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Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes
Abstract
Context:
The incidence of bladder cancer is three to four times greater in men than in women. However, women are diagnosed with more advanced disease at presentation and have less favorable outcomes after treatment.
Objective:
To review the literature on potential biologic mechanisms underlying differential gender risk for bladder cancer, and evidence regarding gender disparities in bladder cancer presentation, management, and outcomes.
Evidence acquisition:
A literature search of English-language publications that included an analysis of the association of gender with bladder cancer was performed using Pubmed. Ninety-seven articles were selected for analysis with the consensus of all authors.
Evidence synthesis:
It has been shown that the gender difference in bladder cancer incidence is independent of differences in exposure risk, including smoking status. Potential molecular mechanisms include disparate metabolism of carcinogens by hepatic enzymes between men and women, resulting in differential exposure of the urothelium to carcinogens. In addition, the activity of the sex steroid hormone pathway may play a role in bladder cancer development, with demonstration that both androgens and estrogens have biologic effects in bladder cancer in vitro and in vivo. Importantly, gender differences exist in the timeliness and completeness of hematuria evaluation, with women experiencing a significantly greater delay in urologic referral and undergoing guideline-concordant imaging less frequently. Correspondingly, women have more advanced tumors at the time of bladder cancer diagnosis. Interestingly, higher cancer-specific mortality has been noted among women even after adjusting for tumor stage and treatment modality.
Conclusions:
Numerous potential biologic and epidemiologic factors probably underlie the gender differences observed for bladder cancer incidence, stage at diagnosis, and outcomes. Continued evaluation to define clinical applications for manipulation of the sex steroid pathway and to improve the standardization of hematuria evaluation in women may improve future patient outcomes and reduce these disparities.
Patient summary:
We describe the scientific basis and clinical evidence to explain the greater incidence of bladder cancer in men and the adverse presentation and outcomes for this disease in women. We identify goals for improving patient survival and reducing gender disparities in bladder cancer.
... Bladder cancer ranks as the tenth most prevalent cancer globally and poses a considerable challenge to healthcare systems, primarily due to its high treatment costs per patient [1][2][3]. These expenses arise from the comprehensive treatment regimens and the necessary follow-up care involving invasive and expensive procedures [2,3]. ...
... Bladder cancer ranks as the tenth most prevalent cancer globally and poses a considerable challenge to healthcare systems, primarily due to its high treatment costs per patient [1][2][3]. These expenses arise from the comprehensive treatment regimens and the necessary follow-up care involving invasive and expensive procedures [2,3]. Unfortunately, advancements in treatment modalities and the enhancement of life quality resulting from these interventions have not kept pace with those seen in other cancer types, highlighting an urgent need for new alternatives to alleviate this burden. ...
... Unfortunately, advancements in treatment modalities and the enhancement of life quality resulting from these interventions have not kept pace with those seen in other cancer types, highlighting an urgent need for new alternatives to alleviate this burden. A contemporary approach is essential, with urinary biomarkers representing a promising development toward more patient-centric treatments [2][3][4][5]. However, significant efforts are still required to ensure these options become widely accessible and meet the standards of existing treatment methods. ...
The mTOR signaling pathway has a main role in integrating extracellular and intracellular signals, acting as a key regulator of proliferation, growth, metabolism, and survival. Research conducted over the past 10 years has revealed that the mTOR pathway is activated in numerous cellular processes, including angiogenesis, tumor formation, adipogenesis, insulin resistance, and T‐lymphocyte activation. Furthermore, it is dysregulated in various human diseases, including type 2 diabetes and cancer. Recently, nanoparticles (NPs) have been formulated for cancer treatment. Treatment of several cancers such as uterine cancer, lung cancer, gastric cancer, bone cancer, and glioma have been reported by the silver NPs green‐synthesized by plant extracts. This study reports on the green manufacture of silver NPs utilizing Panax ginseng and its antibladder cancer properties that follow the PI3K‐Akt‐mTOR pathway. The NPs were described using UV‐Vis, XRD, FE‐SEM, and FT‐IR. The biological aspects were the focus of a recent study. The MTT examination was used to evaluate the cytotoxic potentials of Ag NPs on HUVEC and TCCSUP cancer cells after the cells were exposed to them for 48 h. Ag NPs with a spherical shape and an appropriate average size of 43.71 nm were shown to have a crystallinity structure in the results. When exposed to Ag NPs, the cancer cell's viability diminished, resulting in an IC50 value of 154 μg/mL. An mTOR pathway in‐depth examination indicated that Ag NPs influence apoptosis and cell proliferation in TCCSUP through the pathway modulation. Additionally, the antioxidant evaluation showed that Ag NPs' IC50 value regarding DPPH was 62 μg/mL. The pathway inhibited the cell cycle and induced the apoptosis triggered by Ag NPs. Therefore, in the treatment of bladder carcinoma, Ag NPs may prove to be a beneficial natural anticancer agent.
... [4] Patient demographic factors associated with inferior survival outcomes with bladder cancer include Black race, female gender, and low socioeconomic status. [5][6][7][8] However, prior studies reviewed data from older datasets with inconsistent data for Asian/Pacific Islanders and Hispanic patients. They did not review survival data for Native American/Alaskan Native patients. ...
... [9][10][11] While the female gender is associated with worse outcomes, it is unclear whether this is due to differences in tumor biology or delays in care. [8,12] Surveillance, Epidemiology, and End Result (SEER) database analysis can assess the impact of patient-and disease-associated factors on clinical outcomes, clarifying existing disparities in cancer care. ...
... These factors likely contribute to the worse outcomes in women. [5,6,8,11,12,[18][19][20] Even among patients with NMIBC, recent SEER databases reviewed by Seo et al., which cover 1988-2006 data, showed better OS in men (HR, 0.96; 95% CI: 0.93-0.99). [9] This represents the small but existing difference in outcomes between men and women with early-stage disease. ...
Purpose
Limited data are available on the impact of socioeconomic disparities on the survival of patients with non-muscle invasive urothelial carcinoma (NMIBC).
Methods
We analyzed the Surveillance, Epidemiology, and End Results database to review the effects of sex, race, location, and socioeconomic factors on the survival of patients with NMIBC. We calculated 5-year overall survival (OS) and cancer-specific survival (CSS) using the log-rank test. The impact of socioeconomic factors on OS and CSS was analyzed using the Cox proportional hazards model adjusted for clinical characteristics. Hazard ratios (HR) and survival rates were reported with 95% confidence intervals (CI).
Results
Analysis of 3831 patients showed that older age was associated with worse OS (HR 1.08 [1.08–1.09]) and CSS (HR 1.05 [1.04–1.06]). Women and men had similar OS (HR 0.91 [0.82–1.01]) and CSS (HR 1.12 [0.95–1.32]). Black patients had worse OS (HR 1.33 [1.08–1.62] and CSS [HR 1.54 [1.13–2.05]) than their White counterparts. Patients with an annual household income below 70,000 for both OS (HR 1.79 [1.37–2.33]) and CSS (HR 1.924 [1.26–2.89]).
Conclusions
There were no gender differences in survival outcomes of NMIBC. Older age, Black, American Indian/Alaskan Native, and patients with a household income below $40,000 appear to have worse survival. However, the area of residence did not seem to affect patient survival.
... Bladder cancer exhibits a gender disparity, with lower incidences but more aggressive and advanced presentations in females, leading to notable variability in prognoses. [22][23][24][25][26] However, the sex-mediated distinctions in treatment tolerability are not well understood. Our study indicates that males are more likely to be BCG-intolerant. ...
... In addition, biological differences in pharmacokinetics, hepatic metabolism of carcinogens, and sex steroid hormone synthesis pathways, factors known to affect prognoses, may also influence tolerability in ways not yet elucidated. 23,29,30 We also identified hypertension and lower pre-treatment hemoglobin levels as predictors of BCG intolerability, suggesting that patients with pre-existing comorbidities may exhibit reduced tolerance. Prior studies have reported an increased risk of bladder cancer and recurrence; however, hypertension has not been previously identified as a predictor for intolerability. ...
Background: Intravesical Bacillus Calmette–Guérin (BCG) is the standard treatment for intermediate-risk, high-grade, and high-risk non-muscle invasive bladder cancer (NMIBC). However, it is associated with adverse effects, potentially causing treatment interruptions or discontinuation. Objectives: This study analyzed the tolerability and efficacy of induction BCG, with associated patient- and disease-related factors. Methods: A retrospective analysis was conducted on BCG-naive patients diagnosed with high-grade NMIBC, who received induction BCG at our institution between 2011 and 2021. Tolerability was defined as the completion of a 6-week induction course of BCG without treatment interruption or discontinuation. Multivariable logistic regression was performed to determine risk factors associated with the inability to tolerate treatment. Results: Induction BCG was given to 203 NMIBC patients, where 147 (72%) patients tolerated the treatment. Treatment interruptions occurred in 44 (22%) patients, while 12 (5.9%) patients discontinued the treatment. The median length of interruption was 1 week, primarily due to concerns about urinary tract infection (UTI) (n = 18, 41%) or gross hematuria (n = 5, 11%). No significant difference in 1-year recurrence rates was observed between those who tolerated BCG and those who did not (50% vs. 48%). Risk factors associated with the inability to tolerate induction BCG included male sex (odds ratio [OR] = 5.76, p < 0.01), hypertension (OR = 3.47, p = 0.02), and low pre-treatment hemoglobin levels (OR = 0.73, p = 0.03). Conclusion: Inability to tolerate BCG occurred in 28% of patients, with 5.9% experiencing discontinuation. Interruptions were short, mostly concerning UTI, and rarely leading to discontinuation. Poor tolerability was associated with male sex, hypertension, and low pre-treatment hemoglobin levels, highlighting critical targets for reducing the risk of BCG interruption or discontinuation.
... Men are three to four times more likely than environmental carcinogen exposure. Men are three to four times more likely than women to have the disease, and the risk increases significantly with age, with the majority of cases occurring in those over 65 years of age [4,5]. Tobacco smoke carcinogens are discharged in urine and directly damage the bladder epithelium, making it the major risk factor, accounting for 50-65% of all cases [4]. ...
... Men are three to four times more likely than women to have the disease, and the risk increases significantly with age, with the majority of cases occurring in those over 65 years of age [4,5]. Tobacco smoke carcinogens are discharged in urine and directly damage the bladder epithelium, making it the major risk factor, accounting for 50-65% of all cases [4]. Other major risk factors include a history of recurrent urinary tract infections (UTIs), chronic inflammation, occupational exposure to aromatic amines and polycyclic hydrocarbons, and pelvic radiation therapy [6,7]. ...
Bladder cancer (BCa) is a highly recurrent malignancy that requires sensitive and noninvasive diagnostic and predictive markers. Conventional diagnostic tools, such as cystoscopy and urine cytology, are far from ideal in terms of sensitivity, specificity, and patient compliance. In this narrative review, the development of novel urinary markers for the diagnosis of BCa is highlighted, with a focus on their application in the clinical arena, detection accuracy, and future potential. An extensive analysis of new urinary biomarkers, including proteinuria-based tests, DNA methylation biomarkers, and RNA-based molecular panels, has been conducted. Various molecular tests, such as Cxbladder®, Bladder EpiCheck®, and UroSEEK, are highly sensitive and clinically valid. Urinary biomarkers provide a promising noninvasive alternative for traditional BCa diagnostics with enhanced specificity and the possibility of early diagnosis. Future research should focus on large-scale clinical validation and standardization of biomarkers to facilitate their use in routine clinical practice.
... In bladder cancer, for example, sex-related heterogeneity in hepatic pathways is responsible for the varying degradation of carcinogens, leading to differential exposure of the urothelium to these harmful substances. 15 Tobacco, a known carcinogen for bladder cancer, has a more pronounced effect on males because of the restriction of the enzyme uridine 5 ′ -diphosphoglucuronosyltransferase by androgen receptors, impairing the hepatic detoxification of aromatic amines found in tobacco. 16 Additionally, the activity of sex steroid hormone pathways plays a critical role in the development of bladder cancer. ...
