and a range of emerging applications in pathology. The translation of AI into clinical practice will require applications to be embedded seamlessly within digital pathology workflows, driving an integrated approach to diagnostics and providing pathologists with new tools that accelerate workflow and improve diagnostic consistency and reduce errors. The clearance of digital pathology for primary diagnosis in the US by some manufacturers provides the platform on which to deliver practical AI. AI and computational pathology will continue to mature as researchers, clinicians, industry, regulatory organizations and patient advocacy groups work together to innovate and deliver new technologies to health care providers: technologies which are better, faster, cheaper, more precise, and safe.
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23
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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: 24] [Impact Index Per Article: 4.0] [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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24
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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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25
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Ushimado K, Kobayashi N, Hikichi M, Tsukamoto T, Urano M, Utsumi T. Inverse correlation between Ki67 expression as a continuous variable and outcomes in luminal HER2-negative breast cancer. FUJITA MEDICAL JOURNAL 2019; 5:72-78. [PMID: 35111506 PMCID: PMC8766244 DOI: 10.20407/fmj.2018-021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 01/24/2019] [Indexed: 11/09/2022]
Abstract
OBJECTIVES Few studies to date have investigated the prognostic significance of Ki67 expression as a continuous variable in breast cancer. This study aimed to evaluate the impact of Ki67 expression as a dichotomous or continuous variable on outcomes in estrogen receptor (ER)+ and human epidermal growth factor receptor 2 (HER2)- breast cancer. METHODS Survival analysis was performed to estimate the likelihood of distant recurrence and death in retrospective data from 794 patients with ER+/HER2- breast cancer. We assessed the relationship between outcomes and two Ki67 cutoffs, 14% and 20%, and the Ki67 labeling index as a continuous variable. RESULTS In univariate analysis, T stage, lymph node involvement, histological grade, progesterone receptor status, and Ki67 expression at the two cutoffs and as a continuous variable were identified as significant prognostic factors for distant disease-free survival (DDFS) and overall survival (OS). There were no statistical differences in DDFS and OS between women with Ki67 expression of <14% and 14-<20%. Multivariate analysis showed that Ki67 expression ≥20% was an independent prognostic indicator for DDFS. Regarding the risk of distant metastasis, the 20% cutoff was more reliable than 14%. We also found that Ki67 expression as a continuous variable was an independent prognostic factor for DDFS and OS in multivariate analyses. CONCLUSIONS High Ki67 expression is associated with a survival disadvantage in patients with ER+/HER2- breast cancer, indicating that these patients might have a higher risk of recurrence after primary treatment and might therefore benefit from individualized treatment.
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Affiliation(s)
- Kaori Ushimado
- Department of Breast Surgery, Fujita Health University,
School of Medicine, Toyoake, Aichi,
Japan
| | - Naomi Kobayashi
- Department of Breast Surgery, Fujita Health University,
School of Medicine, Toyoake, Aichi,
Japan
| | - Masahiro Hikichi
- Department of Breast Surgery, Fujita Health University,
School of Medicine, Toyoake, Aichi,
Japan
| | - Tetsuya Tsukamoto
- Department of Diagnostic Pathology, Fujita Health
University, School of Medicine,
Toyoake, Aichi, Japan
| | - Makoto Urano
- Department of Diagnostic Pathology, Fujita Health
University, School of Medicine,
Toyoake, Aichi, Japan
| | - Toshiaki Utsumi
- Department of Breast Surgery, Fujita Health University,
School of Medicine, Toyoake, Aichi,
Japan
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Higher Ki67 expression in fibroblast like cells at invasive front indicates better clinical outcomes in oral squamous cell carcinoma patients. Biosci Rep 2018; 38:BSR20181271. [PMID: 30341240 PMCID: PMC6246770 DOI: 10.1042/bsr20181271] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/21/2018] [Accepted: 10/03/2018] [Indexed: 01/05/2023] Open
Abstract
Background: Ki67 has been a key role for the treatment options and prognosis evaluation in some kinds of tumors; however, the spatial expression of Ki67 in oral squamous cell carcinoma (OSCC) has not been fully-evaluated. Therefore, in the present study, we aimed to elucidate the prognosis value of Ki67 spatial expression including in different cell types and at different compartments of tumor in OSCC patients. Methods: Immunohistochemical expression of Ki67 in tumor cells (TCs) and fibroblast like cells (FLCs) at center of tumor (CT) and invasive front (IF) was evaluated in 109 OSCC patients. Then correlations of Ki67 expressions with clinicopathological parameters were analyzed by Chi-square test, and survival curves were evaluated by Kaplan-Meier methods. Furthermore, univariate and multivariate analysis were performed to assess the diagnostic values of Ki67 expression by the Cox regression model. Results: Ki67 expression in TCs was much higher than in FLCs both at CT and IF compartments, but Ki67 expression in TCs was simultaneously higher at CT than that at IF (P=0.0004), which was converse to Ki67 expression in FLCs (P<0.0001). Additionally, high Ki67 expression in FLCs at IF was significantly associated with poor tumor differentiation (P=0.003), worse depth of invasion (DOI, P=0.027) and worst pattern of invasion (WPOI, P=0.041), but Ki67 expression in TCs had no correlation with clinical parameters no matter at CT or IF. Moreover, patients with higher Ki67 expression in TCs at CT had significantly increased risk for OS (overall survival; HR:1.935, 95% CI: 1.181-4.823, P=0.0395) and DFS (disease-free survival; HR: 2.974, 95% CI:1.189-5.023, P=0.046). On contrary, higher Ki67 expression in FLCs at IF was correlated with better OS (HR: 0.15, 95% CI: 0.018-0.846, P=0.0396) and DFS (HR: 0.15, 95% CI: 0.018-0.947, P=0.0445). Whereas, Ki67 expression both at TCs in IF and at FLCs in CT had no significant prognostic value for OS and DFS. Furthermore, Cox multivariate analysis revealed that Ki67 expression in FLCs at IF could not be an independent prognostic factor for OSCC patients. Conclusion: These results show that higher Ki67 expression in FLCs at IF indicated better clinical outcomes for OSCC patients.
