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Background: Partial cystectomy (PC) offers potential benefits for select patients with muscle-invasive bladder cancer (MIBC). However, the oncologic efficacy of PC may be compromised due to the underutilization of standard-of-care modalities, such as neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND). We aimed to assess factors influencing the incorporation of NAC and PLND with PC and evaluate their impact on overall survival (OS). Methods: We identified 2,832 patients with cT2-4N0M0 bladder cancer (BCa) who underwent PC between 2004 and 2019 using the National Cancer Database (NCDB). The primary endpoint was OS. Kaplan-Meier analysis compared OS in treatment modalities in PC patients. Multivariate Cox Proportional Hazards (CPH) model assessed the impact of age, sex, race, insurance, income, Charlson-Deyo Index (CDI), clinical T-stage, facility type, histology, surgical margins, NAC, PLND adequacy [≥10 lymph node (LN) yield], and adjuvant radiation treatment on OS. Multivariate logistic regressions were performed to examine predictors of NAC and PLND receipt in PC patients. Results: Two hundred and thirty-one patients received multi-agent NAC with PC. NAC treatment with PLND was associated with significantly improved OS (P<0.001). Median OS was 43.9 months in patients treated with PC alone, while median OS was not reached in PC patients treated with NAC & PLND. Furthermore, patients who received NAC without any PLND had a median OS of 50.6 months, while those treated with PLND without NAC had a median OS of 76.5 months. This persisted in the adjusted CPH model, where private insurance, NAC, and PLND significantly improved OS, especially when PLND yielded ≥10 LN. Conversely, age >80 years old, CDI >2, cT3-4, positive margins, and adjuvant radiation all increased adjusted mortality risk. After controlling for clinicopathologic variables, females were less likely to receive PLND [odds ratio (OR) 0.719, P=0.005], while NAC was more likely administered to PC patients diagnosed from 2016-2019 (OR 5.295, P<0.001). PC patients who received NAC were more likely to have PLND performed as part of their treatment regimen (OR 2.189, P<0.001). Additionally, patients treated at academic centers were more likely to have NAC administered and PLND performed (OR 1.745, P=0.003; OR 2.465, P<0.001, respectively). Conclusions: Despite guideline recommendations, the utilization of NAC and PLND with PC remains insufficient. Our analysis underscores the significant OS benefit of these recommended treatments as part of MIBC care. Importantly, we highlight a gradual increase in NAC and PLND receipt in recent years, centered largely at academic facilities. Notably, gender disparities exist in PLND receipt, emphasizing the need for further investigation.

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Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

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Bladder cancer (BCa) stands out as a highly prevalent malignant tumor affecting the urinary system. The Sex determining region Y-box protein family is recognized for its crucial role in BCa progression. However, the effect of Sex determining region Y-box 7 (SOX7) on BCa progression has not been fully elucidated. Herein, RNA-sequencing, western blot (WB), immunohistochemistry (IHC), immunofluorescence (IF) and tissue microarray were utilized to assess SOX7 expression in vitro and in vivo. Additionally, SOX7 expression, prognosis, and SOX7 + cytoglobin (CYGB) score were analyzed using R software. In vitro and vivo experiments were performed with BCa cell lines to validate the effect of SOX7 knockdown and overexpression on the malignant progression of BCa. The results showed that SOX7 exhibits low expression in BCa. It functions in diverse capacities, inhibiting the proliferative, migratory, and invasive capabilities of BCa. In addition, the experimental database demonstrated that SOX7 binds to the promoter of DNA methyltransferase 3 beta (DNMT3B), leading to the transcriptional inhibition of DNMT3B. This subsequently results in a reduced methylation of CYGB promoter, ultimately inhibiting the tumor progression of BCa. SOX7 + CYGB scores were significantly linked to patient prognosis. In conclusion, SOX7 inhibits the malignant progression of BCa via the DNMT3B/CYGB axis. Additionally, the SOX7 + CYGB score is capable of predicting the prognostic outcomes of BCa patients. Therefore, SOX7 and CYGB may play an important role in the progression of bladder cancer, and they can be used as prognostic markers of bladder cancer patients.

