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Abstract Purpose We aimed to assess the impact of GATA3 binding protein (GATA3) gene copy number alterations on tumor aggressiveness, patient prognosis, and GATA3 protein expression in a large urothelial bladder cancer cohort. Methods A tissue microarray containing over 2,700 urothelial bladder cancers (pTa-pT4) was analyzed retrospectively using dual-labeling fluorescence in-situ hybridization (FISH) with probes for GATA3 (10p14) and centromere 10. GATA3 copy number gains were categorized as GATA3 elevation (ratio GATA3/centromere ≥ 2/≤4), low-level amplification (ratio > 4/≤12), and high-level amplification (ratio > 12) and deletions were divided between homozygous and heterozygous. Results GATA3 copy number gain was detected in 9.9% of 2,213 interpretable tumors, including 2.0% with GATA3 elevation, 3.2% with low-level amplification, and 4.7% with high-level amplification. The frequency of high-level amplification increased from pTa G2 low (0%) to pTa G3 tumors (12% [CI 0.07;0.21]; p

Claudin-4 is an integral membrane protein of tight junctions, and its expression is frequently altered in epithelial cancers. Non-muscle-invasive urothelial bladder cancer (NMIBC) is a common neoplasm with an unpredictable clinical course that requires more precise stratification and risk assessment. The aim of this study was to investigate the association between Claudin-4 expression and clinicopathologic features of NMIBC, and to assess the predictive impact of Claudin-4 regarding to disease prognosis. The study comprised tumor tissue samples obtained from 441 patients with urothelial bladder cancer who had undergone transurethral resection. Samples were embedded in tissue microarrays and analyzed immunohistochemically for Claudin-4 expression. High expression was found in 41.6% of pTa and 47.8% of pT1 tumors. High Claudin-4 expression significantly correlated to high histologic grade (p = 0.002), and hematuria (p = 0.038). High Claudin-4 expression was more frequently observed in tumors with divergent differentiation, early invasive cancers associated with carcinoma in situ, and recurrent disease, however, these associations were not statistically significant. Kaplan--Meier survival analysis failed to indicate a significant difference in overall survival between the patients with high and low Claudin-4 expression. Conversely, recurrence-free survival was significantly associated with Claudin-4 expression (p = 0.023). In conclusion, overexpression of Claudin-4 is associated with high tumor grade and shorter recurrence-free survival. As an indicator of aggressive tumor behavior, Claudin-4 may serve as a potentially useful and accessible addition to the pathohistological panel for the prediction of clinical behavior of urothelial bladder cancer, as well as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Bladder cancer is one of the most frequently occurring cancers worldwide. At diagnosis, 75% of urothelial bladder cancer cases have non-muscle invasive bladder cancer while 25% have muscle invasive or metastatic disease. Aberrantly activated fibroblast growth factor receptor (FGFR)-3 has been implicated in the pathogenesis of bladder cancer. Activating mutations of FGFR3 are observed in around 70% of NMIBC cases and ~ 15% of MIBCs. Activated FGFR3 leads to ligand-independent receptor dimerization and activation of downstream signaling pathways that promote cell proliferation and survival. FGFR3 is an important therapeutic target in bladder cancer, and clinical studies have shown the benefit of FGFR inhibitors in a subset of bladder cancer patients. c-MYC is a well-known major driver of carcinogenesis and is one of the most commonly deregulated oncogenes identified in human cancers. Studies have shown that the antitumor effects of FGFR inhibition in FGFR3 dependent bladder cancer cells and other FGFR dependent cancers may be mediated through c-MYC, a key downstream effector of activated FGFR that is involved tumorigenesis. This review will summarize the current general understanding of FGFR signaling and MYC alterations in cancer, and the role of FGFR3 and MYC dysregulation in the pathogenesis of urothelial bladder cancer with the possible therapeutic implications.

Background: Bladder cancer, a highly fatal disease, poses a significant threat to patients. Positioned at 19q13.2-13.3, LIG1, one of the four DNA ligases in mammalian cells, is frequently deleted in tumour cells of diverse origins. Despite this, the precise involvement of LIG1 in BLCA remains elusive. This pioneering investigation delves into the uncharted territory of LIG1's impact on BLCA. Our primary objective is to elucidate the intricate interplay between LIG1 and BLCA, alongside exploring its correlation with various clinicopathological factors. Methods: We retrieved gene expression data of para-carcinoma tissues and bladder cancer (BLCA) from the GEO repository. Single-cell sequencing data were processed using the "Seurat" package. Differential expression analysis was then performed with the "Limma" package. The construction of scale-free gene co-expression networks was achieved using the "WGCNA" package. Subsequently, a Venn diagram was utilized to extract genes from the positively correlated modules identified by WGCNA and intersect them with differentially expressed genes (DEGs), isolating the overlapping genes. The "STRINGdb" package was employed to establish the protein-protein interaction (PPI) network.Hub genes were identified through the PPI network using the Betweenness Centrality (BC) algorithm. We conducted KEGG and GO enrichment analyses to uncover the regulatory mechanisms and biological functions associated with the hub genes. A machine-learning diagnostic model was established using the R package "mlr3verse." Mutation profiles between the LIG1^high and LIG1^low groups were visualized using the BEST website. Survival analyses within the LIG1^high and LIG1^low groups were performed using the BEST website and the GENT2 website. Finally, a series of functional experiments were executed to validate the functional role of LIG1 in BLCA. Results: Our investigation revealed an upregulation of LIG1 in BLCA specimens, with heightened LIG1 levels correlating with unfavorable overall survival outcomes. Functional enrichment analysis of hub genes, as evidenced by GO and KEGG enrichment analyses, highlighted LIG1's involvement in critical function such as the DNA replication, cellular senescence, cell cycle and the p53 signalling pathway. Notably, the mutational landscape of BLCA varied significantly between LIG1high and LIG1low groups. Immune infiltrating analyses suggested a pivotal role for LIG1 in immune cell recruitment and immune regulation within the BLCA microenvironment, thereby impacting prognosis. Subsequent experimental validations further underscored the significance of LIG1 in BLCA pathogenesis, consolidating its functional relevance in BLCA samples. Conclusions: Our research demonstrates that LIG1 plays a crucial role in promoting bladder cancer malignant progression by heightening proliferation, invasion, EMT, and other key functions, thereby serving as a potential risk biomarker. [ABSTRACT FROM AUTHOR]

