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Freitas R, Peixoto A, Santos LL, Ferreira JA. Glycan-based therapeutic approaches for bladder cancer: Overcoming clinical barriers. Biochim Biophys Acta Rev Cancer 2025; 1880:189327. [PMID: 40274080 DOI: 10.1016/j.bbcan.2025.189327] [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: 01/03/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Abstract
Bladder cancer (BLCA) remains a significant global health concern, being characterized by high incidence, recurrence, and mortality rates. Disease heterogeneity and rapid progression pose major challenges for effective management and identification of actionable biomarkers. Conventional therapies often fail to successfully achieve disease control, urging the development of novel, personalized approaches. In recent years, anti-tumour immunotherapy approaches in both pre-clinical and clinical settings have boomed. However, the efficacy of these strategies has been limited by the low mutational burden in some tumours, which hinders neoantigen presentation and the identification of BLCA-specific signatures. Cancer-associated aberrant glycosylation presents a unique opportunity for identifying BLCA-specific glycosignatures and developing innovative targeted therapeutics. This review provides a comprehensive overview of the clinical challenges in BLCA management and emerging novel therapies. Furthermore, it highlights the potential of glycosylation alterations as a unique opportunity for developing glycan-based therapies, potentially revolutionizing BLCA treatment strategies.
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Affiliation(s)
- Rui Freitas
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; INEB - Institute for Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal; Health School of University Fernando Pessoa, 4249-004 Porto, Portugal; Department of Surgical Oncology, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal..
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Kayar K, Kayar R, Karabay E, Ozdemir BB, Tosun C, Gumrukcu G, Ozturk MI, Yucebas OE. Prognostic role of pathological substaging in high-grade pT1 bladder cancer undergoing BCG therapy: Insights on recurrence and progression. Urol Oncol 2025:S1078-1439(25)00174-7. [PMID: 40413062 DOI: 10.1016/j.urolonc.2025.05.004] [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: 01/22/2025] [Revised: 04/21/2025] [Accepted: 05/02/2025] [Indexed: 05/27/2025]
Abstract
INTRODUCTION/OBJECTIVES Bladder cancer is a common malignancy, with pT1 tumors carrying a higher risk of recurrence and progression compared to other non-muscle-invasive bladder cancers (NMIBC). Substaging of pT1 tumors into superficial (pT1a) and deeper (pT1b) invasion into the lamina propria has shown potential prognostic value. This study investigates the impact of pT1 substaging on predicting progression and recurrence in patients with high-grade pT1 bladder cancer treated with Bacillus Calmette-Guérin (BCG) therapy. MATERIALS AND METHODS A retrospective analysis was conducted on 99 patients with primary high-grade pT1 bladder cancer who underwent transurethral resection of the bladder tumor (TURBT) followed by BCG therapy. Patients were stratified into pT1a and pT1b subgroups based on pathological findings. Predictors of disease progression and recurrence were assessed using logistic regression, adjusting for age, tumor size, carcinoma in situ (CIS), and multiplicity. RESULTS Of the 99 patients, 71.7% were classified as pT1a, and 28.3% as pT1b. Disease progression was significantly more frequent in pT1b cases (P < 0.001), particularly in the presence of concurrent CIS (P = 0.002). Logistic regression identified pT1b substaging (odds ratio [OR]: 28.9, 95% confidence interval [CI]: 12.4-58.7) and CIS (OR: 8.65, 95% CI: 3.21-18.8) as independent predictors of progression. DISCUSSION Pathological substaging of pT1 bladder cancer provides critical prognostic insights. Patients with pT1b tumors, especially those with concurrent CIS, are at higher risk for disease progression and may benefit from intensified management strategies. Incorporating pT1 substaging into routine pathological evaluations can improve risk stratification and inform individualized treatment planning.
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Affiliation(s)
- Kemal Kayar
- Department of Urology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.
| | - Ridvan Kayar
- Department of Urology, Van Training and Research Hospital, University of Health Sciences, Van, Türkiye
| | - Emre Karabay
- Department of Urology, Acibadem M.A. Aydinlar University, School of Medicine, Acıbadem Hospital, Istanbul, Turkey
| | - Bugrahan Buhur Ozdemir
- Department of Urology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
| | - Cagatay Tosun
- Department of Urology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
| | - Gulistan Gumrukcu
- Department of Pathology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
| | - Metin Ishak Ozturk
- Department of Urology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
| | - Omer Ergin Yucebas
- Department of Urology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
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Campistol M, Lozano F, Carrion A, Raventós CX, Morote J, Trilla E. Active Surveillance in Non-Muscle Invasive Bladder Cancer: A Systematic Review. Cancers (Basel) 2025; 17:1714. [PMID: 40427211 PMCID: PMC12110289 DOI: 10.3390/cancers17101714] [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: 04/13/2025] [Revised: 05/06/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Bladder cancer is the ninth most common cancer globally, with most cases classified as non-muscle-invasive bladder cancer (NMIBC). While transurethral resection of the bladder tumor (TURBT) remains the gold-standard treatment, its complications, high recurrence rates, and economic burden have prompted interest in alternative strategies like active surveillance (AS) for low-grade and low-grade NMBIC recurrences. AS minimizes surgical interventions and patient burden, but lacks standardized protocols for inclusion criteria and follow-up schedules. Most studies suggest intensive monitoring during the first year, with criteria often based on tumor size, number, and grade. ACQUISITION OF EVIDENCE A comprehensive literature search was conducted in December 2024 using Pubmed, Cochrane, and Trip databases to identify studies on AS for low-grade NMBIC recurrences. Only English studies were included, with Boolean operators used to refine the search. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Population, Intervention, Comparison and Outcomes (PICO) selection criteria were followed. The Newcastle-Ottawa quality assessment scale was used to analyze the quality of the included studies. EVIDENCE SYNTHESIS This systematic review included 11 studies evaluating AS for NMIBC. Early studies, such demonstrated AS as a feasible alternative to TURBT, with low progression rates. Subsequent research confirmed its safety in selected patients, with tumor growth and positive cytology being the main reasons for intervention. More recent investigations, further supported AS as a viable strategy, highlighting the low risk of stage and grade progression and its potential to reduce surgical interventions. CONCLUSIONS AS may be considered an alternative approach for low-risk NMIBC recurrences. However, there is need for prospective studies and personalized approaches to optimize AS, addressing follow-up strategies, inclusion criteria and progression thresholds.
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Affiliation(s)
- Míriam Campistol
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
| | - Fernando Lozano
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
- Research Unit in Biomedicine and Translational Oncology, Research Institute Vall Hebron University Hopital (VHIR), 08035 Barcelona, Spain
| | - Albert Carrion
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
- Research Unit in Biomedicine and Translational Oncology, Research Institute Vall Hebron University Hopital (VHIR), 08035 Barcelona, Spain
| | - Carles Xavier Raventós
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
- Research Unit in Biomedicine and Translational Oncology, Research Institute Vall Hebron University Hopital (VHIR), 08035 Barcelona, Spain
| | - Juan Morote
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
- Research Unit in Biomedicine and Translational Oncology, Research Institute Vall Hebron University Hopital (VHIR), 08035 Barcelona, Spain
| | - Enrique Trilla
- Department of Urology, Vall d’Hebron Hospital, Passeig de la Vall d’Hebron 119, 08035 Barcelona, Spain; (F.L.); (A.C.); (C.X.R.); (J.M.); (E.T.)
- Department of Surgery, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain
- Research Unit in Biomedicine and Translational Oncology, Research Institute Vall Hebron University Hopital (VHIR), 08035 Barcelona, Spain
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Kir G, Cecikoglu GE, Aydin A, Yildirim A. The clinical relevance of cut-off percentage for high-grade urothelial carcinoma within low-grade urothelial carcinoma: A determining factor? Urol Oncol 2025; 43:329.e9-329.e21. [PMID: 39505583 DOI: 10.1016/j.urolonc.2024.10.016] [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: 06/03/2024] [Revised: 09/21/2024] [Accepted: 10/14/2024] [Indexed: 11/08/2024]
Abstract
AIMS The aim of the study was to analyze the cut-off value for the percentage of the high-grade (HG) component that has clinical significance in urothelial carcinoma (UC). MATERIAL AND METHODS The study included a total of 362 patients, mixed-grade UC (MGUC) patients were classified as Combine Group (CG) 1 based on the presence of less than 5% HG areas. High-grade papillary UC (HGPUC) patients were grouped based on HG component proportions: CG2 (≥5%-<50% HG), CG3 (≥50%-<100% HG), and pure HGPUC (PHGPUC) for 100% HG components. RESULTS There was a statistically significant difference between low-grade papillary UC (LGPUC) and CG1, CG2, or CG3, as well as LGPUC and PHGPUC, in terms of cancer-specific survival (CSS) (hazard ratio (HR) = 19.85, 95% confidence interval (CI) = 2.30-171.10 P = 0.007, HR = 28.38, 95% CI = 3.50-229.97 P = 0.002, HR = 18.64, 95% CI = 2.26-153.64 P = 0.007, and HR = 35.41, 95% CI = 4.61-271.72 P < 0.001, respectively). There was no statistically significant difference between PHGPUC and CG1, CG2, or CG3 in terms of CSS. CONCLUSIONS These findings suggest that even the presence of less than 5% HGPUC within LGPUC significantly impacts CSS. Furthermore, the increase in the percentage of HGPUC beyond 5% does not substantially influence the CSS. Based on these findings, disclosing the percentage of the high-grade component may be crucial for future patient management and treatment.
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Affiliation(s)
- Gozde Kir
- Pathology Department, Istanbul Medeniyet University Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey; Dr.Erkin Caddesi. Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi, Patoloji Laboratuarı, Kadıköy-Istanbul, Turkey.
| | - Gozde Ecem Cecikoglu
- Pathology Department, Amasya Sabuncuoglu Serefeddin Training and Research Hospital, Amasya, Turkey; Kirazlıdere Caddesi, Amasya Sabuncuoğlu Şerefeddin Eğitim ve Araştırma Hastanesi Patoloji Laboratuvarı, Amasya, Turkey
| | - Abdullah Aydin
- Pathology Department, Istanbul Medeniyet University Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey; Dr.Erkin Caddesi. Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi, Patoloji Laboratuarı, Kadıköy-Istanbul, Turkey
| | - Asif Yildirim
- Urology Department, Istanbul Medeniyet University Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey; Dr. Erkin caddesi, Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi Üroloji birimi, Kadıköy-Istanbul, Turkey
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Yuan Y, Chu G, Ma Q, Liang Z, Liang Y, Niu H. Multiscale screening and identifying specific targets for artesunate in suppressing bladder cancer. Front Pharmacol 2025; 16:1584502. [PMID: 40303931 PMCID: PMC12037512 DOI: 10.3389/fphar.2025.1584502] [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: 02/27/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025] Open
Abstract
Background Bladder cancer (BLCA) is a highly aggressive urinary malignancy with high mortality in advanced stages, posing a significant health risk. Artesunate (ART), a derivative of artemisinin, has been demonstrated with potent anti-tumor activity in some studies, yet its specific targets for BLCA and the molecular mechanisms have not been fully elucidated. Purpose This study screened potential targets of ART against BLCA through network pharmacology, followed by molecular docking simulations and experimental validation in vitro and in vivo to elucidate the underlying mechanisms. Methods This study identified the critical targets of BLCA and ART by employing multiscale screening from public databases, and a protein-protein interaction (PPI) network was constructed. Molecular docking simulations confirmed the stable binding of ART to the identified tumor-related targets promoting BLCA progression. These computational findings were further validated through experiments in vivo and in vitro, ensuring robust and reliable results. Results Based on network pharmacology analysis, the effects of ART on BLCA were multifaceted. Molecular docking simulations confirmed the binding stability of ART with core targets. The experiments in vitro proved that ART could inhibit BLCA cell proliferation and migration by downregulating the expression of BCL-2, inducing Caspase 3-mediated apoptosis, resulting in cell cycle arrest and suppressing the PI3K/Akt/mTOR classical pathway involved in BLCA growth and metabolism. Studies in vivo also confirmed that ART had significant anti-tumor effects with minimal side effects. Conclusion This study identified the mechanism by which ART inhibited BLCA through multiple specific targets, revealing its potential anti-cancer pathways and laying the foundation for the clinical application of traditional Chinese medicine in BLCA therapy.
