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New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis
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New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (13 September 2024) | Viewed by 16796

Special Issue Editors

Prof. Pierfrancesco Bassi

E-Mail Website
Guest Editor
Department of Urology, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS di Roma, Università Cattolica del Sacro Cuore di Roma, Largo Agostino Gemelli 8, 00168 Rome, Italy
Interests: medical therapy for urothelial cancer; surgery for urothelial cancer; oncologic robotic surgery; reconstructive surgery; cancer biology
Dr. Giuseppe Palermo

E-Mail Website
Guest Editor
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Interests: prostate cancer; bladder cancer; BPH
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Urothelial cancers are the sixth most common tumors in developed countries. Bladder tumors account for 90–95% of UCs and are the most common urinary tract malignancy; by contrast, upper urinary tract UCs are uncommon and account for only 5–10% of UCs. In recent yearsm new urothelial biomarkers have been proposed in their diagnostic and prognostic role; liquid biopsy has arisen as an important tool for urothelial cancer early detection and prognosis, identifying different pathways of cell signaling, proliferation, and apoptosis changes in tumor biology and progression. New immunotherapy agents based on checkpoint inhibitor-optimized cancer therapy and oncologic outcomes have emerged, and device-assisted therapy (EMDA, thermochemotherapy) has been outlined as a preserving approach to recurrent non-muscle invasive bladder disease, while the minimally invasive approach of robotic surgery has been found to reduce adverse events and hospital stay when major urologic surgery is needed. The purpose of this Special Issue is to identify and summarize the latest innovations in urothelial cancer management, overcome present challenges and open new paths to future strategies.

Prof. Pierfrancesco Bassi
Dr. Giuseppe Palermo
Guest Editors

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Keywords

  • liquid biopsy
  • robotic surgery
  • device assisted therapy
  • immunotherapy
  • PDL-1 inhibitors
  • urinary tumor DNA
  • bladder cancer
  • upper urinary tract cancer

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Published Papers (9 papers)

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Research

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37 pages, 11713 KiB  
Article
Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer
by Lukas M. Bollmann, Friedrich Lange, Alexandra Hamacher, Lukas Biermann, Linda Schäker-Hübner, Finn K. Hansen and Matthias U. Kassack
Cancers 2024, 16(19), 3374; https://doi.org/10.3390/cancers16193374 - 2 Oct 2024
Viewed by 777
Abstract
Background/Objectives. Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain [...] Read more.
Background/Objectives. Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain inhibitors (BETis) on the potency of cisplatin in two pairs of sensitive and cisplatin-resistant bladder cancer cell lines. Cisplatin-resistant J82cisR and T24 LTT were 3.8- and 24-fold more resistant to cisplatin compared to the native cell lines J82 and T24. In addition, a hybrid compound (compound 20) comprising structural features of an HDACi and a BETi was investigated. Results. We found complete (J82cisR) or partial (T24 LTT) reversal of chemoresistance upon combination of entinostat, JQ1, and cisplatin. The same was found for the BETis JQ35 and OTX015, both in clinical trials, and for compound 20. The combinations were highly synergistic (Chou Talalay analysis) and increased caspase-mediated apoptosis accompanied by enhanced expression of p21, Bim, and FOXO1. Notably, the combinations were at least 4-fold less toxic in non-cancer cell lines HBLAK and HEK293. Conclusions. The triple combination of entinostat, a BETi, and cisplatin is highly synergistic, reverses cisplatin resistance, and may thus serve as a novel therapeutic approach for bladder cancer. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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Graphical abstract