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MicroRNA (miRNA) is a pivotal biomarker in the diagnosis of various cancers, including bladder cancer (BCa). Despite their significance, the low abundance of miRNA presents a substantial challenge for sensitive and reliable detection. We introduce an innovative, highly sensitive assay for miRNA expression quantification that is both enzyme-free and portable. This method leverages the synergy of target recycling and entropy-driven assembly (EDA) for enhanced sensitivity and specificity. The proposed method possesses several advantages, including i) dual signal amplification through target recycling and EDA, which significantly boosts sensitivity with a lower limit of detection of 2.54 fM; ii) elimination of enzyme requirements, resulting in a cost-effective and stable signal amplification process; and iii) utilization of a personal glucose meter (PGM) for signal recording, rendering the method portable and adaptable to diverse settings. In summary, this PGM-based approach holds promising potential for clinical molecular diagnostics, offering a practical and efficient solution for miRNA analysis in cancer detection.

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Bladder cancer (BCa) is the most common genitourinary malignancy, with a high global incidence and recurrence rate that is paired with an increasing caregiver burden and higher financial cost, in addition to increasing morbidity and mortality worldwide. Histologically, BCa is categorized into non-muscle invasive, muscle invasive, and metastatic BCa, on the basis of which the therapeutic strategy is determined. Despite all innovations and recent advances in BCa research, conventional therapies such as chemotherapy, immunotherapy, radiotherapy, and surgery fall short in the complete management of this important malignancy. Besides this worrying trend, the molecular basis of BCa development also remains poorly understood. Burgeoning evidence from experimental and clinical studies suggests that oxidative stress resulting from an imbalance between reactive oxygen species (ROS) generation and the body's antioxidant production plays an integral role in BCa development and progression. Hence, ROS-induced oxidative stress-related pathways are currently under investigation as potential therapeutic targets of BCa. This review focuses on our current understanding regarding ROS-associated pathways in BCa pathogenesis and progression, as well as on antioxidants as potential adjuvants to conventional BCa therapy.

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Bladder cancer (BCa) is the sixth most prevalent cancer in men and seventeenth most prevalent cancer in women worldwide. Current treatment paradigms have limited therapeutic impact, suggesting an urgent need for the investigation of novel therapies. To best emulate the progression of human BCa, a pre-clinical intravesical murine model is required in conjunction with existing non-invasive imaging modalities to detect and evaluate cancer progression. Non-invasive imaging modalities reduce the number of required experimental models while allowing for longitudinal studies of novel therapies to investigate long-term efficacy. In this review, we discuss the individual and multi-modal use of non-invasive imaging modalities; bioluminescence imaging (BLI), micro-ultrasound imaging (MUI), magnetic resonance imaging (MRI), and positron emission tomography (PET) in BCa evaluation. We also provide an update on the potential and the future directions of imaging modalities in relation to intravesical murine models of BCa.

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BACKGROUND: As a novel type of the prevalent post-transcriptional modifications, N7-methylguanosine (m7G) modification is essential in the tumorigenesis, progression, and invasion of many cancers, including bladder cancer (BCa). However, the integrated roles of m7G-related lncRNAs in BCa remain undiscovered. This study aims to develop a prognostic model based on the m7G-related lncRNAs and explore its predictive value of the prognosis and anti-cancer treatment sensitivity. METHODS: We obtained RNA-seq data and corresponding clinicopathological information from the TCGA database and collected m7G-related genes from previous studies and GSEA. Based on LASSO and Cox regression analysis, we developed a m7G prognostic model. The Kaplan-Meier (K-M) survival analysis and ROC curves were performed to evaluate the predictive power of the model. Gene set enrichment analysis (GSEA) was conducted to explore the molecular mechanisms behind apparent discrepancies between the low- and high-risk groups. We also investigated immune cell infiltration, TIDE score, TMB, the sensitivity of common chemotherapy drugs, and the response to immunotherapy between the two risk groups. Finally, we validated the expression levels of these ten m7G-related lncRNAs in BCa cell lines by qRT-PCR. RESULTS: We developed a m7G prognostic model (risk score) composed of 10 m7G-related lncRNAs that are significantly associated with the OS of BCa patients. The K-M survival curves revealed that the high-risk group patients had significantly worse OS than those in the low-risk group. The Cox regression analysis confirmed that the risk score was a significant independent prognostic factor for BCa patients. We found that the high-risk group had higher the immune scores and immune cell infiltration. Furthermore, the results of the sensitivity of common anti-BCa drugs showed that the high-risk group was more sensitive to neoadjuvant cisplatin-based chemotherapy and anti-PD1 immunotherapy. Finally, qRT-PCR revealed that AC006058.1, AC073133.2, LINC00677, and LINC01338 were significantly downregulated in BCa cell lines, while the expression levels of AC124312.2 and AL158209.1 were significantly upregulated in BCa cell lines compared with normal cell lines. CONCLUSION: The m7G prognostic model can be applied to accurately predict the prognosis and provide robust directions for clinicians to develop better individual-based and precise treatment strategies for BCa patients.