... 16 Additionally, the activity of sex steroid hormone pathways plays a critical role in the development of bladder cancer. 15 Notably, prostate cancer has the highest incidence and mortality rates among urological cancers in Chinese males, mirroring the global trends. 17 The prostate is an androgen-dependent organ present only in males, and most prostate cancers retain this androgen dependence, at least in the early stages. ...
Background
As global aging intensifies, urological cancers pose increasing health and economic burdens. In China, home to one-fifth of the world's population, monitoring the distribution and determinants of these cancers and simulating the effects of health interventions are crucial for global and national health.
Methods
With Global Burden of Disease (GBD) China database, the present study analyzed age-sex-specific patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) in China and its 34 provinces as well as the association between gross domestic product per capita (GDPPC) and these patterns. Importantly, a multi-attentive deep learning pipeline (iTransformer) was pioneered to model the spatiotemporal patterns of urological cancers, risk factors, GDPPC, and population, to provide age-sex-location-specific long-term forecasts of urological cancer burdens, and to investigate the impacts of risk-factor-directed interventions on their future burdens.
Findings
From 1990 to 2021, the incidence and prevalence of urological cancers in China has increased, leading to 266,887 new cases (95% confidence interval: 205,304–346,033) and 159,506,067 (12,236,0000–207,447,070) cases in 2021, driven primarily by males aged 55+ years. In 2021, Taiwan, Beijing, and Zhejiang had the highest age-standardized incidence rate (ASIR) and age-standardized prevalence rates of urological cancer in China, highlighting significant regional disparities in the disease burden. Conversely, the national age-standardized mortality rate (ASMR) has declined from 6.5 (5.1–7.8) per 100,000 population in 1990 to 5.6 (4.4–7.2) in 2021, notably in Jilin [−166.7% (−237 to −64.6)], Tibet [−135.4% (−229.1 to 4.4)], and Heilongjiang [−118.5% (−206.5 to −4.6)]. Specifically, the national ASMR for bladder and testicular cancers reduced by −32.1% (−47.9 to 1.9) and −31.1% (−50.2 to 7.2), respectively, whereas prostate and kidney cancers rose by 7.9% (−18.4 to 43.6) and 9.2% (−12.2 to 36.5). Age-standardized DALYs, YLDs, and YLLs for urological cancers were consistent with ASMR. Males suffered higher burdens of urological cancers than females in all populations, except those aged <5 years. Regionally and provincially, high GDPPC provinces have the highest burden of prostate cancer, while the main burden in other provinces is bladder cancer. The main risk factors for urological cancers in 2021 are smoking [accounting for 55.1% (42.7–67.4)], high body mass index [13.9% (5.3–22.4)], and high fasting glycemic index [5.9% (−0.8 to 13.4)] for both males and females, with smoking remarkably affecting males and high body mass index affecting females. Between 2022 and 2040, the ASIR of urological cancers increased from 10.09 (9.19–10.99) to 14.42 (14.30–14.54), despite their ASMR decreasing. Notably, prostate cancer surpassed bladder cancer as the primary subcategory, with those aged 55+ years showing the highest increase in ASIR, highlighting the aging-related transformation of the urological cancer burden. Following the implementation of targeted interventions, smoking control achieved the greatest reduction in urological cancer burden, mainly affecting male bladder cancer (−45.8% decline). In females, controlling smoking and high fasting plasma glucose reduced by 5.3% and 5.8% ASMR in urological cancers. Finally, the averaged mean-square-Percentage-Error, absolute-Percentage-Error, and root-mean-square Logarithmic-Error of the forecasting model are 0.54 ± 0.22, 1.51 ± 1.26, and 0.15 ± 0.07, respectively, indicating that the model performs well.
Interpretation
Urological cancers exhibit an aging trend, with increased incidence rates among the population aged 55+ years, making prostate cancer the most burdensome subcategory. Moreover, urological cancer burden is imbalanced by age, sex, and province. Based on our findings, authorities and policymakers could refine or tailor population-specific health strategies, including promoting smoking cessation, weight reduction, and blood sugar control.
Funding
10.13039/100000865Bill & Melinda Gates Foundation.
... Certainly, women have different anatomy with recurrent urinary tract infections, a different sex hormonal profile, and intrinsic differences in local and systemic immune systems 11,12 . At the same time, men show higher smoking rates and occupational carcinogen exposure, potentially impacting sex disparities in tumor incidence 10,13 . ...
... Despite the higher incidence of urothelial cancer overall among males, female-gender patients have more advanced-stage tumors at the primary diagnosis, more frequent recurrence or progression, and, overall, poor outcomes 7-9 . Biological and immunological differences underlying sex-driven disparities in urothelial carcinoma are widely investigated, from androgen and estrogen expression to differential mutations, gene expression, metabolic enzymes, and urinary microbiome profile [10][11][12][13] . These findings emphasize the importance of understanding the factors potentially involved in sex-specific differences in immunotherapy response. ...
Gender- and sex-based disparities in response to immune-checkpoint inhibitors (ICI) has been reported in a variety of tumor types. Women have different anatomy with recurrent urinary tract infections, a different sex hormonal profile, and intrinsic differences in local and systemic immune systems and urobiome composition. Existing literature data in a pan-cancer context reveal contradictory results, and real-world evidence in urothelial carcinoma (UC) is lacking. This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic urothelial carcinoma (mUC) patients progressing or recurring after platinum-based therapy and treated with pembrolizumab as a part of routine clinical care. A total of 1039 patients, treated from January 1st, 2016 to December 31st, 2023 in 68 cancer centers were included. Our data showed that women with metastatic urothelial carcinoma treated with pembrolizumab had shorter OS than men, with a 13% advantage in the 5-year OS rate for male patients. A deeper understanding of these results may inform sex-stratification in future prospective clinical trials and help develop strategies to reduce the magnitude of the sex disparities observed in urothelial cancer outcomes.
... It is a major economic burden on the healthcare system and is well known to be associated with sex bias [1]. Sex differences in Bca incidence have been observed in epidemiological and clinical studies, with a male-to-female risk ratio of 3:1 in terms of diagnosis [2,3]. Although smoking and exposure to occupational carcinogens are factors that contribute to the sex-dependent differences in Bca incidence, Bca still occurs in males after controlling exposure to these carcinogenic factors [4][5][6]. ...
... Androgens are likely to contribute to sexual dimorphism in Bca by directly and indirectly influencing various cellular processes, such as the synthesis of cytokines, growth factors, and vasoactive substances. Sex hormone-binding globulin (SHBG) is involved in binding to sex hormones and regulating their biological activity [2]. Nevertheless, establishing these associations conclusively through randomized controlled trials poses considerable challenges. ...
Background
Males have a three times higher risk of a diagnosis of bladder cancer (Bca) than females. Sex hormone-binding globulin (SHBG) may be associated with Bca risk. However, the sex-specific role of SHBG in Bca remains unclear. In this study, we aimed to determine the role of SHBG in Bca.
Methods
A sex-specific univariable Mendelian randomization (MR) analysis involving 369,426 men and 395,375 women was conducted to assess the causal relationship between SHBG and testosterone and Bca risk. Sensitivity analyses and multivariable MR were conducted to confirm the robustness of our results. Linkage disequilibrium score regression assessed the genetic correlation between these diseases influenced by heredity.
Results
Univariable MR results showed that one-SD elevated SHBG was related to a low risk of Bca in males (OR: 0.60, 95% CI: 0.39–0.93; p = 0.022) but had no benefit in females. Genetically predicted BT was positively associated with Bca risk in males (OR: 1.59; 95% CI: 1.06–2.40; p = 0.027). In multivariable MR, higher SHBG levels were not related to male Bca risk after controlling for BT.
Conclusions
Our findings do not provide evidence to support a causal relationship between SHBG and Bca risk in males although an association was observed in the univariable analysis. Further research is needed to identify the underlying pathways.
... Bladder cancer (BLCA) is a common malignant tumor that arises from the abnormal proliferation of urothelial cells on the inner surface of the bladder. 1 As one of the top 10 most common cancers in the world, BLCA poses a heavy burden on public health. 2,3 According to whether the tumor invades the bladder wall muscle layer, BLCA patients are divided into nonmuscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC accounts for 70% to 80% of cases and has a favorable prognosis but has a high recurrence rate. ...
... 6 This heterogeneity arises from subclonal evolution during tumor progression, metastasis, and treatment, leading to diverse molecular profiles and cellular phenotypes. 7 Single-cell analysis reveals a dynamic landscape where tumor cells exhibit both epithelial and mesenchymal-like 2 Cancer Informatics transcriptional states, with bidirectional plasticity between these states occurring within and among tumor subclones. For example, a dominant transcriptional state characterized by low PPARG expression has been associated with an aggressive tumor phenotype. ...
Backgrounds
Bladder cancer (BLCA) has a high degree of intratumor heterogeneity, which significantly affects patient prognosis. We performed single-cell analysis of BLCA tumors and organoids to elucidate the underlying mechanisms.
Methods
Single-cell RNA sequencing (scRNA-seq) data of BLCA samples were analyzed using Seurat, harmony, and infercnv for quality control, batch correction, and identification of malignant epithelial cells. Gene set enrichment analysis (GSEA), cell trajectory analysis, cell cycle analysis, and single-cell regulatory network inference and clustering (SCENIC) analysis explored the functional heterogeneity between malignant epithelial cell subpopulations. Cellchat was used to infer intercellular communication patterns. Co-expression analysis identified co-expression modules of the anti-apoptotic subpopulation. A prognostic model was constructed using hub genes and Cox regression, and nomogram analysis was performed. The tumor immune dysfunction and exclusion (TIDE) algorithm was applied to predict immunotherapy response.
Results
Organoids recapitulated the cellular and mutational landscape of the parent tumor. BLCA progression was characterized by mesenchymal features, epithelial-mesenchymal transition (EMT), immune microenvironment remodeling, and metabolic reprograming. An anti-apoptotic tumor subpopulation was identified, characterized by aberrant gene expression, transcriptional instability, and a high mutational burden. Key regulators of this subpopulation included CEBPB, EGR1, ELF3, and EZH2. This subpopulation interacted with immune and stromal cells through signaling pathways such as FGF, CXCL, and VEGF to promote tumor progression. Myofibroblast cancer-associated fibroblasts (mCAFs) and inflammatory cancer-associated fibroblasts (iCAFs) differentially contributed to metastasis. Protein-protein interaction (PPI) network analysis identified functional modules related to apoptosis, proliferation, and metabolism in the anti-apoptotic subpopulation. A 5-gene risk model was developed to predict patient prognosis, which was significantly associated with immune checkpoint gene expression, suggesting potential implications for immunotherapy.
Conclusions
We identified a distinct anti-apoptotic tumor subpopulation as a key driver of tumor progression with prognostic significance, laying the foundation for the development of new therapeutic strategies to improve patient outcomes.
... Bladder cancer (BC) is a common malignancy of the genitourinary system that develops primarily in the bladder mucosa. It has a global presence and is one of the genitourinary cancers with higher incidence and mortality rates, with a significantly higher incidence in men than in women [1][2][3][4]. The complex pathogenesis of BCa is closely linked to factors such as smoking, chemical exposure, chronic infections, and individual genetics [5,6]. ...
... Finally, we identified five genes, COMMD9, GPS1, PSMB5, VHL and WDR5, as independent prognostic factors for BCa by LASSO regression, univariate and multivariate Cox regression analyses. In clinical practice, age, metastasis and lymph node status are important prognostic factors in BCa [1][2][3][4]. Using a holistic approach integrating molecular and clinical prognostic factors, we found that five neddylation-related genes (COMMD9, GPS1, PSMB5, VHL and WDR5), Gene Set Enrichment Analysis (GSEA) was employed to delve into the roles of GPS1 and VHL-related genes in specific biological pathways relevant to bladder cancer, shedding light on the intricate mechanisms underlying disease progression. ...