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Affiliation(s)
- Yi Yuan
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guangdi Chu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qingyue Ma
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhijuan Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ye Liang
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haitao Niu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
- Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Cao M, Yang G, Zhao T, Zhang L, Wang D, Cao Y, Chen H, Jin D, Zhang R, Hao Y, Huang L, Liu W, Zhang Y, Xue N, Xue W. Development and Validation of the UriMee Model: A Methylation-based Diagnostic Tool for Early Diagnosis of Urothelial Carcinoma. Eur Urol Oncol 2025:S2588-9311(25)00079-3. [PMID: 40240254 DOI: 10.1016/j.euo.2025.03.004] [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: 09/05/2024] [Revised: 02/24/2025] [Accepted: 03/11/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND AND OBJECTIVE Urothelial carcinoma (UC) is a common malignancy that imposes a significant health care burden. Current diagnostic methods are limited by their invasiveness and low sensitivity, particularly for detecting low-grade tumors. Noninvasive, accurate, and reliable diagnostic tests for an early diagnosis of UC are urgently needed. METHODS UC-specific DNA methylation biomarkers were identified by combining public datasets from The Cancer Genome Atlas and Gene Expression Omnibus with a cohort from Renji Hospital (n = 50). Using the Least Absolute Shrinkage and Selection Operator regression, we developed a diagnostic model, termed the UriMee model, by selecting key biomarkers from a model cohort (n = 322) and subsequently validating it in an independent cohort (n = 131). The diagnostic performance of the assay was evaluated and compared with that of urine cytology. KEY FINDINGS AND LIMITATIONS At 30% threshold probability, the UriMee model demonstrated high sensitivity (92%) and specificity (92%) in distinguishing UC cases, with particularly strong performance in early-stage tumors (83% sensitivity for Ta, 93% for T1, and 100% for Tis). It significantly outperformed urine cytology, offering greater sensitivity (90% vs 25%, p < 0.001) while maintaining comparable specificity. Additionally, the model was highly effective in identifying upper tract urothelial carcinoma (UTUC), achieving sensitivity of 96%. The study's limitations include the necessity for larger multicenter studies and long-term follow-up to validate the findings and assess the test's effectiveness across diverse populations, as well as its utility in monitoring disease progression and recurrence. CONCLUSIONS The UriMee test demonstrated high sensitivity and specificity, particularly in detecting early-stage tumors and UTUC, significantly outperforming traditional methods.
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Affiliation(s)
- Ming Cao
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Guoliang Yang
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Tingting Zhao
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China; Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translation Research Center, Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Lianhua Zhang
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Dandan Wang
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Yang Cao
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Haige Chen
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Di Jin
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Ruiyun Zhang
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yuping Hao
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Longfei Huang
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Wei Liu
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Yang Zhang
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Na Xue
- GloriousMed Clinical Laboratory Co. Ltd., Shanghai, China
| | - Wei Xue
- Department of Urology, Renji Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
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Rousseau C, Baumgartner P, Heymann MF, Taupin M, Geffroy M, Chatal JF, Gautier G, Allam N, Gaschet J, Eychenne R, Guérard F, Gestin JF, Varmenot N, Chérel M. Preclinical and Clinical Feasibility Studies as the First Step Before Forthcoming Intravesical Instillation of [ 211At]At-anti-CA-IX Antibody (ATO-101™) Study in Patients with Non-Muscle-Invasive Bladder Cancer Unresponsive to Standard of Care. Cancers (Basel) 2025; 17:1190. [PMID: 40227816 PMCID: PMC11987989 DOI: 10.3390/cancers17071190] [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: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/25/2025] [Indexed: 04/15/2025] Open
Abstract
INTRODUCTION Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [211At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. METHODS The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [211At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [89Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. RESULTS The measurement of the affinity constant of [211At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [89Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [211At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. CONCLUSIONS Preclinical and clinical data demonstrate the promising therapeutic role of 211At-targeted alpha agents in NMIBC, and the [211At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years.
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Affiliation(s)
- Caroline Rousseau
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
| | - Pierre Baumgartner
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
| | - Marie-Françoise Heymann
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Research Pathology Platform, Tumor Heterogeneity and Precision Medicine, F-44800 Saint-Herblain, France
| | - Manon Taupin
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Research Pathology Platform, F-44800 Saint-Herblain, France
| | - Maïwenn Geffroy
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
| | - Jean-François Chatal
- Atonco, Pôle Bio-Ouest Laennec, Rue du Moulin de la Rousselière, F-44800 Saint-Herblain, France;
| | - Gaëlle Gautier
- Chelatec, 1 Rue Aronnax, F-44817 Saint-Herblain, France;
| | - Nadia Allam
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
| | - Joëlle Gaschet
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
| | - Romain Eychenne
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint-Herblain, France
| | - François Guérard
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
| | - Jean-François Gestin
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
| | - Nicolas Varmenot
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint-Herblain, France
| | - Michel Chérel
- Institut de Cancérologie de l’Ouest, F-44800 Saint-Herblain, France; (P.B.); (M.-F.H.); (M.T.); (M.G.); (N.A.); (J.G.); (J.-F.G.); (N.V.); (M.C.)
- Nantes Université, INSERM, CNRS, CRCI2NA, Univ Angers, F-44000 Nantes, France; (R.E.); (F.G.)
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8
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Feng Z, Mei Y, Chen H, Li L, Jin T, Li X, Gou X, Chen Y. Starvation-induced HBP metabolic reprogramming and STAM2 O-GlcNAcylation facilitate bladder cancer metastasis. Sci Rep 2025; 15:8480. [PMID: 40075080 PMCID: PMC11903858 DOI: 10.1038/s41598-025-92579-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Metabolic reprogramming and epigenetic alternations are implicated in tumor progression and metastasis, but the metabolic and epigenetic mechanisms underlying lymphatic and distant metastasis of bladder cancer (BCa) remain poorly understood. In this study, we provide the first evidence that glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the crucial rate-limiting switch of the hexosamine biosynthesis pathway (HBP), is considerably upregulated in the nutrient-scarce microenvironment and causes a high O-GlcNAcylation of signal transducing adaptor molecule 2 (STAM2), further facilitating lymphatic and distant metastasis of BCa. Inhibition of GFAT1 and O-GlcNAcylation impairs STAM2-induced metastasis. Mechanistically, O-GlcNAcylation of STAM2 at serine 375 augments protein stability by inhibiting proteasome degradation and ubiquitination. In addition, STAM2 O-GlcNAcylation facilitates Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) phosphorylation, thus activating the epithelial‒mesenchymal transition. In summary, these results reveal a novel metabolic and epigenetic link mediating tumor metastasis, and indicate that targeting GFAT1 and STAM2 O-GlcNAcylation may serve as a promising treatment strategy for BCa progression.
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Affiliation(s)
- Zhenwei Feng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yuhua Mei
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Haonan Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
| | - Li Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Tian Jin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
| | - Xinyuan Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xin Gou
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China.
| | - Yong Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuan Jiagang, Yuzhong District, Chongqing, 400010, China.
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9
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Yazdani Nia I, Ambale-Venkatesh B. Editorial for "Multiparametric MRI-Based Deep Learning Radiomics Model for Assessing 5-Year Recurrence Risk in Non-Muscle Invasive Bladder Cancer". J Magn Reson Imaging 2025; 61:1457-1458. [PMID: 39258759 DOI: 10.1002/jmri.29592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 05/22/2024] [Indexed: 09/12/2024] Open
Affiliation(s)
- Iman Yazdani Nia
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medicine, John's Hopkins University, Baltimore, Maryland, USA
| | - Bharath Ambale-Venkatesh
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medicine, John's Hopkins University, Baltimore, Maryland, USA
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10
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Zhu RL, Kaufmann JD, Phan MD, Patel S, Ayanambakkam A, Stratton KL. Paradoxical Emergence of Cutaneous Squamous Cell Carcinoma During Pembrolizumab Treatment for Non-muscle Invasive Bladder Cancer and Subsequent Successful Therapeutic Adjustments. Cureus 2025; 17:e80293. [PMID: 40201877 PMCID: PMC11977670 DOI: 10.7759/cureus.80293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2025] [Indexed: 04/10/2025] Open
Abstract
Pembrolizumab is a well-established immune checkpoint inhibitor option for patients with locally advanced or metastatic urothelial cell carcinoma and has had emerging use in the treatment of bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Additionally, it is a preferred treatment option in patients with unresectable cutaneous squamous cell carcinoma (cSCC). Here, we present a 73-year-old patient with BCG-unresponsive NMIBC treated with pembrolizumab and intravesical gemcitabine who developed a locally advanced cSCC of the lower extremity. The emergence of cSCC during the initial treatment regimen for NMIBC was notable given that the patient lacked traditional risk factors for cSCC and since pembrolizumab is indicated for the management of both cancers. Therapeutic adjustments were made to address the new cSCC, with pembrolizumab being discontinued and replaced with cetuximab. The new regimen was tolerated well, and follow-up over the next year demonstrated the resolution of the cSCC following these changes. In addition to highlighting the rare possibility of a secondary malignancy arising as an adverse event, this report underscores the importance of early identification and individualized therapeutic adjustments for optimizing patient outcomes.
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Affiliation(s)
- Ryan L Zhu
- Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Jaisa D Kaufmann
- Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Minh D Phan
- Department of Internal Medicine, Division of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Sanjay Patel
- Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Adanma Ayanambakkam
- Department of Internal Medicine, Division of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - Kelly L Stratton
- Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
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11
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Wang M, Chen W, Li M, Lin F, Zhong J, Ouyang W, Cai C, Zeng G, Liu H. TE-RPA: One-tube telomerase extension recombinase polymerase amplification-based electrochemical biosensor for precise diagnosis of urothelial carcinoma. Biosens Bioelectron 2025; 271:117042. [PMID: 39662170 DOI: 10.1016/j.bios.2024.117042] [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: 07/07/2024] [Revised: 11/18/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
Telomerase demonstrates potential as a non-invasive urinary biomarker for urothelial carcinoma (UC); however, current detection methods are either labor-intensive or exhibit suboptimal performance. There is a need for alternative approaches to enable rapid and early diagnosis of UC. In this study, we propose TE-RPA, which combines telomerase extension (TE) with recombinase polymerase amplification (RPA) for one-tube isothermal amplification. The GC content and length of the telomerase substrate were first considered during the screening process. TE-RPA exponential amplification was initiated by the addition of MgOAc along with a forward primer derived from the products of telomerase-mediated extension and a corresponding reverse primer. The amplification product from TE-RPA was subsequently detected using CRISPR-Cas12a system for trans-cleavage of signal probes on the surface of screen-printed electrode in an electrochemical biosensor, resulting in a current change that reflects the corresponding concentration of telomerase. The TE-RPA/CRISPR-Cas12a/electrochemical sensing platform achieves a limit of detection (LOD) for telomerase activity as low as a single-cell level. In addition, the platform attained an area under the curve (AUC) value of 0.9589 in a clinical evaluation involving urine samples from 43 suspected UC patients. Overall, our proposed platform not only offers an efficient method for telomerase isothermal amplification but also provides a portable and precise diagnostic tool for UC.
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Affiliation(s)
- Mengting Wang
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Wenzhe Chen
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Mingzhao Li
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Fuyang Lin
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Jiehui Zhong
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Wenrui Ouyang
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China
| | - Chao Cai
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
| | - Guohua Zeng
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
| | - Hongxing Liu
- Guangdong Provincial Key Laboratory of Urology, Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Institute of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, China.
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12
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Barkay O, Keskin E. Intravesical BCG: A Double-Edged Sword? The Untold Story of Infection Risks. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:379. [PMID: 40142190 PMCID: PMC11943905 DOI: 10.3390/medicina61030379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/28/2025]
Abstract
Background and Objectives: Intravesical Bacillus Calmette-Guérin (BCG) therapy remains a cornerstone in the treatment of non-muscle-invasive bladder carcinoma due to its efficacy in reducing recurrence and progression rates. However, its use is associated with various complications-including urinary tract infections (UTIs)-which necessitates further exploration. This study aims to analyze UTIs occurring during intravesical BCG treatment, emphasizing the microbial spectrum, resistance patterns, and risk factors from an infectious diseases and clinical microbiology perspective. Materials and Methods: A retrospective analysis was conducted on 240 patients diagnosed with non-muscle-invasive bladder carcinoma who received intravesical BCG therapy between 2010 and 2021. Data were collected from hospital records, including demographic characteristics, comorbidities, number of intravesical BCG cycles, and microbiological findings. UTIs were classified based on susceptibility patterns, and statistical analyses were performed to determine associations between clinical variables and UTI risk. Results: UTIs developed in 39.1% (n = 94) of patients, with 25.8% (n = 62) caused by susceptible pathogens and 13.3% (n = 32) by resistant pathogens. The most common causative agent was Escherichia coli (80.7% in susceptible UTIs, 43.8% in resistant UTIs), followed by Pseudomonas aeruginosa and Klebsiella pneumoniae. The presence of diabetes mellitus and chronic kidney disease significantly increased the risk of developing a UTI (p < 0.05). A higher number of intravesical BCG cycles correlated with increased UTI occurrence (p < 0.001). Serum C-reactive protein (CRP) levels were significantly elevated in patients with resistant UTIs, while procalcitonin levels were not a reliable predictor of UTI occurrence. Conclusions: Intravesical BCG therapy is associated with a significant incidence of UTIs, particularly among patients with predisposing comorbidities. The increasing prevalence of antibiotic-resistant infections underscores the need for careful monitoring and targeted antimicrobial stewardship strategies. CRP may serve as a useful adjunctive marker for UTI diagnosis in this setting. Future studies should focus on optimizing infection control measures and refining diagnostic criteria to differentiate between BCG-related inflammation and infectious complications.
