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Aguiar-Ibáñez R, Mbous YPV, Sharma S, Chawla E. Assessing the clinical, humanistic, and economic impact of early cancer diagnosis: a systematic literature review. Front Oncol 2025; 15:1546447. [PMID: 40177242 PMCID: PMC11962897 DOI: 10.3389/fonc.2025.1546447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/24/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction There is a clear consensus among healthcare providers on the advantages of early cancer detection and treatment. However, no in-depth review has yet fully presented the clinical, humanistic, and economic benefits of early cancer diagnosis compared to late detection across a broad range of tumor types. Methods A systematic literature review was conducted to determine the clinical, humanistic, and economic benefits of early cancer diagnosis, as opposed to late diagnosis, as reported in non-interventional studies conducted worldwide. Searches were conducted using electronic databases (MEDLINE and Embase), conference repositories and grey literature. Observational studies in adults diagnosed with bladder cancer, gastric cancer, head and neck cancer (HNC), melanoma, non-small cell lung cancer (NSCLC), renal-cell carcinoma (RCC), and triple negative breast cancer (TNBC) were eligible for inclusion if they reported survival, health-related quality of life (HRQoL), healthcare resource utilization and/or costs, according to stage at diagnosis. Identified records were screened and extracted by two independent reviewers, and discrepancies were resolved by a third reviewer. The quality of studies was assessed using the Newcastle-Ottawa scale and the Larg and Moss adapted checklist. Results Of the 3,159 records identified, 103 studies were included in this review. The general trend showed worse clinical, humanistic, and economic outcomes when patients were diagnosed at a later stage compared to an earlier stage. Patients diagnosed at an earlier stage, had on average, substantially higher survival rates and lower mortality rates across all cancer types and incurred lower resource utilization and costs (with available evidence for patients with NSCLC, TNBC, and HNC), compared to those diagnosed at a more advanced/later stage. Limited evidence on the humanistic burden suggested that with a more advanced stage at diagnosis, patients with bladder cancer experienced reduced HRQoL. Conclusion Early cancer diagnosis (i.e., cancer diagnosed at earlier stages or with lower grades) was associated with longer survival, improved quality of life and lower healthcare costs and resource utilization compared to diagnosis of cancer at later stages or higher grades, as reported by overall survival (OS) and HRQoL outcomes. These findings emphasize the importance of screening and early detection of cancer to improve outcomes among patients diagnosed with cancer.
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Wei JR, Lu MY, Wei TH, Fleishman JS, Yu H, Chen XL, Kong XT, Sun SL, Li NG, Yang Y, Ni HW. Overcoming cancer therapy resistance: From drug innovation to therapeutics. Drug Resist Updat 2025; 81:101229. [PMID: 40081221 DOI: 10.1016/j.drup.2025.101229] [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: 12/26/2024] [Revised: 02/18/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.
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Affiliation(s)
- Jin-Rui Wei
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China; The First Clinical College of Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Meng-Yi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Tian-Hua Wei
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Joshua S Fleishman
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Hui Yu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiao-Li Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiang-Tu Kong
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Shan-Liang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
| | - Nian-Guang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ye Yang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Hai-Wen Ni
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China.
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Johnson AM, Johnson A, Hines RB, Zhu X. Racial differences in carcinoma-in-situ and non-muscle-invasive bladder cancer mortality: Accounting for insurance status, black segregation, and neighborhood poverty. Cancer Epidemiol 2025; 94:102728. [PMID: 39673918 DOI: 10.1016/j.canep.2024.102728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 09/22/2024] [Accepted: 12/07/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND Few Bladder Cancer (BC) studies have examined the role of area-level variables. The purpose of this study was to examine racial differences in BC survival to elucidate if insurance status and contextual covariates could explain Black disadvantage in survival. METHOD Using the Fine-Gray subdistribution hazard models (sHR), five-year survival time was calculated from the date of diagnosis until the last day of follow-up or the date of death due to BC in Florida 2000-2014 (n = 32,321). Non-BC deaths were considered a competing risk. In all models, individual-level clinical and demographic variables were adjusted for and we included the exposures of interest for Carcinoma-in-Situ (CIS) and Non-Muscle-Invasive BC(NMIBC), separately. RESULTS In CIS-Patients, living in neighborhoods with higher levels of segregation was associated with 50 % to 2-fold increase in sHR (medium level segregation sHR= 1.50, 95 % CI: 1.06-2.13; high level segregation sHR= 2.07, 95 % CI: 1.25-3.43). Uninsured CIS patients had more than 2-fold increased sHR compared to those with private insurance (sHR=2.34, 95 % CI: 1.05-5.24). In NMIBC patients, living in areas with level of poverty resulted in 10 % the hazard of death increased when compared to low poverty (high poverty sHR=1.11, 95 % CI: 1.01-1.21). Uninsured and Medicaid covered NMIBC patients had an increased sHR (uninsured sHR=2.05, 95 % CI: 1.62-2.59; Medicaid sHR=1.36, 95 % CI: 1.11-1.67). For both CIS and NMIBC patients, the Black/White survival gap decreased when insurance and contextual variables were included. CONCLUSION This study identified BC survival rates were different for Black and White patients in Florida and found that those observed gaps were, to some extent, linked to broader social factors. We recommend that future cancer studies examining racial disparities incorporate area-level variables to offer a more nuanced understanding of these complex disparities.
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Affiliation(s)
- Asal M Johnson
- Stetson University, Department of Environmental Sciences and Studies, Public Health Program, United States.
| | - Allen Johnson
- Rollins College, Department of Health Professions, Public Health Program, United States
| | - Robert B Hines
- University of Central Florida College of Medicine, Department of Population Health Sciences, United States
| | - Xiang Zhu
- University of Central Florida College of Medicine, The Burnett School of Biomedical Sciences, United States
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He J, Dong C, Song X, Qiu Z, Zhang H, Jiang Y, Liu T, Man X. Methyltransferase-like 7B participates in bladder cancer via ACSL3 m 6A modification in a ferroptosis manner. Biol Direct 2025; 20:9. [PMID: 39833962 PMCID: PMC11744867 DOI: 10.1186/s13062-025-00597-z] [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: 08/09/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Bladder cancer (BC) is a malignant tumor. Methyltransferase-like 7B (MEETL7B) is a methyltransferase and its role in BC has not yet been revealed. METHOD Stable METTL7B knockdown or overexpression were achieved by lentiviral transduction in SW780 and TCCSUP cell lines. Xenografts tumors were established via subcutaneous injection of stable transfectants in BALB/c mice. RESULTS A database search indicated that METTL7B was elevated in BC and it was validated in BC cell lines. METTL7B silencing suppressed cell proliferation and tumorigenesis in vitro and in vivo. Besides, METTL7B knockdown induced cell cycle arrest in G1 phase with a reduction in cyclin D1(CCND1), CDK4, and CDK6 levels and an elevation in CDKN2D levels in cells. Considering that ferroptosis is emerging as a therapeutic target for cancer, and the possible relationship between METTL7B and antioxidant enzymes. We, here, examined that ectopic METTL7B expression abolished ferroptosis markers in cells raised by Erastin treatment, including the production of lipid ROS, the increased cellular iron and MDA content, the decreased gene expression of ACSL3, FANCD2, and FADS2, as well as the mitochondrial injury observed by electron microscopy. Mechanically, ectopic METTL7B expression promoted m6A modification on ACSL3 mRNA. Gain of functional experiment exhibited that METTL7B inhibited Erastin-induced ferroptosis via ACSL3. Overexpressed PLAGL2 is identified as a possible independent predictor in BC and bioinformatics predicted the potential binding sites between PLAGL2 and METTL7B promoter region. Dual luciferase and chromatin immunoprecipitation analysis provided evidence that PLAGL2 directly binds to METTL7B promoter region. CONCLUSIONS METTL7B is involved in BC development and progression. METTL7B may mediate m6A modification on ACSL3 mRNA to negatively regulate ferroptosis in BC cells, which provides a potential therapeutic target for BC via ferroptosis.
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Affiliation(s)
- Jiani He
- Department of Surgical Oncology and Breast Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
| | - Changming Dong
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
- Institute of Urology, China Medical University, Shenyang, Liaoning, China
| | - Xiandong Song
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
- Institute of Urology, China Medical University, Shenyang, Liaoning, China
- Department of Urology, Shenyang Fifth People Hospital, Shenyang, Liaoning, China
| | - Zhongkai Qiu
- Institute of Urology, Benxi Central Hospital, 29 Shengli Road, Mingshan District, Benxi, Liaoning, China
| | - Hao Zhang
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
- Institute of Urology, China Medical University, Shenyang, Liaoning, China
| | - Yuanjun Jiang
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
- Institute of Urology, China Medical University, Shenyang, Liaoning, China
| | - Tao Liu
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China
- Institute of Urology, China Medical University, Shenyang, Liaoning, China
| | - Xiaojun Man
- Department of Urology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, China.
- Institute of Urology, China Medical University, Shenyang, Liaoning, China.
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Gupta KB, Taylor TL, Panda SS, Thangaraju M, Lokeshwar BL. Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers. Cancers (Basel) 2024; 16:3108. [PMID: 39272966 PMCID: PMC11394085 DOI: 10.3390/cancers16173108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.
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Affiliation(s)
| | - Truett L Taylor
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Siva S Panda
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Augusta University, Augusta, GA 30912, USA
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Bal L Lokeshwar
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
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Chen D, Cao H, Zheng X, Wang H, Han Z, Wang W. Immune checkpoint gene signature assesses immune infiltration profiles in bladder cancer and identifies KRT23 as an immunotherapeutic target. BMC Cancer 2024; 24:1024. [PMID: 39160525 PMCID: PMC11331755 DOI: 10.1186/s12885-024-12790-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND In the past few decades, researchers have made promising progress, including the development of immune checkpoint inhibitors (ICIs) in the therapy of bladder cancer (BLCA). Existing studies mainly focus on single immune checkpoint inhibitors but lack relevant studies on the gene expression profiles of multiple immune checkpoints. METHODS RNA-sequencing profiling data and clinical information of BLCA patients and normal human bladder samples were acquired from the Cancer Genome Atlas and Gene Expression Omnibus databases and analyzed to identify different expression profiles of immune checkpoint genes (ICGs) after consensus clustering analysis. Based on the 526 intersecting differentially expressed genes, the LASSO Cox regression analysis was utilized to construct the ICG signature. RESULTS According to the expression of ICGs, BLCA patients were divided into three subtypes with different phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature were independent predictors of outcome in BLCA patients, and was correlated with the immune infiltration, the expression of ICGs and chemotherapeutic effect. CONCLUSIONS This study systematically and comprehensively analyzed the expression profile of immune checkpoint genes, and established the ICG signature to investigate the differences in ICGs expression and tumor immune microenvironment, which will help risk stratification and accelerate precision medicine. Finally, we identified KRT23 as the most critical model gene, and highlighted KRT23 as a potential target to enhance immunotherapy against BLCA.
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Affiliation(s)
- Dongshan Chen
- Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China
- Department of Urology, Qilu Hospital of Shandong University, Wenhuaxi Road #107, Jinan, 250012, China
| | - Haoyuan Cao
- Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China
| | - Xiang Zheng
- Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China
| | - Haojun Wang
- Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China
| | - Zengchi Han
- Department of Urology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, NO.1 Jingba Road, Shizhong District, Jinan, 250001, China.
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China.
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Gao M, Guo H, Xu H, Jin X, Liu Y, Chen Z, Wang X. Analysis of cell death-related genes to evaluate the prognostic and immunotherapeutic value in bladder cancer. Heliyon 2024; 10:e33200. [PMID: 39005901 PMCID: PMC11239709 DOI: 10.1016/j.heliyon.2024.e33200] [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: 01/08/2024] [Revised: 06/11/2024] [Accepted: 06/17/2024] [Indexed: 07/16/2024] Open
Abstract
To enhance therapeutic approaches, we created a distinctive pattern utilizing the cell demise indicator (CDI) to predict the effectiveness of immunotherapy in individuals with bladder carcinoma (BLCA). Hub prognostic CDIs were identified from the TCGA database using differential gene expression and survival analysis, encompassing 763 genes across 13 death modes. The subtype assessment was employed to evaluate the impact of these genes on the prognosis and immunotherapeutic outcomes in patients with BLCA. The LASSO regression method was used to identify significant CDIs, while Cox regression and nomogram analyses were conducted to explore the impact of CDIs on prognosis. CHMP4C and GSDMB were selected as the hub genes for the following research. Subsequently, These two central genes underwent further investigation to explore their association with immunotherapy, followed by an analysis of their potential regulatory network. Subtype analysis showed that these CDIs were significantly associated with the prognosis and immunotherapy of BLCA patients. The regulatory network in BLCA was evaluated through the establishment of the lncRNA XIST/NEAT1-CDIs-miR-146a-5p/miR-429 axis. Immunohistochemical analysis revealed a significant up-regulation of CHMP4C in bladder cancer tissues, which was strongly associated with an unfavorable prognosis for BLCA patients. Moreover, our findings provide compelling evidence that CHMP4C plays a pivotal role in promoting BLCA progression through the activation of the epithelial-mesenchymal transition (EMT) pathway. These findings highlight the negative impact of CHMP4C on BLCA patient prognosis, while also providing insights into the oncogenic mechanisms and immunotherapy in which CHMP4C may be involved.