... Moreover, the high proportion of male patients (83.91%) may result in the underrepresentation of gender-specific biological factors like hormonal variations and lifestyle differences, potentially skewing the analysis of the TyG index's relationship with NMIBC prognosis. Previous research has indicated that tumour biology and treatment responses in female NMIBC patients may differ from those in male patients (48). Given the low proportion of female patients in this study, the findings are likely to reflect the characteristics of the male cohort more prominently, which limits the generalizability of the results. ...
Background
Bladder carcinoma (BCa) is a prevalent urological malignancy characterised by high recurrence and progression rates, posing significant challenges in clinical management. The triglyceride-glucose (TyG) index has emerged as a promising prognostic marker for metabolic health in various cancers. This study explores the prognostic value of the TyG index in non-muscle-invasive bladder cancer (NMIBC), with a focus on its association with high-grade recurrence-free survival (RFS) and progression-free survival (PFS) and the mediating role of systemic inflammation.
Methods
A total of 230 patients diagnosed with NMIBC between October 2017 and October 2022 were included in this retrospective study. Clinical and pathological data were collected alongside follow-up treatment outcomes. Mediation analysis was conducted to quantify the role of systemic inflammation, using markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-8 (IL-8), in the relationship between the TyG index and patient prognosis.
Results
The TyG index was identified as a significant, non-linear prognostic factor for both RFS and PFS. An inverted U-shaped relationship was observed, with inflexion points at 9.186 and 9.168 for RFS and PFS, respectively. Below these thresholds, the TyG index was positively associated with worse outcomes (RFS: HR = 3.37, 95% CI = 1.77–6.41, P < 0.001; PFS: HR = 3.54, 95% CI = 1.65–7.58, P = 0.001). Mediation analysis revealed systemic inflammation as a critical intermediary, contributing significantly to the observed associations.
Conclusion
These findings suggest that the TyG index could serve as a valuable tool for risk stratification and prognostic assessment in NMIBC. Its integration into clinical decision-making frameworks may improve personalised management strategies, particularly by targeting systemic inflammation as a modifiable factor.
... The staging of bladder cancer depends on the extent of tumor invasion, the involvement of lymph nodes, and the presence of distant metastasis. The higher the stage, the poorer the prognosis for the patient is generally 31,32 . The incidence of bladder cancer is higher in men than in women, with a ratio of about 3:1. ...
Bladder cancer is the most common malignant tumor of the urinary tract. In this study, 90 lupane triterpene derivatives, previously synthesized in the laboratory, were systematically evaluated for their potential effects against bladder cancer by cytotoxicity screening against five urinary tumor cell lines. Bioinformatics and molecular dynamics methods were used to investigate the mechanism of action of compound 27 in depth. Most of the derivatives effectively inhibited tumor cell growth, and structure–activity relationship analysis revealed that introducing an indole moiety significantly enhanced the biological activity. The peak activity was reached when the dibromoalkyl chain length was C = 5 (IC50 = 1.121 μM). By integrating transcriptomic data and TCGA findings, we identified 11 key targets, among which DUSP5 and SCG2 showed significant differential expression. Further analysis revealed meaningful insights into the clinical association, 10-year survival prognosis, and immune infiltration. The present study further clarified the effects of compound 27 on the expression of DUSP5 and SCG2 in tumor cells after treatment by a combination of RNA-seq and RT-qPCR. Molecular docking confirmed the stable binding of compound 27 to DUSP5, which was confirmed by molecular dynamics simulations. Compound 27 inhibited bladder cancer progression by upregulating DUSP5 expression and negatively regulating the p38 MAPK pathway, modulating the immune response and promoting apoptosis.
... worldwide. 1 In the United States, the current incidence rate of bladder cancer is 15.8 per 100 000 population with more than 82 000 new cases and more than 16 000 deaths each year. 2 The fact that men have four times the incidence rate as that of women 1 might reflect the difference between men and women in historical smoking prevalence and exposure to occupational carcinogens. 3 Smoking is an established major risk factor for bladder cancer and accounts 30-50% of bladder cancer cases. 4 However, identifying factors other than smoking, especially modifiable ones such as dietary factors, can improve our understanding of bladder cancer aetiology and may provide opportunities for bladder cancer prevention. ...
Objective
Low carbohydrate diet (LCD), a summary score considering sources of all macronutrients in a dietary pattern, is defined by lower intakes of carbohydrates and higher intakes of proteins and fats. Research on the role of LCD and risk of bladder cancer is scare. We, therefore, prospectively examined the association between LCS scores and bladder cancer risk.
Patients and Methods
We used data from the Singapore Chinese Health Study, a prospective cohort study of 63 275 participants aged 45–74 living in Singapore who were recruited during 1993–1998 period. LCD scores were derived from the semi‐quantitative food frequency questionnaire at baseline. Bladder cancer cases were identified through record linkage with the Singapore cancer registry. Cox proportional hazard regression method was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for bladder cancer in relation with LCD scores.
Results
After 17.6 years of follow‐up with 819 573 person‐years, 250 participants developed bladder cancer. We found a statistically significant, positive association for bladder cancer risk with increasing level of animal‐based LCD (HRper‐SD increment = 1.16, 95% CI: 1.02–1.32; Ptrend = 0.01), but a null association with an increased level of plant‐based LCD (HRper‐SD increment = 1.08, 95% CI: 0.91–1.28, Ptrend = 0.78).
Conclusion
In summary, we showed that an LCD diet with fat and protein from animal‐based food was associated with increased risk while an LCD diet with fat and protein derived mainly from plant‐based food was not associated with bladder cancer risk. Our findings have implications for diet modifications in the prevention and control program of bladder cancer.
... Также у женщин на момент постановки диагноза чаще выявляется более высокая клиническая стадия заболевания [28,30,31]. По данным большинства исследований, такая статистика связана с более поздней диагностикой, несмотря на наличие клинических симптомов, таких как гематурия. ...
Background. Bladder cancer (С67) remains a serious problem of modern medicine without an established system of active detection. Among male population, bladder cancer is close to such malignant neoplasms as kidney cancer and systemic neoplasms of the lymphatic and hematopoietic tissues, while among female population to oral and brain neoplasms. In terms of 5-year cumulative, observed and relative survival bladder cancer is similar to malignant tumors of the parotid gland (С07) and leukemias (С91–96). Bladder cancer has a higher tendency to recurrence and progression.
Aim. To study for the first time on population level current dynamics of morbidity, mortality, accuracy of registering of patients with bladder cancer in Russia and to evaluate specifics of annual mortality of the patients based on the Population Cancer Registry (PCR) database of the Northwestern Federal District of the Russian Federation (NWFD RF).
Materials and methods . Materials of the International Agency for the Research on Cancer, P.A. Herzen Moscow Oncology Research Institute and N.N. Petrov National Medical Research Center of Oncology reference books were used. Detailed characteristics of the analytical values were established based on the NWFD RF PCR database. For calculation of annual bladder cancer mortality, 27,431 observations were selected from the PCR database.
Results and conclusion . The study allowed to determine the specifics of bladder cancer morbidity in the world, Russia, and NWFD RF, establish age characteristics of the registered bladder cancer cases. Dynamics of bladder cancer morbidity and mortality in Russia and NWFD RF were demonstrated. The negative effect of COVID-19 pandemic was observed. Positive dynamics in mortality and quality of follow-up for patients with bladder cancer were shown. Based in the PCR NWFD RF database, specifics of annual mortality of patients with bladder cancer were determined.
... It is primarily treated with transurethral resection of the bladder (TURB) followed by intravesical instillation therapy [3,4]. However, NMIBC has a significant recurrence risk, with 80% of patients experiencing relapse within five years [5] and 30% progressing to muscle-invasive disease [6], which results in high lifetime treatment costs during long term follow-up [7,8]. ...
Purpose
To prospectively evaluate the value of Vesical Imaging Reporting and Data System (VI‑RADS) prior to initial transurethral resection of the bladder (TURB) in predicting residual tumor at second TURB and subsequent prognosis of patients.
Methods
We enrolled suspected bladder cancer patients and scheduled multiparametric magnetic resonance imaging (mpMRI) of bladder for them before initial TURB. Second TURB were conducted based on initial resection reports, with comparisons made between patients with VI-RADS scores <3 and ≥3 regarding residual tumor rate, recurrence-free survival (RFS) and progression-free survival (PFS). Predictive efficacy of VI-RADS was assessed using Chi-square tests, logistic and Cox regression analyses, ROC curves, and Kaplan-Meier analyses.
Results
A total of 108 patients were included, and residual tumors were detected in 25.0% (27/108) of them at second TURB, with a significant difference between patients with VI-RADS score <3 and ≥3 (8/81 vs. 19/27, p <0.001). VI-RADS ≥3 demonstrated a sensitivity of 70.4%, specificity of 90.1%, positive predictive value (PPV) of 70.4%, and negative predictive value (NPV) of 90.1%. Stratified analysis showed VI-RADS achieved a NPV of 95.2% for disease-free Ta patients, while 84.6% for T1 patients. After a median follow-up of 30 months for the 92 patients, 24 experienced tumor recurrence. VI-RADS ≥3 was found to be an independent predictor of tumor recurrence (HR = 4.297, p = 0.003).
Conclusions
VI-RADS ≥3 is associated with higher residual tumor rate at second TURB and higher recurrence risk. It might be an option for omitting second TURB when VI-RADS is <3, especially for Ta patients.
... This rare presentation highlighted several challenges in terms of diagnostic and therapeutic management. Firstly, urothelial carcinoma diagnoses are uncommon in young women without risk factors [1][2][3][4]. Secondly, the association between EGFR mutation and urothelial carcinoma is also uncommon. ...
Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25–50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.
... The male-to-female ratio of urinary bladder malignancy is 3:4 [1]. In terms of disease progression, 30% of cases of non-muscle-invasive bladder cancer (NMIBC) progress to invasive disease after initial therapy, and 80% of cases relapse within five to seven years [2,3]. Upon radical cystectomy, the five-year survival rate for T2 tumors is 68%; however, for locally advanced tumors, it is only 25%-30% [4,5]. ...
Background
Worldwide, bladder cancer is one of the more common types of cancer. This study was conducted to evaluate the Vesical Imaging Reporting and Data System (VI-RADS) score for the diagnosis of muscle-invasive bladder cancer (MIBC). Additionally, the VI-RADS scores were compared with various relevant parameters and cancer stages.
Materials and methods
A prospective observational study design was used. The study was carried out in the Urology Department of the Indira Gandhi Institute of Medical Sciences (IGIMS) in Patna, India. It was conducted over a period of one and a half years, i.e., from December 2022 to July 2024. Overall, 71 patients were enrolled in the study.
Results
With a cut-off score of ≥3 for T2 (muscle-invasive), sensitivity and specificity were 93.75% (79.19% to 99.23%) and 76.92% (60.67% to 88.87%), respectively. With a cut-off score of VI-RADS ≥4 for muscle invasion, sensitivity and specificity were 62.5% (43.69% to 78.90%) and 89.74% (75.78% to 97.13%), respectively. VI-RADS scores of 1 and 2 were fairly accurate for non-muscle invasion, while scores of 4 and 5 were highly predictive of muscle invasion. A VI-RADS score of 3 remained the grey zone.
Conclusion
It is easy to interpret the VI-RADS score and assess detrusor muscle invasion. The present study on VI-RADS shows reliability for local staging and for differentiating non-MIBC (NMIBC) and MIBC. Among the VI-RADS scores, it was found that the result was statistically significant between high-grade and low-grade cancer, with a p-value <0.001.
... This trend was not observed in females. BC is the 10th most common cancer worldwide, with the highest incidence among males [8, 11,24,25]. In some countries, the incidence of BC in females has increased, while in males, it has decreased or remained stable [24]. ...