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Affiliation(s)
- Orçun Barkay
- Infectious Diseases and Clinical Microbiology Department, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24002, Turkey
| | - Ercüment Keskin
- Urology Department, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan 24002, Turkey;
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13
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Juric I, Fink EE, Qiu H, Desprez PE, Ravi A, Holton M, Makarov V, Almassi N, Min B, Getz G, Chan TA, Alban T, Ting AH, Lee BH. Single Cell RNA-sequencing of BCG naïve and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM-mediated immune-suppressive pathway. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.13.638074. [PMID: 40027617 PMCID: PMC11870429 DOI: 10.1101/2025.02.13.638074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Non-muscle invasive bladder cancer (NMIBC) represents 70-80% patients with newly diagnosed bladder cancer, and Bacillus Calmette-Guérin (BCG) remains a cornerstone treatment for intermediate-and high-risk NMIBC to prevent disease recurrence and progression. However, many patients experience recurrence after induction BCG, posing significant challenges in the management of the disease. We conducted single cell RNA sequencing on freshly collected NMIBC samples, distinguishing between those naïve to BCG treatment and those that recurred post-BCG treatment. We observed a clear activation of inflammatory pathways across cell types during recurrence, but these were not associated with canonical immune checkpoint or T cell exhaustion phenotypes. Analysis of cell-to-cell communication revealed enhanced interactions between T cells and urothelial cells in BCG-recurrence, predominantly modulated by CD6 and ALCAM. Furthermore, we found CD6 hi T cells to be immunosuppressed and enriched in recurrent samples, suggesting a potential role for CD6 as an immune evasion signal in NMIBC. SIGNIFICANCE These findings uncover a novel mechanism responsible for bladder cancer recurrence after BCG treatment. Enhanced T cell-urothelial cell communication in recurrent tumors mediated by CD6 and ALCAM leads to an immunosuppressed state. Thus, CD6 may have potential as a therapeutic target to augment BCG response in non-muscle invasive bladder cancer.
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14
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Siddhartha R, Singhai A, Goel A, Garg M. CD105-microvessel density analysis and its clinical value in urothelial carcinoma of bladder patients. Biomarkers 2025; 30:23-36. [PMID: 39668728 DOI: 10.1080/1354750x.2024.2435876] [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: 07/21/2024] [Accepted: 11/24/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND Endoglin/CD105-microvessel density (CD105-MVD) is identified as one of the most potential methods for semi-quantification of angiogenesis in human cancer tissues. Present study aimed to examine the diagnosticand prognostic value of CD105-MVD in two clinically distinct subtypes of urothelial carcinoma of bladder (UCB) namely non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) patients. METHODS Message expression of endoglin was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and MVD measurement was done by immunohistochemical staining in 90 UCB [NMIBC: 60; MIBC: 30] patients. SEM studies were carried out to examine tumor vasculature and extent of neoangiogenesis in NMIBC and MIBC patients. RESULTS Elevated message expression of CD105 showed statistical significance with tumor stage, grade, smoking/tobacco chewing history in NMIBC andage in MIBC cohort. Higher values of CD105-MVD showed statistical relevance with tumor stage, grade, size, smoking/tobacco chewing history in NMIBC cohort. Kaplan Meier test identified high CD105-MVD as strong predictor of poor RFS in NMIBC patients. CONCLUSIONS Association of CD105 expression and MVD with the clinicohistopathological features as well as poor survival outcomes potentially identify it as a preferred marker of clinical significance in a given cohort of UCB patients.Clinical significanceStrong association of CD105 at message level with the demographics of UCB patients identifies it as a marker of diagnosis in a given cohort of patients.Survival analysis examined CD105-MVD as an independent strong predictor of poor recurrence free survival in NMIBC patients.Present study provides clear evidence of increased vascular density, vascular sprouts proliferation and new blood vessel formation with disease aggressiveness indicating CD105 as a preferred marker of neoangiogenesis in the given cohort of patients.The study describes CD105-MVD as a biomarker of diagnosis and prognosis with the sensitivity of 91.67% and 93.33% in a given cohort of NMIBC and MIBC patients.
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Affiliation(s)
- Rohit Siddhartha
- Department of Biochemistry, University of Lucknow, Lucknow, India
| | - Atin Singhai
- Department of Pathology, King George's Medical University, Lucknow, India
| | - Apul Goel
- Department of Urology, King George's Medical University, Lucknow, India
| | - Minal Garg
- Department of Biochemistry, University of Lucknow, Lucknow, India
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15
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Jeong MS, Baek SW, Yang GE, Mun JY, Kim JA, Kim TN, Nam JK, Choi YH, Lee JS, Chu IS, Leem SH. Chemoresistance-motility signature of molecular evolution to chemotherapy in non-muscle-invasive bladder cancer and its clinical implications. Cancer Lett 2025; 610:217339. [PMID: 39608442 DOI: 10.1016/j.canlet.2024.217339] [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] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024]
Abstract
Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature confirmed interaction with cancer-associated fibroblasts (CAFs). The high-CrM groups mainly included NMIBC patients with poor prognosis (progression-free survival analysis by log-rank test based on UROMOL cohort, p < 0.001), T1-high grade, high European Association of Urology (EAU) risk score, and also included MIBC patients with a history of metastases. Additionally, relative ineffectiveness was observed for BCG (the chi-square test based on BRS cohort, p = 0.02) and immune checkpoint inhibitors (ICIs) in patients with high-CrM. In addition, we identified five drugs that can be used with gemcitabine in these patients, including doxorubicin, docetaxel, paclitaxel, napabucacin, and valrubicin, and verified their efficacy. This study provides insights into NMIBC progression to MIBC via molecular evolution. The CrM signature can assess NMIBC prognosis and BCG treatment response, suggesting alternative treatments. Furthermore, these results need to be prospectively validated.
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Affiliation(s)
- Mi-So Jeong
- Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, South Korea
| | - Seung-Woo Baek
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea
| | - Gi-Eun Yang
- Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Health Sciences, The Graduated of Dong-A University, Busan, 49315, South Korea
| | - Jeong-Yeon Mun
- Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - Jeong Ah Kim
- Center for Scientific Instrumentation, Korea Basic Science Institute, Chungbuk, 28119, South Korea
| | - Tae-Nam Kim
- Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Biomedical Research Institute and Pusan National University Hospital, Busan, 49241, South Korea
| | - Jong-Kil Nam
- Department of Urology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 50612, South Korea
| | - Yung-Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Anti-Aging Research Center, Dong-eui University, Busan, 47227, South Korea
| | - Ju-Seog Lee
- Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA
| | - In-Sun Chu
- Bioneer Corporation, Daejeon, 34013, South Korea
| | - Sun-Hee Leem
- Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Department of Health Sciences, The Graduated of Dong-A University, Busan, 49315, South Korea.
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16
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Tang J, Fan L, Huang T, Yang R, Yang X, Liao Y, Zuo M, Zhang N, Zhang J. Development and external validation of a model to predict recurrence in patients with non-muscle invasive bladder cancer. Front Immunol 2025; 15:1467527. [PMID: 39867903 PMCID: PMC11757240 DOI: 10.3389/fimmu.2024.1467527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/16/2024] [Indexed: 01/28/2025] Open
Abstract
Background Most patients initially diagnosed with non-muscle invasive bladder cancer (NMIBC) still have frequent recurrence after urethral bladder tumor electrodesiccation supplemented with intravesical instillation therapy, and their risk of recurrence is difficult to predict. Risk prediction models used to predict postoperative recurrence in patients with NMIBC have limitations, such as a limited number of included cases and a lack of validation. Therefore, there is an urgent need to develop new models to compensate for the shortcomings and potentially provide evidence for predicting postoperative recurrence in NMIBC patients. Methods Clinicopathologic characteristics and follow-up data were retrospectively collected from 556 patients with NMIBC who underwent transurethral resection of bladder tumors by electrocautery (TURBT) from January 2014 to December 2023 at the Affiliated Hospital of Zunyi Medical University and 167 patients with NMIBC who underwent the same procedure from January 2018 to April 2024 at the Third Affiliated Hospital of Zunyi Medical University. Independent risk factors affecting the recurrence of NMIBC were screened using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis. Cox risk regression models and randomized survival forest (RSF) models were developed. The optimal model was selected by comparing the area under the curve (AUC) of the working characteristics of the subjects in both and presented as a column-line graph. Results The study included data from 566 patients obtained from the affiliated hospital of Zunyi Medical University and 167 patients obtained from the third affiliated hospital of Zunyi Medical University. Tumor number, urine leukocytes, urine occult blood, platelets, and red blood cell distribution width were confirmed as independent risk factors predicting RFS by Lasso-Cox regression analysis. The Cox proportional risk regression model and RSF model were constructed based on Lasso, which showed good predictive efficacy in both training and validation sets, especially the traditional Cox proportional risk regression model. In addition, the discrimination, consistency, and clinical utility of the column-line graph were assessed using C-index, area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Patients at high risk of recurrence can be identified early based on risk stratification. Conclusion Internal and external validation has demonstrated that the model is highly discriminative and stable and can be used to assess the risk of early recurrence in NMIBC patients and to guide clinical decision-making.
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Affiliation(s)
- Jiajia Tang
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Longmei Fan
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Tianyu Huang
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Rongrong Yang
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Xinqi Yang
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Yuanjian Liao
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Mingshun Zuo
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Neng Zhang
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
| | - Jiangrong Zhang
- School of Nursing, Zunyi Medical University, Zunyi, China
- Department of Urology, the Affiliated Hospital of ZunYi Medical University, Zunyi, China
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17
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Yoshihara K, Ito K, Kimura T, Yamamoto Y, Urabe F. Single-cell RNA sequencing and spatial transcriptome analysis in bladder cancer: Current status and future perspectives. Bladder Cancer 2025; 11:23523735251322017. [PMID: 40034247 PMCID: PMC11864234 DOI: 10.1177/23523735251322017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/23/2025] [Indexed: 03/05/2025]
Abstract
Background Bladder cancer is one of the most prevalent malignancies, and the mechanisms underlying its progression and the role of the tumor microenvironment (TME) are unclear. Recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) enable detailed analysis of the cellular heterogeneity, gene expression, and cell-cell interactions in bladder diseases. Methodology We conducted a comprehensive search for recent articles that have investigated bladder diseases using scRNA-seq and ST. Results scRNA-seq and ST have led to significant discoveries in bladder disease research. These technologies have enabled the identification of multiple molecular subtypes within individual tumors and of the mechanisms of treatment resistance. Additionally, molecular differences based on gender have been explored, explaining the heterogeneity of the incidence and progression of bladder cancer. These findings deepen our understanding of the pathology of bladder diseases and highlight the transformative potential of scRNA-seq and ST in identifying novel biomarkers and therapeutic targets. Conclusions Integrating scRNA-seq and ST has considerably enhanced our understanding of tumor heterogeneity and the tumor microenvironment within tissues. These insights may lead to the development of personalized therapies and the improvement of patient outcomes. Several challenges, such as technical limitations and access difficulties, need to be addressed for the future clinical application of these technologies.
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Affiliation(s)
- Kentaro Yoshihara
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kagenori Ito
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Fumihiko Urabe
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
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18
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Chakra MA, Lassila R, El Beayni N, Mott SL, O'Donnell MA. Prognostic role of the neutrophil/lymphocyte ratio in high-risk BCG-naïve non-muscle-invasive bladder cancer treated with intravesical gemcitabine/docetaxel. BJU Int 2025; 135:125-132. [PMID: 39082304 DOI: 10.1111/bju.16486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2024]
Abstract
OBJECTIVES To investigate the role of pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in the prediction of response to sequential intravesical therapy, gemcitabine and docetaxel (Gem/Doce), given to patients with bacille Calmette-Guérin (BCG)- naïve high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS A retrospective analysis was conducted on 115 patients who received intravesical Gem/Doce for high-risk NMIBC between January 2011 and December 2021. Data were computed as the median (interquartile range [IQR]) or mean (standard deviation [sd]). Cox regression analysis was performed to determine if neutrophilia, NLR, platelet counts, and PLR before instillation therapy were predictive of recurrence-free survival (RFS) and overall survival (OS). Predictive performance was estimated using Uno's C-statistic. RESULTS The median (IQR) follow-up for the overall cohort was 23 (13-36) months. The mean (sd) values for NLR, PLR and platelet counts were 3.4 (2.3), 142.2 (85.5), and 225.2 (75.1) × 109/L, respectively. NLR was associated with RFS, with a hazard ratio of 1.32 (95% confidence interval CI 1.19-1.46). Concordance analysis showed that NLR had a good ability to predict RFS (C-index: 0.7, P < 0.01). The PLR and platelet count were not associated with RFS and did not predict recurrence. In terms of OS, none of these cellular inflammatory markers showed any prediction value. CONCLUSION Pre-treatment NLR provides some predictive accuracy for RFS in high-risk BCG-naïve patients receiving Gem/Doce. Further prospective trials are needed to validate this finding.