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Affiliation(s)
- Mingde Gao
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Haifeng Guo
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Haifei Xu
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Xiaoxia Jin
- Department of Pathology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Yushan Liu
- Department of Pathology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Zhigang Chen
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
| | - Xiaolin Wang
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, Nantong 226300, China
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Kurabayashi A, Fukuhara H, Furihata K, Iwashita W, Furihata M, Inoue K. Photodynamic Diagnosis and Therapy in Non-Muscle-Invasive Bladder Cancer. Cancers (Basel) 2024; 16:2299. [PMID: 39001362 PMCID: PMC11240600 DOI: 10.3390/cancers16132299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/17/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
Bladder cancer (BC) possesses distinct molecular profiles that influence progression depending on its biological nature and delivered treatment intensity. Muscle-invasive BC (MIBC) and non-MIBC (NMIBC) demonstrate great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. Transurethral resection of bladder tumor (TURBT) is the standard of care in treating NMIBC and serves both diagnostic and therapeutic purposes despite the prevalent recurrence and progression among many patients. In particular, flat urothelial carcinoma in situ and urothelial carcinoma with lamina propria invasion are the major precursors of MIBC. A new-generation photosensitizer, 5-Aminolevulinic acid (5-ALA), demonstrates high tumor specificity by illuminating the tumor lesion with a specific wavelength of light to produce fluorescence and has been studied for photodynamic diagnosis to detect precise tumor areas by TURBT. Additionally, it has been applied for treatment by producing its cytotoxic reactive oxygen species, as well as screening for urological carcinomas by excreting porphyrin in the blood and urine. Moreover, 5-ALA may contribute to screening before and after TURBT in NMIBC. Here, we summarize the updated evidence and ongoing research on photodynamic technology for NMIBC, providing insight into the potential for improving patient outcomes.
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Affiliation(s)
- Atsushi Kurabayashi
- Department of Pathology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
| | - Hideo Fukuhara
- Department of Urology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
| | - Kaoru Furihata
- Department of Pathology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
| | - Waka Iwashita
- Department of Pathology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
| | - Mutsuo Furihata
- Department of Pathology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
| | - Keiji Inoue
- Department of Urology, Kochi Medical School, Nankoku 783-8505, Kochi, Japan
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Chen Y, Huang M, Lu J, Zhang Q, Wu J, Peng S, Chen S, Zhang Y, Cheng L, Lin T, Chen X, Huang J. Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer. ENVIRONMENTAL TOXICOLOGY 2024; 39:509-528. [PMID: 37310098 DOI: 10.1002/tox.23860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/17/2023] [Accepted: 05/28/2023] [Indexed: 06/14/2023]
Abstract
Cisplatin-based chemotherapy is considered the primary treatment option for patients with advanced bladder cancer (BCa). However, the objective response rate to chemotherapy is often unsatisfactory, leading to a poor 5-year survival rate. Furthermore, current strategies for evaluating chemotherapy response and prognosis are limited and inefficient. In this study, we aimed to address these challenges by establishing a chemotherapy response type gene (CRTG) signature consisting of 9 genes and verified the prognostic value of this signature using TCGA and GEO BCa cohorts. The risk scores based on the CRTG signature were found to be associated with advanced clinicopathological status and demonstrated favorable predictive power for chemotherapy response in the TCGA cohort. Meanwhile, tumors with high risk scores exhibited a tendency toward a "cold tumor" phenotype. These tumors showed a low abundance of T cells, CD8+ T cells and cytotoxic lymphocytes, along with a high abundance of cancer-associated fibroblasts. Moreover, they displayed higher mRNA levels of these immune checkpoints: CD200, CD276, CD44, NRP1, PDCD1LG2 (PD-L2), and TNFSF9. Furthermore, we developed a nomogram that integrated the CRTG signature with clinicopathologic risk factors. This nomogram proved to be a more effective tool for predicting the prognosis of BCa patients. Additionally, we identified Rac family small GTPase 3 (RAC3) as a biomarker in our model. RAC3 was found to be overexpressed in chemoresistant BCa tissues and enhance the chemotherapeutic resistance of BCa cells in vitro and in vivo by regulating the PAK1-ERK1/2 pathway. In conclusion, our study presents a novel CRTG model for predicting chemotherapy response and prognosis in BCa. We also highlight the potential of combining chemotherapy with immunotherapy as a promising strategy for chemoresistant BCa and that RAC3 might be a latent target for therapeutic intervention.
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Affiliation(s)
- Yuelong Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, PR China
| | - Ming Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Junlin Lu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Qiang Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Jilin Wu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Shengmeng Peng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Siting Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Yangjie Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Liang Cheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, PR China
| | - Xu Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, PR China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, PR China
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10
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Liu X, Qiu Z, Zhang X, Su Z, Yi R, Zou D, Xie C, Jin N, Long W, Liu X. Generalized machine learning based on multi-omics data to profile the effect of ferroptosis pathway on prognosis and immunotherapy response in patients with bladder cancer. ENVIRONMENTAL TOXICOLOGY 2024; 39:680-694. [PMID: 37647346 DOI: 10.1002/tox.23949] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/26/2023] [Accepted: 08/13/2023] [Indexed: 09/01/2023]
Abstract
INTRODUCTION Bladder cancer (BLCA) affects millions of people worldwide, with high rates of incidence and mortality. Ferroptosis proves to be a novel form of cell death process that is triggered by oxidative stress. METHODS We procured a total of 25 single nuclear RNA-seq (snRNA-seq) samples from GSE169379 in GEO database. We obtained different cohorts of BLCA patients from the TCGA and GEO databases for model training and validation. A total of 369 ferroptosis-related genes (FRGs) were selected from the FerrDb database. AUCell analysis was performed to assign ferroptosis scores to all the cell types. Weighted Gene Co-Expression Network Analysis (WGCNA), COX, and LASSO regression analysis were conducted to retain and finalize the genes of prognostic values. Various bioinformatic approaches were utilized to depict immune infiltration profile. We conducted a series of colony formation analysis, flow cytometry and western blot (WB) analysis to determine the role of SKAP1 in BLCA. RESULTS We divided the cells into high ferroptosis group and low ferroptosis group according to ferroptosis activity score, and then screened 2150 genes most associated with ferroptosis by differential expression analysis, which are related to UV-induced DNA damage, male hormone response, fatty acid metabolism and hypoxia. Subsequently, WGCNA algorithm further screened 741 ferroptosis related genes from the 2150 genes for the construction of prognostic model. Lasso-Cox regression analysis was used to construct the prognostic model, and the prognostic model consisting of 6 genes was obtained, namely JUN, SYT1, MAP3K8, GALNT14, TCIRG1, and SKAP1. Next, we constructed a nomogram model that integrated clinical factors to improving the accuracy. In addition, we performed drug sensitivity analyses in different subgroups and found that Staurosporine, Rapamycin, Gemcitabine, and BI-2536 may be candidates for the drugs treatment in high-risk populations. The ESTIMATE results showed higher stromal scores, immune scores, and ESTIMATE scores in the low-risk group, indicating a higher overall immunity level and immunogenicity of tumor microenvironment (TME) in this group, and tumor immune dysfunction and exclusion (TIDE) analysis confirmed a better response to immunotherapy in the low-risk group. Finally, we selected the oncogene SKAP1 in the prognostic gene for in vitro validation, and found that SKAP1 directly regulated BLCA cell proliferation and apoptosis. CONCLUSION We identified a set of six genes, JUN, SYT1, MAP3K8, GALNT14, TCIRG1, and SKAP1, that exhibited significant potential in stratification of BLCA patients with varying prognosis. In addition, we uncovered the direct regulatory effect of SKAP1 on BLCA cell proliferation and apoptosis, shedding some light on the role of FRGs in pathogenesis of BLCA.
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Affiliation(s)
- Xinyu Liu
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Ziran Qiu
- Department of Surgical Oncology, Loudi City Central Hospital, Loudi, China
| | - Xiongfeng Zhang
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Zhouhua Su
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Renzheng Yi
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Debo Zou
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Chaoqun Xie
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Na Jin
- Department of Surgical Oncology, Loudi City Central Hospital, Loudi, China
| | - Weibing Long
- Department of Urology, Loudi City Central Hospital, Loudi, China
| | - Xiaobing Liu
- Department of Urology, Loudi City Central Hospital, Loudi, China
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11
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Öztürk H, Karapolat İ. Evaluation of response to gemcitabine plus cisplatin-based chemotherapy using positron emission computed tomography for metastatic bladder cancer. World J Clin Cases 2023; 11:8447-8457. [PMID: 38188218 PMCID: PMC10768499 DOI: 10.12998/wjcc.v11.i36.8447] [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: 09/22/2023] [Revised: 11/10/2023] [Accepted: 12/06/2023] [Indexed: 12/22/2023] Open
Abstract
BACKGROUND The purpose of the present study was to examine retrospectively the contribution of 18Fluorodeoxyglucose positron emission tomography computed tomography (18FDG-PET/CT) to the evaluation of response to first-line gemcitabine plus cisplatin-based chemotherapy in patients with metastatic bladder cancer. AIM To evaluate the response to Gemcitabine plus Cisplatin -based chemotherapy using 18FDG-PET/CT imaging in patients with metastatic bladder cancer. METHODS Between July 2007 and April 2019, 79 patients underwent 18FDG-PET/CT imaging with the diagnosis of Metastatic Bladder Carcinoma (M-BCa). A total of 42 patients (38 male, 4 female) were included in the study, and all had been administered Gemcitabine plus Cisplatin-based chemotherapy. After completion of the therapy, the patients underwent a repeat 18FDG-PET/CT scan and the results were compared with the PET/CT findings before chemotherapy according to European Organisation for the Research and treatment of cancer criteria. Mean age was 66.1 years and standard deviation was 10.7 years (range: 41-84 years). RESULTS Of the patients, seven (16.6%) were in complete remission, 17 (40.5%) were in partial remission, six (14.3%) had a stable disease, and 12 (28.6%) had a progressive disease. The overall response rate was 57.1 percent. CONCLUSION 18FDG-PET/CT can be considered as a successful imaging tool in evaluating response to first-line chemotherapy for metastatic bladder cancer. Anatomical and functional data obtained from PET/CT scans may be useful in the planning of secondline and thirdline chemotherapy.
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Affiliation(s)
- Hakan Öztürk
- Department of Urology, Izmir University of Economics, Karsiyaka Izmir 35330, Turkey
| | - İnanç Karapolat
- Department of Nuclear Medicine, School of Medicine, İzmir Tınaztepe University, Izmir 35000, Turkey
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12
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Chen J, Tang Y, Liu H, Sun G, Liu H, Zhao J, Wang Z, Zhang Y, Lou F, Cao S, Qin J, Wang H, Liao B, Zeng H. The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response. Cancer Med 2023; 12:22370-22380. [PMID: 37986697 PMCID: PMC10757100 DOI: 10.1002/cam4.6725] [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: 08/22/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND The mutational pattern of homologous recombination repair (HRR)-associated gene alterations in Chinese urothelial carcinoma (UC) necessitates comprehensive sequencing efforts, and the clinical implications of HRR gene mutations in UC remain to be elucidated. MATERIALS AND METHODS We delineated the mutational landscape of 343 Chinese UC patients from West China Hospital and 822 patients from The Cancer Genome Atlas (TCGA) using next-generation sequencing (NGS). Data from 182 metastatic UC patients from MSK-IMPACT cohort were used to assess the association between HRR mutations and immunotherapy efficacy. Comprehensive transcriptomic analysis was performed to explore the impact of HRR mutations on tumor immune microenvironment. RESULTS Among Chinese UC patients, 34% harbored HRR gene mutations, with BRCA2, ATM, BRCA1, CDK12, and RAD51C being the most prevalently mutated genes. Mutational signatures contributing to UC differed between patients with and without HRR mutations. Signature 22 for exposure to aristolochic acid was only observed in Chinese UC patients. The presence of HRR mutations was correlated with higher tumor mutational burden, neoantigen burden, and PD-L1 expression. Importantly, patients with HRR mutations exhibited significantly improved prognosis following immunotherapy compared to those without HRR mutations. CONCLUSIONS Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.
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Affiliation(s)
- Junru Chen
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yanfeng Tang
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | | | - Guangxi Sun
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Haoyang Liu
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Junjie Zhao
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Zilin Wang
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | | | - Feng Lou
- Acornmed Biotechnology Co., Ltd.BeijingChina
| | - Shanbo Cao
- Acornmed Biotechnology Co., Ltd.BeijingChina
| | - Jiayue Qin
- Acornmed Biotechnology Co., Ltd.TianjinChina
| | - Huina Wang
- Acornmed Biotechnology Co., Ltd.BeijingChina
| | - Banghua Liao
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Hao Zeng
- Department of Urology, Institute of Urology, West China HospitalSichuan UniversityChengduSichuanChina
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13
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Islam F, Nath N, Zehravi M, Khan J, Jashim SBT, Charde MS, Chakole RD, Kumar KP, Babu AK, Nainu F, Khan SL, Rab SO, Emran TB, Wilairatana P. Exploring the role of natural bioactive molecules in genitourinary cancers: how far has research progressed? NATURAL PRODUCTS AND BIOPROSPECTING 2023; 13:39. [PMID: 37843642 PMCID: PMC10579213 DOI: 10.1007/s13659-023-00400-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/17/2023] [Indexed: 10/17/2023]
Abstract
The primary approaches to treat cancerous diseases include drug treatment, surgical procedures, biotherapy, and radiation therapy. Chemotherapy has been the primary treatment for cancer for a long time, but its main drawback is that it kills cancerous cells along with healthy ones, leading to deadly adverse health effects. However, genitourinary cancer has become a concern in recent years as it is more common in middle-aged people. So, researchers are trying to find possible therapeutic options from natural small molecules due to the many drawbacks associated with chemotherapy and other radiation-based therapies. Plenty of research was conducted regarding genitourinary cancer to determine the promising role of natural small molecules. So, this review focused on natural small molecules along with their potential therapeutic targets in the case of genitourinary cancers such as prostate cancer, renal cancer, bladder cancer, testicular cancer, and so on. Also, this review states some ongoing or completed clinical evidence in this regard.