Background
Cancer incidence may be linked to cumulative exposure to environmental factors, including diet, lifestyle behaviors, licit drug use (such as tobacco), and endogenous processes. Tobacco smoking (TS) is strongly associated with bladder cancer (BC) and lung-bronchial cancer (LBC). This study aimed to analyze TS, BC, and LBC rates; their correlation with sex and age; and the risk of subsequent primary cancers among BC and LBC patients in non-Hispanic white Americans (NHWAs) from 13 U.S. states.
Methods
The percentage of smokers in 13 U.S. states from 2000 to 2016 was obtained from the Centers for Disease Control and Prevention (CDC) database. LBC and BC cases in NHWAs from 2000 to 2016 were analyzed as single primary cancers or as the first of two or more neoplasms using the United States Surveillance, Epidemiology, and End Results (SEER) database.
Results
The percentage of NHWA smokers decreased in all 13 U.S. states evaluated in this study from 2000 to 2016. Over 17 years, the incidence rates of BC were 36.37 and 11.66 cases per 100,000 among men and women, respectively, while those of LBC were 68.21 and 61.53 cases per 100,000, respectively. The highest incidence rates of BC and LBC occurred in individuals over 64 years of age: BC in New York (208.9 per 100,000 men) and Massachusetts (54.33 per 100,000 women), and LBC in Kentucky (503.1 per 100,000 men; 298.5 per 100,000 women). The incidence rates of BC and LBC were correlated in most states, especially in Massachusetts, California, New Jersey, and New York. Among the 657,117 patients with LBC, 4.3% had a second type of cancer, while among the 240,461 patients with BC, 14.3% had a second type.
Conclusion
Despite a significant decrease in the number of smokers in the United States between 2000 and 2016, the incidence of BC in men and LBC in women has not followed a similar decline. The odds ratio of a patient diagnosed with primary BC developing a second neoplasm is 3.3 times greater than that of a patient diagnosed with primary LBC.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13690-025-01585-5.
... Furthermore, while quitting smoking significantly lowers bladder cancer risk, the reduction is less pronounced in women than in men [6]. These sex differences carry significant clinical implications for the pathogenesis, diagnosis, and prognosis of bladder cancer [7]. ...
Tobacco is a significant risk factor for bladder cancer, with notable disparities in smoking rates and cancer prevalence between sex. Our objective is to assess the sex- and age-specific burden of bladder cancer attributable to smoking in China from 1990 to 2021, and predict its future trends over the next 15 years using GBD study data.
All data were extracted from the 2021 GBD study, utilizing metrics such as mortality rates, disability-adjusted life years (DALYs), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR) to describe the burden of smoking-attributable bladder cancer in China. We employed joinpoint and age-period-cohort (APC) analysis methods to elucidate the epidemiological characteristics of bladder cancer. Frontier analysis was used to visually demonstrate the potential for burden reduction based on the development level of each country or region. We applied the ARIMA model to fit and predict the future burden of smoking-attributable bladder cancer in China for the next 15 years.
From 1990 to 2021, the number of deaths and DALYs due to smoking-attributable bladder cancer in China significantly increased. However, ASMR and ASDR decreased for both sexs but males experiencing a higher burden. Population aging drove the decline in ASMR and ASDR, despite rising absolute deaths and DALYs. Joinpoint regression yielded average annual percentage changes (AAPC) of − 1.23 for ASMR and − 1.38 for ASDR, with the rate of change being lower in males than in females. The impact of age, period, and cohort on mortality rates varied. There was a slight increase in relative health inequality in the bladder cancer burden among countries of different income levels. By 2036, ASDR and ASMR for smoking-related bladder cancer in China are expected to continue decreasing, with this trend being more pronounced in males.
Over the past three decades, the number of deaths and DALYs due to smoking-related bladder cancer in China has significantly increased across different sexs and age groups, while ASMR and ASDR have shown a declining trend, reflecting certain public health progress. This trend is especially evident among males and is primarily driven by population aging and demographic effects. The inequality among countries of different income levels has slightly increased. The burden of smoking-related bladder cancer in China is projected to continue declining by 2036, particularly among males. Therefore, precise prevention and intervention strategies targeting different sexs and age groups are essential to further alleviate the public health burden of smoking-related bladder cancer.
... This phenomenon may be due to advances in diagnostics, early detection, and more effective treatment of BCa, available in more advanced health care systems. The level of socioeconomic development may significantly impact the risk of developing this cancer [5]. The global distribution of new cases of BCa in 2022 is presented in Figure 1. ...
Bladder cancer (BCa) is among the most frequently diagnosed urinary tract cancers, characterized by a high recurrence rate and significant clinical heterogeneity. Effective diagnosis and treatment of BCa demand continuous advancements in medical technologies, particularly given the limitations of classical methods such as cystoscopy and urine cytology. A comprehensive search of PubMed and Web of Science was conducted using relevant keywords to structure this narrative review. Additionally, specialist journals were reviewed. Only articles in English were included, with selection based on titles, abstracts, and availability of full texts. In recent years, biomarkers have emerged as crucial tools complementing traditional techniques, providing more precise, sensitive, and non-invasive methods for early detection, prognosis, and monitoring treatment response in BCa. Molecular, genetic, and protein biomarkers enable a deeper understanding of BCa biology, creating opportunities for personalized therapy tailored to individual patient needs. However, despite their potential, certain challenges remain, including standardization, validation, and integration into routine clinical practice. This review highlights recent advancements in BCa biomarkers and their transformative potential in oncological care. It underscores the importance of incorporating these innovations to refine diagnostic and therapeutic approaches, ultimately improving patient outcomes. Modern diagnostic and prognostic tools for BCa can enhance treatment outcomes by enabling early disease detection and reducing recurrence risks. This progress promises to improve patients’ quality of life by minimizing disease burden and fostering effective, tailored care strategies.
... A similar pattern was also found in Chinese, Japanese, and Korean patients. It has been shown that bladder cancer outcomes are remarkably worse in female than male patients [41]. Females have more advanced bladder cancer at the time of diagnosis than males, but their survival disadvantage persists even after adjusting for tumor stage and treatment modality. ...
Asian Americans (AA) in the United States represent a heterogenous population from various ethnic backgrounds. We compared cancer and cardiovascular disease (CVD) mortality between various AA groups and Non-Hispanic White (NHW) patients diagnosed with urologic cancer.
We assembled a population-based cohort that included 389,114 prostate cancer, 98,721 renal cell cancer, and 126,485 bladder cancer patients. Cumulative cancer and CVD mortality were compared between AA and NHW groups, accounting for competing risk of death. Multivariable Cox models were used to quantify the cause-specific hazard ratio (HR) with a 95% confidence interval (CI), comparing AA subgroups (Chinese, Japanese, Korean, Filipino, Vietnamese, Other Southeast Asian, and Indian/Pakistani) to NHW patients.
AA ethnic subgroups had a lower or comparable mortality from prostate cancer compared with NHW patients (HR ranged 0.51–1.03). No overall difference was observed for renal cell cancer death, but an increased mortality was observed for Filipino (HR = 1.10; 95% CI, 1.00–1.22) and Other Southeast Asian (HR = 1.50; 95% CI, 1.06–2.12) patients that included Laotian, Hmong, Kampuchean, and Thai ethnicity. Although reduced mortality from bladder cancer (HR = 0.88; 95% CI, 0.83–0.93) was observed compared to NHW patients, an increased mortality was seen among Other Southeast Asians (HR = 1.63; 95% CI, 1.15–2.30). CVD mortality varied across AA ethnicities, with higher mortality observed in Filipino and Other Southeast Asian (HR ranged 1.23–2.40) compared with Chinese patients.
Large heterogeneity exists in mortality among AA patients diagnosed with urologic cancer, with higher mortality from cancer and CVD observed in Filipino and Other Southeast Asian patients.
... In 2022, more than 610,000 cases of bladder cancer (BCa) were diagnosed and more than 220,000 deaths were caused worldwide [1][2][3]. Urothelial carcinoma accounts for approximately 90% of BCa cases and strongly threatens the survival of patients [4,5]. Radical cystectomy is recommended as the standard treatment for muscle-invasive bladder cancer [6]. ...
... Many patients are initially diagnosed with advanced muscleinvasive bladder cancer (MIBC), where current therapies often fail to prevent high mortality and metastasis rates [2,21]. Thus, early diagnosis and prediction of malignant progression of bladder cancer are increasingly crucial. ...
Bladder cancer (BLCA) is one of the most common tumors of the urinary tract. The diagnosis of BLCA is mostly by invasive tests, which are damaging and unsuitable for early screening. Current non‐invasive diagnostic modalities are insufficient in sensitivity and specificity. Therefore, novel diagnostic markers are urgently needed to facilitate early detection of bladder cancer. tRNA‐derived small RNAs (tsRNAs) are considered to be novel and potentially biologically functional non‐coding RNAs (ncRNAs). tsRNAs have been used to help early diagnosis of a variety of tumors. However, whether tsRNAs in BLCA are altered or involved in BLCA progression or regulation remains unclear. Here, we identified a group of up‐regulated tsRNAs in BLCA by sequencing tsRNAs in the plasma of BLCA patients and normal controls and further screened two highly correlated tsRNAs with BLCA in the training set and validation set, which were named as tRF‐1:28‐chrM.Ser‐TGA and tiRNA‐1:34‐Glu‐CTC‐1‐M2. ROC analyses of the expression profiles of these two tsRNAs by the validation set identified a high diagnostic value. We also found that circulating tRF‐1:28‐chrM.Ser‐TGA and tiRNA‐1:34‐Glu‐CTC‐1‐M2 were specifically expressed and released by BLCA cells and were positively correlated with the degree of disease malignancy. In vitro and in vivo experiments revealed that the two tsRNAs exacerbated BLCA progression and played a role in promoting tumor lipid metabolism. Our study screened two plasma tsRNAs that could serve as valuable early screening and diagnostic biomarkers for BLCA and is also expected to provide potential novel molecular targets for the treatment of BLCA.
... These results are interesting in the light of women being known to suffer from more advanced disease upon diagnosis (Mallin et al. 2011;Dobruch et al. 2016;Cárdenas-Turanzas et al. 2006;Danforth et al. 2020;Hasan et al. 2022). With respect to disease recurrence and progression among NMIBC patients the literature is inconclusive (Kluth et al. 2013;Palou et al. 2012;Lobo et al. 2024). ...
Purpose
To systematically analyze gender-specific differences in recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) as well as adverse events and quality of Life (QoL) as secondary aims in NMIBC patients undergoing cytostatic intravesical chemotherapy.
Methods
A systematic review and meta-analysis were conducted on studies published between 1976 and 2024, following PRISMA guidelines. MEDLINE, Embase and Cochrane Library were used as literature sources. No restrictions were made concerning language, study region or publication type. Data from 12 studies encompassing 1,527 patients were analyzed. Outcomes were assessed using random-effects models, with gender as a primary variable of interest. A risk of bias assessment was done using the ROBINS-I tool or RoB2 as appropriate.
Results
The pooled analysis demonstrated no statistically significant gender-specific differences in RFS (HR = 1.0625, 95% CI 0.8094–1.0526) or PFS (HR = 1.0861, 95% CI 0.7038–1.6760). Data on CSS and OS were insufficient for meaningful conclusions. Two included studies analyzed in univariate or multivariate regression gender as risk factor for recurrence or progression, but gender was not a significant risk factor. Adverse events and QoL outcomes were notably underreported, with no gender-specific data available.
Conclusions
While this study found no significant gender-based differences in NMIBC outcomes following intravesical chemotherapy, the findings are limited by the small number of studies, underrepresentation of women, and inconsistent reporting of critical outcomes. Future research should prioritize gender-focused analyses and explore the molecular and genetic basis of potential differences to inform precision medicine and equitable care.
... Urothelial bladder cancer (UBC) is the seventh most common cancer in men worldwide and ranks seventeenth in women [1] . Men are three to four times more likely than women to develop bladder cancer [2] . Early detection and intervention are crucial, yielding a 90% overall survival rate. ...