Bladder cancer is one of the most frequently occurring cancers worldwide. At diagnosis, 75% of urothelial bladder cancer cases have non-muscle invasive bladder cancer while 25% have muscle invasive or metastatic disease. Aberrantly activated fibroblast growth factor receptor (FGFR)-3 has been implicated in the pathogenesis of bladder cancer. Activating mutations of FGFR3 are observed in around 70% of NMIBC cases and ~ 15% of MIBCs. Activated FGFR3 leads to ligand-independent receptor dimerization and activation of downstream signaling pathways that promote cell proliferation and survival. FGFR3 is an important therapeutic target in bladder cancer, and clinical studies have shown the benefit of FGFR inhibitors in a subset of bladder cancer patients. c-MYC is a well-known major driver of carcinogenesis and is one of the most commonly deregulated oncogenes identified in human cancers. Studies have shown that the antitumor effects of FGFR inhibition in FGFR3 dependent bladder cancer cells and other FGFR dependent cancers may be mediated through c-MYC, a key downstream effector of activated FGFR that is involved tumorigenesis. This review will summarize the current general understanding of FGFR signaling and MYC alterations in cancer, and the role of FGFR3 and MYC dysregulation in the pathogenesis of urothelial bladder cancer with the possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) expression has been recognized as a potential biomarker for various cancers, yet its diagnostic and prognostic significance in urothelial bladder cancer (BCa) requires further investigation. Methods: In this prospective single-center study, we aimed to assess the feasibility and diagnostic adequacy of PD-L1 expression analysis using cytoinclusion in BCa patients. We enrolled consecutive patients undergoing endoscopic transurethral resection of bladder tumor (TURBT), repeat TURBT, or robot-assisted radical cystectomy. Urinary and tissue specimens were collected from these patients for cytoinclusion and histopathological analysis to evaluate PD-L1 expression. Results: Out of 29 patients, PD-L1 expression was detected from cytoinclusion in 42.8% (3 out of 7), 10% (1 out of 10), and 66.8% (8 out of 12) of patients with negative/papilloma, low-grade, and high-grade tumors, respectively. Conversely, histopathological analysis identified PD-L1 expression in 57.2% (4 out of 7), 30% (3 out of 10), and 83.3% (10 out of 12) of patients with negative/papilloma, low-grade, and high-grade tumors, respectively. The diagnostic concordance between cytoinclusion and histopathology was 85.7%, 80%, and 83.3% in patients with negative/papilloma, low-grade, and high-grade tumors, respectively. Conclusions: Our study underscores the promise of cytoinclusion as a minimally invasive method for quantifying urinary PD-L1 percentages. This approach could serve as both a potential prognostic and diagnostic indicator, easily obtainable from urine samples. Standardizing this technique could facilitate its widespread use as a valuable tool. [ABSTRACT FROM AUTHOR]

Sex-specific discrepancies in bladder cancer (BCa) are reported, and new studies imply that microbiome may partially explain the diversity. We aim to provide characterization of the bladder microbiome in both sexes diagnosed with non-muscle-invasive BCa with specific insight into cancer grade. In our study, 16S rRNA next-generation sequencing was performed on midstream urine, bladder tumor sample, and healthy-appearing bladder mucosa. Bacterial DNA was isolated using QIAamp Viral RNA Mini Kit. Metagenomic analysis was performed using hypervariable fragments of the 16S rRNA gene on Ion Torrent Personal Genome Machine platform. Of 41 sample triplets, 2153 taxa were discovered: 1739 in tumor samples, 1801 in healthy-appearing bladder mucosa and 1370 in midstream urine. Women were found to have smaller taxa richness in Chao1 index than men (p = 0.03). In comparison to low-grade tumors, patients with high-grade lesions had lower bacterial diversity and richness in urine. Significant differences between sexes in relative abundance of communities at family level were only observed in high-grade tumors.

Background/Objectives: Bladder urothelial carcinoma is a frequent malignant tumor of the urinary system, characterized by its high rates of recurrence and resistance to chemotherapy. This study explored the beneficial effects of overexpressing WW domain-containing oxidoreductase (WWOX) in AY-27 cells encapsulated in an injectable gelatin hydrogel for potential therapeutic applications in bladder cancer. Methods: AY-27 cells were genetically transduced with lentiviruses (LV) to overexpress WWOX (LV-WWOX) and subsequently encapsulated in a gelatin hydrogel. The mechanical properties and morphology of the hydrogels were assessed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The therapeutic efficacy of this approach was evaluated using an F344/AY-27 rat orthotopic bladder cancer model, in which the LV-WWOX-hydrogel (H-LV-WWOX) was administered via intravesical instillation. Results: The gelatin hydrogel formulation demonstrated excellent biocompatibility, stability, and controlled release. In a rat orthotopic model, intravesical instillation of H-LV-WWOX significantly enhanced local immune responses, resulting in notable tumor regression. Compared to the sham-treated group, this approach reduced systemic toxicity and improved overall treatment outcomes. The anticancer effect of WWOX can be attributed to its ability to amplify TNF-α-induced reactive oxygen species (ROS) generation. This ROS-mediated pathway leads to enhanced apoptosis and DNA damage in cancer cells, highlighting the potential mechanism through which WWOX exhibits tumor-suppressive activities. Conclusions: These findings support the therapeutic potential of WWOX overexpression in gelatin hydrogels for bladder cancer treatment and warrant further clinical investigation.

Serum lymphocyte-derived biomarkers substantially impact prognosis of bladder cancer. This study evaluated the preoperative serum lymphocyte-derived biomarkers in patients with muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). In this single-institution retrospective study, data of patients who underwent transurethral resection of the bladder tumour (TURBT) and re-TURBT for urothelial bladder cancer from January 2020 to December 2021 was assessed. The demographic data and clinical characteristics of patients were obtained from the medical records. The preoperative neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were calculated. Out of 69 patients included, 44 were diagnosed with MIBC and 25 had NMIBC. The mean (SD) age was 62.5 (10.87) years and majority of patients were men (n = 51, 73.91%). In NMIBC group, 17 patients had low grade and 27 had high grade papillary urothelial carcinoma. The mean (SD) NLR and PLR was significantly higher in MIBC group (5.37 [2.81] and 247.12 [157.4]) compared to NMIBC group (3.03 [0.85] and 115.22 [29.15]) (p = 0.0005 and 0.0004). The mean (SD) LMR was significantly lower in MIBC group (3.17 [1.10]) compared to NMIBC group (6.05 [2.44]) (p < 0.0001). The significantly higher values of NLR, PLR and lower values of LMR observed in the preoperative stage in the MIBC group compared to the NMIBC group indicate a potential association between these serum lymphocyte-derived biomarkers and the presence of muscle invasiveness in bladder cancer. [ABSTRACT FROM AUTHOR]

Peimenine (PEI) is a steroid alkaloid substance isolated from Fritillaria thunbergii bulbs. It has various pharmacological activities, such as relief from coughs and asthma, expectorant properties, antibacterial effects, sedative qualities, and anti‐inflammatory properties. Notably, PEI can effectively inhibit the proliferation and tumor formation of liver cancer and osteosarcoma cells by inducing autophagic cell death. However, the precise effect and mechanisms of PEI on urothelial bladder cancer (UBC) cells remain uncertain. Thus, this study aims to investigate the impact of PEI on UBC cells both in vivo and in vitro. The IC50 values of BIU‐87 and EJ‐1 cells after 48 h were 710.3 and 651.1 μg/mL, respectively. Additionally, PEI blocked the cell cycle in BIU‐87 and EJ‐1 cells during the G1 phase. Furthermore, it hindered the migration of BIU‐87 and EJ‐1 cells substantially. PEI significantly inhibited the tumor development of EJ‐1 cells within the xenograft tumor model in vivo. Mechanically, PEI augmented the protein and mRNA expression of BIM, BAK1, and Cytochrome C (CYCS) in UBC cells. Taken together, PEI suppressed the proliferation of UBC cells both in vitro and in vivo by inducing cell death and cell cycle arrest, suggesting that PEI could be applied in the treatment of UBC. [ABSTRACT FROM AUTHOR]