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Bladder cancer (BCa) is associated with significant morbidity, with development linked to environmental, lifestyle, and genetic causes. Recurrence presents a significant issue and is managed in the clinical setting with intravesical chemotherapy or immunotherapy. In order to address challenges such as a limited supply of BCG and identifying cases likely to recur, it would be advantageous to use molecular biomarkers to determine likelihood of recurrence and treatment response. Here, we review microRNAs (miRNAs) that have shown promise as predictors of BCa recurrence. MiRNAs are also discussed in the context of predicting resistance or susceptibility to BCa treatment.

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Non-muscle invasive bladder cancer (NMIBC) accounts for ~70-75% of total bladder cancer tumors and requires effective early intervention to avert progression. The cornerstone of high-risk NMIBC treatment involves trans-urethral resection of the tumor followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG therapy is commonly accompanied by significant lower urinary tract symptoms (LUTS) including urinary urgency, urinary frequency, dysuria, and pelvic pain which can undermine treatment adherence and clinical outcomes. Despite this burden, the mechanisms underlying the development of BCG-induced LUTS have yet to be characterized. This review provides a unique perspective on the mechanisms thought to be responsible for the development of BCG-induced LUTS by focussing on the sensory nerves responsible for bladder sensory transduction. This review focuses on how the physiological response to BCG, including inflammation, urothelial permeability, and direct interactions between BCG and sensory nerves could drive bladder afferent sensitization leading to the development of LUTS. Additionally, this review provides an up-to-date summary of the latest clinical data exploring interventions to relieve BCG-induced LUTS, including therapeutic targeting of bladder contractions, inflammation, increased bladder permeability, and direct inhibition of bladder sensory signaling. Addressing the clinical burden of BCG-induced LUTS holds significant potential to enhance patient quality of life, treatment compliance, and overall outcomes in NMIBC management. However, the lack of knowledge on the pathophysiological mechanisms that drive BCG-induced LUTS has limited the development of novel and efficacious therapeutic options. Further research is urgently required to unravel the mechanisms that drive BCG-induced LUTS.

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Background: To compare the survival outcomes of patients over 85 years of age with bladder cancer. Methods: We used data collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier (KM) curves were generated for overall survival with 95% confidence intervals (CIs). Cox proportional hazard models were used to estimate the hazard ratios among cases in different groups. Results: Of the 9,321 patients who met the inclusion criteria, 6,703 (71.9%) were men and 2,618 (28.1%) were women, with a mean (standard deviation) age of 88.68 (3.216) years. The median follow-up time of this cohort was 18 months. In the low-grade non-muscle-invasive bladder cancer (LG NMIBC) group, our analysis showed that no further treatment led to a better prognosis after the first transurethral bladder tumor resection (TURBT). In the high-grade NMIBC (HG NMIBC) cohort, major therapy was correlated with better OS in univariable and multivariable analyses [hazard ratio (HR) 0.450; 95% CI: 0.351-0.577]. Trimodal therapy gave a better prognosis in the muscle-invasive bladder cancer (MIBC) cohort (HR 1.395; 95% CI: 1.147-1.697). In addition, none of the county factors were risk factors for prognosis in multivariable analysis. Conclusions: Minor and major therapies do not have a better prognosis after TURBT in LG NMIBC. Major therapy has better oncological outcomes in LG NMIBC and MIBC than minor therapy. Trimodal therapy leads to longer OS in MIBC. In addition, none of the county factors were risk factors for prognosis.

