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Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 12996

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Dr. Ioannis Zachos

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Guest Editor

Department of Urology, Faculty of Medicine, School of Health Sciences, University of Thessaly, University Hospital of Larissa, 41100 Larissa, Greece
Interests: urothelial carcinoma; biomarker; diagnosis; treatment; prognosis

Dr. Panagiotis Vlachostergios

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Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
Interests: identification of biomarkers for prostate; kidney and bladder cancer; neuroendocrine prostate cancer; PSMA theranostics; upper tract urothelial carcinoma; treatment-resistant urothelial carcinoma; genomics and immunogenomics for urological cancers
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Dear Colleagues,

The second most frequently diagnosed urological tumor worldwide is urothelial carcinoma (UC), which involves the bladder and upper urinary tract. Approximately 70-75% of the cases are non-invasive or low grade. Urine cytology and cystoscopy are the basic methods for the investigation of hematuria. If abnormal tissue is cystoscopically found, then a transurethral biopsy is recommended. Although cystoscopy is the gold standard for the diagnosis of UCs, there are two disadvantages: it is invasive and costly. On the other hand, cytology is less sensitive for low-grade tumors. The success of treatment is correlated with the detection of UCs in the early stages. Moreover, recurrence and progression dominate the natural history of UC. Hence, there has been a lot of research in order to identify biological markers for the diagnosis of UC in order to fill the gap of cystoscopy and urine cytology, therefore leading to the era of precision medicine. Many biomarkers have been studied in different clinical situations such as prognosis, diagnosis and treatment. However, there are some drawbacks in finding the appropriate biomarkers that are validated and utilized in clinical practice. First, the detection of a reliable marker is difficult due to a lack of accuracy. Secondly, the process of validation is too complex to be introduced into daily clinical practice, and finally, they must be evaluated into preclinical as well as prospective studies in larger cohorts. Therefore, the current American Urological Association (AUA) and European Association of Urology (EAU) guidelines draw attention against the use of biomarkers instead of cystoscopy and urine cytology. Clearly, it is of great interest to identify new potential biomarkers which will facilitate the management of patients suffering from UC, meaning that these markers will allow for a reliable and timely diagnosis, treatment and prognosis.

Dr. Ioannis Zachos
Dr. Panagiotis Vlachostergios
Guest Editors

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Keywords

urothelial carcinoma
biomarker
diagnosis
treatment
prognosis

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Published Papers (8 papers)

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Research

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11 pages, 891 KiB

Open AccessArticle

Clinical and Pathological Characteristics of Bladder Cancer in Patients Aged 18–45 Undergoing Transurethral Resection of Bladder Tumor

by Alexei Croitor, Vlad Dema, Silviu Latcu, Razvan Bardan, Dorin Novacescu, Vlad Barbos, Alis Dema and Alin Cumpanas

Biomedicines 2024, 12(11), 2449; https://doi.org/10.3390/biomedicines12112449 - 25 Oct 2024

Viewed by 559

Abstract

Background and Objectives: Bladder cancer in patients under 45 is poorly characterized and rarely described, with variabilities in clinical outcomes and tumor properties. Our study aimed to elucidate the clinical and pathological features and outcomes of bladder cancer in this younger demographic to better inform management strategies. Materials and Methods: We conducted a retrospective analysis at the Urology Department of “Pius Brînzeu” County Emergency Clinical Hospital in Timișoara, Romania, on 60 patients aged 18–45 who underwent transurethral resection of bladder tumor (TURBT) during a 9-year period. Results: The cohort had a mean age of 38.5 ± 5.6 years with a male predominance (70%). Most tumors were non-muscle-invasive (NMIBC; 80%), with 16.7% being papillary urothelial neoplasms of low malignant potential (PUNLMP), 50% stage pTa, and 30% stage pT1. High-grade tumors were present in 43.3% of the patients. Recurrence occurred in 40% of the patients, while progression was observed in 16.7%. The 3-year overall survival rate was 93.3%, and the progression-free survival rate was 83.3%. Patients with high-grade tumors had a significantly higher recurrence rate (61.5% vs. 23.5%, p = 0.003) and lower survival rates compared to those with low-grade tumors. Conclusions: Young patients predominantly present with low-to-intermediate-stage tumors, yet a significant portion exhibit high-grade tumors associated with poorer outcomes. These findings suggest that while bladder cancer in younger patients tends to be less invasive, aggressive follow-up and treatment are crucial in those with high-grade tumors. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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15 pages, 1661 KiB