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27
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Tian JY, Guo FJ, Zheng GY, Ahmad A. Prostate cancer: updates on current strategies for screening, diagnosis and clinical implications of treatment modalities. Carcinogenesis 2018; 39:307-317. [PMID: 29216344 DOI: 10.1093/carcin/bgx141] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/29/2017] [Indexed: 01/23/2023] Open
Abstract
Prostate cancer is the most common cancer in men by way of diagnosis and a leading cause of cancer-related deaths. Early detection and intervention remains key to its optimum clinical management. This review provides the most updated information on the recent methods of prostate cancer screening, imaging and treatment modalities. Wherever possible, clinical trial data has been supplemented to provide a comprehensive overview of current prostate cancer research and development. Considering the recent success of immunotherapy in prostate cancer, we discuss cell, DNA and viruses based, as well as combinatorial immunotherapeutic strategies in detail. Furthermore, the potential of nanotechnology is increasingly being realized, especially in prostate cancer research, and we provide an overview of nanotechnology-based strategies, with special emphasis on nanotheranostics and multifunctional nanoconstructs. Understanding these recent developments is critical to the design of future therapeutic strategies to counter prostate cancer.
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Affiliation(s)
- Jing-Yan Tian
- Department of Urology, Second Division of the First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Feng-Jun Guo
- Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Guo-You Zheng
- Department of Urology, Second Division of the First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Aamir Ahmad
- Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
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28
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Rebbeck TR. Prostate Cancer Disparities by Race and Ethnicity: From Nucleotide to Neighborhood. Cold Spring Harb Perspect Med 2018; 8:a030387. [PMID: 29229666 PMCID: PMC6120694 DOI: 10.1101/cshperspect.a030387] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Prostate cancer (CaP) incidence, morbidity, and mortality rates vary substantially by race and ethnicity, with African American men experiencing among the highest CaP rates in the world. The causes of these disparities are multifactorial and complex, and likely involve differences in access to screening and treatment, exposure to CaP risk factors, variation in genomic susceptibility, and other biological factors. To date, the proportion of CaP that can be explained by environmental exposures is small and differences in the role factors play by race or ethnicity is poorly understood. In the absence of additional data, it is likely that environmental factors do not contribute greatly to CaP disparities. In contrast, CaP has one of the highest heritabilities of all major cancers and many CaP susceptibility genes have been identified. Some CaP loci, including the risk loci found at chromosome 8q24, have consistent effects in all racial/ethnic groups studied to date. However, replication of many susceptibility loci across race or ethnicity remains limited. It is likely that inequities in health care access strongly influences CaP disparities. CaP is a disease with a complex multifactorial etiology, and therefore any approach attempting to address racial/ethnic disparities in CaP must consider the many sources that influence risk, outcomes, and disparities.
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Affiliation(s)
- Timothy R Rebbeck
- Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02215
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29
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Beyene DA, Naab TJ, Kanarek NF, Apprey V, Esnakula A, Khan FA, Blackman MR, Brown CA, Hudson TS. Differential expression of Annexin 2, SPINK1, and Hsp60 predict progression of prostate cancer through bifurcated WHO Gleason score categories in African American men. Prostate 2018; 78:801-811. [PMID: 29682763 PMCID: PMC7257440 DOI: 10.1002/pros.23537] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 03/27/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Although studies have observed several markers correlate with progression of prostate cancer (PCa), no specific markers have been identified that accurately predict the progression of this disease, even in African American (AA) men who are generally at higher risk than other ethnic groups. The primary goal of this study was to explore whether three markers could predict the progression of PCa. METHOD We investigated protein expression of Annexin 2 (ANX2), serine peptidase inhibitor, kazal type 1(SPINK1)/tumor-associated trypsin inhibitor (TATI), and heat shock protein 60 (Hsp60) in 79 archival human prostate trans-rectal ultrasound (TRUS) biopsy tissues according to a modified World Health Organization (WHO) classification: normal (WHO1a), Gleason Score (GS6 (WHO1b), GS7 subgroups (WHO2 = 3 + 4, WHO3 = 4 + 3), GS8 (WHO4), and GS9-10 (WHO5). AA men aged 41-90 diagnosed from 1990 to 2013 at Howard University were included. Automated staining assessed expression of each biomarker. Spearman correlation assessed the direction and relationship between biomarkers, WHO and modified WHO GS, age, and 5-year survival. A two-tailed t-test and ANOVA evaluated biomarkers expression in relationship to WHO normal and other GS levels, and between WHO GS levels. A logistic and linear regression analysis examined the relationship between biomarker score and WHO GS categories. Kaplan-Meier curves graphed survival. RESULTS ANX2 expression decreased monotonically with the progression of PCa while expression of SPINK1/TATI and Hsp60 increased but had a more WHO GS-specific effect; SPINK1/TATI differed between normal and GS 2-6 and HSP60 differed between GS 7 and GS 2-6. WHO GS was found to be significantly and negatively associated with ANX2, and positively with SPINK1/TATI and Hsp60 expression. High SPINK1/TATI expression together with the low ANX2 expression at higher GS exhibited a bi-directional relationship that is associated with PCa progression and survival. CONCLUSION Importantly, the data reveal that ANX2, and SPINK1/TAT1 highly associate with WHO GS and with the transition from one stage of PrCa to the next in AA men. Future research is needed in biracial and larger population studies to confirm this dynamic relationship between ANX2 and SPINK1 as independent predictors of PCa progression in all men.