Using preimmunotherapy stool samples collected from patients enrolled in the PURE-01 clinical trial, testing neoadjuvant pembrolizumab in patients with muscle-invasive bladder cancer, we identified some bacterial taxa that were enriched differentially in responders and nonresponders to immunotherapy. Among those, the genus Sutterella was enriched in responders, while the species Ruminococcus bromii was enriched in nonresponders. We further used an animal model of bladder cancer to provide further evidence suggesting a negative role of R. bromii in anti–PD-1 efficacy. However, further studies are needed to confirm our findings. Neoadjuvant pembrolizumab has been shown to be a valid treatment for patients affected by muscle-invasive bladder cancer (MIBC), as demonstrated in the PURE-01 clinical trial (NCT02736266). Among the tumor-extrinsic factors influencing immunotherapy efficacy, extensive data highlighted that the microbiome is a central player in immune-mediated anticancer activity. This report aimed to investigate the composition and role of stool microbiome in patients enrolled in the PURE-01 clinical trial. An orthotopic animal model of bladder cancer (MB49-Luc) was used to support some of the findings from human data. An analysis of stool microbiome before pembrolizumab was conducted for 42 patients, of whom 23 showed a pathologic response. The information in the preclinical model of orthotopic bladder cancer treated with anti–PD-1 antibody or control isotype was validated. Linear discriminant analysis effect size and linear models were used to identify the bacterial taxa enriched in either responders or nonresponders. The identified taxa were also tested for their association with event-free survival (EFS). Survival at 31 d after tumor instillation was used as the study endpoint in the preclinical model. Responders and nonresponders emerged to differ in terms of enrichment for 16 bacterial taxa. Of these, the genus Sutterella was enriched in responders, while the species Ruminococcus bromii was enriched in nonresponders. The negative impact of R. bromii on anti–PD-1 antibody activity was also observed in the preclinical model. EFS and survival of the preclinical model showed a negative role of R. bromii. We found different stool bacterial taxa associated with the response or lack of response to neoadjuvant pembrolizumab. Moreover, we provided experimental data about the negative role of R. bromii on immunotherapy response. Further studies are needed to externally validate our findings and provide mechanistic insights about the host-pathogen interactions in MIBC. Using prepembrolizumab stool samples collected from patients enrolled in the PURE-01 clinical trials, we identified some bacterial taxa that were enriched in patients who either responded or did not respond to immunotherapy. Using an animal model of bladder cancer, we gathered further evidence of the negative impact of the Ruminococcus bromii on immunotherapy efficacy. Further studies are needed to confirm the current findings and test the utility of these bacteria as predictive markers of immunotherapy response. [ABSTRACT FROM AUTHOR]

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway. [ABSTRACT FROM AUTHOR]

Our data revealed that miR-17-5p is enriched in the urine exosomes of muscle-invasive bladder cancer. Further investigation showed that miR-17-5p functions as a tumor promoter both in vitro and in vivo, possibly by targeting ARID4B and influencing the immune system. These findings imply that miR-17-5p might be a novel target for bladder cancer treatment. Background: Urothelial bladder cancer (BCa) is a common malignant tumor of the urinary system. It has been identified that exosomal miRNAs contribute to the development of BCa. However, its significance and mechanism in the malignant biological behavior of BCa remain unclear. In this study, the influence of exosomal miRNAs on BCa progression was investigated. Methods: High-throughput sequencing was conducted to analyze the microRNA-expression profile in urinary exosomes to screen out the key miRNA of muscle-invasive bladder cancer (MIBC). Then, candidate miRNA expression was verified and validated in urinary exosomes and tissue samples. To address the potential role of the candidate miRNA, we overexpressed and knocked down the candidate miRNA and explored its activity in BCa cell lines. Furthermore, the target gene of the selected miRNA was predicted and validated. Results: The expression profile of miRNAs revealed increased expression of miR-17-5p in MIBC urinary exosomes, and this was later confirmed in urinary exosomes and tissue samples. Cell function studies revealed that exosomal miR-17-5p significantly promoted the growth and invasion of BCa cells. Bioinformatics and luciferase experiments demonstrated that the ARID4B mRNA 3' UTR might be the binding site for miR-17-5p. Low ARID4B levels were linked to high-grade BCa patients and were associated with a better prognosis. Conclusion: Elevated miR-17-5p contributes to BCa progression by targeting ARID4B and influencing the immune system. Based on these findings, miR-17-5p has the potential to be a new therapeutic target for the treatment of BCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Cisplatin-based resistance is an old concern for advanced urothelial bladder cancer (UBC) patients. This work aimed to study the metabolic profiles of three pairs of cisplatin-sensitive (CS) and cisplatin-resistant (CR) UBC cell lines. A tendency was observed towards an intensified glycolytic metabolism in two of the CR cell lines, especially in the CR cells showing higher levels of cisplatin resistance. However, in this cell line, a shift towards alternative metabolic routes involving lactate uptake, lipid biosynthesis and glutamate metabolism occurred with time. The remaining cell line seemed to engage in a metabolic reprogramming, recovering the preference for oxygen consumption. Thus, CR UBC cells displayed deep metabolic alterations that likely depended on their molecular backgrounds. Advanced urothelial bladder cancer (UBC) patients are tagged by a dismal prognosis and high mortality rates, mostly due to their poor response to standard-of-care platinum-based therapy. Mediators of chemoresistance are not fully elucidated. This work aimed to study the metabolic profile of advanced UBC, in the context of cisplatin resistance. Three isogenic pairs of parental cell lines (T24, HT1376 and KU1919) and the matching cisplatin-resistant (R) sublines were used. A set of functional assays was used to perform a metabolic screening on the cells. In comparison to the parental sublines, a tendency was observed towards an exacerbated glycolytic metabolism in the cisplatin-resistant T24 and HT1376 cells; this glycolytic phenotype was particularly evident for the HT1376/HT1376R pair, for which the cisplatin resistance ratio was higher. HT1376R cells showed decreased basal respiration and oxygen consumption associated with ATP production; in accordance, the extracellular acidification rate was also higher in the resistant subline. Glycolytic rate assay confirmed that these cells presented higher basal glycolysis, with an increase in proton efflux. While the results of real-time metabolomics seem to substantiate the manifestation of the Warburg phenotype in HT1376R cells, a shift towards distinct metabolic pathways involving lactate uptake, lipid biosynthesis and glutamate metabolism occurred with time. On the other hand, KU1919R cells seem to engage in a metabolic rewiring, recovering their preference for oxidative phosphorylation. In conclusion, cisplatin-resistant UBC cells seem to display deep metabolic alterations surpassing the Warburg effect, which likely depend on the molecular signature of each cell line. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression and clinical significance of silent information regulator 2 (SIRT2) form tissue of urothelial bladder cancer(UBC) and the effects of down-regulation of SIRT2 on the proliferation, invasion and migration of bladder cancer cells. Methods The expression of SIRT2 protein was detected in 95 samples of urothelial bladder cancer tissues and 39 paracancerous tissues using the immunohistochemical EnVision method. Its relationship with clinicopathological parameters was analyzed. The expression of SIRT2 mRNA in bladder cancer cell lines was detected by RT-qPCR, and the expression levels of SIRT2 protein in bladder cancer cell lines, 12 pairs of fresh bladder cancer tissues were detected by Western blot. Lentiviral infection was used to stably downregulate the SIRT2 gene in bladder cancer cell line T24. CCK8 and cell colony assays were performed to detect changes in cell proliferation ability and Transwell assay to detect changes in cell invasion and migration activity. Results The positive expression rate of SIRT2 in urothelial bladder cancer tissues was 84%(80/95), which was higher than that in normal uroepithelial tissues (5%, 2/39) (PConclusions SIRT2 is highly expressed in bladder uroepithelial carcinoma, and interfers with SIRT2 significantly and so inhibites bladder cancer cell proliferation, invasion and migration.