... To account for multiple comparisons, a false-discovery rate (FDR) threshold of 0.05 was employed to define statistical significance. Stratified analyses according to gender and age groups (≤ 50, 50-60, 60-70, > 70 years) were conducted given the substantial disparity in disease risk for these groups 64,65 . Association analyses were performed using R 66 ; all P values are two-sided. ...
Genome-wide association studies (GWAS) have detected several susceptibility variants for urinary bladder cancer, but how gene regulation affects disease development remains unclear. To extend GWAS findings, we conducted a transcriptome-wide association study (TWAS) using PrediXcan to predict gene expression levels in whole blood using genome-wide genotype data for 6180 bladder cancer cases and 5699 controls included in the database of Genotypes and Phenotypes (dbGaP). Logistic regression was used to estimate adjusted gene-level odds ratios (OR) per 1-standard deviation higher expression with 95% confidence intervals (CI) for bladder cancer risk. We further assessed associations for individual single-nucleotide polymorphisms (SNPs) used to predict expression levels and proximal loci for genes identified in gene-level analyses with false-discovery rate (FDR) correction. TWAS identified four genes for which expression levels were associated with bladder cancer risk: SLC39A3 (OR = 0.91, CI = 0.87–0.95, FDR = 0.015), ZNF737 (OR = 0.91, CI = 0.88–0.95, FDR = 0.016), FAM53A (OR = 1.09, CI = 1.05–1.14, FDR = 0.022), and PPP1R2 (OR = 1.09, CI = 1.05–1.13, FDR = 0.049). Findings from this TWAS enhance our understanding of how genetically-regulated gene expression affects bladder cancer development and point to potential prevention and treatment targets.
... 3 In prostate cancer, androgen receptor (AR) directly interacts with FOXA1, driving cancer growth and survival. 4 BLCA incidence is 3-4 times higher in males 5,6 ; however, when diagnosed with BLCA, women tend to present with more advanced disease stages compared to men, resulting in poorer treatment outcomes and higher mortality rates. 7,8 Emerging research suggests that AR may facilitate the occurrence, progression, and recurrence of BLCA, potentially leading to the observed sex disparities. ...
... It is hypothesised that sex hormones could also provoke BCA development. 9 Compared to black individuals, white people and Asians are more likely to acquire BCA. ...
Bladder cancer remains a significant global health concern, being the 10th most common malignancy worldwide and the 6th most common neoplasia in males, with alarming annual incidence and mortality rates. The current narrative review was planned to delve into the multifaceted landscape of bladder cancer, exploring its epidemiology, risk factors and diagnostic modalities. While white light cystoscopy has long been considered the gold standard for bladder cancer diagnosis and surveillance, the emergence of blue light cystoscopy has ushered in a new era of early detection. Numerous studies have demonstrated BLC's superiority in reducing the risk of progression and recurrence of this lethal cancer. However, the widespread adoption of this technology remains elusive. Recent advancements in diagnostic procedures have revolutionised imaging modalities, with blue light cystoscopy and narrow-band imaging emerging as promising replacements for white light cystoscopy. Clinical trials have underscored the superior performance of blue light cystoscopy over white light cystoscopy, with reduced recurrence and progression rates. For non-muscle invasive bladder cancer, Bacillus Calmette-Guérin immunotherapy remains the gold standard adjuvant therapy, while cystectomy is considered for cases resistant to Bacillus Calmette-Guérin or with a high risk of progression. Transurethral resection of bladder tumour followed by intravesical chemotherapy is a key intervention for early-stage bladder cancer. Blue light cystoscopy is poised to overcome the limitations of white light cystoscopy by providing comprehensive visualisation of neoplastic boundaries, particularly benefiting late-detected squamous-type non-muscle invasive urothelial carcinomas associated with lower survival rates. The current findings highlighted the transformative potential of blue light cystoscopy and other emerging diagnostic techniques, offering a ray of hope in the battle against bladder cancer, while emphasising the need for wider adoption and integration into clinical practice. Key Words: Bladder carcinoma, Blue light cystoscopy, White light cystoscopy, Urothelial carcinoma, Non-muscle invasive carcinoma, Narrow-band imaging.
... In humans, the prognosis of UC is poorer in females than in males, the reasons for which have not yet been identified. [39][40][41] Therefore, this model may be useful for gaining new insights into the mechanisms by which sex differences affect the prognosis of UC in clinical practice. ...
Animal models of N‐butyl‐N‐(4‐hydroxy butyl) nitrosamine (BBN)‐induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN‐induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi‐omics analyses, including whole‐exome, whole‐transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi‐omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf‐related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf‐related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non‐engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.
... On a global scale, bladder cancer holds the second position among urological malignancies in terms of prevalence, while it ranks ninth among all malignancies and stands as the 13th leading contributor to cancer-related deaths worldwide (1). The main risk factors include old age, smoking, pelvic radiation therapy, the use of cyclophosphamide, and an enlarged prostate and urinary retention in men, which may also increase the risk of cancer due to the presence of carcinogens in the urine (2). ...
Introduction
Bladder cancer was recognized as one of the most common malignant tumors in the urinary system, and treatment options remained largely limited to conventional surgery, radiotherapy, and chemotherapy, which limited patient benefits.
Methods
Researchers constructed an RNA transcriptome map of bladder cancer by integrating single-cell RNA sequencing and clinical data, identifying potential molecular targets for diagnosis and treatment. We also verified the antitumor activity of the target through in vitro experiment.
Results
A distinct tumor cell subpopulation characterized by elevated S100A8 expression exhibited high copy number variation, high stemness, and low differentiation. It interacted with myeloid cells via the MIF-(CD74+CD44) and MIF-(CD74+CXCR4) signaling pathways. This study underscored KDELR2’s role in promoting cell proliferation, invasion, and migration, providing new therapeutic insights. Prognostic analysis revealed that KDELR2 correlated with poor survival, higher immune scores, and increased macrophage infiltration.
Discussion
The findings suggested that patients with high KDELR2 expression might benefit from immune checkpoint therapy. KDELR2 was also shown to enhance bladder cancer cell proliferation, invasion, and migration, highlighting it as a promising target for macrophage-focused drug development.
... Although men have a higher risk of developing a bladder tumor, women tend to be diagnosed more frequently, with >6-month delay, and to present with a more advanced stage at diagnosis [18,19]. This could be due to different symptoms at presentation, especially a lower frequency of macroscopic hematuria and higher occurrence of urinary tract irritative symptoms, leading to overlooked bladder tumors and an increased rate of the development of metastatic disease [19]. ...
Gender differences in prevalence, tumor invasiveness, response to treatment, and clinical outcomes exist in different types of cancer. The aim of this article is to summarize the sex disparities in bladder cancer diagnosis and treatment and try to suggest areas for improvement. Although men are at a higher risk of developing bladder tumors, women tend to be diagnosed with more advanced stages at diagnosis and are more likely to present with upfront muscle-invasive disease. Non-urothelial histological subtypes are more frequently reported in women. Regarding non-muscle-invasive bladder cancer (NMIBC), several studies have shown that women have a higher risk of disease recurrence after treatment with Bacillus Calmette–Guerin, due to different immunogenicities. In localized muscle-invasive bladder cancer (MIBC), neoadjuvant chemotherapy and cystectomy are less likely to be performed on women and sexual-sparing procedures with neobladder diversion are rarely offered. Finally, women appear to have a poorer prognosis than men, potentially due to the sex-associated intrinsic features of hosts and tumors that may drive differential therapeutic responses, particularly to immune-based therapies. Women are also more likely to develop severe adverse events related to systemic therapies and are underrepresented in randomized studies, leading to a gap between the real world and trials. In conclusion, studies investigating the role of sex and gender are urgently needed to improve the management of urothelial carcinoma.
... Sin embargo, en muchas ocasiones, se atribuye a infecciones del tracto urinario, lo que puede resultar en un retraso en el diagnóstico del CV en este grupo poblacional. Este retraso diagnóstico, a su vez, conlleva un empeoramiento de la supervivencia específica del cáncer y de la supervivencia global en mujeres 12,13 . ...
... Studies suggest that women may be more susceptible to bladder cancer than men (Scosyrev et al., 2009). Interestingly, the incidence of bladder cancer is approximately three to four times higher in men than in women (Krabbe et al., 2015;Dobruch et al., 2016). Several studies have explored the potential molecular Serious adverse events identified for EV and Erdafitinib using WHO-VigiAccess, including life-threatening events, hospitalization, and disease progression. ...
Introduction
Enfortumab vedotin (EV) and Erdafitinib are effective therapeutic drugs for bladder cancer patients following post-chemotherapy and immunotherapy. This study assessed adverse drug reactions (ADRs) from both drugs, comparing their safety profiles to guide clinical use.
Methods
A retrospective descriptive analysis was conducted on ADR reports for EV and Erdafitinib from the World Health Organization (WHO)-VigiAccess database. Data on patient demographics, system organ classes (SOCs), global patient regions, symptoms, and ADRs frequencies were analyzed and compared.
Results
As of 2024, 3,438 ADR reports were identified (2,257 for EV and 1,181 for Erdafitinib). The number of adverse reaction reports for EV is significantly higher than that for Erdafitinib. Among them, the SOC with the most adverse signals is gastrointestinal disorders, with the top five reports being nausea, gastrointestinal disorders, dry mouth, abdominal pain, and diarrhea. The top five reported adverse events (AEs) for EV are as follows: skin and subcutaneous tissue disorders (20.70%), general disorders and administration site conditions (14.23%), nervous system disorders (11.12%), gastrointestinal disorders (7.78%), and metabolism and nutrition disorders (6.47%). In contrast, the top five AEs for Erdafitinib are: general disorders and administration site conditions (25.36%), skin and subcutaneous tissue disorders (10.94%), gastrointestinal disorders (10.19%), eye disorders (9.21%), and injury poisoning and procedural complications (7.31%).
Conclusion
Our study identified and compared potential and novel ADRs between EV and Erdafitinib, providing key insights into their safety profiles and highlighting the need for personalized treatment strategies based on individual patient risk factors.
... Bladder cancer (BC) affects over 430,000 people annually, ranking as the tenth cancer type [1,2]. It primarily occurs in men, with a significantly higher incidence than in women [3]. BC, accounting for 90-95% of Urothelial carcinomas, is typically diagnosed at an advanced age, with a median patient age of 73 years [4,5]. ...
Background
SLC35F6 negatively regulates outer mitochondrial membrane permeability and positively regulates apoptotic signaling pathways and cell population proliferation. The biological function of SLC35F6 in bladder cancer (BC) remains inadequately established. This study evaluates the expression and clinical significance of SLC35F6 in BC, assesses its prognostic value and explores its relationship with key immune-related molecules in the tumor microenvironment.
Methods
Combining bioinformatics tools and immunohistochemistry (IHC) analysis, the expression of SLC35F6 was analyzed through IHC in the tissues of 145 BC patients treated at the Affiliated Hospital of Nantong University from 2004 to 2009. The relationship between SLC35F6 expression levels and significant clinicopathological factors was examined using the chi-square test. Prognostic values were analyzed using the COX regression model and the Kaplan-Meier survival curve. Analysis of the receiver operating characteristic curve was conducted to assess the predictive performance of SLC35F6 in BC patients.
Results
The expression levels of both SLC35F6 mRNA and protein were elevated in BC tissue relative to benign tissue. Kaplan-Meier analysis indicated that patients exhibiting elevated SLC35F6 protein expression had a worse prognosis. Multivariate Cox regression analysis confirmed that SLC35F6, TNM stage and grade are independent risk factors for bladder cancer. SLC35F6, when analyzed alongside clinical pathological factors, enhances the accuracy of survival predictions for Bladder Urothelial Carcinoma (BLCA) patients.