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Affiliation(s)
- Desta A Beyene
- Research Service, Veteran Affairs Medical Center, Washington, District of Columbia
- Howard University Cancer Center, Washington, District of Columbia
- Department of Biochemistry and Molecular Biology, Washington, District of Columbia
| | - Tammey J Naab
- Howard University Cancer Center, Washington, District of Columbia
- Department of Pathology, College of Medicine, Washington, District of Columbia
| | - Norma F Kanarek
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Victor Apprey
- National Human Genome Center, Howard University, Washington, District of Columbia
| | - Ashwini Esnakula
- Howard University Cancer Center, Washington, District of Columbia
- Department of Pathology, College of Medicine, Washington, District of Columbia
| | - Farahan A Khan
- Howard University Cancer Center, Washington, District of Columbia
- Department of Pathology, College of Medicine, Washington, District of Columbia
| | - Marc R Blackman
- Research Service, Veteran Affairs Medical Center, Washington, District of Columbia
| | - Collis A Brown
- Howard University Cancer Center, Washington, District of Columbia
- Department of Pharmacology, College of Medicine, Washington, District of Columbia
| | - Tamaro S Hudson
- Research Service, Veteran Affairs Medical Center, Washington, District of Columbia
- Howard University Cancer Center, Washington, District of Columbia
- Department of Pharmacology, College of Medicine, Washington, District of Columbia
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30
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Hui S, Guo-Qi Z, Xiao-Zhong G, Chun-Rong L, Yu-Fei L, Dong-Liang Y. IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma. Hum Pathol 2018; 81:138-147. [PMID: 30031101 DOI: 10.1016/j.humpath.2018.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 02/08/2023]
Abstract
Malignant peritoneal mesothelioma (MPeM) is an incurable cancer with poor prognosis, and several biomarkers have been suggested for screening of MPeM. The aim of our study was to evaluate the prognostic significances of IMP3 and Fli-1 in MPeM. Diagnostic biopsies of 44 MPeM patients were centrally collected and were immunohistochemically analyzed for expression of IMP3, Fli-1, and Ki-67. Labeling was assessed by 2 pathologists. Complete clinical information and follow-up were obtained from patients' records. Carcinomas expressed Fli-1 in 42 (95.5%) of 44 specimens, and IMP3 in 23 (52.3%) of 44 specimens. Spearman ρ analysis revealed that Fli-1 expression was related to both histologic type and Ki-67 labeling index (Ki-67LI; r = -0.500, P < .05; r = 0.358, P < .05), and IMP3 expression was related to Ki-67LI (r = 0.401, P < .05). A Kaplan-Meier analysis and univariate Cox regression analysis showed that tumor-directed treatment, a lower peritoneal carcinomatosis index, stage I, lower Ki-67LI, and lower level of IMP3 expression had a statistically significantly positive effect on overall survival; Fli-1 did not affect overall survival in the univariate analysis (hazard ratio [HR], 1.026; P = .904). A Kaplan-Meier analysis showed the correlation between IMP3-Fli-1 and overall survival, whereas univariate and multivariate Cox regression analyses did not confirm the correlation. Cox regression analysis revealed that IMP3 expression (HR, 2.311 [95% confidence interval, 1.190-4.486]; P = .013) and no tumor-directed treatment (HR, 0.189 [95% confidence interval, 0.086-0.416]; P = .000) retained independent prognostic significance, both with negative effect on OS. IMP3, along with tumor-directed treatment protocols, is a powerful prognosticator in patients with MPeM.
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Affiliation(s)
- Song Hui
- Department of Gastroenterology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, China
| | - Zheng Guo-Qi
- Department of Gastroenterology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, China.
| | - Guo Xiao-Zhong
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, China
| | - Liu Chun-Rong
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, China
| | - Liang Yu-Fei
- Department of Gastroenterology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, China
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31
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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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32
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Tang J, Gui C, Qiu S, Wang M. The clinicopathological significance of Ki67 in papillary thyroid carcinoma: a suitable indicator? World J Surg Oncol 2018; 16:100. [PMID: 29855303 PMCID: PMC5984434 DOI: 10.1186/s12957-018-1384-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 04/05/2018] [Indexed: 12/14/2022] Open
Abstract
Background To explore Ki67 expression in papillary thyroid carcinoma (PTC) and its clinical-pathological significance. Methods A total of 776 consecutive PTC and benign thyroid disease patients underwent thyroidectomy at Shanghai General Hospital from January 2013 to December 2015 and were retrospectively analysed. Ki67 expression was determined in the PTC and benign thyroid disease tissues, and other clinicopathological factors were identified via statistical analyses. Results The Ki67 expression intensity in the PTC group was significantly higher than that in the benign thyroid disease group. In the PTC group, a tumour size ≥ 1 cm and coexistence with thyroiditis were significantly associated with the Ki67 expression intensity. The TGAb and TPOAb plasma levels were linearly correlated with the Ki67 expression intensity. Moreover, the tumour size and Ki67 expression intensity also showed a linear correlation. Receiver operating characteristic (ROC) curve analysis suggested that the optimal cut-off value of Ki67 was 2.50%. Two groups divided by Ki67 cut-off values showed significant differences in the recurrence survival rate. Conclusions Ki67 is a suitable biomarker for distinguishing PTC from benign thyroid disease. Ki67 expression was related to the tumour size, thyroiditis and plasma levels of TGAb and TPOAb in PTC. Ki67 could be used as a prognostic indicator in PTC. Patients with high Ki67 expression are more likely to experience disease recurrence.
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Affiliation(s)
- Jingdong Tang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China.,Department of Surgery, Shanghai Pudong Hospital, Fudan University, No. 2800 Gongwei Road, Shanghai, 201399, China
| | - Chunyi Gui
- Nursing Department, Eye & ENT Hospital, Fudan University, No. 83 Fenyang Road, Shanghai, 200031, China
| | - Shenglong Qiu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China
| | - Min Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China. .,Oncology Department, Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD, 21287, USA.
