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Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer

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

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 10618

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Special Issue Editors

Dr. Julieta Alexandra Pereira Afonso

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Guest Editor

1. School of Medicine, University of Minho, 4710-057 Braga, Portugal
2. ICVS/3B's PT Government Associate Laboratory, 4710-057 Braga, Portugal
Interests: bladder cancer; chemoresistance; immunotherapy resistance; cancer metabolism; Warburg effect; monocarboxylate transporters; CD147; tumor microenvironment; cancer-associated fibroblasts
Special Issues, Collections and Topics in MDPI journals

Dr. Maria de Fátima Monginho Baltazar

E-Mail Website
Guest Editor

1. School of Medicine, University of Minho, 4710-057 Braga, Portugal
2. ICVS/3B’s PT Government Associate Laboratory, 4710-057 Braga, Portugal
Interests: cancer glycolytic metabolism; new metabolic biomarkers in cancer; cancer drug resistance; drug discovery in cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bladder cancer is the tenth most commonly diagnosed malignancy and the thirteenth leading cause of cancer-related death worldwide, and its incidence is gradually increasing. Elevated rates of recurrence and progression in patients with localized disease, and resistance to classical cisplatin-based chemotherapy in patients displaying muscle-invasive and metastatic tumors, make direct and indirect costs of patient care higher than in any other type of cancer. Molecular profiling is definitively altering diagnosis, surveillance and the treatment landscape of bladder cancer. Minimally invasive diagnostic approaches are evolving, and therapeutic options for advanced disease have been expanded with immune checkpoint inhibitors, targeted therapies and antibody drug conjugates. Despite these developments, resistance to classical and novel therapeutics occurs in a considerable proportion of patients, and the challenge of unravelling the underlying mechanistic insights remains. Biomarkers for the proper identification of patients who will better respond to therapy are also being investigated, and new potential therapeutic targets will certainly arise. This Special Issue will highlight recent advances and future perspectives in diagnosis and treatment strategies for bladder cancer, from basic research to clinical applications that ultimately aim to improve diagnosis, monitoring and management of bladder cancer patients.

You may choose our Joint Special Issue in Current Oncology.

Dr. Julieta Alexandra Pereira Afonso
Dr. Maria de Fátima Monginho Baltazar
Guest Editors

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Keywords

bladder cancer
non-muscle invasive
muscle-invasive
diagnosis
treatment
resistance to treatment
biomarkers
therapeutic targets

Published Papers (6 papers)

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Research

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13 pages, 1996 KiB

Open AccessArticle

Relevance of HOTAIR rs920778 and rs12826786 Genetic Variants in Bladder Cancer Risk and Survival

by Eduarda P. Martins, Joana Vieira de Castro, Rita Fontes, Sara Monteiro-Reis, Rui Henrique, Carmen Jerónimo and Bruno M. Costa

Cancers 2024, 16(2), 434; https://doi.org/10.3390/cancers16020434 - 19 Jan 2024

Viewed by 797

Abstract

The long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is associated with oncogenic features in bladder cancer and is predictive of poor clinical outcomes in patients diagnosed with this disease. In this study, we evaluated the impact of the HOTAIR single nucleotide polymorphisms rs920778 and rs12826786 on bladder cancer risk and survival. This case-control study included 106 bladder cancer patients and 199 cancer-free controls. Polymorphisms were evaluated through PCR-restriction fragment length polymorphism. The odds ratio and 95% confidence intervals were tested using univariable and multivariable logistic regressions. The effects on patient survival were evaluated using the log-rank test and Cox regression models. Our data showed that the HOTAIR rs920778 and rs12826786 genetic variants are not associated with the risk of developing bladder cancer. Nevertheless, survival analyses suggested that the HOTAIR rs920778 TT genotype and rs12826786 CC genotype are associated with increased survival in male bladder cancer patients and in patients, both male and female, who have primary tumors with a pathological stage of pT2. Together, these results suggest that, despite not being associated with bladder cancer risk, HOTAIR rs920778 and rs12826786 polymorphisms might represent new prognostic factors in this type of cancer. This is particularly important as these polymorphisms might be easily evaluated in bladder cancer patients in a minimally invasive manner to better predict their clinical outcomes. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

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15 pages, 3056 KiB

Open AccessArticle

Diagnostic and Prognostic Roles of Urine Nectin-2 and Nectin-4 in Human Bladder Cancer

by Makito Miyake, Nobutaka Nishimura, Sayuri Ohnishi, Yuki Oda, Takuya Owari, Kenta Ohnishi, Yosuke Morizawa, Shunta Hori, Daisuke Gotoh, Yasushi Nakai, Kazumasa Torimoto, Tomomi Fujii, Nobumichi Tanaka and Kiyohide Fujimoto

