Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma.
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ABSTRACT:
SUBMITTER: Yassaie O
PROVIDER: S-EPMC8366114 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lack of appropriate biomarkers has hampered early detection of urothelial cancer (UC), therefore, development of biomarkers for its diagnosis at earlier stages is of importance. Laminin-332 (Ln-332, formerly Ln-5), a component of basement membranes, consists of Ln-?3, Ln-?3, and Ln-?2 polypeptides. However, monomeric Ln-?2 alone is frequently expressed in malignant neoplasms. If Ln-?2 is also expressed in UC and secreted into the urine, its detection could be useful for UC diagnosis. Here, we evaluated Ln-?2 levels from 60 patients with urinary diseases (including UC) by Western blotting, and detected it in approximately 53% of UC cases. Using immunohistochemistry, we confirmed Ln-?2 expression in UC tissues that were positive for Ln-?2, whereas Ln-?3 expression was absent. We next developed a sandwich enzyme-linked immunosorbent assay and applied it for screening 39 patients with non-muscle invasive UC and 61 patients with benign urologic diseases. The Ln-?2 levels were higher in UC patients than in those with benign urologic diseases. Ln-?2 was detected even in patients with earlier stages of UC, such as Ta, T1, or carcinoma in situ. The sensitivity of Ln-?2 testing for UC was 97.4%, and the specificity was 45.9%, using a cut-off of 0.5 ?g/g?crn. Ln-?2 had greater diagnostic value for detecting non-muscle invasive UC compared to conventional urine cytology and available biomarkers for UC, and may be useful as a urine biomarker for the diagnosis and monitoring of UC.
| S-EPMC4714663 | biostudies-other
Project description:The development of targeted therapies and the resurgence of immunotherapy offer enormous potential to dramatically improve the outlook for patients with invasive urothelial carcinoma (InvUC). Optimization of these therapies, however, is crucial as only a minority of patients achieve dramatic remission, and toxicities are common. With the complexities of the therapies, and the growing list of possible drug combinations to test, highly relevant animal models are needed to assess and select the most promising approaches to carry forward into human trials. The animal model(s) should possess key features that dictate success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). While it may not be possible to create these collective features in experimental models, these features are present in naturally-occurring InvUC in pet dogs. Naturally occurring canine InvUC closely mimics muscle-invasive bladder cancer in humans in regards to cellular and molecular features, molecular subtypes, biological behavior (sites and frequency of metastasis), and response to therapy. Clinical treatment trials in pet dogs with InvUC are considered a win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. This review will provide an overview of canine InvUC, the similarities to the human condition, and the potential for dogs with InvUC to serve as a model to predict the outcomes of targeted therapy and immunotherapy in humans.
| S-EPMC5929349 | biostudies-other
Project description:BackgroundThe role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear.MethodsIn a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point.ResultsA total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group.ConclusionsIn this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
| S-EPMC8215888 | biostudies-literature
Project description:Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma.
| S-EPMC4872187 | biostudies-literature
Project description:Muscle-invasive bladder urothelial carcinoma (MIBC) is characteristic of high mortality and high recurrence. Distinguishing the prognostic risk of MIBC at the molecular level of miRNA expression is rarely performed and thus of great significance for the management and treatment of MIBC in clinics. Adaptive lasso Cox's proportional hazards model was used to explore the relationship between differential expression miRNAs (DEmiRNAs) and MIBC survival. Furthermore, we evaluated the epithelial-mesenchymal transition (EMT) score and immune infiltration abundance by exploring EMT signature genes and TIMER database, respectively. A total of 8 DEmiRNAs were detected to be associated with the survival rate of MIBC by using the lasso Cox algorithm. Through the linear combination of these 8 DEmiRNAs, we constructed a calculated marker, which could be used to distinguish the prognosis risk in both TCGA dataset (HR?=?2.03, 95% CI?=?(1.47, 2.83)) and independent validation dataset (HR?=?7.74, 95% CI?=?(1.05, 56.93)). Meanwhile, the constructed marker had reasonably high predictive values of the AUC (area under the curve) in the TCGA dataset and validation dataset being 0.73 and 0.63, respectively. In addition, we observed that the expression values of let-7c, miR-100, and miR-145 were associated with EMT score and the abundance of macrophage in tumor tissue as well. This newly identified risk score signature based on the combination of 8 miRNAs could significantly predict the prognostic risk of MIBC and might provide insight into immunotherapy and targeted therapy of MIBC.