11 pages, 804 KiB  
Article
The Significant Associations between Epigenetic Clocks and Bladder Cancer Risks
by Yang Deng, Chia-Wen Tsai, Wen-Shin Chang, Yifan Xu, Maosheng Huang, Da-Tian Bau and Jian Gu
Cancers 2024, 16(13), 2357; https://doi.org/10.3390/cancers16132357 - 27 Jun 2024
Viewed by 1323
Abstract
Bladder cancer is an age-related disease, with over three-quarters of cases occurring in individuals aged 65 years and older. Accelerated biological aging has been linked to elevated cancer risks. Epigenetic clocks serve as excellent predictors of biological age, yet it remains unclear whether [...] Read more.
Bladder cancer is an age-related disease, with over three-quarters of cases occurring in individuals aged 65 years and older. Accelerated biological aging has been linked to elevated cancer risks. Epigenetic clocks serve as excellent predictors of biological age, yet it remains unclear whether they are associated with bladder cancer risk. In this large case–control study, we assessed the associations between four well-established epigenetic clocks—HannumAge, HorvathAge, GrimAge, and PhenoAge—and bladder cancer risk. Utilizing single nucleotide polymorphisms (SNPs), which were identified in a genome-wide association study (GWAS), linked to these clocks as instruments, we constructed a weighted genetic risk score (GRS) for each clock. We discovered that higher HannumAge and HorvathAge GRS were significantly associated with increased bladder cancer risk (OR = 1.69 per SD increase, 95% CI, 1.44–1.98, p = 1.56 × 10−10 and OR = 1.09 per SD increase, 95% CI, 1.00–1.19, p = 0.04, respectively). Employing a summary statistics-based Mendelian randomization (MR) method, inverse-variance weighting (IVW), we found consistent risk estimates for bladder cancer with both HannumAge and HorvathAge. Sensitivity analyses using weighted median analysis and MR-Egger regression further supported the validity of the IVW method. However, GrimAge and PhenoAge were not associated with bladder cancer risk. In conclusion, our data provide the first evidence that accelerated biological aging is associated with elevated bladder cancer risk. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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11 pages, 686 KiB  
Article
Non-Surgical Bladder-Sparing Multimodal Management in Organ-Confined Urothelial Carcinoma of the Urinary Bladder: A Population-Based Analysis
by Mario de Angelis, Andrea Baudo, Carolin Siech, Letizia Maria Ippolita Jannello, Francesco Di Bello, Jordan A. Goyal, Zhe Tian, Nicola Longo, Ottavio de Cobelli, Felix K. H. Chun, Fred Saad, Shahrokh F. Shariat, Luca Carmignani, Giorgio Gandaglia, Marco Moschini, Francesco Montorsi, Alberto Briganti and Pierre I. Karakiewicz
Cancers 2024, 16(7), 1292; https://doi.org/10.3390/cancers16071292 - 27 Mar 2024
Cited by 2 | Viewed by 1224
Abstract
Background: Trimodal therapy is considered the most validated bladder-sparing treatment in patients with organ-confined urothelial carcinoma of the urinary bladder (T2N0M0). However, scarce evidence exists regarding cancer-specific mortality (CSM) differences between trimodal therapy and other non-extirpative multimodal treatment options such as radiotherapy alone [...] Read more.
Background: Trimodal therapy is considered the most validated bladder-sparing treatment in patients with organ-confined urothelial carcinoma of the urinary bladder (T2N0M0). However, scarce evidence exists regarding cancer-specific mortality (CSM) differences between trimodal therapy and other non-extirpative multimodal treatment options such as radiotherapy alone after transurethral resection (TURBT + RT) or chemotherapy alone after transurethral resection (TURBT + CT). Methods: Within the Surveillance, Epidemiology, and End Results database (2004–2020), we identified T2N0M0 patients treated with either trimodal therapy, TURBT + CT, or TURBT + RT. Temporal trends described trimodal therapy vs. TUBRT + CT vs. TURBT + RT use over time. Survival analyses consisting of Kaplan–Meier plots and multivariable Cox regression (MCR) models addressed CSM according to each treatment modality. Results: 3729 (40%) patients underwent TMT vs. 4030 (43%) TURBT + CT vs. 1599 (17%) TURBT + RT. Over time, trimodal therapy use (Estimating annual percent change, EAPC: +1.2%, p = 0.01) and TURBT + CT use increased (EAPC: +1.5%, p = 0.01). In MCR models, relative to trimodal therapy, TURBT + CT exhibited 1-14-fold higher CSM and TURBT + RT 1.68-fold higher CSM. In a subgroup analysis, TURBT + RT was associated with 1.42-fold higher CSM than TURBT + CT (p < 0.001). Conclusions: Strict trimodal therapy that includes both CT and RT after TURBT offers the best cancer control. When strict trimodal therapy cannot be delivered, cancer-specific survival outcomes appear to be superior with TURBT + chemotherapy compared to TURBT + RT. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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12 pages, 1668 KiB  
Article
Performance of Node-RADS Scoring System for a Standardized Assessment of Regional Lymph Nodes in Bladder Cancer Patients
by Costantino Leonardo, Rocco Simone Flammia, Sara Lucciola, Flavia Proietti, Martina Pecoraro, Bruno Bucca, Leslie Claire Licari, Antonella Borrelli, Eugenio Bologna, Nicholas Landini, Maurizio Del Monte, Benjamin I. Chung, Carlo Catalano, Fabio Massimo Magliocca, Ettore De Berardinis, Francesco Del Giudice and Valeria Panebianco
Cancers 2023, 15(3), 580; https://doi.org/10.3390/cancers15030580 - 18 Jan 2023
Cited by 19 | Viewed by 3818
Abstract