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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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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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Berlin A, Castro-Mesta JF, Rodriguez-Romo L, Hernandez-Barajas D, González-Guerrero JF, Rodríguez-Fernández IA, González-Conchas G, Verdines-Perez A, Vera-Badillo FE. Prognostic role of Ki-67 score in localized prostate cancer: A systematic review and meta-analysis. Urol Oncol 2017. [PMID: 28648414 DOI: 10.1016/j.urolonc.2017.05.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Ki-67 for quantifying tumor proliferation is widely used. In localized prostate cancer (PCa), despite a suggested predictive role of Ki-67 for outcomes after therapies, it has not been incorporated into clinical practice. Herein, we conduct a systematic review and meta-analysis of the literature reporting the association of Ki-67 and disease outcomes in PCa treated radically. METHODS Medline and EMBASE databases were searched without date or language restrictions, using "KI67" and "prostate cancer" MeSH terms. Studies reporting Ki-67 association with clinical outcomes (disease-free survival [DFS], biochemical failure-free survival, rate of distant metastases [DM], disease-specific survival [DSS], or overall survival [OS], or all of these) in patients with PCa managed actively were included, and relevant data extracted by 2 independent reviewers. Odds ratios (OR) were weighted and pooled in a meta-analysis using Mantel-Haenszel random-effect modeling. RESULTS Twenty-one studies comprising 5,419 patients met eligibility for analysis, and 67.6% of patients had low Ki-67. Mean Ki-67 was 6.14%. High Ki-67 was strongly associated with worse clinical outcomes. DFS was better in those patients with low Ki-67 at 5 and 10 years (OR = 0.32, 95% CI: 0.23-0.44, P<0.00001; OR = 0.31, 95% CI: 0.20-0.48, P<0.00001). Similarly, low Ki-67 was related to improved DSS at 5 and 10 years (OR = 0.15, 95% CI: 0.10-0.21, P<0.00001; OR = 0.16, 95% CI: 0.06-0.40, P<0.00001). Association between low Ki-67 scores with improved OS (OR = 0.47; 95% CI: 0.37-0.61; P<0.00001) and high Ki-67 scores with DM at 5 years (OR = 4.07; 95% CI: 2.52-6.58; P<0.00001) was consistently observed. CONCLUSIONS High Ki-67 expression in localized PCa is a factor of poor prognosis for DSS, biochemical failure-free survival, DFS, DM, and OS after curative-intent treatments. Incorporation into clinical routine of this widely available and standardized biomarker should be strongly considered.
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Affiliation(s)
- Alejandro Berlin
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Julio F Castro-Mesta
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Laura Rodriguez-Romo
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - David Hernandez-Barajas
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Juan F González-Guerrero
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Iván A Rodríguez-Fernández
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Galileo González-Conchas
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Adrian Verdines-Perez
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México
| | - Francisco E Vera-Badillo
- Centro Universitario Contra el Cáncer, Hospital Universitario, Universidad Autónoma de Nuevo León, Monterrey, México; Department of Medical Oncology, Faculty of Medicine, Queen's University, Kingston, Ontario, Canada.
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López IH, Parada D, Gallardo P, Gascón M, Besora A, Peña K, Riu F, Arquez Pianetta M, Abuchaibe O, Torres Royò L, Arenas M. Prognostic correlation of cell cycle progression score and Ki-67 as a predictor of aggressiveness, biochemical failure, and mortality in men with high-risk prostate cancer treated with external beam radiation therapy. Rep Pract Oncol Radiother 2017; 22:251-257. [PMID: 28479874 DOI: 10.1016/j.rpor.2017.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 01/09/2017] [Accepted: 02/25/2017] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES Ki-67 is a proliferation marker in prostate cancer. A prognostic RNA signature was developed to characterize prostate cancer aggressiveness. The aim was to evaluate prognostic correlation of CCP and Ki-67 with biochemical failure (BF), and survival in high-risk prostate cancer patients (pts) treated with radiation therapy (RT). METHODS CCP score and Ki-67 were derived retrospectively from pre-treatment paraffin-embedded prostate cancer tissue of 33 men diagnosed from 2002 to 2006. CCP score was calculated as an average expression of 31 CCP genes. Ki-67 was determined by IHC. Single pathologist evaluated all tissues. Factors associated to failure and survival were analyzed. RESULTS Median CCP score was 0.9 (-0-1 - 2.6). CCP 0: 1 pt; CCP 1: 19 pts; CCP 2: 13 pts. Median Ki-67 was 8.9. Ki-67 cutpoint was 15.08%. BF and DSM were observed in 21% and 9%. Ki-67 ≥ 15% predicted BF (p = 0.043). With a median follow-up of 8.4 years, 10-year BF, OS, DM and DSM for CCP 1 vs. CCP 2 was 76-71% (p = 0.83), 83-73% (p = 0.86), 89-85% (p = 0.84), and 94-78% (p = 0.66). On univariate, high Ki-67 was correlated with BF (p = 0.013), OS (p = 0.023), DM (p = 0.007), and DSM (p = 0.01). On Cox MVA, high Ki-67 had a BF trend (p = 0.063). High CCP score was not correlated with DSM. CONCLUSIONS High Ki-67 significantly predicted outcome and provided prognostic information. CCP score may improve accuracy stratification. We did not provide prognostic correlation of CCP and DSM. It should be validated in a larger cohort of pts.
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Key Words
- ADT, androgen deprivation therapy
- Biomarkers
- CCP genes
- CCP, cell cycle progression
- CSS, cause-specific survival
- CTCv3.0, common terminology criteria for adverse events
- CTV, clinical target volume
- DFS, disease-free survival
- DMFS, distant metastasis free survival
- FFbF, freedom from biochemical failure
- GI, gastrointestinal
- GU, genitourinary
- Gy, gray
- HE, hematoxylin and eosin
- IHC, immunohistochemical
- Ki-67
- OS, overall survival
- PCa, prostate cancer
- PSA, prostate specific antigen
- Prostate cancer
- RT, radiation therapy
- pts, patients
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Affiliation(s)
- Iván Henríquez López
- Radiation Oncology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - David Parada
- Pathology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Pablo Gallardo
- Faculty of Medicine, University Hospital of Sant Joan, Reus, Tarragona, Spain
| | - Marina Gascón
- Radiation Oncology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Arnau Besora
- Bioinformatics, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Karla Peña
- Pathology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Francesc Riu
- Pathology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Miquel Arquez Pianetta
- Radiation Oncology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Oscar Abuchaibe
- Department of Radiation Oncology, Virgilio Galvis Ramirez Cancer Centre, Bucaramanga, Colombia
| | - Laura Torres Royò
- Radiation Oncology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
| | - Meritxell Arenas
- Radiation Oncology Department, University Hospital of Sant Joan, Institute d'Investigació Sanitaria Pere Virgili (IISPV), Reus, Tarragona, Spain
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Abstract
Prostate cancer rates vary substantially by race, ethnicity, and geography. These disparities can be explained by variation in access to screening and treatment, variation in exposure to prostate cancer risk factors, and variation in the underlying biology of prostate carcinogenesis (including genomic propensity of some groups to develop biologically aggressive disease). It is clear that access to screening and access to treatment are critical influencing factors of prostate cancer rates; yet, even among geographically diverse populations with similar access to care (eg, low- and medium-income countries), African descent men have higher prostate cancer rates and poorer prognosis. To date, the proportion of prostate cancer that can be explained by environmental exposures is small, and the effect of these factors across different racial, ethnic, or geographical populations is poorly understood. In contrast, prostate cancer has one of the highest heritabilities of all major cancers. Numerous genetic susceptibility markers have been identified from family-based studies, candidate gene association studies, and genome-wide association studies. Some prostate cancer loci, including the risk loci found at chromosome 8q24, have consistent effects in all groups studied to date. However, replication of many susceptibility loci across race, ethnicity, and geography remains limited, and additional studies in certain populations (particularly in men of African descent) are needed to better understand the underlying genetic basis of prostate cancer.