| S-EPMC6925814 | biostudies-literature
Project description:Muscle-invasive bladder urothelial carcinoma (MIBC) is a highly invasive cancer, which leads to prevalent recurrence and poor prognosis. Exploring the association of DNA methylation and the prognosis of MIBC will thus be of important value in clinical management and treatment. Bumphunter method and adaptive lasso regression were used to explore the relationship between different methylation regions (DMRs) and the prognosis of MIBC. Next, we constructed a risk prognosis model and validated this model. Moreover, the performance of this risk model was examined by using time-dependent receiver operating characteristic curve (ROC). We identified 58,449 different methylation sites and 490 different methylation regions. Among them, 11 DMRs were associated with the prognosis of MIBC through rigorous screening. Through the linear combination of 11 DMRs, a putative marker was developed, which can distinguish the survival risk in both the training dataset (HR = 2.58, 95% CI = (1.64, 4.05)) and the verification dataset (HR = 2.77, 95% CI = (1.25, 6.15)). Relatively high predictive values were observed from this model for training dataset (AUC = 0.791) and verification dataset (AUC = 0.668). Stratified analysis showed that the association was independent of gender. A nomogram was additionally generated to predict 5-year survival probability containing risk score and pathological stage. Its performance was evaluated by applying calibration curve. The methylation signature risk model based on 11 DMRs may be a reliable prognostic signature for MIBC, which provides new insights into development of individualized therapy for MIBC.
| S-EPMC7722798 | biostudies-literature
Project description:Background:Elucidation of epigenetic alterations in bladder cancer will lead to further understanding of the biology of the disease and hopefully improved therapies. Our aim was to perform an integrative epigenetic analysis of invasive urothelial carcinoma of the bladder to identify the epigenetic abnormalities involved in the development and progression of this cancer. Methods:Pre-processed methylation data and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. An R package MethylMix was used to perform an analysis incorporating both methylation and gene expression data on all samples, as well as a subset analysis comparing patients surviving less than 2 years and patients surviving more than 2 years. Genes associated with poor prognosis were individually queried. Pathway analysis was performed on statistically significant genes identified by MethylMix criteria using ConsensusPathDB. Validation was performed using flow cytometry on bladder cancer cell lines. Results:A total of 408 patients met all inclusion criteria. There were a total of 240 genes differentially methylated by MethylMix criteria. Review of individual genes specific to poor-prognosis patients revealed the majority to be candidate tumor suppressors in other cancer types. Pathway analysis showed increase in methylation of genes involved in antioxidant pathways including glutathione and NRF2. Genes involved in estrogen metabolism were also hypermethylated while genes involved in the EGFR pathway were found to be hypomethylated. EGFR expression was confirmed to be elevated in six bladder cancer cell lines. Conclusions:In patients with invasive urothelial carcinoma, we found differential methylation in patients with better and worse prognosis after cystectomy. Differentially methylated genes are involved in many relevant oncologic pathways, including EGFR and antioxidant pathways, that may be a target for therapy or chemoprevention.
| S-EPMC5809922 | biostudies-literature
Project description:Object: CK14 expression is an important marker of basal/squamous-like (BASQ)-type muscle-invasive bladder carcinoma, and this molecularly defined subtype has a poor prognosis and a distinct response to chemotherapy. However, CK14 expression and its clinicopathological and molecular significance in papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) remain unknown. Herein, we investigated the prognostic implications of immunohistochemical (IHC) staining for CK14 and the transcriptional characteristics associated with CK14 expression in papillary NMIUTUC. Materials and Methods: IHC staining for CK14 was conducted in 204 papillary NMIUTUC specimens. Positive CK14 IHC staining was defined as a positive signal in >0% of tumor cells. RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors. Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003). Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780). Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor ?-nuclear factor-?B, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype. In addition, with a p < 0.05 and |fold change| ?2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors. Functional analysis of these genes revealed several networks and gene ontology terms related to the positive regulation of cellular proliferation in CK14-positive tumors. Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002). Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity. We propose that CK14 IHC staining can be a useful biomarker of BASQ-type papillary NMIUTUC that can be applied in daily practice with the aim of precision oncology.
| S-EPMC7193093 | biostudies-literature
Project description:Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis.
| S-EPMC6966549 | biostudies-literature
Project description:Immunohistochemical (IHC) staining for CK5/6 and CK20 was reported to be correlated with the prognosis of early urothelial carcinoma in a way contrary to that of advanced tumors for unknown reasons. We aimed to characterize the gene expression profiles of subgroups of non-muscle-invasive papillary high-grade upper tract urothelial carcinoma (UTUC) classified by CK5/6 and CK20 expression levels: group 1 (CK5/6-high/CK20-low), group 2 (CK5/6-high/CK20-high), and group 3 (CK5/6-low/CK20-high). Expression of group 3 was predictive of worse prognosis of non-muscle-invasive papillary high-grade UTUC. Transcriptional analysis revealed 308 differentially expressed genes across the subgroups. Functional analyses of the genes identified cell adhesion as a common process differentially enriched in group 3 compared to the other groups, which could explain its high-risk phenotype. Late cell cycle/proliferation signatures were also enriched in group 3 and in some of the other groups, which may be used as a prognostic biomarker complementary to CK5/6 and CK20. Group 2, characterized by low levels of genes associated with mitogen-activated protein kinase and tumor necrosis factor signaling pathways, was hypothesized to represent the least cancerous subtype considering its normal urothelium-like IHC pattern. This study would facilitate the application of easily accessible prognostic biomarkers in practice.
| S-EPMC6386996 | biostudies-literature