Cancers 2023, 15(9), 2565; https://doi.org/10.3390/cancers15092565 - 29 Apr 2023

Cited by 1 | Viewed by 1576

Abstract

The clinical utility of urine nectins in bladder cancer (BCa) is unclear. We investigated the potential diagnostic and prognostic values of urine Nectin-2 and Nectin-4. Levels of urine Nectin-2, Nectin-4, and NMP-22 were quantified using an enzyme-linked immunosorbent assay in 122 patients with BCa, consisting of 78 with non-muscle-invasive BCa (NMIBC) and 44 with muscle-invasive BCa (MIBC), and ten healthy controls. Tumor nectin expression in MIBC was evaluated with immunohistochemical staining of transurethral resection specimens. The level of urine Nectin-4 (mean: 18.3 ng/mL) was much higher than that of urine Nectin-2 (mean: 0.40 ng/mL). The sensitivities of Nectin-2, Nectin-4, NMP-22, and cytology assays were 84%, 98%, 52%, and 47%, respectively; their specificities were 40%, 80%, 100%, and 100%, respectively. Both urine Nectin-2 and Nectin-4, though not NMP-22, were found to be significantly more sensitive than cytology. A four-titer grouping based on levels of urine Nectin-2/Nectin-4 (low/high, high/high, low/low, and high/low) showed a high capability for discriminating between NMIBC and MIBC. Neither urine Nectin-2 nor Nectin-4 levels had a significant prognostic value in NMIBC or MIBC. Urine levels correlated with tumor expression and serum levels in the Nectin-4 analysis, but not in the Nectin-2 analysis. Urine nectins are potential diagnostic biomarkers for BCa. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

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11 pages, 1128 KiB

Open AccessArticle

Replacement Instead of Discontinuation of Bacillus Calmette-Guérin Instillation in Non-Muscle-Invasive Bladder Cancer

by Po-Ting Lin, Wei-Kang Hung, Ying-Hsu Chang, Ming-Li Hsieh, Chung-Yi Liu, Liang-Kang Huang, Yuan-Cheng Chu, Hung-Cheng Kan, Po-Hung Lin, Kai-Jie Yu, Cheng-Keng Chuang, Chun-Te Wu, See-Tong Pang and I-Hung Shao

Cancers 2023, 15(4), 1345; https://doi.org/10.3390/cancers15041345 - 20 Feb 2023

Viewed by 1490

Abstract

Background: To evaluate the efficacy of intravesical chemotherapy replacement in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), who underwent bacillus Calmette-Guérin (BCG) instillation but discontinued due to global shortages or toxicity of BCG. Methods: This retrospective study included patients with intermediate- and high-risk NMIBC who received BCG intravesical instillation. Those who discontinued the treatment were divided into the pure BCG group and chemotherapy replacement group. Comparisons between these groups were performed. The primary endpoint was bladder recurrence-free survival (RFS). Results: A total of 480 patients were included. Baseline characteristics were similar between groups, but the total instillation times were higher in the chemotherapy replacement group than in the pure BCG group (n = 14.9 vs. 10.5). The chemotherapy replacement group had a better three-year RFS (p = 0.022). On multivariate analysis, the pure BCG group had significantly increased all-time and 3-year recurrences (hazard ratio 2.015 and 2.148) compared to the chemotherapy replacement group. Conclusions: Chemotherapy replacement has a better three-year RFS than no instillation in patients with intermediate- and high-risk NMIBC who received BCG instillation but facing treatment stoppage. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

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33 pages, 6100 KiB

Open AccessArticle

Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy

by Julieta Afonso, Céline Gonçalves, Marta Costa, Débora Ferreira, Lúcio Santos, Adhemar Longatto-Filho and Fátima Baltazar

Cancers 2023, 15(3), 982; https://doi.org/10.3390/cancers15030982 - 03 Feb 2023

Cited by 7 | Viewed by 3076

Abstract

Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in “in vitro” and “in vivo” preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell’s viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

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14 pages, 275 KiB

Open AccessArticle

Perioperative Complications and Oncologic Outcomes after Radical Cystectomy in End-Stage Renal Disease Patients with Bladder Cancer Obtained Using a Standardized Reporting System

by Yu-Liang Liu, Chun-Te Wu, Yu-Chao Hsu, Miao-Fen Chen, Chih-Shou Chen, Chung-Sheng Shi and Yun-Ching Huang

Cancers 2022, 14(14), 3512; https://doi.org/10.3390/cancers14143512 - 19 Jul 2022