Open AccessArticle

Biomarker Profiling of Upper Tract Urothelial Carcinoma Only and with Synchronous or Metachronous Bladder Cancer

by Sara Meireles, Carolina Dias, Diana Martins, Ana Marques, Nuno Dias, Luís Pacheco-Figueiredo, João Silva, Carlos Martins Silva, Miguel Barbosa, Luís Costa, José Manuel Lopes and Paula Soares

Biomedicines 2024, 12(9), 2154; https://doi.org/10.3390/biomedicines12092154 - 23 Sep 2024

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Abstract

Background: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes. Methods: A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan–Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients. Results: No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508–8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513–3.190, p = 0.597). Conclusions: This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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15 pages, 5195 KiB

Open AccessArticle

Prediction of Non-Muscle Invasive Papillary Urothelial Carcinoma Relapse from Hematoxylin–Eosin Images Using Deep Multiple Instance Learning in Patients Treated with Bacille Calmette–Guérin Immunotherapy

by Julius Drachneris, Mindaugas Morkunas, Mantas Fabijonavicius, Albertas Cekauskas, Feliksas Jankevicius and Arvydas Laurinavicius

Biomedicines 2024, 12(2), 360; https://doi.org/10.3390/biomedicines12020360 - 3 Feb 2024

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Abstract

The limited reproducibility of the grading of non-muscle invasive papillary urothelial carcinoma (NMIPUC) necessitates the search for more robust image-based predictive factors. In a cohort of 157 NMIPUC patients treated with Bacille Calmette–Guérin (BCG) immunotherapy, we explored the multiple instance learning (MIL)-based classification approach for the prediction of 2-year and 5-year relapse-free survival and the multiple instance survival learning (MISL) framework for survival regression. We used features extracted from image patches sampled from whole slide images of hematoxylin–eosin-stained transurethral resection (TUR) NPMIPUC specimens and tested several patch sampling and feature extraction network variations to optimize the model performance. We selected the model showing the best patient survival stratification for further testing in the context of clinical and pathological variables. MISL with the multiresolution patch sampling technique achieved the best patient risk stratification (concordance index = 0.574, p = 0.010), followed by a 2-year MIL classification. The best-selected model revealed an independent prognostic value in the context of other clinical and pathologic variables (tumor stage, grade, and presence of tumor on the repeated TUR) with statistically significant patient risk stratification. Our findings suggest that MISL-based predictions can improve NMIPUC patient risk stratification, while validation studies are needed to test the generalizability of our models. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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10 pages, 282 KiB

Open AccessArticle

Methylation Analysis of Urinary Sample in Non-Muscle-Invasive Bladder Carcinoma: Frequency and Management of Invalid Result

by Francesco Pierconti, E. D. Rossi, V. Fiorentino, A. Bakacs, A. Carlino, E. Navarra, E. Sacco, A. Totaro, G. Palermo, L. M. Larocca and M. Martini

Biomedicines 2023, 11(12), 3288; https://doi.org/10.3390/biomedicines11123288 - 12 Dec 2023