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Affiliation(s)
- Mohamad Abou Chakra
- Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Riitta Lassila
- Unit of Coagulation Disorders, Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland
- Research Program Unit in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Nancy El Beayni
- Unit of Coagulation Disorders, Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sarah L Mott
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
| | - Michael A O'Donnell
- Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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19
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Myszka A, Ciesla M, Siekierzynska A, Sendera A, Constantinou C, Karpinski P, Wysiadecki G, Balawender K. Predictive Molecular Biomarkers of Bladder Cancer Identified by Next-Generation Sequencing-Preliminary Data. J Clin Med 2024; 13:7701. [PMID: 39768623 PMCID: PMC11677048 DOI: 10.3390/jcm13247701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/12/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The majority of patients with bladder cancer suffer from tumour recurrence. Identifying prognostic factors for tumour recurrence is crucial for treatment and follow-up in affected patients. The study aimed to assess the impact of somatic mutations in bladder cancer on patient outcomes and tumour recurrence. Methods: The study group comprised 46 patients with urothelial bladder cancers referred for transurethral resection of the tumour. A molecular study on tumour-derived DNA was performed using next-generation sequencing. Somatic mutations were screened in 50 genes involved in carcinogenesis. Results: We identified 81 variants in 23 genes, including 54 pathogenic mutations, 18 likely pathogenic variants, and 9 variants of unknown significance. The most frequently mutated genes were FGFR3, PIK3CA, and TP53 in 52%, 35%, and 24% of tumours, respectively. The average tumour-free survival was significantly longer in cases with mutations in the PIK3CA gene (p = 0.02), and mutations in the PIK3CA gene were associated with a decreased risk of tumour recurrence (Hazard Ratio = 0.26; 95% CI: 0.11-0.62; p = 0.018). Conclusions: The PIK3CA gene was shown to be a predictive marker of a low risk of bladder tumour recurrence. Molecular screening of bladder cancers supported predictive biomarkers of tumour recurrence and showed that tumour-free survival is molecularly determined.
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Affiliation(s)
- Aleksander Myszka
- Institute of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.C.); (A.S.); (K.B.)
| | - Marek Ciesla
- Institute of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.C.); (A.S.); (K.B.)
| | - Aleksandra Siekierzynska
- Department of Biotechnology and Plant Physiology, University of Rzeszow, 35-601 Rzeszow, Poland;
| | - Anna Sendera
- Institute of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.C.); (A.S.); (K.B.)
| | | | - Pawel Karpinski
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Grzegorz Wysiadecki
- Department of Normal and Clinical Anatomy, Medical University of Lodz, 90-752 Łodz, Poland;
| | - Krzysztof Balawender
- Institute of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland; (M.C.); (A.S.); (K.B.)
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20
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Gu Y, Wang J, Luo Z, Luo X, Lin LL, Ni S, Wang C, Chen H, Su Z, Lu Y, Gan LY, Chen Z, Ye J. Multiwavelength Surface-Enhanced Raman Scattering Fingerprints of Human Urine for Cancer Diagnosis. ACS Sens 2024; 9:5999-6010. [PMID: 39420643 DOI: 10.1021/acssensors.4c01873] [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] [Indexed: 10/19/2024]
Abstract
Label-free surface-enhanced Raman spectroscopy (SERS) is capable of capturing rich compositional information from complex biosamples by providing vibrational spectra that are crucial for biosample identification. However, increasing complexity and subtle variations in biological media can diminish the discrimination accuracy of traditional SERS excited by a single laser wavelength. Herein, we introduce a multiwavelength SERS approach combined with machine learning (ML)-based classification to improve the discrimination accuracy of human urine specimens for bladder cancer (BCa) diagnosis. This strategy leverages the excitation-wavelength-dependent SERS spectral profiles of complex matrices, which are mainly attributed to wavelength-related vibrational changes in individual analytes and differences in the variation ratios of SERS intensity across different wavelengths among various analytes. By capturing SERS fingerprints under multiple excitation wavelengths, we can acquire more comprehensive and unique chemical information on complex samples. Further experimental examinations with clinical urine specimens, supported by ML algorithms, demonstrate the effectiveness of this multiwavelength strategy and improve the diagnostic accuracy of BCa and staging of its invasion with SERS spectra from increasing numbers of wavelengths. The multiwavelength SERS holds promise as a convenient, cost-effective, and broadly applicable technique for the precise identification of complex matrices and diagnosis of diseases based on body fluids.
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Affiliation(s)
- Yuqing Gu
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Jiayi Wang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China
| | - Zhewen Luo
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Xingyi Luo
- College of Physics and Center for Quantum Materials and Devices, Chongqing University, Chongqing 401331, P. R. China
| | - Linley Li Lin
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Shuang Ni
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Cong Wang
- Beijing Key Laboratory of Microstructure and Properties of Solids, Institute of Microstructure and Property of Advanced Materials, College of Materials Science and Engineering, Beijing University of Technology, Beijing 100124, P. R. China
| | - Haoran Chen
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Zehou Su
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Yao Lu
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
| | - Li-Yong Gan
- College of Physics and Center for Quantum Materials and Devices, Chongqing University, Chongqing 401331, P. R. China
| | - Zhou Chen
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
- Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Jian Ye
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, P. R. China
- Institute of Medical Robotics, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China
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21
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Monjaras-Avila CU, Luque-Badillo AC, Bacon JVM, Wyatt AW, So A, Chavez-Munoz C. A novel approach to engineering three-dimensional bladder tumor models for drug testing. Sci Rep 2024; 14:26883. [PMID: 39506094 PMCID: PMC11542063 DOI: 10.1038/s41598-024-78440-0] [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: 04/30/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024] Open
Abstract
Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients' cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air-liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients' cells. To demonstrate the 3D cancer model's effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model's superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies.
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Affiliation(s)
- C U Monjaras-Avila
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - A C Luque-Badillo
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - J V M Bacon
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
| | - A W Wyatt
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - A So
- Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - C Chavez-Munoz
- Department of Medicine, Faculty of Medicine, University of British Columbia, H.B. 2660 Oak Street, Vancouver, BC, V6H3Z6, Canada.
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22
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Abou Heidar N, Mahmood AW, Khan M, Harrington G, Ahmad A, Abdelhaq D, Colan N, Whitt J, Sullivan D, Howlader M, Plecas Z, Ahmed Z, Jing Z, Li Q, Guru KA, Hussein AA. Does Ta Low-grade Urothelial Carcinoma of the Bladder With Focal High-grade Features Carry Worse Prognosis? The Roswell Park Comprehensive Cancer Center Experience. Urology 2024; 193:136-142. [PMID: 38914229 DOI: 10.1016/j.urology.2024.06.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/21/2024] [Accepted: 06/13/2024] [Indexed: 06/26/2024]
Abstract
OBJECTIVE To describe the management and outcomes of patients with Ta predominantly low-grade urothelial carcinoma with focal high-grade features (FHG) (<5%), compared to those with Ta low grade (LG) and Ta high grade (HG). METHODS Retrospective review of all patients who underwent transurethral resection of bladder tumor between 2005 and 2023. Patients with Ta disease were identified and categorized into LG, FHG, and HG. Kaplan Meier method was used to depict high-grade recurrence, T-stage progression, and radical cystectomy-free survival. RESULTS Four hundred forty-nine patients with Ta disease were identified (LG 48%, FHG 12%, and HG 40%). Patients with FHG (32%) had a second-look transurethral resection of bladder tumor more frequently compared to LG (7%) and HG (29%) (P <.01). They received intravesical therapy more frequently compared to LG (36% vs 20%) but lower than HG (55%) (P <.01). They received radical cystectomy less frequently (7% compared to 20% for HG and 11% for LG, P = .01). HG recurrence-free survival at 1, 3, and 5years was HG (68%, 52%, and 43%), FHG (74%, 53%, and 49%), and LG (87%, 79%, and 73%) (log-rank P <.01). T progression-free survival at 1, 3, and 5years was HG (84%, 77%, and 70%), FHG (92%, 82%, and 82%), and LG (94%, 89%, and 85%) (log-rank P = .02). Cystectomy-free survival at 1, 3, and 5years was HG (92%, 84%, and 80%), FHG (96%, 94%, and 94%), and LG (99%, 95%, and 92%) (log-rank P <.01). CONCLUSION Patients with Ta FHG seem to behave more like Ta HG disease in terms of high-grade recurrences, but they are less likely to experience T-stage progression and convert to cystectomy.
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Affiliation(s)
- Nassib Abou Heidar
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Abdul Wasay Mahmood
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Mohammad Khan
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Grace Harrington
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Ali Ahmad
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Dawod Abdelhaq
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Nicholas Colan
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Jor'Dan Whitt
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Daniel Sullivan
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Muhsinah Howlader
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Zachary Plecas
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Zaineb Ahmed
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Zhe Jing
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Qiang Li
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Khurshid A Guru
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Ahmed A Hussein
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
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23
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Huang J, Lin L, Mao D, Hua R, Guan F. Prognostic value of neutrophil-to-lymphocyte ratio in patients with non-muscle-invasive bladder cancer with intravesical Bacillus Calmette-Guérin immunotherapy: a systematic review and meta-analysis. Front Immunol 2024; 15:1464635. [PMID: 39507536 PMCID: PMC11538002 DOI: 10.3389/fimmu.2024.1464635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/03/2024] [Indexed: 11/08/2024] Open
Abstract
Background The predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette-Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy. Methods For this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results Seven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34-5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13-2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy. Conclusion This meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT. Systematic review registration https://inplasy.com/inplasy-2024-7-0058/, identifier 202470058.
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Affiliation(s)
- Jiaguo Huang
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Li Lin
- Department of Science and Education, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Dikai Mao
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Runmiao Hua
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Feifei Guan
- Physical Examination Center, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
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24
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Sharma A, Raghavendra RT, Biswal D, Yadav P, Goel S, Sharma S. Rationale of restaging transurethral resection of bladder tumor in patients with nonmuscle invasive bladder cancer in the current era. Urol Ann 2024; 16:288-291. [PMID: 39600588 PMCID: PMC11587940 DOI: 10.4103/ua.ua_50_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 08/05/2024] [Indexed: 11/29/2024] Open
Abstract
Background We present retrospective data of patients with nonmuscle invasive bladder cancer (NMIBC) who underwent restaging transurethral resection of bladder tumor (Re-TURBT) at a tertiary care center. Materials and Methods Records of all NMIBC patients undergoing Re-TURBT between March 2021 and September 2023 were retrospectively analyzed. Patients were risk stratified based on TURBT pathology. Re-TURBT was performed between 4 and 6 weeks. Adverse features such as number, size, and appearance were noted. Patients with persistent disease at Re-TURBT were counseled for early cystectomy with urinary diversion or intravesical Bacillus Calmette-Guerin (BCG). In case of disease upstaging, patients were counseled for radical cystectomy. Results Thirty-eight NMIBC patients (30 males and 8 females) underwent Re-TURBT. Six patients had residual/persistent disease at 6 weeks, all high risk and high grade (HG, P value not significant, P = 0.31). There was no association with number and appearance of tumors with residual/persistence at 6 weeks. The mean lesion size on imaging in cases with and without residual disease was 3.32 ± 0.86 versus 3.39 ± 0.92 cm, respectively, P value not significant (0.868). There was no residual disease in the low-grade (LG) pT1 group, but HG pTa and pT1 (n = 3) had residual disease. Four HG pT1 patients opted for early cystectomy. Two patients each had pT0 and two pT2. At 3 months of follow-up, urethral strictures were seen both in high risk and intermediate risk. Among four patients who had stricture, meatal stenosis was common (50%, n = 2). Two patients had long-segment stricture requiring perineal urethrostomy with stage I Johannsen repair. All HG pT1 lesion patients eventually underwent cystectomy (3 were under staged and two treated completely with TURBT, one with TURBT + BCG and one patient progressed to metastasis). Conclusion Re-TURBT is essential for the management of HG pTa and HG pT1 lesions for accurate staging and treatment of residual disease. However, LG pT1 patients can safely be excluded from Re-TURBT.