Conclusion
SLC35F6 is upregulated in BC patients compared to normal individuals and is linked to a worse prognosis. SLC35F6 analyzed alongside clinical pathological factors can enhance the accuracy of survival predictions for BLCA patients, suggesting its potential value as a prognostic and predictive biomarker.
Bladder cancer (BC) is a common and lethal condition that presents a considerable risk to public health. Studies have demonstrated that inflammation is pivotal in the onset and advancement of BC. Pyroptosis is a type of programmed cell death distinguished by inflammatory reactions associated with innate immunity. Inhibiting inflammatory cytokine production and modulating pyroptosis-related pathways may provide a potential treatment approach for BC. We predicted and validated the Pyroptosis-related genes and potential biomarkers associated with BC, ultimately predicting therapeutic drugs based on the hub gene targets.
The gene expression profiles for BC were acquired from the Gene Expression Omnibus (GEO) database. Bioinformatics analysis identified gene expression differences associated with pyroptosis in BC. The differently regulated pyroptosis-related genes were validated, and enrichment studies of specific biological processes and associated signaling pathways in BC were performed. Immune infiltration analysis and single-cell analysis were conducted to clarify the immune infiltration characteristics in BC. Therapeutic agents were forecasted based on critical gene targets.
In BC, 27 differentially expressed pyroptosis-related genes were discovered, with CASP8, NLRP3, CASP3, IL18, TP53, GSDME, IL1A, PYCARD, CYCS, and CASP9 recognized as key genes. Enrichment analysis revealed that the occurrence of pyroptosis was primarily associated with inflammation, activation of immune responses, and apoptosis. Additionally, data validation demonstrated that CASP8, NLRP3, CASP3, IL18, TP53, CYCS, and CASP9 were involved in the regulation of pyroptosis. The results of immune infiltration and single-cell analyses further validated that B-cells-memory, T-cells_CD8, T-cells_follicular-helper, Macrophages-M1, Dendritic_cells_activated, and Mast_cells_resting play significant roles in the immune processes of BC. The drug targeting predictions for pivotal genes identified Triethyl phosphate, Regorafenib, Ponatinib, Lenvatinib, Nintedanib, and Quercetin as potential key drugs or compounds for the treatment of BC.
This study elucidated the relationship between the development of BC and mechanisms of cellular senescence, apoptosis, and immunity. It clarified the roles of 27 genes associated with cellular senescence in BC and predicted that Triethyl phosphate, Regorafenib, Ponatinib, Lenvatinib, Nintedanib, and Quercetin may be key drugs or compounds for the treatment of BC.
The rising global incidence of bladder cancer and chemotherapy resistance necessitate novel therapies. Plant-derived compounds, owing to their diverse biological activities and favorable safety profiles, are considered promising candidates for cancer treatment. In this study, we investigated Bousigonine D, a monoterpene indole alkaloid isolated from the roots of Bousigonia mekongensis, for its potential as a therapeutic agent for bladder cancer. Our results show that Bousigonine D effectively inhibits cell proliferation and clonogenic formation, and induces cell cycle arrest at the G0/G1 phase in murine and human bladder cancer cells. Furthermore, Bousigonine D significantly promotes apoptosis in these cells, surpassing the apoptosis-inducing efficacy of cisplatin. Mechanistically, Bousigonine D enhances the generation of reactive oxygen species, disrupts calcium homeostasis, and impairs mitochondrial function, leading to cytoskeletal collapse and caspase-dependent apoptotic cell death. In vivo, Bousigonine D effectively suppresses tumor growth in an orthotopic MB49 mouse model, and importantly, it retains strong anti-tumor efficacy in cisplatin-resistant bladder cancer. Notably, Bousigonine D exhibits low toxicity in major organs, similar to cisplatin, underscoring its potential as a safe and effective treatment for bladder cancer. This study highlights the promising role of plant-derived compounds in cancer therapy and supports further development of Bousigonine D as a novel therapeutic option for bladder cancer.
Urothelial carcinoma is the primary malignancy of the urothelium that has varying radiographic features based on the location of the tumor. Differentiating urothelial carcinoma from renal cell carcinoma is critical as interventions and management methods differ. We present a case of urothelial carcinoma within the calyceal diverticula that was initially suspected to represent Bosniak IV cyst due to cystic renal cell carcinoma. A 71-year-old male with a history of gross hematuria and a previously identified Bosniak II renal cyst underwent further imaging, revealing a Bosniak IV cystic mass with enhancing nodules. Subsequent nephrectomy unveiled noninvasive low-grade papillary urothelial carcinoma within a calyceal diverticulum. This case highlights the complexity of diagnosing urothelial carcinoma within the calyceal diverticula, emphasizing the need for a high index of suspicion. The study contributes to understanding the limitations of imaging modalities, especially in cases involving calcification or stone evaluation. The coexistence of urothelial carcinoma and calyceal diverticula is rare but crucial for accurate diagnosis and treatment. Documenting cases like these is vital for recognizing urothelial carcinoma mimics and ensuring appropriate patient management. The study underscores the significance of distinguishing features of calyceal diverticula and advocates for comprehensive imaging approaches in renal cystic lesions.
Zusammenfassung
Geschlechtsunterschiede in der Medizin spielen mittlerweile eine nicht mehr wegzudenkende Rolle, sowohl in Diagnostik als auch Therapie. Risikofaktoren und Mortalität variieren je nach Geschlecht, Krankheiten äußern sich unterschiedlich. In der Diagnostik müssen je nach Geschlecht unterschiedliche Aspekte in Betracht gezogen werden. Bei Blasenkarzinomen zum Beispiel kommt es bei Frauen häufig zu Verzögerungen bei der Diagnose, weil Hämaturie oft benignen Erkrankungen wie Harnwegsinfekten zugeschrieben wird. Bei Therapieentscheidungen sollte das Geschlecht ebenso eine Rolle spielen. Um ein Beispiel zu nennen, haben Immuncheckpoint-Inhibitoren bei Nierenzellkarzinomen bei Männern ein besseres Ansprechen als bei Frauen. Auch die Outcomes nach onkologischer Therapie bei urologischen Tumoren variieren nach Geschlecht.
Purpose: Although bladder cancer occurs three to 4 times more frequently in men than in women, the relative number of deaths compared to incidence is higher in women, suggesting that women have a worse prognosis than men. Emerging evidence indicates that the activity of the sex steroid hormone pathway may play a role in bladder cancer development, with demonstrations that both androgens and estrogens have biological effects on bladder cancer in vitro and in vivo . This study investigates the influence of sex and menopausal status on recurrence and cancer-specific death (CSD) in bladder cancer patients undergoing radical cystectomy (RC).Materials and Methods: This retrospective analysis included 3,913 patients from the Korean Bladder Cancer Study Group Database who underwent RC between 2010 and 2019. Patients were categorized based on gender and menopausal status (≤50 years: premenopausal; >50 years: postmenopausal). Pathological factors, neoadjuvant chemotherapy, recurrence, and CSD rates were analyzed using chi-square and Fisher exact tests.Results: Among the 3,913 patients, 400 (10.2%) were female. Premenopausal females exhibited significantly lower recurrence rates (28.6%) compared to postmenopausal females (45.7%). CSD rates were similarly reduced in premenopausal females (12.0% vs. 22.2% in postmenopausal females). No significant sex differences in recurrence or CSD were observed among premenopausal patients. Pathological T stage, nodal status, and lymphovascular invasion were significantly associated with recurrence in males, while nodal status alone was significant in females. Neoadjuvant chemotherapy was significantly more frequently administered to male patients under the age of 50, while no difference was observed in the administration of neoadjuvant chemotherapy among female patients based on menopausal status.Conclusion: Hormonal changes associated with menopause significantly influence bladder cancer outcomes in women. Premenopausal hormonal environments seem protective, underscoring the need for further research into hormone-driven mechanisms in bladder cancer.
Midstream urine (MSU) samples are commonly collected at the time of patient evaluation despite known high rates of contamination.
The primary objective of this study was to evaluate the rate of mixed flora results in urine specimens obtained by MSU compared to straight catheterization urine (SCU).
This was a quality improvement project evaluating urine culture results of women who provided either an MSU or SCU sample for analysis. Adult women seen within urogynecology clinics at a tertiary care center between April and August 2023 who had urine cultures performed for any indication were included. Mixed flora was defined as the presence of ≥ 2 non-uropathogens or 1 uropathogen in low quantity (at least 10 times fewer) compared to the concentration of nonsignificant organisms.
Three hundred forty women provided a urine specimen during the study period. SCU collection was performed for 171 (50.3%) women while 169 (49.7%) provided an MSU sample. Overall, 18.8% of urine cultures were reported as mixed flora (33.1% in MSU and 4.7% in SCU, p < 0.001). Mixed flora was more common with MSU specimens (87.5%, p < 0.001) and associated with a higher BMI compared to positive or negative cultures (mixed flora 29.8 kg/m2 ± 16.3, positive or negative cultures 27.8 kg/m2 ± 7.0, p = 0.04). MSU samples had increased odds of urine contamination compared to SCU collection (7.40 aOR, 95% CI 3.01–18.24).
The prevalence of mixed flora was reduced significantly when SCU samples were obtained. Clinicians should consider performing SCU collection when a urine specimen is required for patient evaluation.
Bladder cancer (BC) is the tenth most incident malignancy globally, with substantial morbidity and mortality. Although fourfold more likely to present in males, females have worse oncologic outcomes even when controlling for other known predictors of adverse outcomes such as smoking and delay to treatment. African-American race is also an independent risk factor for advanced disease when diagnosed, as is lower socioeconomic status. Many modifiable risk factors have been associated with BC risk, with tobacco smoking being the leading risk factor and accounting for an estimated 50% of BC cases. Occupational exposures account for 5–10% of BC cases, due to chemicals such as aromatic amines and polycyclic aromatic hydrocarbons. Environmental exposures such as arsenic-containing drinking water, Agent Orange (AO), and residential exposure to hydrocarbons from oil refineries may also increase risk of BC incidence and mortality. Mediterranean diets and fish consumption are among potential protective dietary factors. Genetics also plays a role, with germline mutations in mismatch repair genes and a range of single-nucleotide polymorphisms identified as risk factors (see Chap. 2). In this chapter, we outline the main demographic trends of BC and identify emerging risk factors for incidence, morbidity, and mortality.
Background
Plasma membrane tension-related genes (MTRGs) are known to play a crucial role in tumor progression by influencing cell migration and adhesion. However, their specific mechanisms in bladder cancer (BLCA) remain unclear.
Methods
Transcriptomic, clinical and mutation data from BLCA patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clusters associated with MTRGs were identified by consensus unsupervised cluster analysis. The genes of different clusters were analyzed by GO and KEGG gene enrichment analysis. Differentially expressed genes (DEGs) were screened from different clusters. Consensus cluster analysis of prognostic DEGs was performed to identify gene subtypes. Patients were then randomly divided into training and validation groups, and MTRG scores were constructed by logistic minimum absolute contraction and selection operator (LASSO) and Cox regression analysis. We assessed changes in clinical outcomes and immune-related factors between different patient groups. The single-cell RNA sequencing (scRNA-seq) dataset for BLCA was collected and analyzed from the Tumor Immune Single-cell Hub (TISCH) database. Biological functions were investigated using a series of experiments including quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), wound healing, transwell, etc .
Results
Our MTRG score is based on eight genes (HTRA1, GOLT1A, DCBLD2, UGT1A1, FOSL1, DSC2, IGFBP3 and TAC3). Higher scores were characterized by lower cancer stem cell (CSC) indices, as well as higher tumor microenvironment (TME) stromal and immune scores, suggesting that high scores were associated with poorer prognosis. In addition, some drugs such as cisplatin, paclitaxel, doxorubicin, and docetaxel exhibited lower IC50 values in the high MTRG score group. Functional experiments have demonstrated that downregulation of DCBLD2 affects tumor cell migration, but not proliferation.