The Warburg Effect is characterized by high rates of glucose uptake and lactate production. Monocarboxylate transporters (MCTs) are crucial to avoid cellular acidosis by internal lactate accumulation, being largely overexpressed by cancer cells and associated with cancer aggressiveness. The MCT1-specific inhibitor AZD3965 has shown encouraging results in different cancer models. However, it has not been tested in urothelial bladder cancer (UBC), a neoplasm where rates of recurrence, progression and platinum-based resistance are generally elevated. We used two muscle-invasive UBC cell lines to study AZD3965 activity regarding lactate production, UBC cells' viability and proliferation, cell cycle profile, and migration and invasion properties. An "in vivo" assay with the chick chorioallantoic membrane model was additionally performed, as well as the combination of the compound with cisplatin. AZD3965 demonstrated anticancer activity upon low levels of MCT4, while a general lack of sensitivity was observed under MCT4 high expression. Cell viability, proliferation and migration were reduced, cell cycle was arrested, and tumor growth "in vivo" was inhibited. The compound sensitized these MCT4-low-expressing cells to cisplatin. Thus, AZD3965 seems to display anticancer properties in UBC under a low MCT4-expression setting, but additional studies are necessary to confirm AZD3965 activity in this cancer model. [ABSTRACT FROM AUTHOR]

Abstract The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its effects on T‐DM1 responses in patients with HER2‐positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non‐focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene‐protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker‐evaluable population, composed of screen‐failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2‐positive tumors. In a gene‐protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2‐positive UBC or PC can respond to T‐DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non‐breast tumor types.

Abstract Background Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p

Background: Head-to-head comparisons between ileal conduit (IC) and orthotopic neobladder (ONB) in terms of peri- and postoperative outcomes and complications, in the specific setting of robot-assisted radical cystectomy (RARC), are not available. Objective: To address the impact of the type of urinary diversion (UD, IC vs ONB) on RARC morbidity, as well as operative time (OT), length of stay (LOS), and readmissions. Design, setting, and participants: Urothelial bladder cancer patients treated with RARC at nine high-volume European institutions between 2008 and 2020 were identified. Intervention: RARC with either IC or ONB. Outcome measurements and statistical analysis: Intra- and postoperative complications were collected and reported according to the Intraoperative Complications Assessment and Reporting with Universal Standards recommendations and European Association of Urology guidelines, respectively. Multivariable logistic regression models tested the impact of UD on outcomes, after adjustment for clustering at single hospital level. Results and limitations: Overall, 555 nonmetastatic RARC patients were identified. In 280 (51%) and 275 (49%) patients, an IC and an ONB were performed, respectively. Eighteen intraoperative complications were recorded. The rates of intraoperative complications were 4% in IC patients and 3% in ONB patients (p = 0.4). The median LOS and readmission rates were 10 versus 12 d (p

Urothelial bladder cancer (UBC) is one of the most common malignant tumors in urology, and its occurrence and progression are closely related to the tumor microenvironment (TME). Tumor-associated neutrophils (TAN), as an important type of immune cells in TME, have been proven to have anti-tumor or pro-tumor regulatory effects on various tumors, which are related to their heterogeneity and plasticity. The study on TAN' s bidirectional regulation may provide new targets for tumor treatment. This article reviews the current status of TAN ' s bidirectional regulation research by searching recent literature, and summarizes its research progress in UBC. [ABSTRACT FROM AUTHOR]

Background: Non-muscle-invasive bladder cancer (NMIBC) has a high recurrence rate and muscle-invasive bladder cancer (MIBC) has unfavorable outcomes in urothelial bladder cancer (UBC) patients. Complex UBC-related protein biomarkers for outcome prediction may provide a more efficient management approach with an improved clinical outcome. The aim of this study is to recognize tumor-associated proteins, which are differentially expressed in different stages of UBC patients compared non-cancerous tissues. Methods: The proteome of tissue samples of 42 UBC patients (NMIBC n = 25 and MIBC n = 17) was subjected to two-dimensional electrophoresis (2-DE) combined with Liquid chromatography–mass spectrometry (LC–MS) system to identify differentially expressed proteins. The intensity of protein spots was quantified and compared with Prodigy SameSpots software. Functional, pathway, and interaction analyses of identified proteins were performed using geneontology (GO), PANTHER, Reactome, Gene MANIA, and STRING databases. Results: Twelve proteins identified by LC-MS showed differential expression (over 1.5-fold, p < 0.05) by LC-MS, including 9 up-regulated in NMIBC and 3 up-regulated in MIBC patients. Proteins involved in the detoxification of reactive oxygen species and cellular responses to oxidative stress showed the most significant changes in UBC patients. Additionally, the most potential functions related to these detected proteins were associated with peroxidase, oxidoreductase, and antioxidant activity. Conclusion: We identified several alterations in protein expression involved in canonical pathways which were correlated with the clinical outcomes suggested might be useful as promising biomarkers for early detection, monitoring, and prognosis of UBC. [ABSTRACT FROM AUTHOR]

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Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors’ expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

Abstract Background Urothelial carcinoma is the most common type of bladder cancer worldwide and it has a poor prognosis for patients with distant metastasis. Nomograms are frequently used in clinical research, but no research has evaluated the diagnostic and prognostic factors of distant metastasis in urothelial bladder cancer (UBC). Methods The Surveillance, Epidemiology, and End Results database was used to analyze all patients diagnosed with UBC between 2000 and 2017. Lasso regression was used to identify the potential risk predictive factors for distant metastasis in UBC. Univariate and multivariate Cox proportional hazard regression analyses were performed to determine independent prognostic factors for distant metastasis urothelial bladder cancer (DMUBC). Subsequently, two nomograms were constructed based on the above models. The receiver operating characteristic (ROC), and calibration curves were performed to evaluate the two nomograms. Results The study included 73,264 patients with UBC, with 2,129 (2.9%) having distant metastasis at the time of diagnosis. In the diagnostic model, tumor size, histologic type, and stage N and T were all important risk predictive factors for distant metastasis of UBC. In the prognostic model, age, tumor size, surgery, and chemotherapy were independent factors affecting the prognosis of DMUBC. DCA, ROC, calibration, and Kaplan–Meier (K–M) survival curves reveal that the two nomograms can effectively predict the diagnosis and prognosis of DMUBC. Conclusion The developed nomograms are practical methods for predicting the occurrence risk and prognosis of distant metastasis urothelial bladder cancer patients, which may benefit the clinical decision-making process.

