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Medicina (Kaunas, Lithuania) Jul 2021Bladder cancer (BCa) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. While the clinical approach to BCa has remained... (Review)
Review
Bladder cancer (BCa) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. While the clinical approach to BCa has remained largely unchanged for many years, recent discoveries have paved the way to a new era of diagnosis and management of the disease. BCa-specific mortality started to decrease in the regions with a wide range of activities leading to greater social awareness of the risk factors and the decline in carcinogenic exposure. The urologic community refines the role of transurethral surgery towards more rigorous and high-quality techniques. New agents have been approved for patients with BCG failure who faced radical cystectomy so far. Although radical removal of the bladder is the gold standard for muscle invasive cancer management, the extent and clinical value of lymphadenectomy is currently heavily challenged in randomized trials. Furthermore, alternatives to perioperative chemotherapy have arisen to increase the likelihood of complete treatment delivery and successful oncological outcomes. Finally, improvements in molecular biology and our understanding of tumorigenesis open the era of personalized medicine in bladder cancer. In the present review, the status and future directions in bladder cancer epidemiology, diagnosis and management are thoroughly discussed.
Topics: Cystectomy; Humans; Lymph Node Excision; Neoplasm Invasiveness; Risk Factors; Urinary Bladder Neoplasms
PubMed: 34440955
DOI: 10.3390/medicina57080749 -
Nature Reviews. Disease Primers Oct 2023Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways... (Review)
Review
Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics.
Topics: Humans; Female; Male; Treatment Outcome; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms; Urinary Bladder; Prognosis
PubMed: 37884563
DOI: 10.1038/s41572-023-00468-9 -
Nature Reviews. Cancer Feb 2021The field of research in bladder cancer has seen significant advances in recent years. Next-generation sequencing has identified the genes most mutated in bladder... (Review)
Review
The field of research in bladder cancer has seen significant advances in recent years. Next-generation sequencing has identified the genes most mutated in bladder cancer. This wealth of information allowed the definition of driver mutations, and identification of actionable therapeutic targets, as well as a clearer picture of patient prognosis and therapeutic direction. In a similar vein, our understanding of the cellular aspects of bladder cancer has grown. The identification of the cellular geography and the populations of different cell types and quantifications of normal and abnormal cell types in tumours provide a better prediction of therapeutic response. Non-invasive methods of diagnosis, including liquid biopsies, have seen major advances as well. These methods will likely find considerable utility in assessing minimal residual disease following treatment and for early-stage diagnosis. A significant therapeutic impact on patients with bladder cancer is found in the use of immune checkpoint inhibitor therapeutics. These therapeutics have been shown to cure some patients with bladder cancer and significantly decrease adverse events. These developments provide patients with better monitoring opportunities, unique therapeutic options and greater hope for prolonged survival.
Topics: Animals; Biomarkers, Tumor; Cancer-Associated Fibroblasts; Carcinoma, Transitional Cell; Disease Models, Animal; Epidemiologic Factors; Epigenesis, Genetic; High-Throughput Nucleotide Sequencing; Humans; Immune Checkpoint Inhibitors; Mice; Mutation; Neoplasm Staging; Prognosis; Tumor Microenvironment; Urinary Bladder Neoplasms
PubMed: 33268841
DOI: 10.1038/s41568-020-00313-1 -
CA: a Cancer Journal For Clinicians Sep 2020Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle-invasive and advanced bladder cancer has... (Review)
Review
Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle-invasive and advanced bladder cancer has primarily consisted of platinum-based chemotherapy. Over the past 10 years, innovations in sequencing technologies have led to rapid genomic characterization of bladder cancer, deepening our understanding of bladder cancer pathogenesis and exposing potential therapeutic vulnerabilities. On the basis of its high mutational burden, immune checkpoint inhibitors were investigated in advanced bladder cancer, revealing durable responses in a subset of patients. These agents are now approved for several indications and highlight the changing treatment landscape of advanced bladder cancer. In addition, commonly expressed molecular targets were leveraged to develop targeted therapies, such as fibroblast growth factor receptor inhibitors and antibody-drug conjugates. The molecular characterization of bladder cancer and the development of novel therapies also have stimulated investigations into optimizing treatment approaches for muscle-invasive bladder cancer. Herein, the authors review the history of muscle-invasive and advanced bladder cancer management, highlight the important molecular characteristics of bladder cancer, describe the major advances in treatment, and offer future directions for therapeutic development.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Biomarkers; Clinical Trials as Topic; Combined Modality Therapy; Cystectomy; Humans; Immune Checkpoint Inhibitors; Muscle, Smooth; Neoplasm Invasiveness; Organ Sparing Treatments; Receptors, Fibroblast Growth Factor; Urinary Bladder Neoplasms
PubMed: 32767764
DOI: 10.3322/caac.21631 -
Seminars in Nuclear Medicine Jul 2022In the urinary tract, bladder cancer is the most common malignancy. It is a heterogenous cancer type with approximately 30% presenting as muscle invasive bladder cancer... (Review)
Review
In the urinary tract, bladder cancer is the most common malignancy. It is a heterogenous cancer type with approximately 30% presenting as muscle invasive bladder cancer with a high risk of metastatic spread associated with risk of death from distant metastases. The other 70% of bladder cancer patients present with superficial tumors with tendency of recurrence but in general not life-threatening. Like in other malignancies, accurate and precise staging of bladder cancer is one of the mainstays at the time of diagnosis to select the optimal treatment for each patient. The detection of metastatic spread is of utmost importance for selection of treatment strategy. Hybrid imaging med with FDG PET/CT is widely used in the clinical management of a variety of malignancies. FDG PET/CT is increasingly used for primary staging of muscle invasive bladder cancer and for detection of recurrence after radical cystectomy. Few studies have used FDG PET/CT for response evaluation of neoadjuvant, induction chemotherapy or immunotherapy. Furthermore, small studies have tested non-FDG PET agents with little or no urinary excretions of the tracer. This review provides an update on PET/CT in bladder cancer.