Conclusions
Our study sheds light on the prognostic significance of MTRGs within the TME and their correlation with immune infiltration patterns, ultimately impacting patient survival in BLCA. Notably, our findings highlight DCBLD2 as a promising candidate for targeted therapeutic interventions in the clinical management of BLCA.
Bladder cancer (BC) is the most common urinary tract malignancy. Identifying biomarkers that predict prognosis and immune function in patients with BC can enhance our understanding of its pathogenesis and provide valuable guidance for diagnosis and treatment. Our findings indicate that increased ITGB1 expression is associated with higher clinical grade and stage, establishing ITGB1 as an independent prognostic risk factor for BC. Enrichment analysis revealed that the function of ITGB1 in BC was linked to the extracellular matrix. The experimental results showed that ITGB1 knockdown in the BC cell lines 5637 and RT112 reduced their proliferation, migration, and invasion. Furthermore, ITGB1 suppression promotes apoptosis in BC cells by inhibiting the PI3K‐AKT pathway. A prognostic risk model incorporating CES1, NTNG1, SETBP1, and AIFM3 was developed based on ITGB1, this model can accurately predict patient prognosis based on immunological status. In conclusion, this study shows that knockdown of ITGB1 can restrain the migratory and invasive capabilities of BC cells and accelerate apoptosis, and this role might be associated with PI3K‐AKT, highlighting its potential as a diagnostic marker and therapeutic target for BC.
Background
Due to the clinical characteristic of frequent recurrence in urothelial bladder cancer (UBC), patients face significant health impacts and economic burdens. Therefore, understanding the molecular mechanisms involved in UBC recurrence is crucial for reducing its recurrence rate. The aim of our study is to help urologists and clinical researchers gain a deeper understanding of the changes in the tumor microenvironment (TME) during UBC recurrence.
Methods
We collected 10 samples from primary and recurrent non-muscle-invasive bladder cancer (NMIBC) and performed single-cell RNA sequencing. By distinguishing and annotating cell subpopulations, we identified tissue preferences of some novel cell subgroups. Next, pseudotime trajectory analysis, cell-cell communication analysis, and function enrichment analysis were applied to evaluate the dynamic changes in the TME and biological functions. Finally, we validated the distribution of some of these cell subgroups using multiplex immunofluorescence experiments.
Results
We identified a tumor-associated fibroblast (CAF) subtype with high COL18A1 expression that is highly expressed in recurrent NMIBC, suggesting that the stromal component of the tumor may play a crucial role in the recurrence process. Additionally, pseudotime trajectory analysis revealed a macrophage subtype with high IL-6 expression at the terminal stage of macrophage differentiation, exhibiting significant immunosuppressive features. This indicated the presence of immune exhaustion during NMIBC recurrence. Lastly, we found an upregulation of estrogen in recurrent urothelial cancer cells, which may partially explain the gender disparity observed in UBC.
Conclusion
This study identified several cell subpopulations influencing NMIBC recurrence, which were heavily infiltrated in the TME of recurrent NMIBC. Additionally, the enrichment of estrogen in urothelial cancer cells from various sources suggested a role of sex hormones in NMIBC recurrence.
The redox status is intricately linked to the development and progression of cancer, a process that can be modulated by long non-coding RNAs (lncRNAs). Previous studies have demonstrated that redox regulation can be considered a potential therapeutic approach for cancer. However, the redox-related lncRNA predictive signature specific to bladder cancer (BCa) has yet to be fully elucidated. The purpose of our study is to establish a redox-related lncRNA signature to improve the prognostic prediction for BCa patients. To achieve this, we downloaded transcriptome and clinical data from the Cancer Genome Atlas (TCGA) database. Prognostic redox-related lncRNAs were identified through univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analysis, resulting in the establishment of two risk groups. A comprehensive analysis corresponding to clinical features between high-risk and low-risk groups was conducted. Eight redox-related lncRNAs (AC018653.3, AC090229.1, AL357033.4, AL662844.4, AP003352.1, LINC00649, LINC01138, and MAFG-DT) were selected to construct the risk model. The overall survival (OS) in the high-risk group was worse than that in the low-risk group (p < 0.001). The redox-related lncRNA signature exhibits superior predictive accuracy compared to traditional clinicopathological characteristics. Gene Set Enrichment Analysis (GSEA) showed that the MAPK signaling pathway and Wnt signaling pathway were enriched in the high-risk group. Compared with the low-risk group, patients in the high-risk group demonstrated increased sensitivity to cisplatin, docetaxel, and paclitaxel. Furthermore, IGF2BP2, a potential target gene of MAFG-DT, was found to be overexpressed in tumor tissues and correlated with overall survival (OS). Our study demonstrated that the predictive signature based on eight redox-related lncRNAs can independently and accurately predict the prognosis of BCa patients.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-80026-9.
Objective The purpose of this study was to investigate the effect of Ebselen on the proliferation and migration of bladder cancer cells and to attempt to find the regulatory mechanism to provide a new theoretical basis for the treatment of bladder cancer. Materials and Methods The effects of different concentrations (40 µM, 50 µM and 60 ΜM) of Ebs on the activity, cell cycle, proliferation and migration as well as the evolution of the expression of apoptosis and autophagy-related proteins in T24 and UMUC-3 cell lines were studied. The inhibitory effect of Ebselen on the proliferation and migration of bladder cancer cells was also verified at the animal level. Results The results showed that T24 and UMUC-3 cells significantly reduced cell activity, proliferation ability and migration ability, and the proportion of the G2/M stage was increased considerably. The expression of pro-apoptosis-related protein BAX, cleaved-caspase-3/caspase-3 and autophagy-related proteins Beclin-1 and LC3II/Ⅰ were significantly increased. The expression levels of the proteins BCL-XL, P62, P-PI3K, P-AKT, P-mTOR and STAT3 were significantly decreased. In addition, the tumour volume of mice in the Ebs group was reduced considerably, and the results of H&E staining and immunohistochemical staining also indicated that inflammatory infiltrating cells were significantly reduced in the Ebs group. Meanwhile, the number of cells positive for Ki-67, P63 and STAT3 proteins was significantly decreased. Conclusion We have concluded that Ebs has a significant anti-tumour effect in inducing apoptosis, and autophagy and inhibiting proliferation and migration of BCC cells, which may be achieved by inhibiting proliferation and migration of bladder cancer cells through inhibiting PI3K/AKT/mTOR pathway, activating cellular autophagy, blocking tumour cell cycle as well as inducing apoptosis and down-regulating the expression of STAT3 protein.
The glutathione S-transferase P1 genotype (GSTP1) is involved in the inactivation of cigarette smoke carcinogens, and sequence variation in the gene may alter bladder cancer susceptibility. To examine the association between GSTP1Ile 105Val and bladder cancer, the authors undertook a meta- and pooled analysis. Summary crude and adjusted odds ratios and corresponding 95% confidence intervals were pooled by using a random-effects model. In the meta-analysis (16 studies, 4,273 cases and 5,081 controls), the unadjusted summary odds ratios for GSTP1 Ile/Val and Val/Val compared with GSTP1 Ile/Ile were 1.54 (95% confidence interval: 1.21, 1.99; p < 0.001) and 2.17 (95% confidence interval: 1.27, 3.71; p = 0.005). The association appeared to be the strongest in Asian countries. When the analysis was limited to European descendents (nine studies), the summary odds ratio decreased (odds ratio = 1.24, 95% confidence interval: 1.00, 1.52) (Q = 17.50; p = 0.02). All relevant data previously contributed to the International Study on Genetic Susceptibility to Environmental Carcinogens were pooled (eight studies, 1,305 cases and 1,558 controls). The summary odds ratios were similar to the ones from the meta-analysis. Case-only analyses did not detect an interaction between the GSTP1 genotype and smoking status (never/ever). GSTP1 Ile 105Val appears to be associated with a modest increase in the risk of bladder cancer.
High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer, with highly variable prognosis, poorly understood risk factors, and considerable debate about the role of early cystectomy. We aimed to address these questions through a meta-analysis of outcomes and prognostic factors.
PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology abstracts were searched for cohort studies in HGT1. We pooled data on recurrence, progression, and cancer-specific survival from 73 studies.
Five-year rates of recurrence, progression, and cancer-specific survival were 42% (95% CI, 39% to 45%), 21% (95% CI, 18% to 23%), and 87% (95% CI, 85% to 89%), respectively (56 studies, n = 15,215). In the prognostic factor meta-analysis (33 studies, n = 8,880), the highest impact risk factor was depth of invasion (T1b/c) into lamina propria (progression: hazard ratio [HR], 3.34; P < .001; cancer-specific survival: HR, 2.02; P = .001). Several other previously proposed factors also predicted progression and cancer-specific survival (lymphovascular invasion, associated carcinoma in situ, nonuse of bacillus Calmette-Guérin, tumor size > 3 cm, and older age; HRs for progression between 1.32 and 2.88, P ≤ .002; HRs for cancer-specific survival between 1.28 and 2.08, P ≤ .02).
In this large analysis of outcomes and prognostic factors in HGT1 bladder cancer, deep lamina propria invasion had the largest negative impact, and other previously proposed prognostic factors were also confirmed. These factors should be used for prognostication and patient stratification in future clinical trials, and depth of invasion should be considered for inclusion in TNM staging criteria. This meta-analysis can also help define selection criteria for early cystectomy in HGT1 bladder cancer, particularly for patients with deep lamina propria invasion combined with other risk factors.
© 2015 by American Society of Clinical Oncology.
Objectives
To explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities.
Design
Prospective national audit survey of cancer diagnosis.
Setting
English primary care (2009–2010).
Participants
920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women).
Primary and secondary outcome measures
Proportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care.
Results
Women required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria.
Conclusions
There are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria.
Aims:
Pathological separation of poorly differentiated urothelial and prostate carcinoma is difficult, but imperative because of the impact on patient management. Tumour morphology, in conjunction with a panel of immunohistochemistry (IHC), such as prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), CK7, CK20, p63 and high molecular weight keratins (HMWKs) are usually employed to resolve this issue. Androgen receptor (AR) expression is maintained in high-grade, undifferentiated prostate carcinoma, and thus, could be considered as a potentially useful adjunct to the conventional panel of markers.
Methods:
We performed an institutional review of all cases from 2006 to 2012 in which AR IHC had been performed to determine its diagnostic utility in discriminating between poorly differentiated urothelial and prostate carcinoma. Of the eligible cases (n=40), there were 9 high-grade urothelial carcinomas, 27 prostate carcinomas and 4 with both prostate and bladder tumours. All diagnoses were made by integrating the clinical, radiological, morphological and IHC results.
Results:
In all the prostate carcinomas, there was diffuse, intense nuclear staining for AR. The urothelial tumours were either negative, had cytoplasmic staining or showed occasionally weak nuclear staining. The difference was highly significant with p<0.0001 (Mann-Whitney U test).
Conclusions:
We conclude that AR is an important marker as it is best able to distinguish between poorly differentiated urothelial and prostate carcinoma. AR appears superior to PSA and PSAP, which are not consistently expressed in high-grade prostate carcinoma. Also, high-grade urothelial carcinoma may be negative for CK20, p63/HMWK and occasionally CK7. We advocate the inclusion of AR in the panel of markers to differentiate these tumours.
Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8–20 weeks) or concurrent and subsequent (8–32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non–muscle-invasive disease was present in animals treated with tamoxifen before (5–8 weeks) or after (20–32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
Background:
Bladder cancer (BC) predominantly affects the elderly and is often the cause of death among patients with muscle-invasive disease. Clinicians lack quantitative estimates of competing mortality risks when considering treatments for BC. Our aim was to determine the bladder cancer-specific mortality (CSM) rate and other-cause mortality (OCM) rate for patients with newly diagnosed BC.
Methods:
Patients (n=3281) identified from a population-based cancer registry diagnosed between 1994 and 2009. Median follow-up was 48.15 months (IQ range 18.1–98.7). Competing risk analysis was performed within patient groups and outcomes compared using Gray's test.