Background: Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods: In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. Results: Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12. Conclusions: The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification. As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment. [ABSTRACT FROM AUTHOR]

The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its effects on T‐DM1 responses in patients with HER2‐positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non‐focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene‐protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker‐evaluable population, composed of screen‐failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2‐positive tumors. In a gene‐protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2‐positive UBC or PC can respond to T‐DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non‐breast tumor types. [ABSTRACT FROM AUTHOR]

Purpose: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). Methods: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. Results: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. Conclusion: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC. [ABSTRACT FROM AUTHOR]

Introduction: We aim to evaluate the association between serum hypoxia inducible factor (HIF)-1α level and stage and grade of urothelial bladder cancer (UBC). Methods: A case-control study was conducted at Haji Adam Malik Hospital Medan, Indonesia. Inclusion criteria for case group was subject aged 18 years or older and diagnosed with UBC based on histopathological examination. Control group consisted of gender and age matched healthy subjects. Serum HIF-1α level was determined using ELISA method. Data was analyzed with chi square, Mann Whitney, and independent T tests. Results: A total of 80 subjects were enrolled and divided into case and control groups equally. Most subjects were males with mean age of 69.65 years for case group and 68.25 years for control group. Most subjects had advanced primary tumor and lymph node stages. Only 30% subjects had metastasized UBC. Higher serum HIF-1α level was observed in case group (p < 0.001). Serum HIF-1α level was strongly associated with metastasis stage (p < 0.001), followed by lymph node (p = 0.005) and primary tumor (p = 0. 013) stages. Serum HIF-1α level was not associated with grading (p = 0.134). Conclusions: Serum HIF-1α level is associated with staging but not grading of UBC.

Introduction: Bladder cancer (BLCA) is one of the most lethal diseases. COL10A1 is secreted small-chain collagen in the extracellular matrix associated with various tumors, including gastric, colon, breast, and lung cancer. However, the role of COL10A1 in BLCA remains unclear. This is the first research focusing on the prognostic value of COL10A1 in BLCA. In this research, we aimed to uncover the association between COL10A1 and the prognosis, as well as other clinicopathological parameters in BLCA. Methods: We obtained gene expression profiles of BLCA and normal tissues from the TCGA, GEO, and ArrayExpress databases. Immunohistochemistry staining was performed to investigate the protein expression and prognostic value of COL10A1 in BLCA patients. GO and KEGG enrichment along with GSEA analyses were performed to reveal the biological functions and potential regulatory mechanisms of COL10A1 based on the gene co-expression network. We used the "maftools" R package to display the mutation profiles between the high and low COL10A1 groups. GIPIA2, TIMER, and CIBERSORT algorithms were utilized to explore the effect of COL10A1 on the tumor immune microenvironment. Results: We found that COL10A1 was upregulated in the BLCA samples, and increased COL10A1 expression was related to poor overall survival. Functional annotation of 200 co-expressed genes positively correlated with COL10A1 expression, including GO, KEGG, and GSEA enrichment analyses, indicated that COL10A1 was basically involved in the extracellular matrix, protein modification, molecular binding, ECM-receptor interaction, protein digestion and absorption, focal adhesion, and PI3K-Akt signaling pathway. The most commonly mutated genes of BLCA were different between high and low COL10A1 groups. Tumor immune infiltrating analyses showed that COL10A1 might have an essential role in recruiting infiltrating immune cells and regulating immunity in BLCA, thus affecting prognosis. Finally, external datasets and biospecimens were used, and the results further validated the aberrant expression of COL10A1 in BLCA samples. Conclusions: In conclusion, our study demonstrates that COL10A1 is an underlying prognostic and predictive biomarker in BLCA. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic changes occur in parts of the genome other than in nucleotides. They are considered reversible and are therefore important targets for cancer therapy. Epigenetic changes have been observed in urological cancers, including urothelial carcinoma, and in recent years have been a topic of investigation for the treatment of metastatic bladder cancer that has failed traditional therapy. We performed a review of the current literature to assess the evidence and role for targeted epigenetic therapy in bladder cancer. While we found 25 clinical trials investigating this topic, there have been no phase 3 human clinical trials to date. This is an emerging topic in urology, and future directions involve further research into bladder cancer-specific epigenetic changes, as well as the development of novel agents to target these mutations. Epigenetics is a growing field and in bladder cancer, it is of particular interest in advanced or metastatic disease. As opposed to genetic mutations in which the nucleotide sequence itself is altered, epigenetic alterations refer to changes to the genome that do not involve nucleotides. This is of great interest in cancer research because epigenetic alterations are reversible, making them a promising target for pharmacological agents. While chemoimmunotherapy is the mainstay for metastatic disease, there are few alternatives for patients who have progressed on first- or second-line treatment. By targeting reversible epigenetic alterations, novel epigenetic therapies are important potential treatment options for these patients. A search of clinical registries was performed in order to identify and collate epigenetic therapies currently in human trials. A literature search was also performed to identify therapies that are currently in preclinical stages, whether this be in vivo or in vitro models. Twenty-five clinical trials were identified that investigated the use of epigenetic inhibitors in patients with bladder cancer, often in combination with another agent, such as platinum-based chemotherapy or pembrolizumab. The main classes of epigenetic inhibitors studied include DNA-methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and histone methyltransferase (HMT) inhibitors. At present, no phase 3 clinical trials have been registered. Few trials have published results, though DNMT inhibitors have shown the most promise thus far. Many patients with advanced or metastatic bladder cancer have limited treatment options, particularly when first- or second-line chemoimmunotherapy fails. Epigenetic alterations, which are common in bladder cancer, are potential targets for drug therapies, and these epigenetic agents are already in use for many cancers. While they have shown promise in pre-clinical trials for bladder cancer, more research is needed to assess their benefit in clinical settings. [ABSTRACT FROM AUTHOR]