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Background: Transurethral resection of bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) perfusion is a widely accepted treatment for moderate or high risk non-muscular-invasive bladder cancer (BCa). Despite its effectiveness, the recurrence and progression rate of tumor are still high. We evaluated the predictive role of fluorescence in situ hybridization (FISH) for the response to BCG perfusion in BCa. Methods: Patients with BCa who underwent BCG perfusion and FISH test in our hospital were selected. Logistic regression and Kaplan-Meier methods were used to evaluate the relationship between FISH results and tumor recurrence or progression. COX proportional hazards regression analysis was used to identify risk factors for recurrence or progression. SPSS (version 24.0, IBM Corporation, USA) was used for statistical analysis. Results: Seventy-six patients were included in this study, with a median age of 63.0 (55.0-70.0) years, and a median follow-up time of 19.0 (7.5-29.0) months. Fifteen patients relapsed after BCG perfusion. Before TURBT, 39 patients were positive for FISH and 20 were negative. There was no significant difference in the recurrence rate of BCG after perfusion predicted by preoperative FISH positive (10.3% vs. 10%, P=0.675). No association was found between preoperative FISH and tumor recurrence (P=0.955) or disease progression (P=0.186). After BCG perfusion, 10 patients were FISH positive and 14 patients were FISH negative. There was significant difference in recurrence rate of BCa predicted by positive FISH (100% vs. 7.1%, P<0.001). FISH results were significantly associated with tumor recurrence (P<0.001) and disease progression (P=0.001). Kaplan-Meier and univariate COX proportional hazards regression analysis clarified that FISH positive after BCG perfusion, tumor-node-metastasis (TNM) stage, and multiple tumors were risk factors for tumor recurrence and progression (P<0.05). Tumor TNM stage and FISH positive after BCG perfusion were independent risk factors for recurrence. Conclusions: Positive FISH after BCG perfusion can well predict the risk of recurrence and progression of BCa, and recurrence within six months is more likely. After BCG perfusion, it is better to recommend close follow up in patients with positive FISH.

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BACKGROUND: Bladder cancer (BCa) is a fatal form of cancer worldwide associated with a poor prognosis. Identifying novel drivers of growth and metastasis hold therapeutic potential for the disease. Transport homeostasis between the endoplasmic reticulum and Golgi and the secretion of matrix metalloproteinases (MMPs) mediated by Golgi have been reported to be closely associated with tumor progression. However, to date, mechanistic studies remain limited. RESULTS: Here, we identified KDELR2 as a potential risk factor with prognostic value in patients with BCa, especially those harbouring the KDELR2 amplification. In addition, we found that KDELR2 is a regulator of BCa cell proliferation and tumorigenicity based on bioinformatic analysis with functional studies. Mechanistically, we revealed that KDELR2 could regulate the expression of KIF20A, thus stimulating the expression of MMP2, MMP9 and MKI67. Functionally, the overexpression of KDELR2 and KIF20A markedly promoted proliferation, migration, and invasion in vitro and enhanced tumor growth in vivo, while knockdown of KDELR2 and KIF20A exerted the opposite effects. And the overexpression of KDELR2 also enhanced lymph node metastasis in vivo. CONCLUSIONS: Collectively, our findings clarified a hitherto unexplored mechanism of KDELR2-KIF20A axis in increasing Golgi-mediated secretion of MMPs to drive tumor progression in BCa.

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BACKGROUND: The incidence of bladder cancer (BCa) in male is approximately three to four times higher than in female, but the oncological outcomes in female patients with BCa are significantly worse than in male patients. Although many biomarkers have been identified in recent decades to predict the prognosis of BCa patients, few of them are able to distinguish the prognosis of BCa patients with gender difference. Aromatase encoded by the CYP19A1 gene catalyzes the conversion of androgens to estrogens. In this study, we investigate the prognosis significance of CYP19A1 expression considering the gender difference in BCa patients from four available public databases. METHODS: Four available public databases of BCa, including GSE13507, TCGA-BLCA, E-MTAB-4321, and E-MTAB-1803, were utilized in this analysis. The overall survival (OS) and progression-free survival (PFS) in different stages and genders were evaluated using the Kaplan-Meier analysis based on the optimal cut-off values of CYP19A1 expression. Then, Gene Set Enrichment Analysis (GSEA) were further performed to explore the potential biologic pathways by altering CYP19A1 expression in BCa patients. RESULTS: The results showed that patients with high CYP19A1 expression had a poorer outcome compared with those with low expression in both BCa cohorts in general. Higher CYP19A1 expression in male patients were significantly associated with shorter survival for either non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). However, female NMIBC patients with high CYP19A1 expression were identified to have a better prognosis, whereas high CYP19A1 expression in female MIBC patients were significantly associated with poorer survival. The result of the GSEA showed that different outcomes in female and male patients with NMIBC were related to the interaction of CYP19A1 and the cell-cycle-related pathways. CONCLUSIONS: These findings demonstrated that CYP19A1 expression might have a potential role in distinguishing the prognosis of female BCa patients dependent on tumor stage. Our results provide new insights for aromatase-mediated BCa therapy.