Cited by 4 | Viewed by 1049

Abstract

Background: Numerous studies showed that methylation analysis represents a newly developed urinary marker based on DNA methylation changes in a panel of genomic biomarkers and it could represent a valid tool in terms of the diagnosis and prediction of high-grade urothelial carcinoma recurrences. One of the limits of the use of this new molecular method during a follow-up is represented by the number of invalid tests in routine practice. Method: A total of 782 patients with a diagnosis of non-muscle-invasive high-grade carcinoma (NMIBC) was studied. The Bladder EpiCheck test (BE) was performed together with cytology in all cases within 1 year after the end of treatment. In 402 patients, the urinary samples were voided urine (UV), while, in 380 cases, the samples were collected after bladder washing (IU). For all the patients with invalid BE results, a second BE test was performed following the instructions for use that indicated the test should be repeated with a new urinary sample in the case of an invalid result. Results: Analyzing the two different groups (UV and IU), we found the invalid BE results seemed to be not related to urinary samples (p = 0.13 Fisher’s exact test), suggesting that the collection method was not relevant in order to reduce the number of invalid tests. Conclusions: In the follow-up for NMIBC, for patients for whom a BE test is planned, a combined approach of cytology and a methylation test is recommended in order to repeat the BE test with an invalid result only in those cases with a cytological diagnosis of atypical urothelial cells (AUC) suspicious for high-grade urothelial carcinoma (SHGUC) and high-grade urothelial carcinoma (HGUC). Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

11 pages, 3760 KiB

Open AccessArticle

Overexpression of MicroRNA-138 Affects the Proliferation and Invasion of Urothelial Carcinoma Cells by Suppressing SOX9 Expression

by Yuji Nitta, Tomomi Fujii, Tomoko Uchiyama, Aya Sugimoto, Takeshi Nishikawa, Maiko Takeda, Makito Miyake, Keiji Shimada and Kiyohide Fujimoto

Biomedicines 2023, 11(11), 3064; https://doi.org/10.3390/biomedicines11113064 - 15 Nov 2023

Cited by 1 | Viewed by 1088

Abstract

SRY-box transcription factor 9 (SOX9) is important for sexual differentiation, chondrogenic differentiation, and cell proliferation in cancer. It acts as a target molecule of microRNA (miR)-138 in various tumors and is associated with tumor development and growth. In this study, we analyzed the functions of miR-138 and SOX9 in urothelial carcinoma. SOX9 was highly expressed in invasive urothelial carcinoma tissues. miR-138 precursor transfection of T24 and UMUC2 cells significantly decreased SOX9 expression, indicating that SOX9 is a miR-138 target in urothelial carcinoma. Moreover, miR-138 precursor or SOX9 small interfering RNA (siRNA) transfection decreased the proliferation of urothelial carcinoma cell lines. To further confirm that miR-138–SOX9 signaling is involved in cell proliferation and invasion, urothelial carcinoma cells were transfected with the miR-138 precursor or SOX9 siRNA. This transfection reduced the proliferation and invasion of cells via the promotion of autophagy and apoptosis and G0/G1 cell cycle arrest. These results suggest that miR-138–SOX9 signaling modulates the growth and invasive potential of urothelial carcinoma cells. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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12 pages, 1362 KiB

Open AccessArticle

Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer

by Che-Yuan Hu, Chi-Feng Hung, Pi-Che Chen, Jia-Yu Hsu, Chung-Teng Wang, Ming-Derg Lai, Yuh-Shyan Tsai, Ai-Li Shiau, Gia-Shing Shieh and Chao-Liang Wu

Biomedicines 2023, 11(10), 2598; https://doi.org/10.3390/biomedicines11102598 - 22 Sep 2023