Aim: This study examined BK polyomavirus (BKPyV) genome and viral load in urothelial bladder carcinoma (UBC) and nontumoral bladder tissues. Materials & methods: Quantitative real-time PCR was used to measure viral LT-Ag copy number per cell in 114 fresh-frozen bladder biopsy samples (61 UBC and 53 nontumoral tissue samples). Results: Patients with UBC had a significantly higher mean BKPyV LT-Ag DNA load than those without UBC. In multivariate logistic regression analysis, BKPyV LT-Ag copies/cell and smoking/illicit use of drugs were associated with bladder cancer. Receiver operating characteristic curve analysis identified bladder cancer risk at 0.1 copies/cell. Conclusion: This study found high BKPyV LT-Ag DNA copy numbers in most UBC samples, supporting the hypothesis that BKPyV induces UBC tumorigenesis. BK polyomavirus viral load in urothelial bladder carcinoma and non-UBC tissues were assessed. Normalized viral load of 114 fresh-frozen samples were determined using quantitative real-time PCR. Patients with urothelial bladder carcinoma had a higher viral load. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotherapy with curative intent in the treatment of metastatic malignancies has shown promising results in several types of primary tumors but experience in bladder cancer is limited and scarce. The objective of our retrospective study was to assess the benefit of consolidative radiotherapy directed to the bladder and to residual metastases among patients with metastatic urothelial bladder cancer and with no progression following systemic therapy. In our analysis, radiotherapy was associated with a valuable and promising survival benefit compared with no local treatment following systemic therapy. The benefit of consolidative radiotherapy needs to be confirmed in prospective clinical trials in the future. Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. Materials/methods: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan–Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. Results: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1–9) vs. 3 (1–5) (p = 0.04) at metastatic presentation, and 1 (0–5) vs. 2 (0–5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). Conclusion: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively. [ABSTRACT FROM AUTHOR]

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease. [ABSTRACT FROM AUTHOR]

IntroductionBladder cancer (BLCA) is one of the most lethal diseases. COL10A1 is secreted small-chain collagen in the extracellular matrix associated with various tumors, including gastric, colon, breast, and lung cancer. However, the role of COL10A1 in BLCA remains unclear. This is the first research focusing on the prognostic value of COL10A1 in BLCA. In this research, we aimed to uncover the association between COL10A1 and the prognosis, as well as other clinicopathological parameters in BLCA.MethodsWe obtained gene expression profiles of BLCA and normal tissues from the TCGA, GEO, and ArrayExpress databases. Immunohistochemistry staining was performed to investigate the protein expression and prognostic value of COL10A1 in BLCA patients. GO and KEGG enrichment along with GSEA analyses were performed to reveal the biological functions and potential regulatory mechanisms of COL10A1 based on the gene co-expression network. We used the “maftools” R package to display the mutation profiles between the high and low COL10A1 groups. GIPIA2, TIMER, and CIBERSORT algorithms were utilized to explore the effect of COL10A1 on the tumor immune microenvironment.ResultsWe found that COL10A1 was upregulated in the BLCA samples, and increased COL10A1 expression was related to poor overall survival. Functional annotation of 200 co-expressed genes positively correlated with COL10A1 expression, including GO, KEGG, and GSEA enrichment analyses, indicated that COL10A1 was basically involved in the extracellular matrix, protein modification, molecular binding, ECM-receptor interaction, protein digestion and absorption, focal adhesion, and PI3K-Akt signaling pathway. The most commonly mutated genes of BLCA were different between high and low COL10A1 groups. Tumor immune infiltrating analyses showed that COL10A1 might have an essential role in recruiting infiltrating immune cells and regulating immunity in BLCA, thus affecting prognosis. Finally, external datasets and biospecimens were used, and the results further validated the aberrant expression of COL10A1 in BLCA samples.ConclusionsIn conclusion, our study demonstrates that COL10A1 is an underlying prognostic and predictive biomarker in BLCA.

Background: Urothelial carcinoma is the most common type of bladder cancer worldwide and it has a poor prognosis for patients with distant metastasis. Nomograms are frequently used in clinical research, but no research has evaluated the diagnostic and prognostic factors of distant metastasis in urothelial bladder cancer (UBC). Methods: The Surveillance, Epidemiology, and End Results database was used to analyze all patients diagnosed with UBC between 2000 and 2017. Lasso regression was used to identify the potential risk predictive factors for distant metastasis in UBC. Univariate and multivariate Cox proportional hazard regression analyses were performed to determine independent prognostic factors for distant metastasis urothelial bladder cancer (DMUBC). Subsequently, two nomograms were constructed based on the above models. The receiver operating characteristic (ROC), and calibration curves were performed to evaluate the two nomograms. Results: The study included 73,264 patients with UBC, with 2,129 (2.9%) having distant metastasis at the time of diagnosis. In the diagnostic model, tumor size, histologic type, and stage N and T were all important risk predictive factors for distant metastasis of UBC. In the prognostic model, age, tumor size, surgery, and chemotherapy were independent factors affecting the prognosis of DMUBC. DCA, ROC, calibration, and Kaplan–Meier (K–M) survival curves reveal that the two nomograms can effectively predict the diagnosis and prognosis of DMUBC. Conclusion: The developed nomograms are practical methods for predicting the occurrence risk and prognosis of distant metastasis urothelial bladder cancer patients, which may benefit the clinical decision-making process. [ABSTRACT FROM AUTHOR]

Abstract Background Urothelial bladder cancer (BC) is one of the most prevalent malignancies with high mortality and high recurrence rate. Angiogenesis, tumor growth and metastasis of multiple cancers are partly modulated by CC chemokines. However, we know little about the function of distinct CC chemokines in BC. Methods ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier plotter, cBioPortal, GeneMANIA, and TIMER were used for analyzing differential expression, prognostic value, protein–protein interaction, genetic alteration and immune cell infiltration of CC chemokines in BC patients based on bioinformatics. Results The results showed that transcriptional levels of CCL2/3/4/5/14/19/21/23 in BC patients were significantly reduced. A significant relation was observed between the expression of CCL2/11/14/18/19/21/23/24/26 and the pathological stage of BC patients. BC patients with high expression levels of CCL1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL15, CCL17, CCL18, CCL19, CCL22, CCL25, CCL27 were associated with a significantly better prognosis. Moreover, we found that differentially expressed CC chemokines are primarily correlated with cytokine activity, chemokines receptor binding, chemotaxis, immune cell migration. Further, there were significant correlations among the expression of CC chemokines and the infiltration of several types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Conclusions This study is an analysis to the potential role of CC chemokines in the therapeutic targets and prognostic biomarkers of BC, which gives a novel insight into the relationship between CC chemokines and BC.

• CTLA4 pathway is one of the most important immunological mechanisms of tumor escape. • CTLA4 genetic variants are associated with urothelial bladder cancer (UBC) susceptibility. • The AG genotype of the CTLA4 A>G (rs231775) showed protective effect for the UBC. • The CT genotype of the CTLA4 C>T (rs231779) showed protective effect for the UBC. The study evaluated the relationship between the CTLA4 rs231775 (+49A>G) and rs231779 (+1822C>T) variants and susceptibility, stage, prognosis and response to treatment of the urothelial bladder cancer (UBC). A total of 140 patients with UBC and 145 controls were enrolled. The patients were stratified as non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MICB), metastasis, recurrence, low/moderate/high/very high risk. Demographic, anthropometric, epidemiological, and clinical data were obtained from all individuals using a structured questionnaire. The CTLA4 variants were determined using real-time polymerase chain reaction (qPCR) and the genotypes were tested in the allelic, codominant, dominant, recessive, and overdominant genetic models. The UBC patients were older and mostly smokers (P < 0.001), with greater waist circumference, systolic, and diastolic arterial pressure (P = 0.005, P = 0.006, and P < 0.001, respectively) than controls. A protective effect for the UBC was observed among the patients carrying the heterozygote genotypes of the CTLA4 rs231775 [odds ratio (OR = 0.40; 95% confidence interval (CI): 0.160.98, P = 0.045) and rs231779 (OR = 0.35; 95% CI: 0.14–0.87, P = 0.024). R2 Nagelkerke analysis demonstrated that a model with age and smoking added to the CTLA4 rs231775 SNVs explained 77.0% of the susceptibility to UBC and a model with age and smoking added to the CLTA4 rs231779 explained 77.2% of the susceptibility to UBC. The CTLA4 rs231775 AG and rs231779 CT heterozygous genotypes in the overdominant model together with age and smoking may be useful as potential biomarkers for the UBC susceptibility. [ABSTRACT FROM AUTHOR]