Cited by 1 | Viewed by 1377

Abstract

Background: We investigated the use of a standardized reporting system to study perioperative complications and oncologic outcomes after radical cystectomy in end-stage renal disease (ESRD) patients with bladder cancer. Methods: We reviewed retrospective outcomes in 141 ESRD patients with bladder cancer who underwent radical cystectomy between 2004 and 2015. Complications were graded using the Clavien–Dindo classification system with 0–2 classified as “No Major Complications” and Clavien 3–5 as “Major Complications”. Low-volume surgeons were classified as those performing fewer than nine cases during the study. Fisher’s exact test along with the chi-squared test, two-tailed t tests, logistic regression, and the Cox proportional hazard model were used to evaluate all clinically meaningful covariates. Results: Ninety-nine (99, 70.2%) patients had no major complications, and forty-two (29.8%) patients had major complications. Patients in the major complications group were older, had a higher Charlson comorbidity index (CCI), and had a longer hospitalization duration than those in the no major complications group (all, p < 0.05). Major complications were also more common when the procedure was performed by low-volume surgeons (p = 0.003). In multivariate logistic regression models, CCI ≥ 5 (p = 0.006) and low-volume surgeon (p = 0.004) were independent predictors of major complications. According to multivariate analysis with the Cox hazards regression, male sex, age > 70 years, CCI ≥ 5, bladder cancer stage ≥ 3, lymphovascular invasion, and experiencing major complications were significant poor prognostic factors for overall survival (all, p < 0.05). Conclusions: Accurate reporting of complications is necessary for preoperative counseling, identifying modifiable risk factors, and planning risk mitigation strategies. High comorbidity and low-volume surgeons were interrelated as notable risk factors for major complications. In addition to tumor-related factors, male sex, older age, and major complications significantly influence overall survival. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

Review

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15 pages, 565 KiB

Open AccessReview

Assessing the Performance of 18F-FDG PET/CT in Bladder Cancer: A Narrative Review of Current Evidence

by Mara Bacchiani, Vincenzo Salamone, Eleana Massaro, Alessandro Sandulli, Riccardo Mariottini, Anna Cadenar, Fabrizio Di Maida, Benjamin Pradere, Laura S. Mertens, Mattia Longoni, Wojciech Krajewski, Francesco Del Giudice, David D’Andrea, Ekaterina Laukhtina, Shahrokh F. Shariat, Andrea Minervini, Marco Moschini, Andrea Mari and on behalf of European Association of Urology-Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working Group

Cancers 2023, 15(11), 2951; https://doi.org/10.3390/cancers15112951 - 28 May 2023

Cited by 2 | Viewed by 1558

Abstract

Introduction: Lymph node (LN) involvement is a crucial determinant of prognosis for patients with bladder cancer, and an accurate staging is of utmost importance to better identify timely and appropriate therapeutic strategies. To improve the accuracy of LN detection, as an alternative to traditional methods such as CT or MRI, 18F-FDG PET/CT has been increasingly used. 18F-FDG PET/CT is also used in post-treatment restaging after neoadjuvant chemotherapy. The aim of this narrative literature review is to provide an overview of the current evidence on the use of 18F-FDG PET/CT in the diagnosis, staging, and restaging of bladder cancer, with a particular focus on its sensitivity and specificity for the detection of LN metastasis. We aim to provide clinicians with a better understanding of 18F-FDG PET/CT’s potential benefits and limitations in clinical practice. Materials and Methods: We designed a narrative review starting from a wide search in the PubMed/MEDLINE and Embase databases, selecting full-text English articles that have examined the sensibility and specificity of PET/CT for nodal staging or restaging after neoadjuvant therapy in patients with bladder cancer. The extracted data were analyzed and synthesized using a narrative synthesis approach. The results are presented in a tabular format, with a summary of the main findings of each study. Results: Twenty-three studies met the inclusion criteria: fourteen studies evaluated 18F-FDG PET/CT for nodal staging, six studies examined its accuracy for restaging after neoadjuvant therapy, and three studies evaluated both applications. To date, the use of F-18 FDG PET/TC for detection of LN metastasis in bladder cancer is controversial and uncertain: some studies showed low accuracy rates, but over the years other studies have reported evidence of high sensitivity and specificity. Conclusions: 18F-FDG PET/CT provides important incremental staging and restaging information that can potentially influence clinical management in MIBC patients. Standardization and development of a scoring system are necessary for its wider adoption. Well-designed randomized controlled trials in larger populations are necessary to provide consistent recommendations and consolidate the role of 18F-FDG PET/CT in the management of bladder cancer patients. Full article

(This article belongs to the Special Issue Advances and Perspectives in Diagnosis and Treatment Strategies for Bladder Cancer)

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