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Affiliation(s)
- Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Nikhil Nath
- Department of Pharmacy, International Islamic University Chittagong, Kumira, Chittagong, 4318, Bangladesh
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah, 51418, Kingdom of Saudi Arabia.
| | - Jishan Khan
- Department of Pharmacy, International Islamic University Chittagong, Kumira, Chittagong, 4318, Bangladesh
| | - Sumiya Ben-Ta Jashim
- Department of Pharmacy, International Islamic University Chittagong, Kumira, Chittagong, 4318, Bangladesh
| | - Manoj Shrawan Charde
- Government College of Pharmacy, Vidyanagar, Karad, Satara, 415124, Maharashtra, India
| | - Rita Dadarao Chakole
- Government College of Pharmacy, Vidyanagar, Karad, Satara, 415124, Maharashtra, India
| | - K Praveen Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Govt. of NCT of Delhi, Delhi Pharmaceutical Sciences and Research University (DPSRU), Mehrauli-Badarpur Road, PushpVihar, Sector 3, New Delhi, 110017, India
| | - A Kishore Babu
- Ratnadeep College of Pharmacy, Ratnapur, Jamkhed, Ahmednagar, 413206, Maharashtra, India
| | - Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, 90245, Indonesia
| | - Sharuk L Khan
- Department of Pharmaceutical Chemistry, N.B.S. Institute of Pharmacy, Ausa, 413520, Maharashtra, India
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh.
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI, 02912, USA.
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.
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14
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Wang L, Song R, Ma M, Chen Y, Jiang Y, Li J, Yang Z, Zhang L, Jing M, Wang X, Zhang M, Fan J. Inhibition of autophagy can promote the apoptosis of bladder cancer cells induced by SC66 through the endoplasmic reticulum stress pathway. Chem Biol Interact 2023; 384:110725. [PMID: 37741534 DOI: 10.1016/j.cbi.2023.110725] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 08/18/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
Bladder cancer is among the ten most prevalent cancer types worldwide, and its prognosis has not improved significantly in the past three decades because of cognitive limitations in the molecular mechanisms that drive the malignant progression of bladder cancer. Therefore, there is an urgent need to identify new therapeutic drugs or molecular targets to improve the prognosis of patients with bladder cancer. SC66, a novel allosteric inhibitor of AKT, has recently been reported to exert potent anticancer effects on various cancer cells. However, the mechanisms underlying its anticancer effects in bladder cancer remain largely unknown. Consequently, this study aimed to conduct a series of molecular and cellular biology experiments to verify the anticancer effect and potential mechanism of action of SC66 in bladder cancer in vitro. A xenograft tumor model was established to confirm its anticancer role in vivo. Our results showed that SC66 inhibited cell proliferation, triggered mitochondria-mediated apoptosis, and initiated autophagy in bladder cancer cells dose-dependently. In addition, our results suggested that SC66-caused apoptosis and autophagy were endoplasmic reticulum stress-dependent. Interestingly, the activation of autophagy can partially protect bladder cancer cells from apoptosis under endoplasmic reticulum stress induced by SC66 treatment. This study shows that SC66 exerts its anticancer impact on bladder cancer by inhibiting cell proliferation and inducing apoptosis. It also reveals that inhibiting autophagy can increase the cytotoxic effects of SC66 in bladder cancer. Overall, this is the first study on the anticancer effect of SC66 mediated by the endoplasmic reticulum stress pathway and the first report on the AKT-independent anticancer mechanism of SC66 in bladder cancer. Conclusively, exploring the relationship between apoptosis, autophagy, and endoplasmic reticulum stress induced by SC66 indicates that SC66 is a promising novel agent for patients with bladder cancer.
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Affiliation(s)
- Lu Wang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rundong Song
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Minghai Ma
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuhang Chen
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yunzhong Jiang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianpeng Li
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zezhong Yang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lu Zhang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Minxuan Jing
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinyang Wang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengzhao Zhang
- Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Jinhai Fan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
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15
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Ma S, Sa L, Zhang J, Jiang K, Mi B, Shan L. KDELR2 as a diagnostic and prognostic biomarker of bladder urothelial carcinoma and its correlation with immune infiltration. Genet Mol Biol 2023; 46:e20230002. [PMID: 37791813 PMCID: PMC10548500 DOI: 10.1590/1678-4685-gmb-2023-0002] [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: 01/02/2023] [Accepted: 07/21/2023] [Indexed: 10/05/2023] Open
Abstract
KDELR2 has been reported as a promotive factor for the genesis and progression of several malignancies. However, it is uncertain how it affects bladder urothelial carcinoma (BLCA). Using data extracted from online databases, an enhanced expression of KDELR2 in BLCA tissues was verified. Overexpression of KDELR2 was correlated with advanced clinicopathologic characteristics and unfavourable prognosis of BLCA. Receiver operating characteristic analysis highlighted the potential diagnostic value of KDELR2. Univariate and multivariate logistic regression analyses further revealed the predictive effect of KDELR2 for the prognosis of BLCA. KDELR2 was primarily enriched in biological functions related to organization of the extracellular matrix. TIMER, ssGSEA and GEPIA analyses suggested that KDELR2 expression is positively related to the infiltration of macrophages, Th2 cells and neutrophils. Finally, knocking-down of KDELR2 in T24 cells resulted in reduced proliferation, migration and macrophages recruitment. These results suggest that KDELR2 overexpression is an indicator for poor prognosis of BLCA and it has the potential to be employed as an immunotherapy target for BLCA.
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Affiliation(s)
- Sai Ma
- Air Force Medical University, School of Stomatology, National Clinical Research Centre for Oral Disease, State Key Laboratory of Military Stomatology, Department of Prosthodontics, Shaanxi Key Laboratory of Stomatology, Xi'an, Shaanxi, China
| | - Longqi Sa
- Xi'an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi'an, Shaanxi, China
| | - Jitao Zhang
- Xi'an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi'an, Shaanxi, China
| | - Kuo Jiang
- Xi'an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi'an, Shaanxi, China
| | - Baoguo Mi
- Xi'an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi'an, Shaanxi, China
| | - Lequn Shan
- Xi'an Jiaotong University, Honghui Hospital, Department of Spine Surgery, Xi'an, Shaanxi, China
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16
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Cheng Y, Yu H, Li K, Lv J, Zhuang J, Bai K, Wu Q, Yang X, Yang H, Lu Q. Hsa_circ_0003098 promotes bladder cancer progression via miR-377-5p/ACAT2 axis. Genomics 2023; 115:110692. [PMID: 37532090 DOI: 10.1016/j.ygeno.2023.110692] [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: 01/26/2023] [Revised: 07/20/2023] [Accepted: 07/30/2023] [Indexed: 08/04/2023]
Abstract
Accumulating evidence has proven that circRNAs play vital roles in tumor progression. Nevertheless, the mechanisms underlying circRNAs in bladder cancer (BCa) remain largely unknown. The purpose of this study was to identify the role and investigate the potential molecular mechanisms of hsa_circ_0003098 in BCa. We confirmed that hsa_circ_0003098 expression was significantly upregulated in BCa tissues, of which expression was remarkably associated with poor prognosis. Functionally, overexpression of hsa_circ_0003098 promoted BCa cell proliferation, migration, and invasion in vitro as well as tumor growth in vivo. Mechanistically, hsa_circ_0003098 promoted upregulation of ACAT2 expression and induced cholesteryl ester accumulation via acting as a sponge for miR-377-5p. Thus, hsa_circ_0003098 plays an oncogenic role in BCa and may serve as a potential biomarker and therapeutic target for BCa.
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Affiliation(s)
- Yidong Cheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China; Department of Urology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 21000, Jiangsu Province, PR China
| | - Hao Yu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Kai Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Jiancheng Lv
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Juntao Zhuang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Kexin Bai
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Qikai Wu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China
| | - Xiao Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China.
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China.
| | - Qiang Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 21000, Jiangsu Province, PR China.
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17
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Wasfie T, Atherton JM, Villegas SJ, Korbitz H, Henke A. Small bowel obstruction secondary to metastatic urothelial bladder cancer. SAGE Open Med Case Rep 2023; 11:2050313X231176356. [PMID: 37483266 PMCID: PMC10357062 DOI: 10.1177/2050313x231176356] [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: 01/03/2023] [Accepted: 05/02/2023] [Indexed: 07/25/2023] Open
Abstract
Small bowel obstruction secondary to primary cancer, such as carcinoid and adenocarcinoma, is not unusual. Less frequently, hematological metastasis from breast, lung, and melanoma can occur. However, metastasis from urothelial bladder carcinoma is extremely rare. In this index case, we describe a 71-year-old Caucasian man with a prior history of urothelial bladder carcinoma. He was treated successfully with chemoradiation and local resection a year prior to his current presentation with small bowel obstruction which required surgical resection of a loop of jejunum, which was found to be caused by obstructive, metastatic urothelial bladder carcinoma on pathology. Therefore, one should consider the possibility of secondary obstructive malignant lesions arising from the urinary bladder in such a patient when presented with bowel obstruction and a history of urothelial bladder carcinoma.
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Affiliation(s)
- Tarik Wasfie
- Department of Surgery, Ascension Genesys Hospital, Grand Blanc, MI, USA
| | - Joshua M Atherton
- Central Michigan University School of Medicine, Mount Pleasant, MI, USA
| | - Sergio J Villegas
- Department of Emergency Medicine, Ascension Genesys Hospital, Grand Blanc, MI, USA
| | - Holland Korbitz
- Department of Surgery, Ascension Genesys Hospital, Grand Blanc, MI, USA
| | - Andrew Henke
- Department of Pathology, Ascension Genesys Hospital, Grand Blanc, MI, USA
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18
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Jin Y, Huang S, Wang Z. Identify and validate RUNX2 and LAMA2 as novel prognostic signatures and correlate with immune infiltrates in bladder cancer. Front Oncol 2023; 13:1191398. [PMID: 37519798 PMCID: PMC10373733 DOI: 10.3389/fonc.2023.1191398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
Background Muscle-invasive bladder cancer (MIBC) develops lymph node (LN) metastasis or distant metastasis, leading to recurrence and poor prognosis. The five-year survival rate of MIBC with LN or distant metastasis is only 8.1%; therefore, there is an urgent need to identify reliable biomarkers for prognosis and treatment regimen for patients with bladder cancer (BLCA). Methods SEER database was used to select important clinical characteristics for MIBC. Then, weighted gene co-expression network analysis (WGCNA) was employed to identify differentially expressed genes (DEGs) to recognize significant co-expression modules by calculating the correlation between the modules and clinical data. Furthermore, Cox regression and lasso analysis were applied to screen prognostic hub genes and establish the risk predictive model. Bladder cancer cell lines (UMUC3 and 5637) were used for experimental validation in vitro. Results Cox analysis of 122,600 MIBC patients showed that the N stage was the most important clinical factor. A total of 4,597 DEGs were calculated between N0 and N+ patients, and WGCNA with these DEGs in 368 samples revealed that expression of turquoise was positively and strongly correlated with the N stage. Eight genes were identified as important prognostic candidates using lasso regression based on Cox analysis and STRING database. Combining GEO datasets, literature, and clinical factors, we identified LAMA2 and RUNX2 as novel prognostic biomarkers. CCK8 assay showed that depletion of LAMA2 or RUNX2 significantly inhibited the proliferation of BLCA cells, and flow cytometry indicated that knockdown of LAMA2 or RUNX2 induced the apoptosis of BLCA cells. Transwell assay also showed that silencing of LAMA2 or RUNX2 weakened the migration and invasiveness of BLCA cells. Conclusions We constructed a new eight-gene risk model to provide novel prognostic biomarkers and therapeutic targets for BLCA.
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Affiliation(s)
- Yi Jin
- Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Siwei Huang
- School of Humanities and Management, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhanwang Wang
- Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China
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Miller DT, Sun Z, Grajales V, Pekala KR, Eom KY, Yabes J, Davies BJ, Sabik LM, Jacobs BL. Insurance Type and Area Deprivation Are Associated With Worse Overall Mortality for Patients With Muscle-invasive Bladder Cancer. Urology 2023; 177:81-88. [PMID: 37028521 PMCID: PMC11225579 DOI: 10.1016/j.urology.2023.02.045] [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: 05/09/2022] [Revised: 01/28/2023] [Accepted: 02/02/2023] [Indexed: 04/08/2023]
Abstract
OBJECTIVE To examine the association of area-level socioeconomic status, rural-urban residence, and type of insurance with overall and cancer-specific mortality among patients with muscle-invasive bladder cancer. METHODS Using the Pennsylvania Cancer Registry, which collects demographic, insurance, and clinical information on every patient with cancer within the state, we identified all patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2016 based on clinical and pathologic staging. We used the Area Deprivation Index (ADI) as a surrogate for socioeconomic status and Rural-Urban Commuting Area codes to classify urban, large town, and rural communities. ADI was reported in quartiles, with 4 representing the lowest socioeconomic status. We fit multivariable logistic regression and Cox models to assess the relationship of these social determinants with overall and cancer-specific survival adjusting for age, sex, race, stage, treatment, rural-urban classification, insurance and ADI. RESULTS We identified 2597 patients with non-metastatic muscle-invasive bladder cancer. On multivariable analysis, Medicare (hazards ratio [HR] 1.15), Medicaid (HR 1.38), ADI 3 (HR 1.16) and ADI 4 (HR 1.21) were independent predictors of greater overall mortality (all P < 0.05). Female sex and receipt of non-standard treatment were associated with increased overall mortality and bladder cancer-specific mortality. There was no significant difference in both overall and cancer-specific survival between patients who were non-Hispanic White compared to non-White or between those from urban areas, large towns, or rural locations. CONCLUSION Lower socioeconomic status and Medicare and Medicaid insurance were associated with a greater risk of overall mortality while rural residence was not a significant factor. Implementation of public health programs may help reduce the gap in mortality for low SES at-risk populations.