The increasing incidence of urinary bladder carcinoma is alarming. Approximately seventy percent of these patients are non-muscle invasive bladder cancer (NMIBC). Restage transurethral resection of bladder tumor (TURBT) is the current recommendation for any T1 and or high-grade non muscle invasive bladder cancers (NMIBC) to accurately stage the malignancy. The question whether a second surgery is always required as a restage procedure is still unanswered. The patient's concern about completeness, morbidity, and financial considerations of a major surgery cannot be overlooked. Moreover, it also puts a strain on the already overburdened healthcare system. To answer this question, whether it is oncologically sound to omit a second resection, the current study evaluated the outcomes of patients undergoing restage TURBT, and analyzed the preoperative factors predicting a change in the staging of this malignancy. The study design was a prospective observational including NMIBC patients from September 2018 to February 2020. A total of 72 patients underwent restage TURBT. Their demographic data, imaging and cystoscopic findings, and histopathological data were recorded. The objective was to study the clinico-pathological correlations and factors predicting recurrence and upstaging of tumor in NMIBC patients undergoing restage TURBT. A total of 101 patients were found eligible for restage TURBT. Eventually, 72 underwent restage TURBT. Twelve (16.7%) patient had recurrence at restage while 3(4.16%) were upstaged to T2. Presence of lower urinary tract symptoms (LUTS) was independently associated with the risk of recurrence of same stage compared to no recurrence (p-0.025, OR-8.793, 95% CI-1.316–98.773). Chemical exposure (p-0.042) was also significantly associated with the same. Presence of lymphadenopathy on CT was independently associated with the risk of upstaging compared to no recurrence (p-0.032, OR-18.25, 95% CI-1.292–257.85). The study concluded that in the presence of a well-performed and adequate initial TURBT, restage TURBT could be skipped for further management. However, in small subgroup of patients with lymphadenopathy on preoperative imaging having a higher risk of tumor recurrence and upstaging, and patients with a history of chemical exposure and previous lower urinary tract symptoms having a high risk of recurrence alone, restage TURBT should still be performed to accurately stage the disease. Further studies with large patient cohort are needed to confirm and reinforce the facts proposed. [ABSTRACT FROM AUTHOR]

Recent observational studies linked β-adrenergic receptor blocker use with improved survival in patients with several cancer types, but there is no information on the potential effects of β-blockers in patients with bladder cancer. Literature from pre-clinical studies is also limited, but urothelial cancer can exhibit significant overexpression of β-adrenergic receptors relative to normal urothelial tissue, suggesting that urothelial cancer may benefit from β-blockade therapy. We thus aimed to explore the possible association between β-blocker use and bladder cancer-specific mortality (BCSM) among patients with urothelial bladder cancer. Patients diagnosed during 2006–2014 and identified from the Swedish Cancer Register (n = 16,669) were followed until 31 December 2015. Cox regression was used to evaluate the association of β-blockers dispensed within 90 days prior to cancer diagnosis with BCSM (primary outcome) and all-cause mortality, while controlling for socio-demographic factors, tumor characteristics, comorbidity, other medications and surgical procedures. Hazard ratios (HR) with 95% confidence intervals (CI) were reported. Overall, β-blocker use was associated with lower BCSM [HR 0.88 (95%CI 0.81–0.96)]. Especially use of nonselective β-blockers showed a clear inverse association in comparison with both nonuse [0.66 (0.50–0.86)] and use of other antihypertensive medications [0.72 (0.54–0.95)]. The inverse association was most pronounced among patients with locally advanced/metastatic disease: [0.35 (0.18–0.68)]. A lower-magnitude inverse association was observed for selective β-blocker use [0.91 (0.83–0.99)]. Largely similar inverse associations were observed for hydrophilic [0.82 (0.70–0.95)] and lipophilic [0.91 (0.83–1.00)] β-blocker use. β-blocker use, particularly of the nonselective type, was associated with lower BCSM, especially in patients with locally advanced/metastatic urothelial bladder cancer. [ABSTRACT FROM AUTHOR]

Introduction: We aim to evaluate the association between serum hypoxia inducible factor (HIF)-1α level and stage and grade of urothelial bladder cancer (UBC). Methods: A case-control study was conducted at Haji Adam Malik Hospital Medan, Indonesia. Inclusion criteria for case group was subject aged 18 years or older and diagnosed with UBC based on histopathological examination. Control group consisted of gender and age matched healthy subjects. Serum HIF-1α level was determined using ELISA method. Data was analyzed with chi square, Mann Whitney, and independent T tests. Results: A total of 80 subjects were enrolled and divided into case and control groups equally. Most subjects were males with mean age of 69.65 years for case group and 68.25 years for control group. Most subjects had advanced primary tumor and lymph node stages. Only 30% subjects had metastasized UBC. Higher serum HIF-1α level was observed in case group (p < 0.001). Serum HIF-1α level was strongly associated with metastasis stage (p < 0.001), followed by lymph node (p = 0.005) and primary tumor (p = 0. 013) stages. Serum HIF-1a level was not associated with grading (p = 0.134). Conclusions: Serum HIF-1α level is associated with staging but not grading of UBC. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify a diagnostic panel of serum microRNAs (miRNAs) for the early detection of bladder cancer (BC). Methods: Serum samples were collected from 112 BC patients and 112 normal controls (NCs). A three-stage selection was conducted to identify differentially expressed miRNAs as candidates to construct the diagnostic panel. Further, to explore their potential roles in urothelial BC, bioinformatics analyses, including target genes prediction and functional annotation, were used. Results: Six downregulated miRNAs (miR-1-3p, miR-30a-5p, miR-100-5p, miR-125b-5p, miR-143-3p, and miR-200c-3p) and one upregulated, miR-182-5p, in BC patients' serum were detected compared to NCs and were selected to establish the diagnostic panel. Based on a backward stepwise logistic regression analysis, miR-125b-5p, miR-182-5p, and miR-200c-3p comprehended the diagnostic panel [area under the curve (AUC) = 0.959, sensitivity = 91.67%, specificity = 92.5%]. Conclusion: The panel of three miRNAs had an excellent diagnostic capability, representing a potential non-invasive method for early BC detection. [ABSTRACT FROM AUTHOR]

The commonest malignancy of the urinary tract is bladder cancer, with the commonest presentation being painless visible haematuria. Just like other malignancies, it can spread, commonly to surrounding tissues like the prostate, seminal vesicles, and vagina, distantly to lymph nodes, lungs, liver, and bone, and less commonly to the skin and subcutaneous tissues. This is a case of a man with muscle-invasive bladder cancer who underwent radical radiotherapy. He presented nine days into the course of his radiotherapy with new symptoms of pain, swelling, and discharge, particularly at the penoscrotal junction. Ultrasound scans of the testes were normal, and he was treated as a case of scrotal skin abscess with antibiotics. His symptoms persisted and worsened over time despite treatment and multiple hospital attendances. He developed a discharge of fluid from multiple sinuses in the area. Further cross-sectional imaging and direct visualisation with cystoscopy led to the conclusion that there was a urethral recurrence of his urothelial carcinoma which had extended locally into the soft tissues in the penoscrotal area and caused urocutaneous fistulous tracts. An extensive literature review showed no documented cases of vesicocutaneous fistula from urothelial carcinoma, making this the first reported case of penoscrotal extension of bladder cancer and fistulation after radiotherapy., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Akpala et al.)