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Affiliation(s)
- Timothy R Rebbeck
- Department of Medical Oncology Dana Farber Cancer Institute, Boston, MA; Department of Epidemiology Harvard TH Chan School of Public Health, Boston, MA.
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Park KR, Yun HM, Quang TH, Oh H, Lee DS, Auh QS, Kim EC. 4-Methoxydalbergione suppresses growth and induces apoptosis in human osteosarcoma cells in vitro and in vivo xenograft model through down-regulation of the JAK2/STAT3 pathway. Oncotarget 2016; 7:6960-71. [PMID: 26755649 PMCID: PMC4872761 DOI: 10.18632/oncotarget.6873] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 01/03/2016] [Indexed: 12/18/2022] Open
Abstract
Although the heartwood of Dalbergia odorifera T. Chen (Leguminosae) is an important source of traditional Korean and Chinese medicines, the effects of novel compound methoxydalbergione (4-MD) isolated from Dalbergia odorifera was not reported. Herein, we investigated the effects of the 4-MD in vitro and in vivo against osteosarcoma cells and its molecular mechanisms. 4-MD inhibited the proliferation of osteosarcoma cells and induced apoptosis as evidenced by Annexin V + and TUNEL + cells. This apoptosis was accompanied by upregulation of apoptotic proteins (procaspase-3 and PARP), but downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Survivin). 4-MD inhibited phosphorylation of JAK2 and STAT3 with the inactivation of mitogen-activated protein kinases (MAPKs) and CREB, and the upregulation of PTEN in osteosarcoma cells. Importantly, 4-MD reduced colony formation in soft agar and inhibited tumor growth in mice xenograft model in association with the reduced expression of PCNA, Ki67, p-STAT3, and Survivin. Taken together, the present study for the first time demonstrates that 4-MD exerts in vitro and in vivo anti-proliferative effects against osteosarcoma cells through the inhibition of the JAK2/STAT3 pathway, and suggest the potential for therapeutic application of 4-MD in the treatment of osteosarcoma.
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Affiliation(s)
- Kyung-Ran Park
- Department of Oral and Maxillofacial Regeneration, Kyung Hee University, Seoul, Republic of Korea
| | - Hyung-Mun Yun
- Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth and Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea
| | - Tran-Hong Quang
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea
| | - Hyuncheol Oh
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Korea
| | - Dong-Sung Lee
- Department of Biomedical Chemistry, College of Health and Biomedical Science, Konkuk University, Chung-Ju, Korea
| | - Q-Schick Auh
- Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea
| | - Eun-Cheol Kim
- Department of Oral and Maxillofacial Pathology, School of Dentistry and Research Center for Tooth and Periodontal Regeneration (MRC), Kyung Hee University, Seoul, Republic of Korea
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Angulo JC, Redondo C, Sánchez-Chapado M, Colás B, Ropero S, López JI. Survival predictors in patients with prostate adenocarcinoma with hormonal blockade. Pathol Res Pract 2016; 212:899-903. [PMID: 27502465 DOI: 10.1016/j.prp.2016.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 07/19/2016] [Accepted: 07/22/2016] [Indexed: 10/21/2022]
Abstract
Ki-67 index and clinical-pathological factors such as the Gleason score and the presence of neuroendocrine differentiation have been used for predicting survival in patients with prostate cancer. We examined prostate tissue from 45 patients with advanced prostate cancer who were treated with maximal androgen blockade and analysed their cancer-specific survival (CSS). We assessed the Gleason index, performed an immunohistochemical analysis of Ki-67 (MIB-1) and determined the presence of neuroendocrine differentiation (chromogranin A). A survival study was conducted using Kaplan-Meier curves (log-rank test) and a Cox regression analysis. Twenty-four patients (53.3%) died from the disease, with a mean follow-up of 68.7±7.7 months (56.6% CSS at 5 years and 31.8% at 10 years). In the univariate analysis, survival was associated with an interquartile distribution of Ki-67 (0-5, 6-12%, 13-25%, >25%; log-rank, p=0.01), Gleason 5 (total index 9-10; log-rank, p=0.002) and the presence of metastases during the diagnosis (M1; log-rank, p=0.004) but not to cT category (T3-T4; log-rank, p=0.26) or neuroendocrine differentiation (immunohistochemically positive tumour cell nests; log-rank, p=0.46). The multivariate analysis revealed that a Ki-67 index ≤12% (HR, 0.22; p=0.0009) and the absence of metastases (M0) during diagnosis (HR, 0.17; p=0.0002) were protective factors in this population. In conclusion, Ki-67 proliferation index and the lack of metastases at diagnosis predict CSS in patients with advanced prostate cancer who undergo hormonal blockade. Neuroendocrine differentiation in tumour tissue had no prognostic value in this study.