Cited by 2 | Viewed by 1410

Abstract

Immunotherapy has emerged as a promising modality for cancer treatment. Dendritic cell immunoreceptor (DCIR), a C-type lectin receptor, is expressed mainly by dendritic cells (DCs) and mediates inhibitory intracellular signaling. Inhibition of DCIR activation may enhance antitumor activity. DCIR is encoded by CLEC4A in humans and by Clec4a2 in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting Clec4a2 into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8⁺ T cell immune responses. Various oncolytic adenoviruses have been developed in clinical trials. Previously, we have developed Ad.LCY, an oncolytic adenovirus regulated by Oct4 and hypoxia, and demonstrated its antitumor efficacy. Here, we generated a Clec4a2 shRNA-expressing oncolytic adenovirus derived from Ad.LCY, designated Ad.shDCIR, aimed at inducing more robust antitumor immune responses. Our results show that treatment with Ad.shDCIR reduced Clec4a expression in DCs in cell culture. Furthermore, Ad.shDCIR exerted cytolytic effects solely on MBT-2 bladder cancer cells but not on normal NIH 3T3 mouse fibroblasts, confirming the tumor selectivity of Ad.shDCIR. Compared to Ad.LCY, Ad.shDCIR induced higher cytotoxic T lymphocyte (CTL) activity in MBT-2 tumor-bearing immunocompetent mice. In addition, Ad.shDCIR and Ad.LCY exhibited similar antitumor effects on inhibiting tumor growth. Notably, Ad.shDCIR was superior to Ad.LCY in prolonging the survival of tumor-bearing mice. In conclusion, Ad.shDCIR may be further explored as a combination therapy of virotherapy and immunotherapy for bladder cancer and likely other types of cancer. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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Review

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10 pages, 500 KiB

Open AccessReview

Circulating Tumour DNA and Its Prognostic Role in Management of Muscle Invasive Bladder Cancer: A Narrative Review of the Literature

by Konstantinos Kapriniotis, Lazaros Tzelves, Lazaros Lazarou, Maria Mitsogianni and Iraklis Mitsogiannis

Biomedicines 2024, 12(4), 921; https://doi.org/10.3390/biomedicines12040921 - 21 Apr 2024

Cited by 1 | Viewed by 1275

Abstract

Current management of non-metastatic muscle invasive bladder cancer (MIBC) includes radical cystectomy and cisplatin-based neoadjuvant chemotherapy (NAC), offers a 5-year survival rate of approximately 50% and is associated with significant toxicities. A growing body of evidence supports the role of liquid biopsies including circulating tumour DNA (ctDNA) as a prognostic and predictive marker that could stratify patients according to individualised risk of progression/recurrence. Detectable ctDNA levels prior to radical cystectomy have been shown to be correlated with higher risk of recurrence and worse overall prognosis after cystectomy. In addition, ctDNA status after NAC/neoadjuvant immunotherapy is predictive of the pathological response to these treatments, with persistently detectable ctDNA being associated with residual bladder tumour at cystectomy. Finally, detectable ctDNA levels post-cystectomy have been associated with disease relapse and worse disease-free (DFS) and overall survival (OS) and might identify a population with survival benefit from adjuvant immunotherapy. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

25 pages, 1882 KiB

Open AccessReview

Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

by Mohammad Jad Moussa, Matthew T. Campbell and Omar Alhalabi

Biomedicines 2024, 12(3), 519; https://doi.org/10.3390/biomedicines12030519 - 26 Feb 2024

Cited by 3 | Viewed by 4233

Abstract

Cisplatin-based chemotherapy has been the standard of care in metastatic urothelial cancer (mUC) for more than two decades. However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin. ‘Cisplatin-ineligible’ and ‘platinum-ineligible’ patients lacked effective therapy options. However, the recent combination of enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials. First, we review the working definitions of ‘cisplatin ineligibility’ and ‘platinum ineligibility’ in mUC clinical trials and the standard of care in both categories. Then, we review select clinical trials for frontline treatment of cisplatin- and platinum-ineligible mUC patients on ClinicalTrials.gov. We classify the investigated drugs in these trials by their therapeutic strategies. Alongside chemotherapy combinations, the field is witnessing more immunotherapy combinations with fibroblast growth factor receptor (FGFR) inhibitors, bicycle toxin conjugates, bispecific antibodies, innovative targeted therapies, and many others. Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies. Full article

(This article belongs to the Special Issue Urothelial Carcinoma: Role of Biomarkers in Diagnosis, Prognosis and Treatment)

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