Background: Current cross-sectional imaging modalities exhibit heterogenous diagnostic performances for the detection of a lymph node invasion (LNI) in bladder cancer (BCa) patients. Recently, the Node-RADS score was introduced to provide a standardized comprehensive evaluation of LNI, based on a five-item Likert scale [...] Read more.
Background: Current cross-sectional imaging modalities exhibit heterogenous diagnostic performances for the detection of a lymph node invasion (LNI) in bladder cancer (BCa) patients. Recently, the Node-RADS score was introduced to provide a standardized comprehensive evaluation of LNI, based on a five-item Likert scale accounting for both size and configuration criteria. In the current study, we hypothesized that the Node-RADS score accurately predicts the LNI and tested its diagnostic performance. Methods: We retrospectively reviewed BCa patients treated with radical cystectomy (RC) and bilateral extended pelvic lymph node dissection, from January 2019 to June 2022. Patients receiving preoperative systemic chemotherapy were excluded. A logistic regression analysis tested the correlation between the Node-RADS score and LNI both at patient and lymph-node level. The ROC curves and the AUC depicted the overall diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for different cut-off values (>1, >2, >3, >4). Results: Overall, data from 49 patients were collected. Node-RADS assigned on CT scans images, was found to independently predict the LNI after an adjusted multivariable regression analysis, both at the patient (OR 3.36, 95%CI 1.68–9.40, p = 0.004) and lymph node (OR 5.18, 95%CI 3.39–8.64, p < 0.001) levels. Node-RADS exhibited an AUC of 0.87 and 0.91 at the patient and lymph node levels, respectively. With increasing Node-RADS cut-off values, the specificity and PPV increased from 57.1 to 97.1% and from 48.3 to 83.3%, respectively. Conversely, the sensitivity and NPV decreased from 100 to 35.7% and from 100 to 79.1%, respectively. Similar trends were recorded at the lymph node level. Potentially, Node-RADS > 2 could be considered as the best cut-off value due to balanced values at both the patient (77.1 and 78.6%, respectively) and lymph node levels (82.4 and 93.4%, respectively). Conclusions: The current study lays the foundation for the introduction of Node-RADS for the regional lymph-node evaluation in BCa patients. Interestingly, the Node-RADS score exhibited a moderate-to-high overall accuracy for the identification of LNI, with the possibility of setting different cut-off values according to specific clinical scenarios. However, these results need to be validated on larger cohorts before drawing definitive conclusions. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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10 pages, 3115 KiB  
Article
Bladder Wall Stiffness after Cystectomy in Bladder Cancer Patients: A Preliminary Study
by Sara Monteiro-Reis, João P. S. Ferreira, Ricardo A. Pires, João Lobo, João A. Carvalho, Rui L. Reis, Renato Natal Jorge and Carmen Jerónimo
Cancers 2023, 15(2), 359; https://doi.org/10.3390/cancers15020359 - 5 Jan 2023
Cited by 1 | Viewed by 1947
Abstract
Bladder cancer (BlCa), specifically urothelial carcinomas, is a heterogeneous disease that derives from the urothelial lining. Two main classes of BlCa are acknowledged: the non-muscle invasive BlCa and the muscle-invasive BlCa; the latter constituting an aggressive disease which invades locally and metastasizes systemically. [...] Read more.
Bladder cancer (BlCa), specifically urothelial carcinomas, is a heterogeneous disease that derives from the urothelial lining. Two main classes of BlCa are acknowledged: the non-muscle invasive BlCa and the muscle-invasive BlCa; the latter constituting an aggressive disease which invades locally and metastasizes systemically. Distinguishing the specific microenvironment that cancer cells experience between mucosa and muscularis propria layers can help elucidate how these cells acquire invasive capacities. In this work, we propose to measure the micromechanical properties of both mucosa and muscularis propria layers of the bladder wall of BlCa patients, using atomic force microscopy (AFM). To do that, two cross-sections of both the macroscopically normal urinary bladder wall and the bladder wall adjacent to the tumor were collected and immediately frozen, prior to AFM samples analysis. The respective “twin” formalin-fixed paraffin-embedded tissue fragments were processed and later evaluated for histopathological examination. H&E staining suggested that tumors promoted the development of muscle-like structures in the mucosa surrounding the neoplastic region. The average Young’s modulus (cell stiffness) in tumor-adjacent specimens was significantly higher in the muscularis propria than in the mucosa. Similarly, the tumor-free specimens had significantly higher Young’s moduli in the muscularis propria than in the urothelium. Young’s moduli were higher in all layers of tumor-adjacent tissues when compared with tumor-free samples. Here we provide insights into the stiffness of the bladder wall layers, and we show that the presence of tumor in the surrounding mucosa leads to an alteration of its smooth muscle content. The quantitative assessment of stiffness range here presented provides essential data for future research on BlCa and for understanding how the biomechanical stimuli can modulate cancer cells’ capacity to invade through the different bladder layers. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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Review