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Affiliation(s)
- David T Miller
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
| | - Zhaojun Sun
- Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Valentina Grajales
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Kelly R Pekala
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Kirsten Y Eom
- Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Jonathan Yabes
- Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Benjamin J Davies
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Lindsay M Sabik
- Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Bruce L Jacobs
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Aljabery F, Shabo I, Saudi A, Holmbom M, Olson H, Jahnson S. The emerging role of cell cycle protein p53 expression by tumor cells and M2-macrophage infiltration in urinary bladder cancer. Urol Oncol 2023; 41:148.e9-148.e16. [PMID: 36702703 DOI: 10.1016/j.urolonc.2022.12.005] [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: 09/07/2022] [Revised: 12/04/2022] [Accepted: 12/12/2022] [Indexed: 01/26/2023]
Abstract
PURPOSE To investigate the association between p53 expression in tumor cells and intratumoral macrophage infiltration in muscle-invasive urinary bladder cancer (MIBC) in relation to clinical and pathological variables and outcomes after radical cystectomy. METHODS Tumor specimens of the primary tumor from patients treated with radical cystectomy for MIBC were immunostained with the M2-macrophage-specific marker CD163 and the cell cycle protein p53. The expression of these markers was analyzed in relation to patients´ and tumor characteristics and outcome. RESULTS Out of 100 patients with urinary bladder cancer (UBC) pathological stage T1-4 N0-3 M0, 77% were men. The patients had a median age of 69 years and 80% had nonorgan-confined tumors (pT3-4). Lymph node metastasis was found in 42 (42%) of all patients. P53-positive expressions were found in 63 (63%) patients. Strong macrophage infiltration in the tumor microenvironment was shown in 74 (74%) patients. Combinations of CD163/p53 status were as follows: CD163+/p53+, 50%; CD163+/p53-, 24%; CD163-/p53+, 13%; and CD163-/p53-, 13%. Patients with CD163+/P53+ had higher proportions of organ-confined tumors. CONCLUSIONS In the present series of patients with MIBC treated with cystectomy, we found that high CD163+ macrophage infiltration in the tumor micro-environment often was combined with p53+ cancer cells. This simultaneous expression of p53 by tumor cells and increased infiltration of M2-macrophages in the tumor microenvironment was associated with improved CSS, which might indicate a possible protective effect of M2 macrophages in p53+ tumors. Further investigations are needed to explore the biological relation between mutational burden and immune profile in MIBC.
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Affiliation(s)
- Firas Aljabery
- Department of Urology, and Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden.
| | - Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden; Department of Breast, Endocrine and Sarcoma Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Aus Saudi
- Department of Urology, and Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden
| | - Martin Holmbom
- Department of Urology, and Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden
| | - Hans Olson
- Department of Pathology and Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden
| | - Staffan Jahnson
- Department of Urology, and Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden
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Weinberg L, Aitken SAA, Kaldas P, Fletcher L, Lloyd-Donald P, Le P, Do D, Caruana CB, Walpole D, Ischia J, Ma R, Tan CO, Lee DK. Postoperative complications and hospital costs following open radical cystectomy: A retrospective study. PLoS One 2023; 18:e0282324. [PMID: 36827411 PMCID: PMC9956632 DOI: 10.1371/journal.pone.0282324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 02/26/2023] Open
Abstract
OBJECTIVES To evaluate primarily the relationship between postoperative complications and hospital costs, and secondarily the relationship between postoperative complications and mortality, following radical cystectomy. METHODS Postoperative complications were retrospectively examined for 147 patients undergoing radical cystectomy at a university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo classification system. In-hospital cost was calculated using an activity-based costing methodology. Regression modelling was used to investigate the relationships among a priori selected perioperative variables, complications, and costs. The effect of complications on postoperative mortality was ascertained using time-dependent coefficients in a Cox proportional hazards regression model. RESULTS 135 (92%) patients experienced one or more postoperative complications. The medians of hospital cost for patients who experienced no complications and those who experienced complications were $42,796.3 (29,222.9-53,532.5) and $81,050.1 (49,614.8-122,533.6) respectively, p < 0.001. Hospital costs were strongly associated with complication severity: Clavien-Dindo grade II complications increased costs by 45.2% (p < 0.001, 95% CI 19.1%-76.6%), and Clavien-Dindo grade III to V complications increased costs by 107.5% (p < 0.001, 95% CI 52.4%-181.8%). Each additional count of complication and increase in Clavien-Dindo complication grade increased the risk of mortality 1.28-fold (RR = 1.28, p = 0.006, 95% CI 1.08-1.53) and 2.50-fold (RR = 2.50, p = 0.012 95% CI 1.23-5.07) respectively. CONCLUSIONS These findings demonstrate a high prevalence of complications following cystectomy and significant associated increases in hospital costs and mortality. Postoperative complications are a key target for cost-containment strategies. TRIAL REGISTRATION Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN:12622000057785.
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Affiliation(s)
- Laurence Weinberg
- Department of Anesthesia, Austin Health, Heidelberg, Australia
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Australia
- Department of Critical Care, The University of Melbourne, Austin Health, Heidelberg, Australia
- * E-mail:
| | | | - Peter Kaldas
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Australia
| | - Luke Fletcher
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Australia
- Data Analytics Research and Evaluation (DARE) Centre, Austin Health, Heidelberg, Australia
| | | | - Peter Le
- Department of Anesthesia, Austin Health, Heidelberg, Australia
| | - Daniel Do
- Department of Anesthesia, Austin Health, Heidelberg, Australia
| | | | - Dominic Walpole
- Department of Anesthesia, Austin Health, Heidelberg, Australia
| | - Joseph Ischia
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Australia
| | - Ronald Ma
- Business Intelligence Unit, Austin Health, Heidelberg, Australia
| | - Chong Oon Tan
- Department of Anesthesia, Austin Health, Heidelberg, Australia
| | - Dong-Kyu Lee
- Department of Anesthesiology and Pain Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
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Singhal S, Marwell JG, Khaki AR. Geriatric assessment in the older adult with genitourinary cancer: A narrative review. Front Oncol 2023; 13:1124309. [PMID: 36816955 PMCID: PMC9932692 DOI: 10.3389/fonc.2023.1124309] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
Genitourinary (GU) cancers including bladder, prostate, and kidney cancers affect older adults with a higher prevalence compared to younger adults. GU cancer treatment is associated with poorer outcomes in older adults compared to their younger counterparts. To better identify and support older adults receiving cancer care, oncologic societies recommend the use of a geriatric assessment (GA) to guide management. However, little is known about the implementation and usefulness of the GA in older adults with GU cancers. We performed a narrative review to investigate the utility of the GA in older adults with GU cancers and propose strategies to optimize the real-world use of the GA. Here, we describe a framework to incorporate GA into the routine cancer care of older adults with GU cancers and provide several implications for future research.
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Affiliation(s)
- Surbhi Singhal
- Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Julianna G. Marwell
- Section of Geriatric Medicine, Division of Primary Care and Population Health, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Ali Raza Khaki
- Division of Medical Oncology, Department of Medicine, Stanford University, Stanford, CA, United States
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Wang Y, Qu H, Xu B, Wu J, Lu K, Liu C, Chen S, Chen M. Expression of FOXA1 Is Associated with the Tumor-Infiltrating M2 Macrophage, Cytotoxic T Lymphocyte, and Effect of Chemotherapy in Bladder Cancer. Urol Int 2023; 107:58-63. [PMID: 34706362 PMCID: PMC9909707 DOI: 10.1159/000519129] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 07/21/2021] [Indexed: 01/29/2023]
Abstract
PURPOSE Cisplatin-containing combination chemotherapy has been the standard of care since the late 1980s, but the response rate is <50%. Studies have shown that the efficiency of chemotherapy differs among molecular subtypes of bladder cancer. In this study, we aimed to correlate FOXA1, a marker for differentiation of the basal and luminal subtypes, with tumor immune cell infiltration and the effect of chemotherapy in bladder cancer. MATERIALS AND METHODS Eighty-three patients with bladder cancer treated with chemotherapy were reviewed. Clinicopathological variables for each case were recorded. FOXA1, M2 tumor-associated macrophage (TAM), dendritic cell (DC), and cytotoxic T lymphocyte (CTL) were examined by immunohistochemistry. The relationship between FOXA1, immune cell infiltration, and clinical response to chemotherapy was assessed. RESULTS The overall objective response rate was 34%. The objective response rate for tumors with lower FOXA1 expression was 58% and for tumors with higher FOXA1 expression was 12%. Tumors with infiltrated M2 TAM proportion <3% had a higher objective response rate compared with infiltrated M2 TAM proportion >3% tumors (46% vs. 21%, p = 0.02). Tumors with infiltrated CTL proportion >5% had a higher objective response rate compared with infiltrated CTL proportion <5% tumors (50% vs. 17%, p = 0.002). DCs showed no significant differences. We found that the objective response rate for tumors with lower FOXA1 expression, proportion <3% M2 TAM infiltration, and proportion >5% CTL infiltration is 82%. Lower FOXA1 expression was associated with low M2 TAM infiltration and high CTL infiltration. CONCLUSIONS Thus, we showed that in patients with bladder cancer who received chemotherapy, the higher clinical response rate is associated with low FOXA1 expression, low M2 TAM infiltration, and high CTL infiltration.
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Affiliation(s)
- Yiduo Wang
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China, .,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China,
| | - Huan Qu
- Health Management Center, Zhongda Hospital, Southeast University, Nanjing, China
| | - Bin Xu
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China
| | - Jianping Wu
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China
| | - Kai Lu
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China
| | - Chunhui Liu
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China
| | - Shuqiu Chen
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China
| | - Ming Chen
- Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China,Institute of Urology, Surgical Research Center, Southeast University Medical School, Nanjing, China,*Ming Chen,
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Abou Chawareb E, Ayoub CH, Najdi J, Ghoubaira J, El-Hajj A. Preoperative predictors of prolonged length of stay in radical cystectomy: a retrospective study using the American College of Surgeons-National Surgical Quality Improvement Program Dataset. Ther Adv Urol 2023; 15:17562872231191654. [PMID: 37577029 PMCID: PMC10413889 DOI: 10.1177/17562872231191654] [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: 04/05/2023] [Accepted: 07/14/2023] [Indexed: 08/15/2023] Open
Abstract
Background Radical cystectomy (RC) is considered a complex procedure that entails significant morbidity and mortality. Objectives We aimed to determine pre-operative patient characteristics that help predict a prolonged length of hospital stay (PLOS) following RC. Design and Methods The American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database was used to select patients who underwent RC between the years 2011 and 2020. Prolonged length of stay was defined as a hospital stay ⩾9 days. We compared patient demographics, pre-operative labs, surgical characteristics, and medical history between patients with or without PLOS. Multivariable logistic regression models controlling for pre-operative characteristics and propensity score matching for post-operative complications were conducted to control for possible confounders. Results The analysis yielded details of 19,158 RC patients of which 6007 (31%) patients had a PLOS. Patients with PLOS were more likely to have post-operative complications that could serve as predictors for the PLOS rather than their pre-operative characteristics. Hence, we matched our cohort for these complications. After matching, patient pre-operative characteristics that predict PLOS included female gender (Odds Ratio (OR) = 5.91), 10-year increase in age (OR = 1.15), non-White race (OR = 1.98), partially or totally dependent functional health status (OR = 2.86), bleeding disorders (OR = 4.67), congestive heart failure (OR = 1.59), pre-operative transfusion (OR = 3.03), and a 20-min increase in operative time (OR = 1.01) (p < 0.046). Conclusion Patient demographics and pre-operative factors can help predict PLOS in RC patients. These predictors could serve as tools for patient counseling and risk stratification.
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Affiliation(s)
- Elia Abou Chawareb
- Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Christian Habib Ayoub
- Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Jad Najdi
- Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Joseph Ghoubaira
- Department of Radiology Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Albert El-Hajj
- Division of Urology, Department of Surgery, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon
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Belsey J. A cost-consequences and budget impact analysis of blue light-guided cystoscopy with Hexvix in patients diagnosed with non-muscle-invasive bladder cancer in France. J Med Econ 2023; 26:1398-1406. [PMID: 37800535 DOI: 10.1080/13696998.2023.2267929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/04/2023] [Indexed: 10/07/2023]
Abstract
AIMS French guidelines for the management of non-muscle-invasive bladder cancer recommend that blue-light cystoscopy should be used in patients where the risk of missing residual tumor is highest. Despite evidence for its cost-effectiveness, budgetary concerns have limited uptake in France. The aim of this analysis was to model the cost-consequences of adopting the recommendations in a French urology unit. MATERIALS AND METHODS A budget impact model was developed in Excel, using a decision tree approach derived from guidelines issued by L'Academie franҫaise d'urologie. Risk profiles were derived from an analysis of studies using white-light cystoscopy; estimates for the impact of blue-light cystoscopy were derived from a published Cochrane Review. Costs were based on published tariff prices from L'Agence Technique de L'Information sur L'Hospitalisation. The model allowed results to be tailored to activity levels and projected blue-light usage in the chosen urology unit. RESULTS Two scenarios were evaluated, based on a 3-year time horizon. Full implementation of all recommendations within a large public hospital was estimated to yield incremental costs of €269 per procedure (∼10% increase overall); a more targeted approach within a smaller private hospital yielded incremental costs of €133 per procedure (5% increase overall). LIMITATIONS The basis of the model is a change in the time to first recurrence. There are no data available for subsequent recurrences or progression, both of which could have an influence on expenditure. Secondly, recurrence rates for blue-light cystoscopy were not specifically available for each patient group identified in the guidelines: extrapolation of data may have resulted in bias. Finally, the data were derived from clinical trials, which may not be generalisable to real-world clinical practice. CONCLUSIONS The model has shown that the additional expenditure required to implement blue-light cystoscopy is modest and not disproportionate to the overall cost of care.