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Affiliation(s)
- Javier C Angulo
- Clinical Department, Faculty of Biomedical Sciences, European University of Madrid, Laureate International Universities, Madrid, Spain; Department of Urology, University Hospital of Getafe, Madrid, Spain
| | - Cristina Redondo
- Department of Urology, University Hospital of Getafe, Madrid, Spain
| | - Manuel Sánchez-Chapado
- Department of Urology, University Hospital Príncipe de Asturias, University of Alcala, Alcala de Henares, Madrid, Spain
| | - Begoña Colás
- Department of Systems Biology, Biochemical and Molecular Biology Teaching Unit, University of Alcala, Alcala de Henares, Madrid, Spain
| | - Santiago Ropero
- Department of Systems Biology, Biochemical and Molecular Biology Teaching Unit, University of Alcala, Alcala de Henares, Madrid, Spain
| | - José I López
- Department of Pathology, Cruces University Hospital, BioCruces Institute, University of the Basque Country (UPV/EHU), Barakaldo, Bizkaia, Spain.
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Green WJF, Ball G, Powe D. Does the molecular classification of breast cancer point the way for biomarker identification in prostate cancer? World J Clin Urol 2016; 5:80-89. [DOI: 10.5410/wjcu.v5.i2.80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/27/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
There is significant variation in clinical outcome between patients diagnosed with prostate cancer (CaP). Although useful, statistical nomograms and risk stratification tools alone do not always accurately predict an individual’s need for and response to treatment. The factors that determine this variation are not fully elucidated. In particular, cellular response to androgen ablation and subsequent paracrine/autocrine adaptation is poorly understood and despite best therapies, median survival in castrate resistant patients is only approximately 35 mo. We propose that one way of understanding this is to look for correlates in other comparable malignancies, such as breast cancer, where markers of at least 4 distinct gene clusters coding for 4 different phenotypic subtypes have been identified. These subtypes have been shown to demonstrate prognostic significance and successfully guide appropriate treatment regimens. In this paper we assess and review the evidence demonstrating parallels in the biology and treatment approach between breast and CaP, and consider the feasibility of patients with CaP being stratified into different molecular classes that could be used to complement prostate specific antigen and histological grading for clinical decision making. We show that there are significant correlations between the molecular classification of breast and CaP and explain how techniques used successfully to predict response to treatment in breast cancer can be applied to the prostate. Molecular phenotyping is possible in CaP and identification of distinct subtypes may allow personalised risk stratification way beyond that currently available.
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White NM, Zhao SG, Zhang J, Rozycki EB, Dang HX, McFadden SD, Eteleeb AM, Alshalalfa M, Vergara IA, Erho N, Arbeit JM, Karnes RJ, Den RB, Davicioni E, Maher CA. Multi-institutional Analysis Shows that Low PCAT-14 Expression Associates with Poor Outcomes in Prostate Cancer. Eur Urol 2016; 71:257-266. [PMID: 27460352 DOI: 10.1016/j.eururo.2016.07.012] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 07/06/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer. OBJECTIVE To identify RNA biomarkers associated with aggressive prostate cancer. DESIGN, SETTING, AND PARTICIPANTS Radical prostatectomy microarray and clinical data was obtained from 910 patients in three published institutional cohorts: Mayo Clinic I (N=545, median follow-up 13.8 yr), Mayo Clinic II (N=235, median follow-up 6.7 yr), and Thomas Jefferson University (N=130, median follow-up 9.6 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints. RESULTS AND LIMITATIONS An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion. CONCLUSIONS We discovered that androgen-regulated PCAT-14 is overexpressed in prostate cancer, suppresses invasive phenotypes, and lower expression is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease that could be used to improve patient management. PATIENT SUMMARY We discovered that aberrant prostate cancer associated transcript-14 expression during prostate cancer progression is prevalent across cancer patients. Prostate cancer associated transcript-14 is also prognostic for metastatic disease and survival highlighting its importance for stratifying patients that could benefit from treatment intensification.
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Affiliation(s)
- Nicole M White
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Shuang G Zhao
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA; Beaumont Hospital-Dearborn, Transitional Year Program, Dearborn, MI, USA
| | - Jin Zhang
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
| | - Emily B Rozycki
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Ha X Dang
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
| | - Sandra D McFadden
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Abdallah M Eteleeb
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
| | | | | | | | - Jeffrey M Arbeit
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Robert B Den
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | | | - Christopher A Maher
- Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; Beaumont Hospital-Dearborn, Transitional Year Program, Dearborn, MI, USA; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
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Pascale M, Aversa C, Barbazza R, Marongiu B, Siracusano S, Stoffel F, Sulfaro S, Roggero E, Bonin S, Stanta G. The proliferation marker Ki67, but not neuroendocrine expression, is an independent factor in the prediction of prognosis of primary prostate cancer patients. Radiol Oncol 2016; 50:313-20. [PMID: 27679548 PMCID: PMC5030813 DOI: 10.1515/raon-2016-0033] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 04/28/2016] [Indexed: 12/23/2022] Open
Abstract
Background Neuroendocrine markers, which could indicate for aggressive variants of prostate cancer and Ki67 (a well-known marker in oncology for defining tumor proliferation), have already been associated with clinical outcome in prostate cancer. The aim of this study was to investigate the prognostic value of those markers in primary prostate cancer patients. Patients and methods NSE (neuron specific enolase), ChrA (chromogranin A), Syp (Synaptophysin) and Ki67 staining were performed by immunohistochemistry. Then, the prognostic impact of their expression on overall survival was investigated in 166 primary prostate cancer patients by univariate and multivariate analyses. Results NSE, ChrA, Syp and Ki67 were positive in 50, 45, 54 and 146 out of 166 patients, respectively. In Kaplan-Meier analysis only diffuse NSE staining (negative vs diffuse, p = 0.004) and Ki67 (≤ 10% vs > 10%, p < 0.0001) were significantly associated with overall survival. Ki67 expression, but not NSE, resulted as an independent prognostic factor for overall survival in multivariate analysis. Conclusions A prognostic model incorporating Ki67 expression with clinical-pathological covariates could provide additional prognostic information. Ki67 may thus improve prediction of prostate cancer outcome based on standard clinical-pathological parameters improving prognosis and management of prostate cancer patients.