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31 pages, 2062 KiB  
Review
The Laws of Attraction: Chemokines as Critical Mediators in Cancer Progression and Immunotherapy Response in Bladder Cancer
by Zaineb Hassouneh, Michelle E. Kim, Natalia Bowman, Manjeet Rao, Nu Zhang, Gang Huang, Robert S. Svatek and Neelam Mukherjee
Cancers 2024, 16(19), 3303; https://doi.org/10.3390/cancers16193303 - 27 Sep 2024
Viewed by 1162
Abstract
Bladder cancer (BCa) is a prevalent urogenital malignancy, characterized by a myriad of genetic and environmental risk factors that drive its progression. Approximately 75% of bladder tumors are non-muscle-invasive at diagnosis. For such cases, bladder preservation is often feasible with intravesical chemotherapy or [...] Read more.
Bladder cancer (BCa) is a prevalent urogenital malignancy, characterized by a myriad of genetic and environmental risk factors that drive its progression. Approximately 75% of bladder tumors are non-muscle-invasive at diagnosis. For such cases, bladder preservation is often feasible with intravesical chemotherapy or immunotherapy. However, the high recurrence rates associated with these tumors necessitate multiple cystoscopic examinations and biopsies, leading to significant financial burden and morbidity. Despite bladder tumors exhibiting one of the highest cancer mutational loads, which typically correlates with improved responses to immunotherapy, challenges persist. The tumor microenvironment serves as a nexus for interactions between tumor cells and the immune system, wherein chemokines and chemokine receptors orchestrate the recruitment of immune cells. This review addresses existing gaps in our understanding of chemokine dynamics in BCa by elucidating the specific roles of key chemokines in shaping the immune landscape of the tumor microenvironment (TME). We explore how dysregulation of chemokine signaling pathways contributes to the recruitment of immunosuppressive cell populations, such as Tregs and monocytes, leading to an unfavorable immune response. Additionally, we highlight the potential of these chemokines as predictive biomarkers for tumor progression and treatment outcomes, emphasizing their role in informing personalized immunotherapeutic strategies. By integrating insights into chemokine networks and their implications for immune cell dynamics, this review seeks to provide a comprehensive understanding of the interplay between chemokines and the immune microenvironment in BCa. Furthermore, we discuss the potential of targeting these chemokine pathways as innovative immunotherapeutic strategies, paving the way for enhanced treatment responses and improved patient outcomes. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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19 pages, 556 KiB  
Review
Contemporary Molecular Markers for Predicting Systemic Treatment Response in Urothelial Bladder Cancer: A Narrative Review
by George Dimitrov, Radoslav Mangaldzhiev, Chavdar Slavov and Elenko Popov
Cancers 2024, 16(17), 3056; https://doi.org/10.3390/cancers16173056 - 1 Sep 2024
Viewed by 1444
Abstract
The search for dependable molecular biomarkers to enhance routine clinical practice is a compelling challenge across all oncology fields. Urothelial bladder carcinoma, known for its significant heterogeneity, presents difficulties in predicting responses to systemic therapies and outcomes post-radical cystectomy. Recent advancements in molecular [...] Read more.
The search for dependable molecular biomarkers to enhance routine clinical practice is a compelling challenge across all oncology fields. Urothelial bladder carcinoma, known for its significant heterogeneity, presents difficulties in predicting responses to systemic therapies and outcomes post-radical cystectomy. Recent advancements in molecular cancer biology offer promising avenues to understand the disease’s biology and identify emerging predictive biomarkers. Stratifying patients based on their recurrence risk post-curative treatment or predicting the efficacy of conventional and targeted therapies could catalyze personalized treatment selection and disease surveillance. Despite progress, reliable molecular biomarkers to forecast responses to systemic agents, in neoadjuvant, adjuvant, or palliative treatment settings, are still lacking, underscoring an urgent unmet need. This review aims to delve into the utilization of current and emerging molecular signatures across various stages of urothelial bladder carcinoma to predict responses to systemic therapy. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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16 pages, 718 KiB  
Review
Upper Tract Urothelial Cancer: Guideline of Guidelines
by Savio Domenico Pandolfo, Simone Cilio, Achille Aveta, Zhenjie Wu, Clara Cerrato, Luigi Napolitano, Francesco Lasorsa, Giuseppe Lucarelli, Paolo Verze, Salvatore Siracusano, Carmelo Quattrone, Matteo Ferro, Eugenio Bologna, Riccardo Campi, Francesco Del Giudice, Riccardo Bertolo, Daniele Amparore, Sara Palumbo, Celeste Manfredi and Riccardo Autorino
Cancers 2024, 16(6), 1115; https://doi.org/10.3390/cancers16061115 - 11 Mar 2024
Cited by 4 | Viewed by 1940
Abstract
Background: Upper tract urothelial carcinoma (UTUC) is a rare disease with a potentially dismal prognosis. We systematically compared international guidelines on UTUC to analyze similitudes and differences among them. Methods: We conducted a search on MEDLINE/PubMed for guidelines related to UTUC from 2010 [...] Read more.
Background: Upper tract urothelial carcinoma (UTUC) is a rare disease with a potentially dismal prognosis. We systematically compared international guidelines on UTUC to analyze similitudes and differences among them. Methods: We conducted a search on MEDLINE/PubMed for guidelines related to UTUC from 2010 to the present. In addition, we manually explored the websites of urological and oncological societies and journals to identify pertinent guidelines. We also assessed recommendations from the International Bladder Cancer Network, the Canadian Urological Association, the European Society for Medical Oncology, and the International Consultation on Bladder Cancer, considering their expertise and experience in the field. Results: Among all the sources, only the American Urologist Association (AUA), European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN) guidelines specifically report data on diagnosis, treatment, and follow-up of UTUC. Current analysis reveals several differences between all three sources on diagnostic work-up, patient management, and follow-up. Among all, AUA and EAU guidelines show more detailed indications. Conclusions: Despite the growing incidence of UTUC, only AUA, EAU, and NCCN guidelines deal with this cancer. Our research depicted high variability in reporting recommendations and opinions. In this regard, we encourage further higher-quality research to gain evidence creating higher grade consensus between guidelines. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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Other