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CircRNA-ST6GALNAC6 increases the sensitivity of bladder cancer cells to erastin-induced ferroptosis by regulating the HSPB1/P38 axis. J Transl Med 2022; 102:1323-1334. [PMID: 35945269 DOI: 10.1038/s41374-022-00826-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 06/08/2022] [Accepted: 07/04/2022] [Indexed: 11/08/2022] Open
Abstract
Previous studies have demonstrated that circST6GALNAC6 is a tumor suppressor in bladder cancer. However, the role of circST6GALNAC6 in ferroptosis remains unclear. In the current study, ferroptosis was induced in bladder cancer cells by erastin. Functional experiments showed that overexpression of circST6GALNAC6 promoted ferroptosis of bladder cancer cells in vitro and in vivo. Mechanistic studies revealed that circST6GALNAC6 bound to the N-terminus of small heat shock protein 1 (HSPB1) and thus blocked the erastin-induced phosphorylation of HSPB1 at the Ser-15 site, a phosphorylation site in the protective response to ferroptosis stress. In addition, protein kinase C inhibited circST6GALNAC6-induced ferroptosis by increasing the overall phosphorylation level of HSPB1, further demonstrating the role of phosphorylation activation of HSPB1 in resistance to ferroptosis. Finally, the involvement of the HSPB1/p38 MAPK pathway in the downstream signal transduction of circST6GALNAC6 in bladder cancer ferroptosis regulation was determined. The regulatory mechanism of ferroptosis sensitivity dependent on circST6GALNAC6 expression levels in bladder cancer was revealed as circRNA regulation of various protein functions. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by occupying the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Therefore, enhancing the expression of circST6GALNAC6 to promote ferroptosis or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity is of considerable importance to the development and application of ferroptosis intervention methods in bladder cancer.
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Cheng J, Zhang S, Fan A, Li Y, Xu P, Huang J, He M, Wang H. An immune-related gene signature for the prognosis of human bladder cancer based on WGCNA. Comput Biol Med 2022; 151:106186. [PMID: 36335813 DOI: 10.1016/j.compbiomed.2022.106186] [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: 07/10/2022] [Revised: 08/30/2022] [Accepted: 10/08/2022] [Indexed: 12/27/2022]
Abstract
The innovation of immunotherapy was a milestone in the treatment of bladder cancer (BLCA). However, the treatment benefits varied by individual thus promoting the investigation of the biomarker of the patients. Unfortunately, there were not many effective predictive models, which were desired by clinicians, for BLCA that can predict the prognosis and benefit of immunotherapy. We constructed a three genes prognosis prediction model termed RiskScore based on the result of weighted correlation network analysis (WGCNA) from The Cancer Genome Atlas (TCGA) cohort (n = 406). We then validated the prediction accuracy with three validation cohort(GSE13507 (n = 165), GSE48075(n = 73), GSE32894(n = 224)). We compared the differences in gene expression, immune relate function, and immune infiltration between two groups divided by RiskScore. We further discovered the potential drug target and suitable compounds for high-risk groups. Our results suggested that the low-risk group may be more potential for immunotherapy for they have higher B cell infiltration, higher expression of immune checkpoints(PDCD1, CTLA4), and much more active immune-related pathways(B cell and T cell receptor signaling pathway). The RiskScore showed a well predictive accuracy for the prognosis of BLCA. After Spearman analysis, we found the suitable drug target and compounds for the patients in the high-risk group. The model we constructed is able to predict the prognosis of BLCA patients with ease and accuracy. PLK1 and gefitinib may be utilized for further treatment of BLCA patients.
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Affiliation(s)
- Jiangting Cheng
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sihong Zhang
- Department of Urology, Xuhui Hospital, Fudan University, Shanghai, China
| | - Aoyu Fan
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaohui Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peirong Xu
- Department of Urology, Xuhui Hospital, Fudan University, Shanghai, China
| | - Jiaqi Huang
- Department of Urology, Minhang Hospital, Fudan University, Shanghai, China
| | - Minke He
- Department of Urology, Minhang Hospital, Fudan University, Shanghai, China
| | - Hang Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
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Małkiewicz B, Gurwin A, Karwacki J, Nagi K, Knecht-Gurwin K, Hober K, Łyko M, Kowalczyk K, Krajewski W, Kołodziej A, Szydełko T. Management of Bladder Cancer Patients with Clinical Evidence of Lymph Node Invasion (cN+). Cancers (Basel) 2022; 14:5286. [PMID: 36358705 PMCID: PMC9656528 DOI: 10.3390/cancers14215286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/29/2022] [Accepted: 10/23/2022] [Indexed: 11/29/2022] Open
Abstract
The purpose of this review is to present the current knowledge about the diagnostic and treatment options for bladder cancer (BCa) patients with clinically positive lymph nodes (cN+). This review shows compaction of CT and MRI performance in preoperative prediction of lymph node invasion (LNI) in BCa patients, along with other diagnostic methods. Most scientific societies do not distinguish cN+ patients in their guidelines; recommendations concern muscle-invasive bladder cancer (MIBC) and differ between associations. The curative treatment that provides the best long-term survival in cN+ patients is a multimodal approach, with a combination of neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) with extended pelvic lymph node dissection (ePLND). The role of adjuvant chemotherapy (AC) remains uncertain; however, emerging evidence indicates comparable outcomes to NAC. Therefore, in cN+ patients who have not received NAC, AC should be implemented. The response to ChT is a crucial prognostic factor for cN+ patients. Recent studies demonstrated the growing importance of immunotherapy, especially in ChT-ineligible patients. Moreover, immunotherapy can be suitable as adjuvant therapy in selected cases. In cN+ patients, the extended template of PLND should be utilized, with the total resected node count being less important than the template. This review is intended to draw special attention to cN+ BCa patients, as the oncological outcomes are significantly worse for this group.
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Affiliation(s)
- Bartosz Małkiewicz
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Adam Gurwin
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Jakub Karwacki
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Krystian Nagi
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Klaudia Knecht-Gurwin
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Krzysztof Hober
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Magdalena Łyko
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Kamil Kowalczyk
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Wojciech Krajewski
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Anna Kołodziej
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Tomasz Szydełko
- Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wroclaw Medical University, 50-556 Wroclaw, Poland
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Fu J, Zhang W, Jiang T. Immunogenic cell death mediation patterns reveal novel paradigm for characterizing the immune microenvironment and immunotherapeutic responses in bladder cancer. Front Genet 2022; 13:1035484. [PMID: 36386817 PMCID: PMC9640952 DOI: 10.3389/fgene.2022.1035484] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2023] Open
Abstract
Background: Immunogenic cell death (ICD) plays an important role in several malignancies. However, the role of ICD-mediated patterns in bladder cancer (BCA) remains unknown. Methods: For assessing the ICD-mediated patterns based on the expression of IRGs, 4 large BCA cohorts were obtained. The ICD-mediated patterns of individual samples were quantified as an ICD score by principal component analysis. The correlations of the ICD-mediated patterns with the tumor immune microenvironment (TIME) and responses to immunotherapy were comprehensively evaluated. The IRGs with predictive prognostic values were further validated by in vitro loss of function assays. Results: Two distinct ICD-mediated patterns were established, showing distinct clinical features and immune microenvironment features. Although ICD cluster A was associated with a poor prognosis with a high ICD score, it showed an immune activation state with a more favorable response to immunotherapy and treatment that induced ICD. The ICD-related gene, CALR, was significantly upregulated in the T24 BCA cell line relative to the control SV-HUC-1 cells. Knocking down CALR suppressed T24 cell viability and caused ER stress. Conclusion: We identified the existence of distinct ICD-mediated patterns in BCA closely associated with the remodeling of the TIME. Further in-depth examination of ICD-related features is warranted to obtain a broader prospect for therapeutic innovations and improved prognosis of BCA.
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Affiliation(s)
- Jialei Fu
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Zhang
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Tao Jiang
- Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Akushevich I, Yashkin A, Kovtun M, Yashin AI, Kravchenko J. Underlying mechanisms of change in cancer prevalence in older U.S. adults: contributions of incidence, survival, and ascertainment at early stages. Cancer Causes Control 2022; 33:1161-1172. [PMID: 35799033 PMCID: PMC9360135 DOI: 10.1007/s10552-022-01595-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022]
Abstract
PURPOSE To quantitatively evaluate contributions of trends in incidence, relative survival, and stage at diagnosis to the dynamics in the prevalence of major cancers (lung, prostate, colon, breast, urinary bladder, ovaries, stomach, pancreas, esophagus, kidney, liver, and skin melanoma) among older U.S. adults age 65 +. METHODS Trend partitioning was applied to the Surveillance, Epidemiology, and End Results Program data for 1973-2016. RESULTS Growth of cancer prevalence in older adults decelerated or even decreased over time for all studied cancers due to decreasing incidence and improving survival for most of cancers, with a smaller contribution of the stage at cancer diagnosis. Changes in the prevalence of cancers of the lung, colon, stomach, and breast were predominantly due to decreasing incidence, increasing survival and more frequent diagnoses at earlier stages. Changes in prevalence of some other cancers demonstrated adverse trends such as decreasing survival in localized and regional stages (urinary bladder and ovarian) and growing impact of late-stage diagnoses (esophageal cancer). CONCLUSION While decelerating or decreasing prevalence of many cancers were due to a beneficial combination of decreasing incidence and increasing survival, there are cancers for which decelerating prevalence is due to lack of improvement in their stage-specific survival and/or increasing frequency of diagnosis at advanced stages. Overall, if the observed trends persist, it is likely that the burden associated with cancer prevalence in older U.S. adults will be lower comparing to projections based on constant increasing prevalence have previously estimated.
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Affiliation(s)
- I Akushevich
- Center for Population Health and Aging, Duke University, Durham, NC, USA.
| | - A Yashkin
- Center for Population Health and Aging, Duke University, Durham, NC, USA
| | - M Kovtun
- Center for Population Health and Aging, Duke University, Durham, NC, USA
| | - A I Yashin
- Center for Population Health and Aging, Duke University, Durham, NC, USA
| | - J Kravchenko
- Department of Surgery, Duke University School of Medicine, Duke University, Durham, NC, USA
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Rietbergen DD, van Gennep EJ, KleinJan GH, Donswijk M, Valdés Olmos RA, van Rhijn BW, van der Poel HG, van Leeuwen FW. Evaluation of the Hybrid Tracer Indocyanine Green- 99m Tc-Nanocolloid for Sentinel Node Biopsy in Bladder Cancer-A Prospective Pilot Study. Clin Nucl Med 2022; 47:774-780. [PMID: 35713891 PMCID: PMC9351699 DOI: 10.1097/rlu.0000000000004301] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/05/2022] [Accepted: 05/05/2022] [Indexed: 11/26/2022]
Abstract
RATIONALE In muscle-invasive bladder cancer (MIBC), lymph node invasion has proven to be an independent predictor of disease recurrence and cancer-specific survival. We evaluated the feasibility of targeting the sentinel node (SN) for biopsy in MIBC patients using the hybrid tracer indocyanine green (ICG)- 99m Tc-nanocolloid for simultaneous radioguidance and fluorescence guidance. METHODS Twenty histologically confirmed cN0M0 MIBC patients (mean age, 63.3 years; range, 30-82 years), scheduled for radical cystectomy with SN biopsy and extended pelvic lymph node dissection (ePLND), were prospectively included. Twelve patients were operated on following neoadjuvant chemotherapy. The patients received lymphoscintigraphy as well as SPECT/CT after 4 transurethral injections of ICG- 99m Tc-nanocolloid (mean, 208 MBq; range, 172-229 MBq) around the tumor/scar in the detrusor muscle of the bladder on the day before radical cystectomy. Sentinel node resection was performed under radioguidance and fluorescence guidance. RESULTS Nineteen patients could be analyzed. On preoperative imaging, SNs could be identified in 10 patients (53%; mean, 1.6 SN/patient), which revealed drainage pathways outside the ePLND in 20% of the patients. Interesting to note is that 2 patients (10%) with preoperative nonvisualization displayed fluorescent and radioactive SNs during surgery. Location of the primary tumor near the left lateral side of the bladder seemed to be a factor for nonvisualization. Nodal harvesting with ePLND varied among patients (mean, 23.3). Histopathology confirmed tumor-positive nodes in 4 (21%) of all patients. In the 2 patients where an SN could be identified, the ePLND specimens were tumor-negative. All patients with tumor-positive nodes had advanced disease (stage III). CONCLUSION Sentinel node biopsy in bladder cancer using the hybrid tracer ICG- 99m Tc-nanocolloid is feasible, and preoperative imaging is predictive for the ability to perform SN biopsy in 83% of the patients who displayed an SN. In patients with a successful preoperative SN mapping using lymphoscintigraphy and SPECT/CT, the intraoperative SN guidance and detection were effective, even outside the ePLND area. As such, this study underscores the critical role that preoperative imaging plays in challenging image-guided surgery applications.
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Affiliation(s)
- Daphne D.D. Rietbergen
- From the Interventional Molecular Imaging Laboratory, Department of Radiology
- Nuclear Medicine Section, Department of Radiology
| | | | | | | | - Renato A. Valdés Olmos
- From the Interventional Molecular Imaging Laboratory, Department of Radiology
- Nuclear Medicine Section, Department of Radiology
| | | | | | - Fijs W.B. van Leeuwen
- From the Interventional Molecular Imaging Laboratory, Department of Radiology
- Department of Urology, Leiden University Medical Center, Leiden
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32
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Mori K, Yanagisawa T, Katayama S, Laukhtina E, Pradere B, Mostafaei H, Quhal F, Rajwa P, Moschini M, Soria F, D'andrea D, Abufaraj M, Albisinni S, Krajewski W, Fukuokaya W, Miki J, Kimura T, Egawa S, Teoh JY, Shariat SF. Impact of sex on outcomes after surgery for non-muscle-invasive and muscle-invasive bladder urothelial carcinoma: a systematic review and meta-analysis. World J Urol 2022; 41:909-919. [PMID: 35963957 PMCID: PMC10159976 DOI: 10.1007/s00345-022-04116-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 07/20/2022] [Indexed: 11/29/2022] Open
Abstract
PURPOSE To assess the prognostic value of sex for non-muscle-invasive/muscle-invasive bladder urothelial carcinoma (NMIBC/MIBC) treated with radical surgery. METHODS The PubMed, Web of Science, and Scopus databases were searched in November 2021 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they involved the comparison of the overall, cancer-specific, progression, and recurrence-free survival of patients with NMIBC/MIBC. Formal sex-stratified meta-analyses of these outcomes were performed. RESULTS Thirty-one studies, which included 32,525 patients with NMIBC, and 63 studies, which included 85,132 patients with MIBC, were eligible for review and meta-analysis. Female sex was associated with worse cancer-specific survival (pooled hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.11-1.31) and overall survival (pooled HR, 1.02; 95% CI, 1.00-1.05) in patients with MIBC. In contrast, however, sex was not associated with cancer-specific survival (pooled HR, 1.01; 95% CI, 0.70-1.46), progression-free survival (pooled HR, 1.04; 95% CI, 0.88-1.24), and recurrence-free survival (pooled HR, 1.06; 95% CI, 0.98-1.16) in patients with NMIBC. CONCLUSIONS Sex is associated with an increased risk of worse survival outcomes in patients with MIBC but not in those with NMIBC. Given the genetic and social differences between sexes, sex may represent a key factor in the clinical decision-making process.