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BACKGROUND: Sulfatase 2 (SULF2) is a member of the sulfatase family, and its expression and clinical significance in bladder cancer (BCa) are not currently known. In this study, we attempted to evaluate SULF2 expression in BCa patients who underwent radical cystectomy (RC) and the relationship between SULF2 expression and clinical-pathological characteristics. METHODS: Data on SULF2 expression in BCa tissues was obtained from the Oncomine database and the Gene Expression Omnibus (GEO). The expression of SULF2 and vascular endothelial growth factor-D (VEGF-D) in BCa was evaluated by immunohistochemistry (IHC) in tissues from 203 patients who had undergone RC. We also explored the value of the measurement of SULF2 and VEGF-D expression for diagnosis and prognosis in BCa patients with lymphatic metastasis. RESULTS: We found an increase in SULF2 messenger RNA (mRNA) levels and gene amplification in BCa tissues from the Oncomine database. High expression of SULF2 was detected in 91/203 (44.8%) of BCa patients. Among these patients, 27 of 42 (64.3%) with lymphatic metastasis showed high SULF2 expression. Univariate analysis showed that tumor size, pathological stage, lymphatic metastasis, vascular infiltration, perineural infiltration, hydronephrosis, and VEGF-D and SULF2 expression were related to prognosis in BCa patients, and multivariable Cox regression analysis showed that SULF2 expression was an independent prognostic indicator. Receiver operating characteristic (ROC) analysis revealed that SULF2 expression resulted in an increased area under the curve (AUC) of 0.707, with a sensitivity of 71.4% and a specificity of 61.5%. CONCLUSIONS: The upregulation of SULF2 is associated with poor prognosis in high-grade BCa patients. It might be a novel diagnostic marker for BCa patients with lymphatic metastasis.

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BACKGROUND: At present, the low risk of bladder cancer (BCa)-specific death has allowed for investigation into treatment-related cardiotoxicity. To aid clinicians in selecting appropriate cardiovascular disease screening strategies and interventions, this study explored the heart-specific mortality and prognostic factors of patients with BCa after radical cystectomy (RC), radiotherapy (RT), or chemotherapy (CT), and compared their long-term heart-specific mortality with that of the general male population. METHODS: We identified three different treatments for BCa patients from the Surveillance, Epidemiology, and End Results (SEER) database: RC, RT, and CT. Patients were included from 2000 to 2012 and followed through 2015. A cumulative mortality curve and competitive risk regression model were applied to evaluate the prognostic factors of heart-specific mortality, and standardized mortality ratios (SMRs) were calculated. RESULTS: Of 39,500 men, 30.3%, 18.8%, and 50.9% received RC, RT, and CT, respectively. For patients with a survival period of less than 50 months, tumor-specific death exhibited a rapidly increasing trend, which subsequently flatlined. However, the rates heart-specific mortality and other causes exhibited a tendency to increase stably. The heart-specific and all-cause mortality rates of patients in any age group treated with the three abovementioned strategies were higher than those of the general population. The heart-specific mortality of patients with carcinoma in situ treated with RC and CT exceeded their all-cause mortality, while that of other tumor stages did not. The risks of heart-specific [sub-distribution hazard ratio (SHR) =1.38; 95% confidence interval (CI): 1.22-1.57] and tumor-specific (SHR =1.68; 95% CI: 1.60-1.77) deaths in patients who received RT were higher than those of patients who underwent CT. CONCLUSIONS: The risks of heart-specific and tumor-specific deaths in patients who received RT were higher than those of the RC and CT groups, especially in patients over 65 years of age who received RT.