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12 pages, 2750 KiB  
Systematic Review
CA125 for the Diagnosis of Advanced Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis
by Hsuan-Jen Lin, Rouh-Mei Hu, Hung-Chih Chen, Chung-Chih Lin, Chi-Yu Lee and Che-Yi Chou
Cancers 2023, 15(3), 813; https://doi.org/10.3390/cancers15030813 - 28 Jan 2023
Cited by 2 | Viewed by 2257
Abstract
Background: Urothelial carcinoma of the bladder (UCB) is the second most common genitourinary cancer. This study aims to assess the diagnostic accuracy of CA125 in advanced UCB. Methods: We searched prevalent studies in PubMed, the Cochrane Library, Scopus, Embase, the Web of Science [...] Read more.
Background: Urothelial carcinoma of the bladder (UCB) is the second most common genitourinary cancer. This study aims to assess the diagnostic accuracy of CA125 in advanced UCB. Methods: We searched prevalent studies in PubMed, the Cochrane Library, Scopus, Embase, the Web of Science China National Knowledge Infrastructure database, and Wanfang data before October 2022. Pooled sensitivity, specificity, and summary receiver operating characteristics were used to assess the diagnostic value of CA125. Results: One thousand six hundred forty-one patients from 14 studies were analyzed. UCB stage T3–4N1 was defined as advanced UCB in ten studies; T2–4 was used in three studies; and N1M1 in one study. Patients’ age was between 21 to 92, and 21% to 48.6% of patients were female. The pooled sensitivity was 0.695 (95% confidence interval (CI): 0.426–0.875). The pooled specificity was 0.846 (95% CI: 0.713–0.924). The diagnostic odds ratio was 8.138 (95% CI: 4.559–14.526). The AUC was 0.797. Conclusion: CA125 may provide significant diagnostic accuracy in identifying muscle-invasive, lymph node-involved, and distant metastatic tumors in patients with urothelial carcinoma of the bladder. Limited studies have been conducted on the prognostic role of CA125. More studies are needed for a meta-analysis on the prognostic role of CA125 in UCB. Full article
(This article belongs to the Special Issue New Advances in Urothelial Cancer: Diagnosis, Therapy and Prognosis)
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