Introduction The objective of this study is to find out if there are any differences in upper urinary tract recurrence and overall mortality between patients who underwent a frozen section analysis during radical cystectomy and those who did not. Materials and methods In an observational retrospective cohort study, we evaluated data from 164 patients who underwent radical cystectomy in our institution over a five-year period from 2013 to 2018. Fisher's exact test was applied to find any difference in upper urinary tract recurrence between the two groups. The Kaplan-Meier method and the log-rank (Mantel-Cox) test were used to determine differences or equivalence between treatment groups. Results The sensitivity was 84.6% and the specificity was 95.3% for the frozen section. There was no statistically significant relationship between performing a frozen section and upper urinary tract recurrence, as indicated by Fisher's exact test (p=0.619). The Kaplan-Meier test showed no statistically significant relationship between performing a frozen section analysis and overall mortality. Discussion The use of ureteric frozen section analysis during radical cystectomy is traditionally taught during surgical training, but the evidence base for this practice is sketchy. Frozen section analysis is thought to reduce the chances of local recurrence and arguably upper urinary tract recurrence. The overall upper urinary tract recurrence after radical cystectomy is reported to be 2-6%, consistent with the 3.3% observed in our study. Conclusion Our study demonstrates that while frozen section analysis is sensitive and specific in detecting dysplasia, it does not significantly impact upper tract recurrence or overall mortality., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Al-Gburi et al.)

Guo Y, Zhang H, Xie D, Hu X, Song R, Zhu L. Cancer Manag Res. 2018;10:4371-4380. The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised regarding the alleged duplication of western blot bands in Figure 2 with those from another unrelated article. Specifically, Figure 2F, bands P-gp, appear to have been duplicated with the same bands from Figure 5F, p-AKT in Yang et al, 2018 (https://doi.org/10.3389/fnmol.2017.00437). In addition, western blots bands from Figure 5 also appear to have been duplicated. Specifically, Figure 5B, bands J82/DOX, GAPDH, appear to have been duplicated with the same bands from Figure 5B, T24/DOX, GAPDH. There were also unexpected similarities found between the flow cytometry images shown in Figures 4E and 4F. The authors responded to our queries but were unable to provide an adequate explanation for the duplicated images, nor were they able to provide the original data for their study. The Editor determined the findings of the study were unreliable and requested to retract the article. The authors agreed with this decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

BACKGROUND: Bladder Cancer (BCa) is the tenth most incident malignancy worldwide. BCa is mostly attributed to environmental exposure and lifestyle, particularly tobacco smoking. The Aryl Hydrocarbon Receptor Repressor (AhRR) participates in the induction of many enzymes involved in metabolizing carcinogens, including tobacco smoke components. Additionally, studies have shown that smoking demethylates the (AhRR) gene in blood, suggesting AhRR demethylation as a specific serum smoking biomarker. OBJECTIVE: This study aimed to validate AhRR demethylation as a smoking biomarker in the target tissue and investigate its contribution to bladder carcinogenesis. METHODS: AhRR percent methylation was tested for its association with patient smoking status and oncogenic outcome indicators, particularly p53, RB1, and FGFR3 activating mutations, muscle-invasiveness, and tumor grade, in 180 BCa tissue-based DNA. RESULTS: Results showed significantly higher AhRR percent methylation in muscle-invasive compared to non-muscle invasive tumors (42.86% vs. 33.98%; p = 0.011), while lower AhRR methylation was significantly associated with FGFR3 Codon 248 mutant genotype compared to wild-type (28.11% ± 9.44 vs. 37.87% ± 22.53; p = 0.036). All other tested associations were non-statistically significant. CONCLUSIONS: Although AhRR methylation did not predict smoking status in BCa tumors, it may be a contributor to carcinogenesis and disease progression. Our findings constitute the basis for further research. [ABSTRACT FROM AUTHOR]

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.

Background: Urothelial bladder cancer (BC) is one of the most prevalent malignancies with high mortality and high recurrence rate. Angiogenesis, tumor growth and metastasis of multiple cancers are partly modulated by CC chemokines. However, we know little about the function of distinct CC chemokines in BC.Methods: ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, cBioPortal, GeneMANIA, and TIMER were used for analyzing differential expression, prognostic value, protein-protein interaction, genetic alteration and immune cell infiltration of CC chemokines in BC patients based on bioinformatics.Results: The results showed that transcriptional levels of CCL2/3/4/5/14/19/21/23 in BC patients were significantly reduced. A significant relation was observed between the expression of CCL2/11/14/18/19/21/23/24/26 and the pathological stage of BC patients. BC patients with high expression levels of CCL1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL15, CCL17, CCL18, CCL19, CCL22, CCL25, CCL27 were associated with a significantly better prognosis. Moreover, we found that differentially expressed CC chemokines are primarily correlated with cytokine activity, chemokines receptor binding, chemotaxis, immune cell migration. Further, there were significant correlations among the expression of CC chemokines and the infiltration of several types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells).Conclusions: This study is an analysis to the potential role of CC chemokines in the therapeutic targets and prognostic biomarkers of BC, which gives a novel insight into the relationship between CC chemokines and BC. [ABSTRACT FROM AUTHOR]

Introduction The concordance rate of bladder cancer (BCa) histological variants (HV) between transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) is sub-optimal and is unclear which factors may influence it. The aim of this study was to identify factors that may be correlated to a higher TURBT-RC concordance rate. Material and methods Consecutive patients who had undergone RC between 2000 and 2019 at a single Institution with pathological evidence of HV were included. Patients with diagnosis of HV both at RC and at the previous TURBT were enlisted in the TURBT-RC Concordance Group (CG), whereas patients with only evidence of HV at RC in the TURBT-RC Non-Concordance Group (NCG). Surgical factors evaluated were the source of energy (mono-vs bipolar), surgeon's experience (10 mm represented an independent predictor of concordance [OR 2.95; CI (1.01-8.61); p = 0.048]. Tumor recurrence, focality and dimension, source of energy, surgeon's experience, performance of re-TURBT and total number of specimens at TURBT did not significantly predict the concordance. Conclusions Longer specimens at TURBT yield a higher chance to detect HV before RC. In this light, improving the quality of bladder resection means improving the management of BCa. [ABSTRACT FROM AUTHOR]