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Affiliation(s)
- Amit Sharma
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
| | - R. T. Raghavendra
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
| | - Deepak Biswal
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
| | - Pradhuman Yadav
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
| | - Saryu Goel
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
| | - Satyadeo Sharma
- Department of Urology and Renal Transplant, AIIMS, Raipur, Chhattisgarh, India
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25
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Sari Motlagh R, Ghoreifi A, Yanagisawa T, Kawada T, Ahyai S, Merseburger AS, Abufaraj M, Abern M, Djaladat H, Daneshmand S, Shariat SF. Surveillance of non-muscle-invasive bladder cancer with blue-light cystoscopy: a meta-analysis. BJU Int 2024; 134:526-533. [PMID: 38658172 DOI: 10.1111/bju.16364] [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] [Indexed: 04/26/2024]
Abstract
OBJECTIVE To compare the value of flexible blue-light cystoscopy (BLC) vs flexible white-light cystoscopy (WLC) in the surveillance setting of non-muscle-invasive bladder cancer (NMIBC). METHODS All major databases were searched for articles published before May 2023 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome was the accuracy of flexible BLC vs WLC in detecting bladder cancer recurrence among suspicious bladder lesions. RESULTS A total of 10 articles, comprising 1634 patients, were deemed eligible for the quantitative synthesis. In the meta-analysis focusing on the detection of disease recurrence, there was no difference between flexible BLC and WLC (odds ratio [OR] 1.08, 95% confidence interval [CI] 0.82-1.41)]; the risk difference (RD) showed 1% of flexible BLC, corresponding to a number needed to treat (NNT) of 100. In the subgroup meta-analysis of detection of carcinoma in situ (CIS) only, there was again no significant difference between flexible BLC and WLC (OR 1.19, 95% CI 0.82-1.69), BLC was associated with a RD of 2% (NNT = 50). The positive predictive values for flexible BLC and WLC in detecting all types of recurrence were 72% and 66%, respectively, and for CIS they were 39% and 29%, respectively. CONCLUSION Surveillance of NMIBC with flexible BLC could detect more suspicious lesions and consequently more tumour recurrences compared to flexible WLC, with a increase in the rate of false positives leading to overtreatment. A total of 100 and 50 flexible BLC procedures would need to be performed to find on additional tumor and CIS recurences, respectively. A risk-stratified strategy for patient selection could be considered when using flexible BLC for the surveillance of NMIBC patients.
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Affiliation(s)
- Reza Sari Motlagh
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Alireza Ghoreifi
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - 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
| | - Tatsushi Kawada
- 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
| | - Sascha Ahyai
- Department of Urology, Medical University of Graz, Graz, Austria
| | - Axel S Merseburger
- Department of Urology, Campus Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Mohammad Abufaraj
- Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan
- The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan
| | - Michael Abern
- Department of Urology, Duke University, Durham, NC, USA
| | - Hooman Djaladat
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Siamak Daneshmand
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria
- Department of Urology, Weill Cornell Medical College, New York, NY, USA
- Department of Urology, University of Texas Southwestern, Dallas, TX, USA
- Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan
- Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
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Sheybaee Moghaddam F, Dwabe S, Mar N, Safdari L, Sabharwal N, Goldberg H, Daneshvar M, Rezazadeh Kalebasty A. The Role of Maximal TURBT in Muscle-Invasive Bladder Cancer: Balancing Benefits in Bladder Preservation and Beyond. Cancers (Basel) 2024; 16:3361. [PMID: 39409980 PMCID: PMC11475991 DOI: 10.3390/cancers16193361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/27/2024] [Accepted: 09/28/2024] [Indexed: 10/20/2024] Open
Abstract
Radical cystectomy with lymph node dissection and urinary diversion is the gold-standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC). However, in patients who refuse cystectomy, or in whom cystectomy carries a high risk, bladder-preserving therapies remain potential options. Bladder preservation therapies can include maximal debulking transurethral resection of bladder tumor (TURBT), concurrent chemoradiation therapy, followed by cystoscopy to assess response. At this time, maximal TURBT is recommended for patients prior to the initiation of chemoradiation therapy or in patients with residual bladder tumors after the completion of chemoradiation therapy. That being said, TURBT carries significant risks such as bladder perforation, bleeding, and infection, ultimately risking delayed systemic treatment. Hence, understanding its role within trimodal therapy is crucial to avoid undue suffering in patients. Herein, we review the current literature on the impact of debulking TURBT in non-metastatic MIBC.
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Affiliation(s)
| | - Sami Dwabe
- Department of Medicine, University of California Irvine, Orange, CA 92868, USA
| | - Nataliya Mar
- Department of Medicine, University of California Irvine, Orange, CA 92868, USA
| | - Leila Safdari
- Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Navin Sabharwal
- Department of Urology, University of Irvine, Orange, CA 92868, USA; (N.S.)
| | - Hanan Goldberg
- Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA;
| | - Michael Daneshvar
- Department of Urology, University of Irvine, Orange, CA 92868, USA; (N.S.)
| | - Arash Rezazadeh Kalebasty
- Department of Medicine, University of California Irvine, Orange, CA 92868, USA
- Department of Urology, University of Irvine, Orange, CA 92868, USA; (N.S.)
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27
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Siddhartha R, Goel A, Singhai A, Garg M. Matrix Metalloproteinases -2 and -9, Vascular Endothelial Growth Factor, Basic Fibroblast Growth Factor and CD105- Micro-Vessel Density are Predictive Markers of Non-Muscle Invasive Bladder Cancer and Muscle Invasive Bladder Cancer Subtypes. Biochem Genet 2024. [DOI: 10.1007/s10528-024-10921-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 09/15/2024] [Indexed: 01/12/2025]
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28
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Abulaban A, Yanchenko N, Briski LM, Punnen S, Jorda M, Kryvenko ON. Stromal and Epithelial Architectural Alterations Mimicking Invasion (Pseudoinvasion) in Noninvasive Papillary Urothelial Carcinoma. Arch Pathol Lab Med 2024; 148:1007-1013. [PMID: 38133938 DOI: 10.5858/arpa.2023-0185-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2023] [Indexed: 12/24/2023]
Abstract
CONTEXT.— Retraction artifact, paradoxic maturation/differentiation, desmoplasia, and complex irregular growth are morphologic criteria of invasion in urothelial carcinoma. OBJECTIVE.— To describe changes mimicking invasion in noninvasive papillary urothelial carcinoma (NPUC). DESIGN.— We reviewed 159 consecutive in-house patients with NPUC for either the presence of pseudoinvasion (irregular carcinoma nests within dense hyalinized stroma in the absence of other criteria of invasion) or precursor findings (stromal hyalinization not yet associated with epithelial architectural alteration). We assessed the correlation of these findings with age, sex, evidence of peripheral vascular disease, tumor grade, tumor infarction, and tumor size. We then followed up the patients clinically for tumor recurrence or progression. RESULTS.— We identified 233 separate NPUCs (136 high grade and 97 low grade) in 125 men and 34 women. Of the 233 tumors, 26 (11.2%) had pseudoinvasion and 24 of 233 tumors (10.3%) had precursor findings. Except for complex irregular growth, no other criteria for invasion were seen. Pseudoinvasion and precursor findings were more common in men (47 of 183 [26%] versus 3 of 50 [6%]; P = .003), larger tumors (mean size, 2.6 versus 1.2 cm; P < .001), and tumors with infarction (33 of 50 [66%] versus 29 of 183 [15.8%]; P < .001). In multivariable analysis, tumor size (odds ratio, 1.49; P =.006), male sex (odds ratio, 6.48; P = .007), and the presence of infarction (odds ratio, 6.59; P < .001) were significant variables. Recurrence rates did not differ between patients with and those without pseudoinvasion (31% [5 of 16] versus 42% [45 of 107], respectively; P = .41). None of the tumors with pseudoinvasion progressed to invasive carcinoma. CONCLUSIONS.— Given the correlation with size and presence of infarcted papillae, we suggest the possibility of tumor ischemia/infarction as a plausible etiology of pseudoinvasion. Awareness of this phenomenon is important for the accurate diagnosis of invasion in papillary urothelial carcinoma.
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Affiliation(s)
- Amr Abulaban
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
| | - Natalia Yanchenko
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
| | - Laurence M Briski
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
| | - Sanoj Punnen
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
| | - Merce Jorda
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
| | - Oleksandr N Kryvenko
- From the Department of Pathology and Laboratory Medicine (Abulaban, Yanchenko, Briski, Jorda, Kryvenko), Desai Sethi Urology Institute (Punnen, Jorda, Kryvenko), Department of Radiation Oncology (Kryvenko), and the Sylvester Comprehensive Cancer Center (Briski, Punnen, Jorda, Kryvenko), University of Miami Miller School of Medicine, Miami, Florida
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Haq F, Sabari S, Háček J, Brisuda A, Ambite I, Cavalera M, Esmaeili P, Wan MLY, Ahmadi S, Babjuk M, Svanborg C. Clinical and molecular response to alpha1-oleate treatment in patients with bladder cancer. Cancer Med 2024; 13:e70149. [PMID: 39254154 PMCID: PMC11386334 DOI: 10.1002/cam4.70149] [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: 02/29/2024] [Revised: 06/11/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol. AIMS To investigate if there are dose-dependent effects of alpha1-oleate. MATERIALS AND METHODS Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. RESULTS Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation. DISCUSSION AND CONCLUSIONS These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.
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Affiliation(s)
- Farhan Haq
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Samudra Sabari
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Jaromir Háček
- Department of Pathology and Molecular MedicineMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Antonín Brisuda
- Department of UrologyMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Ines Ambite
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Michele Cavalera
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Parisa Esmaeili
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Murphy Lam Yim Wan
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Shahram Ahmadi
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
| | - Marek Babjuk
- Department of UrologyMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Catharina Svanborg
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversitySweden
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Plumber SA, Tate T, Al-Ahmadie H, Chen X, Choi W, Basar M, Lu C, Viny A, Batourina E, Li J, Gretarsson K, Alija B, Molotkov A, Wiessner G, Lee BHL, McKiernan J, McConkey DJ, Dinney C, Czerniak B, Mendelsohn CL. Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer. Nat Commun 2024; 15:6538. [PMID: 39095358 PMCID: PMC11297265 DOI: 10.1038/s41467-024-50678-2] [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: 08/28/2023] [Accepted: 07/18/2024] [Indexed: 08/04/2024] Open
Abstract
Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
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Affiliation(s)
- Sakina A Plumber
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - Tiffany Tate
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
- Generation Bio, Cambridge, MA, USA
| | | | - Xiao Chen
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA
- Marine College, Shandong University, Weihai, China
| | - Woonyoung Choi
- Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA
| | - Merve Basar
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA
- Harvard Medical School, Cambridge, MA, USA
| | - Chao Lu
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Aaron Viny
- Department of Medicine, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ekatherina Batourina
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jiaqi Li
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kristjan Gretarsson
- Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Besmira Alija
- Department of Medicine, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrei Molotkov
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - Gregory Wiessner
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - Byron Hing Lung Lee
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James McKiernan
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA
| | - David J McConkey
- Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA
| | - Colin Dinney
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bogdan Czerniak
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cathy Lee Mendelsohn
- Department of Urology, Columbia University Irving Medical Center, New York, NY, USA.
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31
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Zucca LER, Laus AC, Sorroche BP, Paro E, Sussuchi L, Marques RF, Teixeira GR, Berardinelli GN, Arantes LMRB, Reis RM, Cárcano FM. Immune-checkpoint gene expression and BCG response in non-muscle invasive bladder cancer. Transl Oncol 2024; 46:102003. [PMID: 38838438 PMCID: PMC11214516 DOI: 10.1016/j.tranon.2024.102003] [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: 12/22/2023] [Revised: 04/05/2024] [Accepted: 05/19/2024] [Indexed: 06/07/2024] Open
Abstract
METHODS One-hundred-six patients diagnosed with non-muscle invasive bladder cancer and treated with intravesical BCG were included and divided into two groups, BCG-responsive (n = 47) and -unresponsive (n = 59). Immunohistochemistry was used to evaluate PD-L1 expression and MSI was assessed by a commercial multiplex PCR kit. The mRNA expression profile of 15 immune checkpoints was performed using the nCounter technology. For in silico validation, two distinct cohorts sourced from the Gene Expression Omnibus (GEO) database were used. RESULTS Among the 106 patients, only one (<1 %) exhibited MSI instability. PD-L1 expression was present in 9.4 % of cases, and no association was found with BCG-responsive status. We found low gene expression of canonic actionable immune checkpoints PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, while high expression was observed for CD276 (B7-H3), CD47, TNFRSF14, IDO1 and PVR (CD155) genes. High IDO1 expression levels was associated with worst overall survival. The PDCD1, CTLA4 and TNFRSF14 expression levels were associated with BCG responsiveness, whereas TIGIT and CD276 were associated with unresponsiveness. Finally, CD276 was validated in silico cohorts. CONCLUSION In NMIBC, MSI is rare and PD-L1 expression is present in a small subset of cases. Expression levels of PDCD1, CTLA4, TNFRSF14, TIGIT and CD276 could constitute predictive biomarkers of BCG responsiveness.