Topics: Fluorodeoxyglucose F18; Humans; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals; Urinary Bladder Neoplasms
PubMed: 34996595
DOI: 10.1053/j.semnuclmed.2021.12.004 -
International Braz J Urol : Official... 2020Standard management of muscle-invasive bladder cancer involves radical cystectomy with pelvic lymph node dissection. However, patients may be ineligible for surgery or... (Review)
Review
BACKGROUND
Standard management of muscle-invasive bladder cancer involves radical cystectomy with pelvic lymph node dissection. However, patients may be ineligible for surgery or may wish to avoid the morbidity of cystectomy due to quality of life concerns. Bladder preservation therapies have emerged as alternatives treatment options that can provide comparable oncologic outcomes while maintaining patients' quality of life.
OBJECTIVE
To review bladder preservation therapies, patient selection criteria, and functional and oncologic outcomes for BPT in muscle-invasive bladder cancer.
MATERIALS AND METHODS
We conducted a comprehensive literature review of bladder preservation therapies in Pubmed and Embase.
DISCUSSION
The ideal patient for BPT has low-volume T2 disease, absence of CIS, absence of hydronephrosis, and a maximal TURBT with regular surveillance. Technological advancements involving cancer staging, TURBT technique, and chemotherapy and radiation therapy regimens have improved BPT outcomes, with oncologic outcomes now comparable to those of radical cystectomy. Advancements in BPT also includes a heightened focus on improving quality of life for patients undergoing bladder preservation. Preservation strategies with most evidence for use include trimodality therapy and partial cystectomy with pelvic lymph node dissection.
CONCLUSIONS
This review highlights the breadth of strategies that aim to preserve a patient's bladder while still optimizing local tumor control and overall survival. Future areas for innovation include the use of predictive biomarkers and implementation of immunotherapy, moving the field towards patient-tailored care.
Topics: Combined Modality Therapy; Cystectomy; Humans; Neoplasm Invasiveness; Neoplasm Staging; Organ Sparing Treatments; Urinary Bladder Neoplasms
PubMed: 31961624
DOI: 10.1590/S1677-5538.IBJU.2020.99.01 -
Drugs Mar 2023Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for... (Review)
Review
Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.
Topics: Adult; Humans; BCG Vaccine; Adjuvants, Immunologic; Administration, Intravesical; Antineoplastic Agents; Urinary Bladder Neoplasms; Interferon-alpha; Neoplasm Invasiveness; Neoplasm Recurrence, Local
PubMed: 36856952
DOI: 10.1007/s40265-023-01846-z -
International Journal of Cancer Dec 2021Bladder cancer represents a highly heterogeneous disease characterized by distinct histological, molecular and clinical phenotypes, and a detailed analysis of tumor cell... (Observational Study)
Observational Study
Bladder cancer represents a highly heterogeneous disease characterized by distinct histological, molecular and clinical phenotypes, and a detailed analysis of tumor cell invasion and crosstalks within bladder tumor cells has not been determined. Here, we applied droplet-based single-cell RNA sequencing (scRNA-seq) to acquire transcriptional profiles of 36 619 single cells isolated from seven patients. Single cell transcriptional profiles matched well with the pathological basal/luminal subtypes. Notably, in T1 tumors diagnosed as luminal subtype, basal cells displayed characteristics of epithelial-mesenchymal transition (EMT) and mainly located at the tumor-stromal interface as well as micrometastases in the lamina propria. In one T3 tumor, muscle-invasive tumor showed significantly higher expression of cancer stem cell markers SOX9 and SOX2 than the primary tumor. We additionally analyzed communications between tumor cells and demonstrated its relevance to basal/luminal phenotypes. Overall, our single-cell study provides a deeper insight into the tumor cell heterogeneity associated with bladder cancer progression.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Disease Progression; Epithelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Muscle, Smooth; Neoplasm Invasiveness; RNA-Seq; Single-Cell Analysis; Tomography, X-Ray Computed; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 34480339
DOI: 10.1002/ijc.33794 -
Cancer Cell May 2021Discovery-driven research and clinical research have worked together to change the outcomes of many cancer patients. We choose urothelial carcinoma as an example to... (Review)
Review
Discovery-driven research and clinical research have worked together to change the outcomes of many cancer patients. We choose urothelial carcinoma as an example to showcase how recent diagnostic and therapeutic innovations have re-shaped cancer clinical practice.
Topics: Carcinoma, Transitional Cell; Humans; Neoplasm Metastasis; Research; Urinary Bladder Neoplasms
PubMed: 33974855
DOI: 10.1016/j.ccell.2021.04.012 -
Molecular Cancer Feb 2022The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic...
PURPOSE
The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity.
RESULTS
Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1).
CONCLUSIONS
Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Heterogeneous-Nuclear Ribonucleoprotein U; Humans; Urinary Bladder Neoplasms
PubMed: 35130920
DOI: 10.1186/s12943-022-01517-9