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Affiliation(s)
- Keiichiro Mori
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takafumi Yanagisawa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Satoshi Katayama
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ekaterina Laukhtina
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Benjamin Pradere
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Hadi Mostafaei
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fahad Quhal
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Pawel Rajwa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Department of Urology, Medical University of Silesia, Zabrze, Poland
| | - Marco Moschini
- Department of Urology, San Raffaele Hospital, Milan, Italy
| | - Francesco Soria
- Division of Urology, Department of Surgical Sciences, University of Studies of Torino, Turin, Italy
| | - David D'andrea
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Mohammad Abufaraj
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan
| | - Simone Albisinni
- Department of Urology, University Clinics of Brussels, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Wojciech Krajewski
- Department of Department of Minimally Invasive and Robotic Urology, Wrocław Medical University, Wroclaw, Poland
| | - Wataru Fukuokaya
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Jun Miki
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Jeremy Yc Teoh
- Department of Surgery, S.H. Ho Urology Centre, The Chinese University of Hong Kong, Hong Kong, China
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. .,Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia. .,Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan. .,Department of Urology, Weill Cornell Medical College, New York, NY, USA. .,Department of Urology, University of Texas Southwestern, Dallas, TX, USA. .,Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. .,Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
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Yu EYW, Zhang H, Fu Y, Chen YT, Tang QY, Liu YX, Zhang YX, Wang SZ, Wesselius A, Li WC, Zeegers MP, Xu B. Integrative Multi-Omics Analysis for the Determination of Non-Muscle Invasive vs. Muscle Invasive Bladder Cancer: A Pilot Study. CURRENT ONCOLOGY (TORONTO, ONT.) 2022; 29:5442-5456. [PMID: 36005168 PMCID: PMC9406560 DOI: 10.3390/curroncol29080430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 12/28/2022]
Abstract
Objectives: The molecular landscape of non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer based on molecular characteristics is essential but poorly understood. In this pilot study we aimed to identify a multi-omics signature that can distinguish MIBC from NMIBC. Such a signature can assist in finding potential mechanistic biomarkers and druggable targets. Methods: Patients diagnosed with NMIBC (n = 15) and MIBC (n = 11) were recruited at a tertiary-care hospital in Nanjing from 1 April 2021, and 31 July 2021. Blood, urine and stool samples per participant were collected, in which the serum metabolome, urine metabolome, gut microbiome, and serum extracellular vesicles (EV) proteome were quantified. The differences of the global profiles and individual omics measure between NMIBC vs. MIBC were assessed by permutational multivariate analysis and the Mann–Whitney test, respectively. Logistic regression analysis was used to assess the association of each identified analyte with NMIBC vs. MIBC, and the Spearman correlation was used to investigate the correlations between identified analytes, where both were adjusted for age, sex and smoking status. Results: Among 3168 multi-omics measures that passed the quality control, 159 were identified to be differentiated in NMIBC vs. MIBC. Of these, 46 analytes were associated with bladder cancer progression. In addition, the global profiles showed significantly different urine metabolome (p = 0.029), gut microbiome (p = 0.036), and serum EV (extracellular vesicles) proteome (p = 0.039) but not serum metabolome (p = 0.059). We also observed 17 (35%) analytes that had been developed as drug targets. Multiple interactions were obtained between the identified analytes, whereas for the majority (61%), the number of interactions was at 11–20. Moreover, unconjugated bilirubin (p = 0.009) and white blood cell count (p = 0.006) were also shown to be different in NMIBC and MIBC, and associated with 11 identified omics analytes. Conclusions: The pilot study has shown promising to monitor the progression of bladder cancer by integrating multi-omics data and deserves further investigations.
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Affiliation(s)
- Evan Yi-Wen Yu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Epidemiology & Biostatistics, School of Public Health, Southeast University, Nanjing 210009, China; (Y.-T.C.); (Y.-X.L.); (Y.-X.Z.)
- Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.W.); (M.P.Z.)
- Correspondence: (E.Y.-W.Y.); (H.Z.)
| | - Hao Zhang
- State Key Laboratory of Bioelectronics, National Demonstration Center for Experimental Biomedical Engineering Education, Southeast University, Nanjing 210096, China
- Nanjing EVLiXiR Biotechnology Co., Ltd., Nanjing 210032, China
- Correspondence: (E.Y.-W.Y.); (H.Z.)
| | - Yuanqing Fu
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China;
- Westlake Intelligent Biomarker Discovery Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
| | - Ya-Ting Chen
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Epidemiology & Biostatistics, School of Public Health, Southeast University, Nanjing 210009, China; (Y.-T.C.); (Y.-X.L.); (Y.-X.Z.)
| | - Qiu-Yi Tang
- Medical School of Southeast University, Nanjing 210009, China;
| | - Yu-Xiang Liu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Epidemiology & Biostatistics, School of Public Health, Southeast University, Nanjing 210009, China; (Y.-T.C.); (Y.-X.L.); (Y.-X.Z.)
| | - Yan-Xi Zhang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Epidemiology & Biostatistics, School of Public Health, Southeast University, Nanjing 210009, China; (Y.-T.C.); (Y.-X.L.); (Y.-X.Z.)
| | - Shi-Zhi Wang
- Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Ministry of Education, Nanjing 210009, China;
| | - Anke Wesselius
- Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.W.); (M.P.Z.)
- School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Wen-Chao Li
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing 210009, China; (W.-C.L.); (B.X.)
| | - Maurice P. Zeegers
- Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.W.); (M.P.Z.)
- School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Bin Xu
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing 210009, China; (W.-C.L.); (B.X.)
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Vlaar JM, Borgman A, Kalkhoven E, Westland D, Besselink N, Shale C, Faltas BM, Priestley P, Kuijk E, Cuppen E. Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer. Sci Rep 2022; 12:10081. [PMID: 35710704 PMCID: PMC9203531 DOI: 10.1038/s41598-022-14256-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/03/2022] [Indexed: 11/09/2022] Open
Abstract
Bladder cancer has a high recurrence rate and low survival of advanced stage patients. Few genetic drivers of bladder cancer have thus far been identified. We performed in-depth structural variant analysis on whole-genome sequencing data of 206 metastasized urinary tract cancers. In ~ 10% of the patients, we identified recurrent in-frame deletions of exons 8 and 9 in the aryl hydrocarbon receptor gene (AHRΔe8-9), which codes for a ligand-activated transcription factor. Pan-cancer analyses show that AHRΔe8-9 is highly specific to urinary tract cancer and mutually exclusive with other bladder cancer drivers. The ligand-binding domain of the AHRΔe8-9 protein is disrupted and we show that this results in ligand-independent AHR-pathway activation. In bladder organoids, AHRΔe8-9 induces a transformed phenotype that is characterized by upregulation of AHR target genes, downregulation of differentiation markers and upregulation of genes associated with stemness and urothelial cancer. Furthermore, AHRΔe8-9 expression results in anchorage independent growth of bladder organoids, indicating tumorigenic potential. DNA-binding deficient AHRΔe8-9 fails to induce transformation, suggesting a role for AHR target genes in the acquisition of the oncogenic phenotype. In conclusion, we show that AHRΔe8-9 is a novel driver of urinary tract cancer and that the AHR pathway could be an interesting therapeutic target.
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Affiliation(s)
- Judith M Vlaar
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Anouska Borgman
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Eric Kalkhoven
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Denise Westland
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Nicolle Besselink
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Charles Shale
- Hartwig Medical Foundation, Amsterdam, The Netherlands
- Hartwig Medical Foundation Australia, Sydney, NSW, Australia
| | - Bishoy M Faltas
- Department of Medicine and Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Peter Priestley
- Hartwig Medical Foundation, Amsterdam, The Netherlands
- Hartwig Medical Foundation Australia, Sydney, NSW, Australia
| | - Ewart Kuijk
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Edwin Cuppen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
- Hartwig Medical Foundation, Amsterdam, The Netherlands.
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circRNA CRIM1 regulates the migration and invasion of bladder cancer by targeting miR182/Foxo3a axis. Clin Transl Oncol 2022; 24:1195-1203. [PMID: 34994952 DOI: 10.1007/s12094-021-02768-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/23/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE To explore the molecular mechanism of circRNA CRIM1 in the regulation of bladder cancer by targeting the miR182/Foxo3a axis. METHODS 50 pairs of cancer tissues and para-cancerous tissues of patients with bladder cancer were collected. RT-PCR method was used to detect the expression of CRIM1 and miR-182. The association between circRNA CRIM1 and clinical data was analyzed. qPCR was used to measure the expression of circRNA CRIM1 and miR-182 in bladder cancer cell UMUC3 and endothelial cell line HUVEC. CRIM1 genes and miR-182 in UMUC3 cell lines were overexpressed and silenced, respectively, to investigate their effects on invasion and migration of bladder cancer, and to detect the changes of miR182/Foxo3a expression. The association between circRNA CRIM1 and miR182/Foxo3a was determined by bioinformatics analysis. RESULTS The results showed that there was a significant association between the expression of circRNA CRIM1 and distal migration. The expression of CRIM1 in adjacent tissues was significantly down-regulated and negatively correlated with distal migration. The overexpression of circRNA CRIM1 reduced migration and invasion processes in bladder cancer cells. After circRNA CRIM1 was overexpressed, the miR-182 was significantly down-regulated. The expression levels of Foxo3a mRNA and proteins were up-regulated after miR-182 silencing of bladder cancer cell line UMUC3. miR-182 silencing inhibited invasion and migration of cancer cells to some extent. In bladder cancer cells and tissues, CRIM1 and Foxo3a were significantly down-regulated, miR-182 was significantly up-regulated. CONCLUSION circRNA CRIM1 regulated the migration and invasion of bladder cancer by targeting the miR182/Foxo3a axis.
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Life expectancy in metastatic urothelial bladder cancer patients according to race/ethnicity. Int Urol Nephrol 2022; 54:1521-1527. [PMID: 35508792 DOI: 10.1007/s11255-022-03221-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/22/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE to compare observed overall survival vs age-adjusted lifetable (LT) derived life expectancy (LE) in metastatic urothelial bladder cancer (MBCa) patients according to race/ethnicity. METHODS We identified Caucasian, African American, Hispanic/Latino and Asian metastatic urothelial bladder cancer patients from 2004 to 2011 within the Surveillance, Epidemiology and End Results database. Social Security Administration tables were used to compute 5 year LE. LT-derived LE was compared to observed overall survival OS. Additionally, we relied on Poisson regression plots to display cancer-specific mortality (CSM) relative to other-cause mortality (OCM) for each race/ethnicity. RESULTS Overall, 2286 MBCa patients were identified. Of those, 1800 (79%) were Caucasian vs 212 (9.3%) African American vs 189 (8.3%) Hispanic/Latino vs 85 (3.7%) Asians. The median age at diagnosis was 71 years for Asians vs 70 for Caucasians vs 67 for Hispanic/Latinos vs 67 for African Americans. African Americans showed the biggest difference between observed OS and LT-predicted LE at five years (- 83.8%), followed by Hispanic/Latinos (- 81%), Caucasians (- 77%) and Asian patients (- 69%). In Poisson regression plots, Hispanic/Latinos displayed the highest cancer-specific mortality rate (88%), while African/Americans showed the highest other cause mortality rate (12%). Conversely, Asian patients displayed the lowest CSM rate (83%) and second lowest OCM rate (7%). CONCLUSIONS African Americans showed the least favorable survival profile in MBCa, despite being youngest at diagnosis. Contrarily, Asians displayed the best survival profile in MBCa, despite being oldest at diagnosis.
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Zhang X, Xiong H, Zhao Y, Lin S, Huang X, Lin C, Mao S, Chen D. Circular RNA LONP2 regulates proliferation, invasion, and apoptosis of bladder cancer cells by sponging microRNA-584-5p. Bioengineered 2022; 13:8823-8835. [PMID: 35358000 PMCID: PMC9161836 DOI: 10.1080/21655979.2022.2054753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Bladder cancer (BC) is the most frequent type of urinary tumor and a barely treatable disease. Although extensive efforts have been invested in the research of BC, the underlying etiology and pathophysiology remain unclear. CircLONP2 is a circular RNA implicated in the development of many cancers, and miR-584-5p and YAP1 have been reported to contribute to the progression of BC. In this research, we presented novel evidence supporting circLONP2/miR-584-5p/YAP1 axis as a novel regulatory module in the progression of BC. We analyzed the expression of circLONP2 between precancerous BC samples and normal tissues using a published RNA-seq dataset. The expression of circLONP2 was also validated in clinical samples and cell lines by quantitative RT-PCR. Small interfering RNA (siRNA) and miRNA inhibitor was utilized to modulate the expression of circLONP2 and miR-584-5p and investigate their functions on cell proliferation and invasion. Luciferase reporter assay and RNA pull-down were performed to confirm the functional interactions among circLONP2/miR-584-5p/YAP1. CircLONP2 was significantly upregulated in precancerous BC tissues and BC cells. CircLONP2 depletion inhibited cell viability, proliferation, and invasion of BC cell lines, which could be partially rescued by miR-584-5p inhibitor. Further experiments indicated that miR-584-5p regulates cell viability, proliferation, and invasion via directly targeting YAP1. In summary, our work indicates that circLONP2 plays an oncogenic function in BC by regulating miR-584-5p/YAP1 axis, and its interaction with miR-584-5p provides a potential strategy to target BC.