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Affiliation(s)
- Luis Eduardo Rosa Zucca
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Instituto do Câncer Brasil, Taubaté, Brazil
| | - Ana Carolina Laus
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
| | | | - Eduarda Paro
- Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, Brazil
| | - Luciane Sussuchi
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
| | - Rui Ferreira Marques
- Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
| | | | | | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal; 3ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal
| | - Flavio Mavignier Cárcano
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Oncoclinicas & Co - Medica Scientia Innovation Research (MEDSIR), Sao Paulo, Brazil.
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32
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Nassira K, Aberkane M, El Moudane A, Haloui A, Bennani A. Unusual Association of Large Cell Neuroendocrine Carcinoma of the Bladder and Prostatic Adenocarcinoma Within a 76-Year-Old Man. Cureus 2024; 16:e67651. [PMID: 39314614 PMCID: PMC11417971 DOI: 10.7759/cureus.67651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 09/25/2024] Open
Abstract
Large cell neuroendocrine carcinoma (LCNEC) is one of the rarest types of bladder cancer, with an aggressive course and a poor prognosis. We report a case of LCNEC of the bladder associated with a prostatic adenocarcinoma. A very rare association, to our knowledge, is described for the first time in the literature. The patient was a 76-year-old non-smoker male, who presented with intermittent hematuria and dysuria. Cystoscopy revealed a lesion on the right lateral bladder wall. Biopsy was in favor of a LCNEC with muscle invasion. The CT scan showed the presence of a second lesion in the prostate, confirmed by histological examination. The patient was treated by neoadjuvant chemotherapy of the cisplatin-etoposide type for large-cell bladder neuroendocrine carcinoma, and hormone therapy with luteinizing hormone-releasing hormone (LH-RH) analogs for prostatic adenocarcinoma, followed by radical surgery. Given the rarity of this tumor, LCNEC treatment lacks precision. Many cases are published with different therapeutic strategies. A literature review would be interesting to codify the therapeutic strategy for this rare tumor.
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Affiliation(s)
- Karich Nassira
- Pathology, Mohammed VI University International Hospital, Oujda, MAR
| | - Mahmoud Aberkane
- Pathology and Laboratory Medicine, Faculty of Medicine and Pharmacy of Oujda, Oujda, MAR
| | | | - Anass Haloui
- Pathology, Faculty of Medicine, Mohammed VI University International Hospital, Mohamed I University, Oujda, MAR
| | - Amal Bennani
- Anatomopathology, Faculty of Medicine and Pharmacy of Oujda, Oujda, MAR
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33
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Li L, Jin T, Hu L, Ding J. Alternative splicing regulation and its therapeutic potential in bladder cancer. Front Oncol 2024; 14:1402350. [PMID: 39132499 PMCID: PMC11310127 DOI: 10.3389/fonc.2024.1402350] [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: 03/17/2024] [Accepted: 07/05/2024] [Indexed: 08/13/2024] Open
Abstract
Bladder cancer is one of the leading causes of mortality globally. The development of bladder cancer is closely associated with alternative splicing, which regulates human gene expression and enhances the diversity of functional proteins. Alternative splicing is a distinctive feature of bladder cancer, and as such, it may hold promise as a therapeutic target. This review aims to comprehensively discuss the current knowledge of alternative splicing in the context of bladder cancer. We review the process of alternative splicing and its regulation in bladder cancer. Moreover, we emphasize the significance of abnormal alternative splicing and splicing factor irregularities during bladder cancer progression. Finally, we explore the impact of alternative splicing on bladder cancer drug resistance and the potential of alternative splicing as a therapeutic target.
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Affiliation(s)
- Lina Li
- College of Medicine, Jinhua University of Vocational Technology, Jinhua, Zhejiang, China
| | - Ting Jin
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Liang Hu
- Department of Urology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Jin Ding
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
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34
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Claps F, Biasatti A, Di Gianfrancesco L, Ongaro L, Giannarini G, Pavan N, Amodeo A, Simonato A, Crestani A, Cimadamore A, Hurle R, Mertens LS, van Rhijn BWG, Porreca A. The Prognostic Significance of Histological Subtypes in Patients with Muscle-Invasive Bladder Cancer: An Overview of the Current Literature. J Clin Med 2024; 13:4349. [PMID: 39124615 PMCID: PMC11313590 DOI: 10.3390/jcm13154349] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Bladder cancer (BC) is the tenth most commonly diagnosed malignancy worldwide. In approximately 25% of cases, it presents as a muscle-invasive disease, requiring a radical treatment. Traditionally, the mainstay of treatment has been radical cystectomy (RC), but in the last decade, bladder-sparing treatments have been gaining growing interest. In particular, trimodal therapy (TMT) seems to yield survival results comparable to RC with less morbidity and better quality of life (QoL) outcomes. In this scenario, we aimed at shedding light on the role of the histological subtypes (HS) of BC and their prognostic significance in muscle-invasive BC (MIBC), treated either surgically or with TMT. We performed a narrative review to provide an overview of the current literature on this topic. When compared with patients diagnosed with conventional urothelial carcinoma (UC) of the same disease stage, survival did not appear to be significantly worse across the reports. But when sub-analyzed for separate subtype, some appeared to be independently associated with adverse survival outcomes such as the micropapillary, plasmacytoid, small-cell, and sarcomatoid subtypes, whereas others did not. Moreover, the optimal management remains to be defined, also depending on the therapeutic susceptibility of each histology. From this perspective, multi-disciplinary assessment alongside the routine inclusion of such entities in randomized clinical trials appears to be essential.
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Affiliation(s)
- Francesco Claps
- Department of Surgical Oncology (Urology), Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1006 BE Amsterdam, The Netherlands; (L.S.M.); (B.W.G.v.R.)
- Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Arianna Biasatti
- Urological Clinic, Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Luca Di Gianfrancesco
- Department of Oncological Urology, Veneto Institute of Oncology (IOV) IRCCS, 35128 Padua, Italy; (L.D.G.); (A.A.); (A.P.)
| | - Luca Ongaro
- Department of Urology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK;
| | - Gianluca Giannarini
- Urology Unit, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy; (G.G.); (A.C.)
| | - Nicola Pavan
- Urology Clinic, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy; (N.P.); (A.S.)
| | - Antonio Amodeo
- Department of Oncological Urology, Veneto Institute of Oncology (IOV) IRCCS, 35128 Padua, Italy; (L.D.G.); (A.A.); (A.P.)
| | - Alchiede Simonato
- Urology Clinic, Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90127 Palermo, Italy; (N.P.); (A.S.)
| | - Alessandro Crestani
- Urology Unit, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy; (G.G.); (A.C.)
| | - Alessia Cimadamore
- Institute of Pathological Anatomy, Department of Medicine, University of Udine, 33100 Udine, Italy;
| | - Rodolfo Hurle
- Department of Urology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy;
| | - Laura S. Mertens
- Department of Surgical Oncology (Urology), Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1006 BE Amsterdam, The Netherlands; (L.S.M.); (B.W.G.v.R.)
| | - Bas W. G. van Rhijn
- Department of Surgical Oncology (Urology), Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1006 BE Amsterdam, The Netherlands; (L.S.M.); (B.W.G.v.R.)
| | - Angelo Porreca
- Department of Oncological Urology, Veneto Institute of Oncology (IOV) IRCCS, 35128 Padua, Italy; (L.D.G.); (A.A.); (A.P.)
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Abou Chakra M, Duquesne I, Peyromaure M, Mott SL, Moussa M, O'Donnell MA. A Multinational, Multi-Institutional Study Assessing the Impact of Diabetes Mellitus on the Prognosis of Patients with Non-Muscle Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin. Nutr Cancer 2024; 76:861-869. [PMID: 38973234 DOI: 10.1080/01635581.2024.2374046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024]
Abstract
The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000-2021), and the US (University of Iowa) (2011-2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort (n = 2332). DM II was reported in 13% of the Phase II trial cohort, 14.4% of the FR/LB cohort, and 33.5% of the US (Iowa) cohort. The median follow-up was 24 months in the Phase II trial cohort, 25 months in the FR/LB cohort, and 48 months in the US (Iowa) cohort. In multivariable Cox regression analyses, DMII was not significantly associated with recurrence or progression of the tumor in any of the cohorts included in this study. DMII may not be a clinical prognostic factor for NMIBC patients treated with BCG. Prospective evaluation is needed.
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Affiliation(s)
- Mohamad Abou Chakra
- Department of Urology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA
| | - Igor Duquesne
- Department of Urology, Cochin Hospital, Paris, France
| | | | - Sarah L Mott
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
| | - Mohamad Moussa
- Department of Urology, Lebanese University, Al Zahraa Hospital, Beirut, Lebanon
| | - Michael A O'Donnell
- Department of Urology, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA
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Saizonou I, Lascombe I, Monnien F, Bedgedjian I, Kleinclauss F, Algros MP, Fauconnet S. Concomitant decrease of E- and A-FABP expression predicts worse survival in urothelial bladder cancer patients. Sci Rep 2024; 14:15390. [PMID: 38965292 PMCID: PMC11224272 DOI: 10.1038/s41598-024-65972-8] [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: 03/13/2023] [Accepted: 06/25/2024] [Indexed: 07/06/2024] Open
Abstract
Non-muscle invasive bladder cancers (NMIBC) pTa-pT1 are depicted by a high risk of recurrence and/or progression with an unpredictable clinical evolution. Our aim was to identify, from the original resection specimen, tumors that will progress to better manage patients. We previously showed that A-FABP (Adipocyte- Fatty Acid Binding Protein) loss predicted NMIBC progression. Here we determined by immunohistochemistry the prognostic value of E-FABP (Epidermal-Fatty Acid Binding Protein) expression in 210 tumors (80 pTa, 75 pT1, 55 pT2-T4). Thus, E-FABP low expression was correlated with a high grade/stage, the presence of metastatic lymph nodes, and visceral metastases (p < 0.001). Unlike A-FABP in NMIBC, E-FABP low expression was not associated with RFS or PFS in Kaplan-Meier analysis. But patients of the overall cohort with a high E-FABP expression had a longer mOS (53.8 months vs. 29.3 months, p = 0.029). The immunohistochemical analysis on the same NMIBC tissue sections revealed that when A-FABP is absent, a high E-FABP expression is detected. E-FABP could compensate A-FABP loss. Interestingly, patients, whose original tumor presents both low E-FABP and negative A-FABP, had the worse survival, those maintaining the expression of both markers had better survival. To conclude, the combined evaluation of A- and E-FABP expression allowed to stratify patients with urothelial carcinoma for optimizing treatment and follow-up.
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Affiliation(s)
- Inès Saizonou
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Isabelle Lascombe
- Université Franche-Comté, SINERGIES - LabEx LipSTIC ANR-11-LABX-0021, 25030, Besançon, France
| | - Franck Monnien
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Isabelle Bedgedjian
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - François Kleinclauss
- CHU Besançon, Service Urologie, Andrologie et Transplantation Rénale, 25000, Besançon, France
| | - Marie-Paule Algros
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Sylvie Fauconnet
- Université Franche-Comté, SINERGIES - LabEx LipSTIC ANR-11-LABX-0021, 25030, Besançon, France.
- CHU Besançon, Service Urologie, Andrologie et Transplantation Rénale, 25000, Besançon, France.
- CHU Besançon, Centre Investigation Clinique, Inserm CIC 1431, 25000, Besançon, France.