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Affiliation(s)
- Mariarosa Pascale
- Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
| | - Cinzia Aversa
- Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
| | - Renzo Barbazza
- Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
| | - Barbara Marongiu
- Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
| | - Salvatore Siracusano
- Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
| | - Flavio Stoffel
- Department of Urology, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Sando Sulfaro
- Department of Laboratory Medicine, S.C. Pathology, Santa Maria degli Angeli Hospital, Pordenone, Italy
| | - Enrico Roggero
- Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
| | - Serena Bonin
- Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
| | - Giorgio Stanta
- Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
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KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach. Br J Cancer 2016; 115:236-42. [PMID: 27336609 PMCID: PMC4947696 DOI: 10.1038/bjc.2016.169] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 03/29/2016] [Accepted: 05/03/2016] [Indexed: 12/19/2022] Open
Abstract
Background: There remains a need to identify and validate biomarkers for predicting prostate cancer (CaP) outcomes using robust and routinely available pathology techniques to identify men at most risk of premature death due to prostate cancer. Previous immunohistochemical studies suggest the proliferation marker Ki67 might be a predictor of survival, independently of PSA and Gleason score. We performed a validation study of Ki67 as a marker of survival and disease progression and compared its performance against another candidate biomarker, DLX2, selected using artificial neural network analysis. Methods: A tissue microarray (TMA) was constructed from transurethral resected prostatectomy histology samples (n=192). Artificial neural network analysis was used to identify candidate markers conferring increased risk of death and metastasis in a public cDNA array. Immunohistochemical analysis of the TMA was carried out and univariate and multivariate tests performed to explore the association of tumour protein levels of Ki67 and DLX2 with time to death and metastasis. Results: Univariate analysis demonstrated Ki67 as predictive of CaP-specific survival (DSS; P=0.022), and both Ki67 (P=0.025) and DLX2 (P=0.001) as predictive of future metastases. Multivariate analysis demonstrated Ki67 as independent of PSA, Gleason score and D'Amico risk category for DSS (HR=2.436, P=0.029) and both Ki67 (HR=3.296, P=0.023) and DLX2 (HR=3.051, P=0.003) as independent for future metastases. Conclusions: High Ki67 expression is only present in 6.8% of CaP patients and is predictive of reduced survival and increased risk of metastasis, independent of PSA, Gleason score and D'Amico risk category. DLX2 is a novel marker of increased metastasis risk found in 73% patients and 8.2% showed co-expression with a high Ki67 score. Two cancer cell proliferation markers, Ki67 and DLX2, may be able to inform clinical decision-making when identifying patients for active surveillance.
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Tretiakova MS, Wei W, Boyer HD, Newcomb LF, Hawley S, Auman H, Vakar-Lopez F, McKenney JK, Fazli L, Simko J, Troyer DA, Hurtado-Coll A, Thompson IM, Carroll PR, Ellis WJ, Gleave ME, Nelson PS, Lin DW, True LD, Feng Z, Brooks JD. Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of >1000 prostatectomies. Prostate Cancer Prostatic Dis 2016; 19:264-70. [PMID: 27136741 DOI: 10.1038/pcan.2016.12] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 02/17/2016] [Accepted: 03/08/2016] [Indexed: 01/07/2023]
Abstract
BACKGROUND Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes. METHODS After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up). RESULTS In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03). CONCLUSIONS In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.
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Affiliation(s)
| | - W Wei
- MD Anderson Cancer Center, Houston, TX, USA
| | - H D Boyer
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - L F Newcomb
- University of Washington, Seattle, WA, USA.,Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - S Hawley
- Canary Foundation, Redwood City, CA, USA
| | - H Auman
- Canary Foundation, Redwood City, CA, USA
| | | | | | - L Fazli
- University of British Columbia, Vancouver, BC, Canada
| | - J Simko
- University of California at San Francisco, CA, USA
| | - D A Troyer
- Eastern Virginia Medical School, Norfolk, VA, USA
| | | | - I M Thompson
- University of Texas Health Sciences Center at San Antonio, TX, USA
| | - P R Carroll
- University of California at San Francisco, CA, USA
| | - W J Ellis
- University of Washington, Seattle, WA, USA.,Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - M E Gleave
- University of British Columbia, Vancouver, BC, Canada
| | - P S Nelson
- University of Washington, Seattle, WA, USA.,Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - D W Lin
- University of Washington, Seattle, WA, USA.,Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - L D True
- University of Washington, Seattle, WA, USA
| | - Z Feng
- MD Anderson Cancer Center, Houston, TX, USA
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Abstract
Although prostate cancer is the most common malignancy to affect men in the Western world, the molecular mechanisms underlying its development and progression remain poorly understood. Like all cancers, prostate cancer is a genetic disease that is characterized by multiple genomic alterations, including point mutations, microsatellite variations, and chromosomal alterations such as translocations, insertions, duplications, and deletions. In prostate cancer, but not other carcinomas, these chromosome alterations result in a high frequency of gene fusion events. The development and application of novel high-resolution technologies has significantly accelerated the detection of genomic alterations, revealing the complex nature and heterogeneity of the disease. The clinical heterogeneity of prostate cancer can be partly explained by this underlying genetic heterogeneity, which has been observed between patients from different geographical and ethnic populations, different individuals within these populations, different tumour foci within the same patient, and different cells within the same tumour focus. The highly heterogeneous nature of prostate cancer provides a real challenge for clinical disease management and a detailed understanding of the genetic alterations in all cells, including small subpopulations, would be highly advantageous.