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Affiliation(s)
- Xu Zhang
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Hao Xiong
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Yong Zhao
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Shengqiang Lin
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Xiang Huang
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Cheng Lin
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Shihui Mao
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
| | - Demin Chen
- Department of Urology, The Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, China
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Mori K, Schuettfort VM, Katayama S, Laukhtina E, Pradere B, Quhal F, Sari Motlagh R, Mostafaei H, Grossmann NC, Rajwa P, Teoh JY, Resch I, Fajkovic H, Moschini M, D'andrea D, Abufaraj M, Karakiewicz PI, Lotan Y, Scherr D, Egawa S, Compérat E, Shariat SF. Prognostic Role of Preoperative Vascular Cell Adhesion Molecule-1 Plasma Levels in Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy. Ann Surg Oncol 2022; 29:5307-5316. [PMID: 35347517 PMCID: PMC9246812 DOI: 10.1245/s10434-022-11575-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 02/21/2022] [Indexed: 01/19/2023]
Abstract
Abstract
Background
Angiogenesis-related marker vascular cell adhesion molecule-1 (VCAM-1) has been shown to be elevated in urothelial carcinoma of the bladder (UCB), but its predictive/prognostic role has not been determined. Thus, this study aimed to investigate the predictive/prognostic role of VCAM-1 for patients who have UCB treated with radical cystectomy (RC).
Methods
The study enrolled 1036 patients with clinically non-metastatic advanced UCB who underwent RC, and plasma VCAM-1 was evaluated preoperatively. The correlation of plasma VCAM-1 with pathologic and survival outcomes was assessed using binominal logistic regression and multivariable Cox regression analyses. Discrimination was assessed using the area under the curve and concordance indices. The clinical net benefit was evaluated using decision curve analysis (DCA).
Results
Preoperative VCAM-1 was significantly elevated in patients with adverse pathologic features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node-metastasis (LNM), ≥pT3 disease, and non-organ-confined disease (NOCD (p < 0.001 for each). Preoperative plasma VCAM-1 was independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in pre- and postoperative multivariable models. Adding VCAM-1 to these predictive models improved their discriminatory ability to predict all outcomes by a significant margin. In the DCA, VCAM-1 addition to the reference models for prediction of LNM, NOCD, RFS, and CSS resulted in relevant improvement.
Conclusions
Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from intensified/multimodal therapy. In addition, VCAM-1 improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making.
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Affiliation(s)
- Keiichiro Mori
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Victor M Schuettfort
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Satoshi Katayama
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Ekaterina Laukhtina
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Benjamin Pradere
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, CHRU Tours, Tours, France
- Université François Rabelais de Tours, PRES Centre Val de Loire, Tours, France
| | - Fahad Quhal
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Reza Sari Motlagh
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hadi Mostafaei
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nico C Grossmann
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, University Hospital Zurich, Zurich, Switzerland
| | - Pawel Rajwa
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Department of Urology, Medical University of Silesia, Zabrze, Poland
| | - Jeremy Yc Teoh
- Department of Surgery, S.H. Ho Urology Centre, The Chinese University of Hong Kong, Hong Kong, China
| | - Irene Resch
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Harun Fajkovic
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Marco Moschini
- Department of Urology, Medical University of Vienna, Vienna, Austria
- Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland
| | - David D'andrea
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Mohammad Abufaraj
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Pierre I Karakiewicz
- Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Canada
| | - Yair Lotan
- Department of Urology, University of Texas Southwestern, Dallas, TX, USA
| | - Douglas Scherr
- Department of Urology, Weill Cornell Medical College, New York, NY, USA
| | - Shin Egawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Eva Compérat
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Shahrokh F Shariat
- Department of Urology, Medical University of Vienna, Vienna, Austria.
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia.
- Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan.
- Department of Urology, University of Texas Southwestern, Dallas, TX, USA.
- Department of Urology, Weill Cornell Medical College, New York, NY, USA.
- Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
- Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria.
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Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol 2022; 5:553-563. [PMID: 35288066 PMCID: PMC10062393 DOI: 10.1016/j.euo.2022.02.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/08/2022] [Accepted: 02/25/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND The programmed death-1 (PD-1) inhibitor nivolumab prolongs disease-free survival in patients with muscle-invasive urothelial carcinoma (MIUC). OBJECTIVE To evaluate the effects of nivolumab on health-related quality of life (HRQoL) after radical resection in patients with MIUC. DESIGN, SETTING, AND PARTICIPANTS We used data from 709 patients in CheckMate 274 (NCT02632409; 282 with programmed death ligand 1 [PD-L1] expression ≥1%), an ongoing randomized, double-blind, placebo-controlled phase 3 trial of adjuvant nivolumab. INTERVENTION Intravenous injection of nivolumab (240 mg) or placebo every 2 wk for ≤1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EQ-5D-3L. Linear mixed-effect models for repeated measures were used to compare nivolumab and placebo on changes in HRQoL. Time to confirmed deterioration (TTCD) of HRQoL was analyzed by Cox proportional hazards regression. RESULTS AND LIMITATIONS In the full HRQoL evaluable population, no clinically meaningful deterioration of HRQoL was observed in either treatment arm. Moreover, nivolumab was noninferior to placebo on changes from baseline for all main outcomes. The median TTCD for fatigue was 41.0 wk for nivolumab and 44.3 wk for placebo (hazard ratio [HR]: 1.11, 95% confidence interval [CI], 0.89-1.39). For the visual analog scale, the median TTCD was not reached for nivolumab and it was 57.6 wk for placebo (HR: 0.78, 95% CI, 0.61-1.00). The median TTCD for the other main outcomes was not reached in either treatment arm. The findings were similar for patients with PD-L1 expression ≥1%. CONCLUSIONS These results demonstrate that nivolumab did not compromise the HRQoL of patients with MIUC in CheckMate 274. PATIENT SUMMARY Nivolumab is being researched as a new treatment for patients with bladder cancer (urothelial carcinoma). We found that nivolumab maintained quality of life while increasing the time until cancer returns in patients whose bladder cancer had spread or grown and who had unsuccessfully tried platinum-containing chemotherapy.
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Affiliation(s)
| | - Matthew D Galsky
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | | | | | | | | | | | | | - Dean F Bajorin
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Lemiński A, Kaczmarek K, Gołąb A, Kotfis K, Skonieczna-Żydecka K, Słojewski M. Increased One-Year Mortality Among Elderly Patients After Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Retrospective, Observational Comparative Study. Clin Interv Aging 2022; 17:255-263. [PMID: 35299721 PMCID: PMC8922233 DOI: 10.2147/cia.s352890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/15/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction Muscle invasive bladder cancer (MIBC) is a common malignancy amongst elderly. Increasing life expectancy, prevalence of smoking, lifelong exposure to environmental pollutants and immunosenescence contribute to growing number of cases. Traditionally, radical cystectomy (RC) with pelvic lymph node dissection (PLND) constituted the mainstay of treatment for MIBC, but despite proven feasibility in elderly population, it has been associated with significant burden of morbidity, mortality, and complications. Study Objective We aimed to re-evaluate the safety and efficacy of RC amongst the elderly patients with MIBC. Material and Methods This single-center, retrospective, observational comparative study was conducted among 568 patients who underwent RC due to MIBC between 2003 and 2021. We evaluated the influence of chronological age (<70 vs ≥70 years) on clinical, demographic, and pathological variables related to MIBC and RC. Results Elderly patients had similar clinical and pathological features of disease compared to their younger counterparts; nonetheless, they more often received simplified urinary diversion, ie ureterostomy (60.25% vs 39.33%, p<0.001) and had no PLND (15.76% vs 8.5%, p=0.01) during RC. Furthermore, more elderly patients were treated for secondary MIBCs and fewer had history of smoking. Severe complication and 90-day mortality rates were comparable between groups; however, the elderly had significantly higher all-cause mortality at one year post RC (46.67% vs 33.25%, p=0.003). On multivariate analysis, one-year mortality risk was independently associated with elderly age (HR=2.119, 95% CI: 1.227–3.660, p=0.007), rural residency (HR=1.760, 95% CI: 1.043–2.968, p=0.034), extravesical extension of tumor (HR=2.109, 95% CI: 1.155–3.850, p=0.015), lymph node metastasis (HR=2.268, 95% CI: 1.290–3.987, p=0.004) and omission of PLND (HR=6.064, 95% CI: 2.926–12.568, p<0.001). Conclusion Radical cystectomy in elderly patients is associated with significant one-year mortality. Our study emphasizes the unmet need for considerate planning of treatment for MIBC in potentially vulnerable groups of elderly patients. Efforts are needed to reliably identify those unlikely to benefit from surgery and facilitate patient-centered choice of alternative therapies.
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Affiliation(s)
- Artur Lemiński
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
- Correspondence: Artur Lemiński, Department of Urology and Urological Oncology, Pomeranian Medical University, al. Powstańców Wielkopolskich 72, Szczecin, 70-111, Poland, Tel +48-91-466-1101, Fax +48-91-466-1100, Email
| | - Krystian Kaczmarek
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
| | - Adam Gołąb
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
| | - Katarzyna Kotfis
- Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University, Szczecin, Poland
- Katarzyna Kotfis, Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University, al. Powstańców Wielkopolskich 72, Szczecin, 70-111, Poland, Tel +48-91-466-1146, Fax +48-91-466-1144, Email
| | | | - Marcin Słojewski
- Department of Urology and Urological Oncology, Pomeranian Medical University, Szczecin, Poland
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Management Trends and Outcomes of Patients Undergoing Radical Cystectomy for Urothelial Carcinoma of the Bladder: Evolution of the University of Southern California Experience over 3,347 Cases. J Urol 2022; 207:302-313. [PMID: 34994657 PMCID: PMC8746892 DOI: 10.1097/ju.0000000000002242] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models. RESULTS In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001). CONCLUSIONS Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.
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Ayoub CH, Dakroub A, El-Asmar JM, Ali AH, Beaini H, Abdulfattah S, El Hajj A. Preoperative MELD score predicts mortality and adverse outcomes following radical cystectomy: analysis of American College of Surgeons National Surgical Quality Improvement Program. Ther Adv Urol 2022; 14:17562872221135944. [PMID: 36407007 PMCID: PMC9669693 DOI: 10.1177/17562872221135944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/12/2022] [Indexed: 08/15/2023] Open
Abstract
Background The model for end-stage liver disease (MELD) has been widely used to predict the mortality and morbidity of various surgical procedures. Objectives We aimed to correlate a high preoperative MELD score with adverse 30-day postoperative complications following radical cystectomy. Design and Methods Patients who underwent elective, non-emergency radical cystectomy were identified from the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2017. Patients were categorized according to a calculated MELD score. The primary outcomes of this study were 30-day postoperative mortality, morbidity, and length of hospital stay following radical cystectomy. For further sensitivity analysis, propensity score matching was used to yield a total of 1387 matched pairs and primary outcomes were also assessed in the matched cohort. Results Compared with patients with a MELD < 10, those with MELD ⩾ 10 had significantly higher rates of mortality [odds ratio (OR) = 1.71, p = 0.004], major complications (OR = 1.42, p < 0.001), and prolonged hospital stay (OR = 1.29, p < 0.001) on multivariate analysis. Following risk-adjustment for race, propensity-matched groups revealed that patients with MELD score ⩾ 10 were significantly associated with higher mortality (OR = 1.85, p = 0.008), major complications (OR = 1.34, p < 0.001), yet similar length of hospital stay (OR = 1.17, p = 0.072). Conclusion MELD score ⩾ 10 is associated with higher mortality and morbidity in patients undergoing radical cystectomy compared with lower MELD scores. Risk-stratification using MELD score may assist clinicians in identifying high-risk patients to provide adequate preoperative counseling, optimize perioperative conditions, and even consider nonsurgical alternatives.
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Affiliation(s)
- Christian Habib Ayoub
- Division of Urology, Department of Surgery,
American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Dakroub
- American University of Beirut Medical School,
American University of Beirut, Beirut, Lebanon
| | - Jose M. El-Asmar
- Division of Urology, Department of Surgery,
American University of Beirut Medical Center, Beirut, Lebanon
| | - Adel Hajj Ali
- Cleveland Clinic, Heart, Vascular &
Thoracic Institute, Cleveland, Ohio, USA
| | - Hadi Beaini
- American University of Beirut Medical School,
American University of Beirut, Beirut, Lebanon
| | - Suhaib Abdulfattah
- American University of Beirut Medical School,
American University of Beirut, Beirut, Lebanon
| | - Albert El Hajj
- Division of Urology, Department of Surgery,
American University of Beirut Medical Center, PO BOX: 11-0236, Riad El Solh,
Beirut 1107 2020, Lebanon
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de Ruiter BM, Keijzer AN, Hulshof MC, Bins AD, de Reijke TM, Oddens JR. Quality of Life following Chemoradiotherapy for Localized Muscle Invasive Bladder Carcinoma: A Systematic Review. Bladder Cancer 2021; 7:463-475. [PMID: 38993986 PMCID: PMC11181811 DOI: 10.3233/blc-210011] [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: 02/02/2021] [Accepted: 07/09/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Health Related Quality of Life (HRQoL) is an important factor regarding treatment for localized Muscle Invasive Bladder Carcinoma (MIBC), as it may affect choice of treatment. The impact of chemoradiotherapy (CRT) for MIBC on HRQoL has not yet been well-established. OBJECTIVE To systematically evaluate evidence regarding HRQoL as assessed by validated questionnaires after definitive treatment with CRT for localized MIBC. METHODS We performed a critical review of PubMed/MEDLINE, EMBASE, and the Cochrane Library in October 2020. Two reviewers independently screened articles for eligibility and assessed the methodological quality of the included articles using Joanna Briggs Institute critical appraisal tools. A narrative synthesis was undertaken. RESULTS Of 579 articles identified, 11 studies were eligible for inclusion, including three RCTs and 8 non-randomized studies, reporting on HRQoL data for 606 CRT patients. Global health declined at End of Treatment (EoT), and recovered 3 months following treatment. Physical function declined from baseline at EoT and recovered between 3 and 24 months and was maintained at 5 years follow up. CRT had little effect on social and emotional function in the short-term, but HRQoL results in the long-term were lower compared to the general population. Urinary function declined from baseline at EoT, but returned to baseline at 6 months following CRT. After initial decline in bowel function, a complete return to baseline occurred 4 years following treatment. The majority of studies assessing sexual function showed no to little effect on sexual function. CONCLUSIONS HRQoL recovers to baseline within 3 months to 2 years in almost all domains. The amount of available evidence regarding HRQoL following CRT for MIBC is limited and the quality of evidence is low.