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Biswas K, Biswas L, Gangopadhyay S, Jana A, Basak T, Manna D, Mandal S. Clinico-demographic Profile of Carcinoma Urinary Bladder-5-Year Experience from a Tertiary Care Centre of Eastern India. Indian J Surg Oncol 2024; 15:206-212. [PMID: 38741638 PMCID: PMC11088605 DOI: 10.1007/s13193-023-01861-2] [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: 05/17/2023] [Accepted: 12/06/2023] [Indexed: 05/16/2024] Open
Abstract
Urinary bladder carcinoma is a disease of the elderly and often presents at an advanced stage due to ignorance and manifestation of symptoms at later stages of the disease. In India, very little data is available regarding the clinico-epidemiological pattern of urinary bladder cancers. In this study, we analysed the clinico-demographic profile of patients with urinary bladder carcinoma, attending a tertiary care centre in Eastern India over the last 5 years. We analysed the database of Oncology OPD of a tertiary care centre in West Bengal in Eastern India and collected the demographic, clinical and treatment data of urinary bladder carcinoma patients who attended our OPD between 2017 and 2021. The objective was to assess the demographic and clinical profile of these patients and compare them with those reported from other parts of India as well as the rest of the world. Majority of patients (70%) were above 50 years of age with a strikingly huge male predominance (male:female = 6.6:1). Transitional cell carcinoma (TCC) was the most common (90%) histology. 67.2% of the cases were muscle-invasive disease at presentation, and 19.3% of the patients presented with metastatic disease with bone (42%) as the most common site of metastasis. Overall, around 22% of patients underwent surgery either with definitive or palliative intent. Sixty-five percent of the patients who received radiotherapy underwent definitive radiation as a part of bladder preservation protocol. Thirty-five percent of all patients received chemotherapy; most of them (50.5%) received chemotherapy as neoadjuvant treatment before definitive therapy. To conclude, it can be said that this study is one of its first from Eastern India and will act as a stepping stone for future studies concentrating on clinico-epidemiological profile, early diagnosis and treatment of carcinoma urinary bladder.
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Affiliation(s)
- Koustav Biswas
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Linkon Biswas
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Soham Gangopadhyay
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Arpan Jana
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Tanmoy Basak
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Debojyoti Manna
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
| | - Srikrishna Mandal
- Department of Radiotherapy, Nilratan Sircar Medical College and Hospital, AJC Bose Road, Kolkata, 700014 West Bengal India
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Qiao Y, Jia Y, Luo L, Li B, Xie F, Wang H, Li S. Development and validation of a nomogram to predict lymph node metastasis in patients with progressive muscle-invasive bladder cancer. Front Oncol 2024; 14:1342244. [PMID: 38817904 PMCID: PMC11137274 DOI: 10.3389/fonc.2024.1342244] [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: 12/05/2023] [Accepted: 05/06/2024] [Indexed: 06/01/2024] Open
Abstract
Purpose To develop and validate a nomogram for preoperative prediction of lymph node metastasis in patients with progressive muscle-invasive bladder cancer. Materials and methods We retrospectively recruited patients, divided them into training and validation cohorts, and gathered patient demographics, pathology data of transurethral bladder tumor resection specimens, imaging findings, and laboratory information. We performed logistic regression analyses, both single-variable and multi-variable, to investigate independent preoperative risk variables and develop a nomogram. Both internal and external validations were conducted to evaluate the predictive performance of this nomogram. Results The training cohort consisted of 144 patients with advanced muscle-invasive bladder cancer, while the validation cohort included 62 individuals. The independent preoperative risk factors identified were tumor pathology grade, platelet count, tumor size on imaging, and lymph node size, which were utilized to develop the nomogram. The model demonstrated high predictive accuracy, as evidenced by the area under the receiver operating characteristic curve values of 0.898 and 0.843 for the primary and external validation cohorts, respectively. Calibration curves and decision curve analysis showed a good performance of the nomogram in both cohorts, indicating its high clinical applicability. Conclusion A nomogram for preoperative prediction of lymph node metastasis in patients with advanced muscle-invasive bladder cancer was successfully developed; its accuracy, reliability, and clinical value were demonstrated. This new tool would facilitate better clinical decisions regarding whether to perform complete lymph node dissection in cases of radical cystectomy.
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Affiliation(s)
- Yi Qiao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuefeng Jia
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Luo
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bin Li
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fei Xie
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hanshu Wang
- Department of Andrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shengxian Li
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Ben Rejeb S, Kouki N, Ben Ghachem D, Khouni H, Bellil K. Prognostic significance of E-Cadherin and B-Catenin in non-muscle invasive bladder cancer. J Immunoassay Immunochem 2024; 45:261-270. [PMID: 38561917 DOI: 10.1080/15321819.2024.2335154] [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] [Indexed: 04/04/2024]
Abstract
Non muscle invasive bladder cancer (NMIBC) has unpredictable outcomes with a variable risk of recurrence and progression. Many clinic-pathological prognostic factors have been identified but remain insufficient, raising the need to investigate new biomarkers. The aim of our study was to assess the prognostic value of the immunohistochemical (IHC) markers E-Cadherin and B-Catenin in NMIBC. All cases of NMIBC were collected between 2008 and 2013. IHC analysis was performed using E-Cadherin and B-Catenin. Reduced or loss of E-Cadherin expression was assessed as abnormal. Only cases with B-Catenin intense membranous staining were considered normal. A correlation was found between abnormal E-Cadherin expression and stage (p = 0.001), grade (p = 0.0000000), recurrence (p = 0.0000000), progression (p = 0.01), recurrence-free survival (p = 0.00000001), and progression-free survival (p = 0.01). A statistically significant association was found between B-Catenin and stage (p = 0. 05), grade (p = 0.02), and recurrence (p = 0.02). The abnormal expression of these markers could help to identify a high-risk subgroup of NMIBC that might benefit from either more accurate follow-up or more aggressive treatment.
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Affiliation(s)
- Sarra Ben Rejeb
- Pathology Department, Security Forces Hospital, Marsa, Tunisia
| | - Nadia Kouki
- Pathology Department, Security Forces Hospital, Marsa, Tunisia
| | | | - Hassen Khouni
- Urology Department, Security Forces Hospital, Marsa, Tunisia
| | - Khadija Bellil
- Pathology Department, Security Forces Hospital, Marsa, Tunisia
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Sturm S, Niegisch G, Windolf J, Suschek CV. Exposure of Bladder Cancer Cells to Blue Light (λ = 453 nm) in the Presence of Riboflavin Synergistically Enhances the Cytotoxic Efficiency of Gemcitabine. Int J Mol Sci 2024; 25:4868. [PMID: 38732087 PMCID: PMC11084806 DOI: 10.3390/ijms25094868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/13/2024] Open
Abstract
Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.
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Affiliation(s)
- Sofia Sturm
- Department of Orthopedics and Trauma Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Günter Niegisch
- Department of Urology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
| | - Joachim Windolf
- Department of Orthopedics and Trauma Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Christoph V. Suschek
- Department of Orthopedics and Trauma Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
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Liu K, Chen H, Li Y, Wang B, Li Q, Zhang L, Liu X, Wang C, Ertas YN, Shi H. Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics. Cancer Lett 2024; 591:216867. [PMID: 38593919 DOI: 10.1016/j.canlet.2024.216867] [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: 01/21/2024] [Revised: 03/20/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.
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Affiliation(s)
- Kuan Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Huijing Chen
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Yanhong Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Bei Wang
- Department of Gynecology, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Qian Li
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Lu Zhang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China
| | - Xiaohui Liu
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Ce Wang
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Turkey; UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, 06800, Turkey.
| | - Hongyun Shi
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, PR China.
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Otvagin VF, Krylova LV, Peskova NN, Kuzmina NS, Fedotova EA, Nyuchev AV, Romanenko YV, Koifman OI, Vatsadze SZ, Schmalz HG, Balalaeva IV, Fedorov AY. A first-in-class β-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer. Eur J Med Chem 2024; 269:116283. [PMID: 38461680 DOI: 10.1016/j.ejmech.2024.116283] [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: 10/23/2023] [Revised: 02/16/2024] [Accepted: 02/23/2024] [Indexed: 03/12/2024]
Abstract
In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.
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Affiliation(s)
- Vasilii F Otvagin
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation.
| | - Lubov V Krylova
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
| | - Nina N Peskova
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
| | - Natalia S Kuzmina
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
| | - Ekaterina A Fedotova
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
| | - Alexander V Nyuchev
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation
| | - Yuliya V Romanenko
- Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation
| | - Oscar I Koifman
- Research Institute of Macroheterocycles, Ivanovo State University of Chemical Technology, 153000, Ivanovo, Russian Federation
| | - Sergey Z Vatsadze
- N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow, 119991, Russian Federation
| | - Hans-Günther Schmalz
- Department of Chemistry, University of Cologne, Greinstrasse 4, 50939, Cologne, Germany
| | - Irina V Balalaeva
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation.
| | - Alexey Yu Fedorov
- Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation.
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Pilala KM, Kotronopoulos G, Levis P, Giagkos GC, Stravodimos K, Vassilacopoulou D, Scorilas A, Avgeris M. MIR145 Core Promoter Methylation in Pretreatment Cell-Free DNA: A Liquid Biopsy Tool for Muscle-Invasive Bladder Cancer Treatment Outcome. JCO Precis Oncol 2024; 8:e2300414. [PMID: 38579191 DOI: 10.1200/po.23.00414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 01/06/2024] [Accepted: 02/13/2024] [Indexed: 04/07/2024] Open
Abstract
PURPOSE The lack of personalized management of bladder cancer (BlCa) results in patients' lifelong post-treatment monitoring with invasive interventions, underlying the urgent need for tailored and minimally invasive health care services. On the basis of our previous findings on miR-143/145 cluster methylation in bladder tumors, we evaluated its clinical significance in pretreatment cell-free DNA (cfDNA) of patients with BlCa. MATERIALS AND METHODS Methylation analysis was performed in our screening cohort (120 patients with BlCa; 20 age-matched healthy donors) by bisulfite-based pyrosequencing. Tumor recurrence/progression for patients with non-muscle-invasive bladder cancer, and progression and mortality for patients with muscle-invasive bladder cancer (MIBC) were used as clinical end point events in survival analysis. Bootstrap analysis was applied for internal validation of Cox regression models and decision curve analysis for assessment of clinical benefit on disease prognosis. RESULTS Decreased methylation of MIR145 core promoter in pretreatment cfDNA was associated with short-term disease progression (multivariate Cox: hazard ratio [HR], 2.027 [95% CI, 1.157 to 3.551]; P = .010) and poor overall survival (multivariate Cox: HR, 2.098 [95% CI, 1.154 to 3.817]; P = .009) of patients with MIBC after radical cystectomy (RC). Multivariate models incorporating MIR145 promoter methylation in cfDNA with tumor stage clearly ameliorated patients' risk stratification, highlighting superior clinical benefit in MIBC prognostication. CONCLUSION Reduced pretreatment cfDNA methylation of MIR145 core promoter was markedly correlated with increased risk for short-term progression and worse survival of patients with MIBC after RC and adjuvant therapy, supporting modern personalized and minimally invasive prognosis. Methylation profiling of MIR145 core promoter in pretreatment cfDNA could serve as a minimally invasive and independent predictor of MIBC treatment outcome and emerge as a promising marker for blood-based test in BlCa.
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Affiliation(s)
- Katerina-Marina Pilala
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Kotronopoulos
- First Department of Urology, "Laiko" General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Levis
- First Department of Urology, "Laiko" General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios-Christos Giagkos
- First Department of Urology, "Laiko" General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Stravodimos
- First Department of Urology, "Laiko" General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dido Vassilacopoulou
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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Ahmadi S, Ambite I, Brisuda A, Háček J, Haq F, Sabari S, Vanarsa K, Mohan C, Babjuk M, Svanborg C. Similar immune responses to alpha1-oleate and Bacillus Calmette-Guérin treatment in patients with bladder cancer. Cancer Med 2024; 13:e7091. [PMID: 38553868 PMCID: PMC10980842 DOI: 10.1002/cam4.7091] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/19/2024] [Accepted: 02/28/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND The molecular content of urine is defined by filtration in the kidneys and by local release from tissues lining the urinary tract. Pathological processes and different therapies change the molecular composition of urine and a variety of markers have been analyzed in patients with bladder cancer. The response to BCG immunotherapy and chemotherapy has been extensively studied and elevated urine concentrations of IL-1RA, IFN-α, IFN-γ TNF-α, and IL-17 have been associated with improved outcome. METHODS In this study, the host response to intravesical alpha 1-oleate treatment was characterized in patients with non-muscle invasive bladder cancer by proteomic and transcriptomic analysis. RESULTS Proteomic profiling detected a significant increase in multiple cytokines in the treatment group compared to placebo. The innate immune response was strongly activated, including IL-1RA and pro-inflammatory cytokines in the IL-1 family (IL-1α, IL-1β, IL-33), chemokines (MIP-1α, IL-8), and interferons (IFN-α2, IFN-γ). Adaptive immune mediators included IL-12, Granzyme B, CD40, PD-L1, and IL-17D, suggesting broad effects of alpha 1-oleate treatment on the tumor tissues. CONCLUSIONS The cytokine response profile in alpha 1-oleate treated patients was similar to that reported in BCG treated patients, suggesting a significant overlap. A reduction in protein levels at the end of treatment coincided with inhibition of cancer-related gene expression in tissue biopsies, consistent with a positive treatment effect. Thus, in addition to killing tumor cells and inducing cell detachment, alpha 1-oleate is shown to activate a broad immune response with a protective potential.