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Prognostic relevance of proliferation markers (Ki-67, PHH3) within the cross-relation of ERG translocation and androgen receptor expression in prostate cancer. Pathology 2015; 47:629-36. [DOI: 10.1097/pat.0000000000000320] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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47
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Li JZ, Zhang Y, Wen B, Li M, Wang YJ. Ability of PITX2 methylation to predict survival in patients with prostate cancer. Onco Targets Ther 2015; 8:3507-12. [PMID: 26648742 PMCID: PMC4664542 DOI: 10.2147/ott.s83914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background The aim of this study was to explore whether candidate gene methylation can effectively predict death from prostate cancer. Methods After reviewing the literature to identify likely candidate genes, we assembled a case-control cohort (in a 1:2 ratio) to explore the distribution of PITX2, WNT5a, SPARC, EPB41L3, and TPM4 methylation levels. The case group comprised 45 patients with a Gleason score ≤7 who had died as a result of prostate cancer, and the control group comprised 90 current prostate cancer patients or those who died of other causes. The methylation possibility of each of the candidate genes were maximized. Univariate conditional logistic was applied for data analysis and to evaluate prediction efficiency of gene methylation on prostate cancer. Results The results indicated that a raised level of PITX2 methylation increased the likelihood of death due to prostate cancer by 10% (odds ratio 1.56, 95% confidence interval 1.17–2.08; P=0.005). Methylation of SPARC was found to be able to distinguish between benign prostate hyperplasia and prostate cancer. Conclusion Methylation of PITX2 is an effective biomarker to predict death from prostate cancer, particularly in patients with a low Gleason score.
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Affiliation(s)
- Jiu-Zhi Li
- Department of Urology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China ; Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People's Republic of China
| | - Yu Zhang
- Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People's Republic of China
| | - Bin Wen
- Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People's Republic of China
| | - Ming Li
- Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People's Republic of China
| | - Yu-Jie Wang
- Department of Urology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China
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Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer. Prostate Cancer Prostatic Dis 2015; 19:40-5. [PMID: 26458958 PMCID: PMC4747832 DOI: 10.1038/pcan.2015.46] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 07/31/2015] [Accepted: 08/06/2015] [Indexed: 01/25/2023]
Abstract
BACKGROUND Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.
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Yamoah K, Johnson MH, Choeurng V, Faisal FA, Yousefi K, Haddad Z, Ross AE, Alshalafa M, Den R, Lal P, Feldman M, Dicker AP, Klein EA, Davicioni E, Rebbeck TR, Schaeffer EM. Novel Biomarker Signature That May Predict Aggressive Disease in African American Men With Prostate Cancer. J Clin Oncol 2015; 33:2789-96. [PMID: 26195723 PMCID: PMC4550692 DOI: 10.1200/jco.2014.59.8912] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE We studied the ethnicity-specific expression of prostate cancer (PC) -associated biomarkers to evaluate whether genetic/biologic factors affect ethnic disparities in PC pathogenesis and disease progression. PATIENTS AND METHODS A total of 154 African American (AA) and 243 European American (EA) patients from four medical centers were matched according to the Cancer of the Prostate Risk Assessment postsurgical score within each institution. The distribution of mRNA expression levels of 20 validated biomarkers reported to be associated with PC initiation and progression was compared with ethnicity using false discovery rate, adjusted Wilcoxon-Mann-Whitney, and logistic regression models. A conditional logistic regression model was used to evaluate the interaction between ethnicity and biomarkers for predicting clinicopathologic outcomes. RESULTS Of the 20 biomarkers examined, six showed statistically significant differential expression in AA compared with EA men in one or more statistical models. These include ERG (P < .001), AMACR (P < .001), SPINK1 (P = .001), NKX3-1 (P = .03), GOLM1 (P = .03), and androgen receptor (P = .04). Dysregulation of AMACR (P = .036), ERG (P = .036), FOXP1 (P = .041), and GSTP1 (P = .049) as well as loss-of-function mutations for tumor suppressors NKX3-1 (P = .025) and RB1 (P = .037) predicted risk of pathologic T3 disease in an ethnicity-dependent manner. Dysregulation of GOLM1 (P = .037), SRD5A2 (P = .023), and MKi67 (P = .023) predicted clinical outcomes, including 3-year biochemical recurrence and metastasis at 5 years. A greater proportion of AA men than EA men had triple-negative (ERG-negative/ETS-negative/SPINK1-negative) disease (51% v 35%; P = .002). CONCLUSION We have identified a subset of PC biomarkers that predict the risk of clinicopathologic outcomes in an ethnicity-dependent manner. These biomarkers may explain in part the biologic contribution to ethnic disparity in PC outcomes between EA and AA men.
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Affiliation(s)
- Kosj Yamoah
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH.
| | - Michael H Johnson
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Voleak Choeurng
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Farzana A Faisal
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Kasra Yousefi
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Zaid Haddad
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Ashley E Ross
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Mohammed Alshalafa
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Robert Den
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Priti Lal
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Michael Feldman
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Adam P Dicker
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Eric A Klein
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Elai Davicioni
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Timothy R Rebbeck
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
| | - Edward M Schaeffer
- Kosj Yamoah, Robert Den, and Adam P. Dicker, Thomas Jefferson University Hospital; Priti Lal, Michael Feldman, and Timothy R. Rebbeck, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Kosj Yamoah, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Michael H. Johnson, Farzana A. Faisal, Ashley E. Ross, and Edward M. Schaeffer, Johns Hopkins University, Baltimore, MD; Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Mohammed Alshalafa, and Elai Davicioni, GenomeDx Biosciences, Vancouver, British Columbia, Canada; and Eric A. Klein, The Cleveland Clinic Foundation, Cleveland, OH
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50
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Abstract
Despite extensive efforts to identify a clinically useful diagnostic biomarker in prostate cancer, no new test has been approved by regulatory authorities. As a result, this unmet need has shifted to biomarkers that additionally indicate presence or absence of "significant" disease. EN2 is a homeodomain-containing transcription factor secreted by prostate cancer into the urine and can be detected by enzyme-linked immunoassay. EN2 may be an ideal biomarker because normal prostate tissue and benign prostatic hypertrophic cells do not secrete EN2. This review discusses the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, inexpensive, and reliable prostate cancer biomarker.
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Affiliation(s)
- Sophie E McGrath
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
| | - Agnieszka Michael
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
| | - Richard Morgan
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
| | - Hardev Pandha
- Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom.
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