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Affiliation(s)
- Ben-Max de Ruiter
- Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Maarten C.C.M. Hulshof
- Department of Radiation Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Adriaan D. Bins
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Theo M. de Reijke
- Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Jorg R. Oddens
- Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
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Li Y, Chen X, Li D, Yang Z, Bai Y, Hu S, Liu Z, Gu J, Zhang X. Identification of prognostic and therapeutic value of CC chemokines in Urothelial bladder cancer: evidence from comprehensive bioinformatic analysis. BMC Urol 2021; 21:173. [PMID: 34893045 PMCID: PMC8665633 DOI: 10.1186/s12894-021-00938-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/30/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Urothelial bladder cancer (BC) is one of the most prevalent malignancies with high mortality and high recurrence rate. Angiogenesis, tumor growth and metastasis of multiple cancers are partly modulated by CC chemokines. However, we know little about the function of distinct CC chemokines in BC. METHODS ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, cBioPortal, GeneMANIA, and TIMER were used for analyzing differential expression, prognostic value, protein-protein interaction, genetic alteration and immune cell infiltration of CC chemokines in BC patients based on bioinformatics. RESULTS The results showed that transcriptional levels of CCL2/3/4/5/14/19/21/23 in BC patients were significantly reduced. A significant relation was observed between the expression of CCL2/11/14/18/19/21/23/24/26 and the pathological stage of BC patients. BC patients with high expression levels of CCL1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL15, CCL17, CCL18, CCL19, CCL22, CCL25, CCL27 were associated with a significantly better prognosis. Moreover, we found that differentially expressed CC chemokines are primarily correlated with cytokine activity, chemokines receptor binding, chemotaxis, immune cell migration. Further, there were significant correlations among the expression of CC chemokines and the infiltration of several types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). CONCLUSIONS This study is an analysis to the potential role of CC chemokines in the therapeutic targets and prognostic biomarkers of BC, which gives a novel insight into the relationship between CC chemokines and BC.
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Affiliation(s)
- Yuxin Li
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Xiong Chen
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Dongjie Li
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Zhiming Yang
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Yao Bai
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Sheng Hu
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Zhenyu Liu
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Jie Gu
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. .,Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
| | - XiaoBo Zhang
- Department of Geriatric Urology, Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. .,Urolithiasis Institute of Central South University, Changsha, Hunan, 410008, People's Republic of China.
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45
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Comprehensive Analysis of CPA4 as a Poor Prognostic Biomarker Correlated with Immune Cells Infiltration in Bladder Cancer. BIOLOGY 2021; 10:biology10111143. [PMID: 34827136 PMCID: PMC8615209 DOI: 10.3390/biology10111143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/29/2021] [Accepted: 11/04/2021] [Indexed: 12/24/2022]
Abstract
Simple Summary The overexpression of Carboxypeptidase A4 (CPA4) has been observed in plenty of types of cancer and has been elucidated to promote tumor growth and invasion; however, its role in bladder urothelial carcinoma (BLCA) is still unclear. Therefore, we aimed to show the prognostic role of CPA4 and its relationship with immune infiltrates in BLCA. We confirmed that the overexpression of CPA4 is associated with shorter overall survival, disease-specific survival, progress-free intervals, and higher dead events. Moreover, we found that several infiltrating immune cells (Th1cell, Th2 cell, T cell exhaustion, and Tumor-associated macrophage) were correlated with the expression of CPA4 in bladder cancer using TIMER2 and GEPIA2. In conclusion, CPA4 may be a novel and great prognostic biomarker based on bioinformation analysis in BLCA. Abstract Carboxypeptidase A4 (CPA4) has shown the potential to be a biomarker in the early diagnosis of certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via the TIMER2, STRING, and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA + GETx database. The connection between CPA4 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan–Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared with matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that the overexpression of CPA4 is linked with shorter OS, DSF(Disease-specific survival), PFI(Progression-free interval), and increased diagnostic potential using Kaplan–Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.
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Derivation and Comprehensive Analysis of Aging Patterns in Patients with Bladder Cancer. DISEASE MARKERS 2021; 2021:3385058. [PMID: 34721733 PMCID: PMC8553474 DOI: 10.1155/2021/3385058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/29/2021] [Indexed: 12/24/2022]
Abstract
Background Aging is an essential risk factor for cancer. However, aging-related genes (ARGs) have not been comprehensively analyzed in bladder cancer (BC). Therefore, the study is aimed at derivating a risk stratification system for BC patients based on ARGs. Methods Public databases were used to acquire ARGs sets, transcriptome files, and clinical data. The “limma” package was then used to screen for differential ARGs while also using univariate Cox regression analysis to explore for prognostic ARGs. The “ConsensusClusterPlus” package was used to perform aging patterns in BC patients based on the above prognostic ARGs. Subsequently, aging patterns were investigated in survival prediction, mutation landscape, immunotherapy, immunological checkpoints, and immune microenvironment. We likewise utilized gene enrichment analysis to explore the biological functions that were behind the findings. To construct a risk signature and nonogram for prognostic prediction, we used LASSO and Cox regression analysis based on differential genes in aging patterns. In addition, we plotted a nomogram and validate the accuracy of the risk signature in GEO and TCGA cohorts. We explored the possible biological mechanism using GSEA analysis and preliminarily identified a hub gene using PPI network. Finally, we validated the expression of hub gene in BC cell lines. Results We screened 84 downregulated ARGs, 74 upregulated ARGs, and 32 prognostic ARGs in the human aging genome resource. The aging patterns based on prognostic genes had excellent survival prediction (p < 0.001) and discriminatory ability in 405 BC patients. In addition, we found no significant differences in aging patterns in mutation analysis, which were all characterized by TP53, TTN, and KMT2D mutations. It is worth noting that cluster B in the aging patterns has a better response to immunotherapy and a more active immune microenvironment (p < 0.05). In addition, gene enrichment analysis showed that aging patterns may be related to biological processes such as Staphylococcus aureus infection, phagosome, and cytokine-cytokine receptor interaction. Subsequently, we constructed a risk signature based on 16 differential genes from different aging patterns and had good survival prediction ability in both GEO and TCGA cohort. Specifically, survival analysis revealed a significantly shorter survival time in the high-risk group than in the low-risk group (TCGA and GEO, p < 0.001). In addition, AUC values in the ROC analysis predicted 1, 3, and 5 years in TCGA cohort that are 0.713, 0.714, and 0.738, respectively. AUC values predicted 1, 3, and 5 years in GEO cohort that are 0.606, 0.663, and 0.718, respectively. There is no doubt that risk score was an independent prognostic factor from results of multivariate Cox regression analysis in BC patients (p < 0.001). There were also significant differences in immune cell infiltration, immune checkpoint, and immune score between the two groups (p < 0.05), but it should not be ignored that the correlation with the HLA expression was weak. Finally, we identified and validated CLIC3 as a hub gene that may be involved in the Wnt signaling pathway, etc. Conclusion We provided robust evidences that aging patterns based on ARGs can guide targeted therapy and survival prediction in BC patients.
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Wang X, Yu J, Chen J, Hou Y, Du Z, Huang H, Tang S, Han Y, Ding C, Xue Z. Copy number variation analysis of m 6 A regulators identified METTL3 as a prognostic and immune-related biomarker in bladder cancer. Cancer Med 2021; 10:7804-7815. [PMID: 34668652 PMCID: PMC8559456 DOI: 10.1002/cam4.3981] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/12/2021] [Accepted: 05/05/2021] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Growing evidence has demonstrated an indispensable role for N6 -methyladenosine (m6 A) in human diseases, but the copy number variations (CNVs) of m6 A regulatory genes in bladder cancer (BLCA) remains largely unknown. METHODS We investigated the CNVs on all known m6 A regulatory genes using the Cancer Genome Atlas (TCGA) database. The association between CNV events and clinicopathological as well as molecular characteristics of BLCA patients were explored. Gene set enrichment analysis (GSEA) was implemented to reveal relative cellular processes. Association between m6 A regulatory genes and immune infiltrates was analyzed by The Tumor Immune Estimation Resource (TIMER) database. RESULTS CNV events of m6 A regulatory genes were frequently observed in BLCA. CNVs of METTL3, METTL14, and METTL16 correlated with molecular characteristics of BLCA patients including TP53 mutation. CNVs of METTL3 associated with the overall survival (OS) of BLCA patients. METTL3 was also associated with several cancer-related cellular processes, including mitotic spindle assembly, G2/M checkpoint, and E2F targets signaling pathway. Besides, the CNVs of m6 A regulatory genes were correlated with specific kinds of immune infiltrates. CONCLUSIONS There are significant correlations between m6 A regulatory genes with CNVs and clinicopathological characteristics. METTL3 with CNVs were associated with the immune infiltrates and performed as a prognostic marker in BLCA.
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Affiliation(s)
- Xiaoshuai Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jingwei Yu
- Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jinbao Chen
- Zhongshan Medical College of Sun Yat-sen University, Guangzhou, China
| | - Yingdong Hou
- Zhongshan Medical College of Sun Yat-sen University, Guangzhou, China
| | - Zefeng Du
- Zhongshan Medical College of Sun Yat-sen University, Guangzhou, China
| | - Haoyang Huang
- Zhongshan Medical College of Sun Yat-sen University, Guangzhou, China
| | - Siqi Tang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Yueyin Han
- Zhongshan Medical College of Sun Yat-sen University, Guangzhou, China
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhicheng Xue
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, China, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Expression of proto-oncogene c-Myc in patients with urinary bladder transitional cell carcinoma. Curr Urol 2021; 15:231-233. [PMID: 35069088 PMCID: PMC8772624 DOI: 10.1097/cu9.0000000000000053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/17/2020] [Indexed: 11/26/2022] Open
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Dillon M, Lopez A, Lin E, Sales D, Perets R, Jain P. Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers. Cancers (Basel) 2021; 13:cancers13205059. [PMID: 34680208 PMCID: PMC8534156 DOI: 10.3390/cancers13205059] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/30/2021] [Accepted: 10/06/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation, and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid and blood cancers. Research often focuses on targeting the pathway to disrupt cancer initiation and progression. We aimed to provide an overview of the pathway’s physiologic role and regulation, interactions with other pathways involved in cancer development, and mutations that lead to malignancy. Several blood and solid cancers are analyzed to illustrate the impact of the pathway’s dysregulation, stemming from mutation or viral induction. Finally, we summarized different approaches to targeting the pathway and the associated novel treatments being researched or having recently achieved approval. Abstract The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
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Zhou L, Wang B, Zhang Y, Yao K, Liu B. Silencing circ‑BIRC6 inhibits the proliferation, invasion, migration and epithelial‑mesenchymal transition of bladder cancer cells by targeting the miR‑495‑3p/XBP1 signaling axis. Mol Med Rep 2021; 24:811. [PMID: 34542161 PMCID: PMC8477182 DOI: 10.3892/mmr.2021.12451] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/14/2021] [Indexed: 01/11/2023] Open
Abstract
Circular RNAs (circRNAs) regulate gene expression by acting as a 'sponge' for microRNAs (miRs) and play crucial roles in tumorigenesis, including in bladder cancer (BC). circRNA‑baculoviral IAP repeat‑containing 6 (circ‑BIRC6) has been reported to participate in the pathogenesis of several cancer types. The present study aimed to elucidate the roles and potential mechanisms of circ‑BIRC6 in the progression of BC. circ‑BIRC6 expression levels in BC cell lines were determined using reverse transcription‑quantitative PCR. Following circ‑BIRC6 knockdown, cell proliferation, invasion and migration were detected using Cell Counting Kit‑8, colony formation, Transwell and wound healing assays, respectively. Western blotting was also conducted to evaluate the expression levels of X‑box binding protein 1 (XBP1) and epithelial‑mesenchymal transition (EMT)‑associated proteins. In addition, rescue experiments were performed using by transfecting a miR‑495‑3p inhibitor into T24 cells following circ‑BIRC6 knockdown. The interactions between circ‑BIRC6, miR‑495‑3p and XBP1 was verified using dual luciferase reporter assays. Moreover, T24 cells with circ‑BIRC6 knockdown and miR‑495‑3p inhibitor transfection were used for the tumor‑bearing experiment. Tumor growth was observed and Ki‑67 expression was determined using immunohistochemistry. The results demonstrated that circ‑BIRC6 expression was upregulated in BC cell lines. Moreover, circ‑BIRC6 knockdown notably attenuated the proliferation, invasion, migration and EMT of BC cells, which was blocked by the miR‑495‑3p inhibitor. It was also identified that circ‑BIRC6 sponged miR‑495‑3p to regulate XBP1 expression. In addition, results from the xenograft experiments indicated that the knockdown of circ‑BIRC6 and miR‑495‑3p expression significantly inhibited tumor growth. It was also found that the expression levels of XBP1, Ki‑67 and EMT‑associated proteins in tumor tissues of the co‑transfection group were markedly restored compared with the circ‑BIRC6 knockdown group. In conclusion, these findings demonstrated that circ‑BIRC6 knockdown suppressed BC tumorigenesis and progression via regulation of the miR‑495‑3p/XBP1 signaling axis, offering a promising therapeutic target for the treatment of BC.
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Affiliation(s)
- Lei Zhou
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Bingzhi Wang
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yichuan Zhang
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Kun Yao
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Bin Liu
- Department of Urology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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