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Affiliation(s)
- Shahram Ahmadi
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversityLundSweden
| | - Ines Ambite
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversityLundSweden
| | - Antonín Brisuda
- Department of UrologyMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Jaromír Háček
- Department of Pathology and Molecular MedicineMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Farhan Haq
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversityLundSweden
| | - Samudra Sabari
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversityLundSweden
| | - Kamala Vanarsa
- Department of Biomedical EngineeringUniversity of HoustonHoustonTexasUSA
| | - Chandra Mohan
- Department of Biomedical EngineeringUniversity of HoustonHoustonTexasUSA
| | - Marek Babjuk
- Department of UrologyMotol University Hospital, 2nd Faculty of Medicine, Charles University PrahaPragueCzech Republic
| | - Catharina Svanborg
- Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of MedicineLund UniversityLundSweden
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Nakagawa R, Nohara T, Kano H, Makino T, Naito R, Iwamoto H, Yaegashi H, Kawaguchi S, Shigehara K, Izumi K, Mizokami A. Does the quality of endoscopic equipment influence the recurrence rate after photodynamic diagnosis-assisted transurethral resection of bladder tumor? Photodiagnosis Photodyn Ther 2024; 46:104023. [PMID: 38401816 DOI: 10.1016/j.pdpdt.2024.104023] [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: 12/15/2023] [Revised: 02/13/2024] [Accepted: 02/21/2024] [Indexed: 02/26/2024]
Abstract
BACKGROUND Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) for nonmuscle-invasive bladder cancer is superior to conventional white-light TURBT for cancer detection. However, when performing PDD-TURBT, cystoscopy findings vary depending on the quality of the endoscopic equipment. In this study, we compared the effects of different types of endoscopic equipment on postoperative outcomes. METHODS Patients who underwent their first PDD-TURBT at our clinic were selected. Patients on whom PDD-TURBT was performed using endoscopic equipment A were sorted into Group A, and patients on whom PDD-TURBT was performed using equipment S were sorted into Group S. The characteristics, recurrence-free survival (RFS), and recurrence frequency of these patients were retrospectively investigated and compared. The prognostic factors for RFS were also analyzed. RESULTS A total of 49 patients were included in Group A and 46 in Group S. In Group S, a higher detection rate (8.2% vs. 30.4 %, p < 0.01) of carcinoma in situ (CIS) was noted. RFS tended to be better in Group S (HR 0.63, p = 0.15). The frequency of recurrence also tended to be lower in Group S (4.92 vs. 3.66 per 10,000 person-days, p = 0.08). Furthermore, CIS (HR 0.30, p = 0.04) and Bacillus Calmette-Guerin therapy (HR: 0.26, p = 0.01) were significant favorable prognostic factors for RFS. CONCLUSION The quality of the endoscopic equipment may influence postoperative recurrence after PDD-TURBT. Higher-quality endoscopic instruments have superior CIS detection capabilities, which can lead to improvements in postoperative outcomes with the appropriate selection of postoperative adjuvant therapy.
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Affiliation(s)
- Ryunosuke Nakagawa
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Takahiro Nohara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
| | - Hiroshi Kano
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tomoyuki Makino
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Renato Naito
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroaki Iwamoto
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroshi Yaegashi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Shohei Kawaguchi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kazuyoshi Shigehara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kouji Izumi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Atsushi Mizokami
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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46
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Yang G, Bai J, Hao M, Zhang L, Fan Z, Wang X. Enhancing recurrence risk prediction for bladder cancer using multi-sequence MRI radiomics. Insights Imaging 2024; 15:88. [PMID: 38526620 DOI: 10.1186/s13244-024-01662-3] [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: 11/02/2023] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
OBJECTIVE We aimed to develop a radiomics-clinical nomogram using multi-sequence MRI to predict recurrence-free survival (RFS) in bladder cancer (BCa) patients and assess its superiority over clinical models. METHODS A retrospective cohort of 229 BCa patients with preoperative multi-sequence MRI was divided into a training set (n = 160) and a validation set (n = 69). Radiomics features were extracted from T2-weighted images, diffusion-weighted imaging, apparent diffusion coefficient, and dynamic contrast-enhanced images. Effective features were identified using the least absolute shrinkage and selection operator (LASSO) method. Clinical risk factors were determined via univariate and multivariate Cox analysis, leading to the creation of a radiomics-clinical nomogram. Kaplan-Meier analysis and log-rank tests assessed the relationship between radiomics features and RFS. We calculated the net reclassification improvement (NRI) to evaluate the added value of the radiomics signature and used decision curve analysis (DCA) to assess the nomogram's clinical validity. RESULTS Radiomics features significantly correlated with RFS (log-rank p < 0.001) and were independent of clinical factors (p < 0.001). The combined model, incorporating radiomics features and clinical data, demonstrated the best prognostic value, with C-index values of 0.853 in the training set and 0.832 in the validation set. Compared to the clinical model, the radiomics-clinical nomogram exhibited superior calibration and classification (NRI: 0.6768, 95% CI: 0.5549-0.7987, p < 0.001). CONCLUSION The radiomics-clinical nomogram, based on multi-sequence MRI, effectively assesses the BCa recurrence risk. It outperforms both the radiomics model and the clinical model in predicting BCa recurrence risk. CRITICAL RELEVANCE STATEMENT The radiomics-clinical nomogram, utilizing multi-sequence MRI, holds promise for predicting bladder cancer recurrence, enhancing individualized clinical treatment, and performing tumor surveillance. KEY POINTS • Radiomics plays a vital role in predicting bladder cancer recurrence. • Precise prediction of tumor recurrence risk is crucial for clinical management. • MRI-based radiomics models excel in predicting bladder cancer recurrence.
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Affiliation(s)
- Guoqiang Yang
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jingjing Bai
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Min Hao
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lu Zhang
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zhichang Fan
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaochun Wang
- Department of Radiology, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
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47
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Oliver-Krasinski JM, Bidot S, Ingram JW, O'Toole KM, McKiernan JM, Tinsley M, Harik LR. Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features. Arch Pathol Lab Med 2024; 148:223-229. [PMID: 37134243 DOI: 10.5858/arpa.2022-0268-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2023] [Indexed: 05/05/2023]
Abstract
CONTEXT.— Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.— To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.— We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.— A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.— Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.
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Affiliation(s)
| | - Samuel Bidot
- the Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Bidot, Tinsley, Harik)
| | - Justin W Ingram
- the Department of Urology, Columbia University Irving Medical Center, New York, New York (Ingram, McKiernan)
| | - Kathleen M O'Toole
- the Department of Pathology and Cell Biology, Columbia University, New York, New York (O'Toole)
| | - James M McKiernan
- the Department of Urology, Columbia University Irving Medical Center, New York, New York (Ingram, McKiernan)
| | - Mazie Tinsley
- the Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Bidot, Tinsley, Harik)
| | - Lara R Harik
- the Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Bidot, Tinsley, Harik)
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48
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Li K, Qi L, Tang G, Xu H, Li Z, Fan B, Li Z, Li Y. Epigenetic Regulation in Urothelial Carcinoma. Curr Mol Med 2024; 24:85-97. [PMID: 36545729 DOI: 10.2174/1566524023666221221094432] [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: 05/24/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 12/24/2022]
Abstract
Urothelial carcinoma (UC) is a common malignancy that remains a clinical challenge: Non-muscle-invasive urothelial carcinoma (NMIUC) has a high rate of recurrence and risk of progression, while muscle-invasive urothelial carcinoma (MIUC) has a high mortality. Although some new treatments, such as immunotherapies, have shown potential effects on some patients, most cases of advanced UC remain incurable. While treatments based on epigenetic mechanisms, whether combined with traditional platinum-based chemotherapy or emerging immunotherapy, show therapeutic advantages. With the advancement of sequencing and bioinformatics, the study of epigenomics, containing DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, is increasingly linked with the occurrence and progression of UC. Since the epigenetics of UC is a constantly developing field of medicine, this review aims to summarize the latest research on epigenetic regulation of UC, generalize the mechanism of epigenetics in UC, and reveal the potential epigenetic therapies in the clinical setting, in order to provide some new clues on the discovery of new drugs based on the epigenetics.
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Affiliation(s)
- Ke Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Lin Qi
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Guyu Tang
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Haozhe Xu
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhi Li
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Bo Fan
- Department of Urology, Xiangya Hospital of Central South University, Changsha, China
| | - Zhongbei Li
- College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Yuan Li
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, China
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49
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Mao C, Xu N. Single-cell Sequencing Data Reveals Aggressive CD68-type Macrophages and Prognostic Models in Bladder Cancer. Curr Med Chem 2024; 31:1523-1538. [PMID: 37622699 DOI: 10.2174/0929867331666230824093312] [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: 05/29/2023] [Revised: 07/17/2023] [Accepted: 08/07/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND The highly heterogeneous, complex pathological histology, and clinical phenotype in bladder cancer (BC) plague the prognostic management of BC to the present day. METHODS This study was conducted using single-cell sequencing data from the gene expression omnibus (GEO) database (GSE135337). A descending, annotated analysis was performed to identify the cell types contributing to BC aggressiveness. BC cell sequencing data from The Cancer Genome Atlas (TCGA) database were then combined with univariate, least absolute shrinkage and selection operator (LASSO), multivariate COX regression analysis to identify biomarkers of BC prognosis to construct a BC. We identified biomarkers of BC prognosis to construct a prognostic risk guidance system for BC. The feedback of patients in different risk strata to immunotherapy was analyzed. Finally, the regulation of prognostic genes on cancer cell activity was verified in vitro by Western blot and cell counting kit-8 (CCK8) assays. RESULTS Macrophages specifically expressing CD68 in BC were the cell type with the highest AUCell score, and CD68 was the biomarker of Tumor-associated macrophages (TAMs). CD68 macrophages were potentially the critical cell type in the aggressive BC subtype. Through univariate, LASSO, multivariate COX-based regression analysis. CTSS, GMFG, ANXA5, GSN, SLC2A3, and FTL were authenticated as prognostic biomarkers (p < 0.05) and composed the Risk Score. Patients in the low-risk group showed an excellent survival advantage (p < 0.01) and immunotherapy feedback. Additionally, inhibition of GSN expression decreased EMT activity to inhibit bladder cancer cell viability. CONCLUSION In conclusion, this study provided feedback on the immune cell types associated with aggressiveness in BC. Importantly, a prognostic management system for BC was created based on the genes involved, providing more insight into the aggressive pathological phenotype as well as the prognosis of BC.
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Affiliation(s)
- Chenyu Mao
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310026, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310026, China
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50
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Zhang Y, Nosseir M, Dyer J. Analysing cause of death during follow-up for non-muscle-invasive bladder cancer: is there a role for watchful waiting? Ann R Coll Surg Engl 2024; 106:57-63. [PMID: 36239948 PMCID: PMC10757883 DOI: 10.1308/rcsann.2022.0099] [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] [Accepted: 06/24/2022] [Indexed: 06/16/2023] Open
Abstract
INTRODUCTION Non-muscle-invasive bladder cancer (NMIBC) patients often require multiple invasive procedures during follow-up. Surveillance guidelines do not adjust for increasing frailty or competing comorbidity. We aim to evaluate the influence of these factors on the natural history of NMIBC and whether this may have implications for appropriate follow-up schedules. METHODS NMIBC patients who died in a 3-year period while on cystoscopic surveillance were identified. Frailty was assessed using the Rockwood Clinical Frailty Scale (CFS): 1-3, no frailty; 4, vulnerable; 5-9, mild/severe frailty. Similarly, three-tier categorisations were performed for comorbidity (Charlson Comorbidity Index) and for anaesthetic risk (American Society of Anesthesiologists' [ASA] score). RESULTS Of the 69 patients, 26 were categorised as no frailty, 20 as vulnerable and 13 as frail. There was no difference in the proportions of those with higher risk NMIBC between the categories. Increasing frailty was associated with reduced overall survival (median 59, 29 and 13 months; p < 0.05) but not recurrence-free survival (p = 0.98) or progression-free survival (p = 0.58). Similar results were obtained using the Charlson Comorbidity Index or ASA score. No frail patients with low/intermediate-risk NMIBC had clinically significant disease progression prior to death. Frail patients with CFS ≥ 4 were found to have similar complications due to bladder cancer itself (p = 0.48) yet almost three times as many complications following cystoscopic procedures during follow-up (p < 0.05). CONCLUSIONS For frail patients with low risk of progression, protocol-driven cystoscopic surveillance may not improve survival and watchful waiting may be more appropriate. Further investigation is required to determine the feasibility of this approach.
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Affiliation(s)
- Y Zhang
- Stockport NHS Foundation Trust, UK
| | | | - J Dyer
- Stockport NHS Foundation Trust, UK
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