Results:
At 5 years after diagnosis, 1246 (40%) patients were dead: 617 (19%) from BC and 629 (19%) from other causes. The 5-year BC mortality rate varied between 1 and 59%, and OCM rate between 6 and 90%, depending primarily on the tumour type and patient age. Cancer-specific mortality was highest in the oldest patient groups. Few elderly patients received radical treatment for invasive cancer (52% vs 12% for patients <60 vs >80 years, respectively). Female patients with high-risk non-muscle-invasive BC had worse CSM than equivalent males (Gray's P<0.01).
Conclusion:
Bladder CSM is highest among the elderly. Female patients with high-risk tumours are more likely to die of their disease compared with male patients. Clinicians should consider offering more aggressive treatment interventions among older patients.
The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
Several studies have suggested an increased risk of bladder cancer among hairdressers, who are occupationally exposed to hair dyes. There has also been concern about a possible increased risk of bladder cancer among users of hair dyes. However, the association between personal hair dye use and bladder cancer risk remains inconclusive.
In this study, we examined associations between personal use of permanent and temporary hair dyes and bladder cancer risk in a population-based case-control study involving 1,385 cases (n = 246 women) and 4,754 controls (n = 2,587 women).
Participants filled out a questionnaire with regard to history of personal hair dye use and risk factors for bladder cancer. Unconditional logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CI), adjusted for age, smoking status, duration of smoking and intensity of smoking.
Analyses were restricted to women as less than 5 % of all men in the study ever used hair dyes. About 50 % of the women ever used hair dyes. Use of temporary hair dyes (OR, 0.77; 95 % CI, 0.58-1.02) or use of permanent hair dyes (OR, 0.87; 95 % CI, 0.65-1.18) was not associated with bladder cancer risk. No clear association between hair dyes and bladder cancer risk was found when dye use was defined by type, duration or frequency of use, dye color, or extent of use. Also, results were similar for aggressive- and non-aggressive bladder cancer. Age, educational level, and smoking status did not modify the association between hair dye use and bladder cancer risk.
The present study does not support an association between personal hair dye use and bladder cancer risk. Also, various types of hair dye, intensity of exposure to hair dyes or dye color do not appear to be important factors for bladder cancer development.
Background: Bladder cancer (BC) predominantly affects the elderly and is often the cause of death among patients with muscleinvasive disease. Clinicians lack quantitative estimates of competing mortality risks when considering treatments for BC. Our aim was to determine the bladder cancer-specific mortality (CSM) rate and other-cause mortality (OCM) rate for patients with newly diagnosed BC. Methods: Patients (n ¼ 3281) identified from a population-based cancer registry diagnosed between 1994 and 2009. Median follow-up was 48.15 months (IQ range 18.1–98.7). Competing risk analysis was performed within patient groups and outcomes compared using Gray’s test. Results: At 5 years after diagnosis, 1246 (40%) patients were dead: 617 (19%) from BC and 629 (19%) from other causes. The 5-year BC mortality rate varied between 1 and 59%, and OCM rate between 6 and 90%, depending primarily on the tumour type and patient age. Cancer-specific mortality was highest in the oldest patient groups. Few elderly patients received radical treatment for invasive cancer (52% vs 12% for patients o60 vs 480 years, respectively). Female patients with high-risk non-muscle-invasive BC had worse CSM than equivalent males (Gray’s Po0.01). Conclusion: Bladder CSM is highest among the elderly. Female patients with high-risk tumours are more likely to die of their disease compared with male patients. Clinicians should consider offering more aggressive treatment interventions among older patients.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population. CA Cancer J Clin 2016. © 2016 American Cancer Society.
Each year the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. A total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the United States in 2015. During the most recent 5 years for which there are data (2007-2011), delay-adjusted cancer incidence rates (13 oldest SEER registries) declined by 1.8% per year in men and were stable in women, while cancer death rates nationwide decreased by 1.8% per year in men and by 1.4% per year in women. The overall cancer death rate decreased from 215.1 (per 100,000 population) in 1991 to 168.7 in 2011, a total relative decline of 22%. However, the magnitude of the decline varied by state, and was generally lowest in the South (15%) and highest in the Northeast (20%). For example, there were declines of 25% to 30% in Maryland, New Jersey, Massachusetts, New York, and Delaware, which collectively averted 29,000 cancer deaths in 2011 as a result of this progress. Further gains can be accelerated by applying existing cancer control knowledge across all segments of the population. CA Cancer J Clin 2015;000:000000. V C 2015 American Cancer Society.
The impact of sex on the prognosis of patients with muscle-invasive bladder cancer (MIBC) is discussed controversially. Reasons for the presumably worse prognosis in female patients may be anatomical differences, different time delays from first symptoms to diagnosis and variations in hormone receptors and tumour biology. This review summarizes literature on this topic published during the period 2012-2015.
Methodological quality of most available studies analysing the impact of sex on prognosis of MIBC is limited by their retrospective design or lacking standardization of study parameters. Time delay from first symptoms to diagnosis in women with bladder cancer seems possible, although a prognostic impact of this delay has not been proven yet. Recent cystectomy-series predominantly show comparable tumour stages, although strongest deterioration of prognosis in female patients is described in younger patients and in cases with lymphovascular invasion. No survival difference between sexes was found in studies with rigorous statistics using propensity score matching. Interpretation of studies analysing the prognostic impact of hormone receptors is limited by methodological shortcomings and missing definitions of subsequent signal pathways.
Analyses of population-based cancer-registries demonstrate a comparatively higher cancer-specific mortality for female patients, but the reason for this difference remains unclear. Interaction between sex and oncologic outcome of patients with MIBC seems to be multifactorial, while to date, an independent prognostic impact of sex cannot be proven validly. Research activities in the future should include parameters mentioned above.
Objectives
Prioritising control of occupationally-related cancers should be evidence based. We have estimated the current burden of cancer in Great Britain attributable to occupation for IARC group 1 and 2A carcinogens.
Methods
We calculated attributable fractions and numbers for mortality/incidence using risk estimates from published literature and national data sources to estimate proportions exposed.
Results
Cancer deaths attributable to occupation in 2005 are 5.3% (8023) (men: 8.2% (6366); women 2.3% (1657)). Attributable incidence estimates are 13694 (4.0%) cancer registrations (men: 10074 (5.7%); women 3620 (2.1%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin, bladder, oesophagus, soft tissue sarcoma and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100+ registrations. Industries/occupations with over 200 cancer registrations include construction, women's shift work, metal working, personal/household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors.
Conclusions
This study is the first detailed cancer burden study using all IARC 1 and 2A carcinogens and quantifying the contribution of individual industry sectors. Our methodology provides a basis for adaptation for use in other countries and global occupational burden estimation and for extension to include social and economic impact evaluation.. The results highlight specific carcinogenic agents and the occupational circumstances and industrial areas where exposures to these agents occurs, facilitating prioritisation of risk reduction strategies.
Female gender and black race are associated with delayed diagnosis and inferior survival in patients with bladder cancer.
We aimed to determine the association between gender, race, and evaluation of microscopic hematuria (an early sign of bladder cancer).
This was a cohort study using a 5 % random sample of fee-for-service Medicare beneficiaries diagnosed with incident hematuria (International Classification of Diseases, Ninth Revision [ICD-9] code 599.7x) between January 2009 and June 2010 in a primary care setting. Beneficiaries with pre-existing explanatory diagnoses or genitourinary procedures were excluded.
The main endpoint was completeness of the hematuria evaluation in the 180 days after diagnosis. Evaluations were categorized as complete, incomplete, or absent based on receipt of relevant diagnostic procedures and imaging studies.
In all, 9,211 beneficiaries met the study criteria. Hematuria evaluations were complete in 14 %, incomplete in 21 %, and absent in 65 % of subjects. Compared to males, females were less likely to have a procedure (26 vs. 12 %), imaging (41 vs. 30 %), and a complete evaluation (22 vs. 10 %) (p < 0.001 for each comparison). Receipt of a complete evaluation did not differ by race. Controlling for baseline characteristics, a complete evaluation was less likely in white women (OR, 0.40 [95 % CI, 0.35-0.46]) and black women (OR, 0.46 [95 % CI, 0.29-0.70]) compared to white men; no difference was found between black and white men.
Women are less likely than men to undergo a complete and timely hematuria evaluation, a finding likely relevant to women's more advanced stage at bladder cancer diagnosis. System-level process improvement between providers of urologic and primary care in the evaluation of hematuria may benefit women harboring malignancy.
The microbiome is a new center of attention for studies on the pathogenesis of human disease by focusing on the alterations of all microorganisms living in a particular site or system of human body, referred as microbiota. Evidence suggests that microbiota could contribute to the pathogenesis of a number of chronic diseases, including cancers, both locally and remotely. Multiple mechanisms have been proposed and/or proven for the microbiota's role in tumorigenesis, such as via induction of chronic inflammation, genotoxicity, bacterium-mediated cell proliferation, and activation of procarcinogens. Emerging data suggest that indigenous microbiota in the urinary tract may play an important role in the tumorigenesis of urothelial carcinoma, similar to other tumors. Future studies are needed to adequately define the microbiota composition and correlate its change with urothelial carcinoma.
Our goal was to investigate the effect of patient and disease characteristics on the probability of cancer-specific death (CSD) in cases of isolated urothelial carcinoma in situ (CIS). We performed a retrospective analysis of patients diagnosed with isolated CIS between 1990 and 2010 identified from the Surveillance, Epidemiology, and End Results (SEER) database. Competing risk analysis using Cox proportional hazard model was used to examine the probability of CSD controlling for possible covariates. Overall (n = 1432), patients were mainly male (75%), mean age at diagnosis was 71 years, median survival 47 months, and 65% of the patients had CIS in their upper urinary tract. Caucasians were the predominant race (90%). CIS was the cause of death in 87/1432(6%) of the total cohort; 69/1239 (6%) of patients who underwent surgery, and 18/193 (9%) of the patients who were managed conservatively (CM). On multivariate analysis, CM [hazard ration (HR) = 2.019, CI: 1.189–3.429, P = 0.009] and female gender (HR = 1.690, CI: 1.041–2.741, P = 0.033) were associated with CSD, while age, site, race and year of diagnosis were non-significant predictors. Female gender and conservative management were positively associated with CSD. Multi-institutional collaboration is needed to validate markers for poor prognosis in cases of isolated CIS.
Purpose:
Bladder cancer (BC) screening is not accepted in part owing to low overall incidence. We used the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Cancer Screening Trial (NLST) to identify optimal high-risk populations most likely to benefit from screening.
Materials and methods:
Data were extracted from PLCO and NLST to stratify risk of BC by overall population, sex, race, age at inclusion, and smoking status. Incidence rates between groups were compared using chi-square test.
Results:
BC was identified in 1,430/154,898 patients in PLCO and 439/53,173 patients in NLST. BCs were grade III/IV in 36.8% and 41.3%. Incidence rates were significantly higher in men than in women (PLCO: 1.4 vs. 0.31/1,000 person-years and NLST: 1.84 vs. 0.6/1,000 person-years, both P<0.0001). In proportional hazards models, male sex, higher age, and duration and intensity of smoking were associated with higher risk of BC (all P<0.0001). In men older than 70 years with smoking exposure of 30 pack-years (PY) and more, incidence rates were as high as 11.92 (PLCO) and 5.23 (NLST) (per 1,000 person-years). In current high-intensity smokers (≥50 PY), the sex disparity in incidence persists in both trials (0.78 vs. 2.99 per 1,000 person-years in PLCO and 1.12 vs. 2.65 per 1,000 person-years in NLST).
Conclusions:
Men older than 60 years with a smoking history of>30 PY had incidence rates of more than 2/1,000 person-years, which could serve as an excellent population for screening trials. Sex differences in the incidence of BC cannot be readily explained by the differences in exposure to tobacco, as sex disparity persisted regardless of smoking intensity.
Purpose:
Men are diagnosed with bladder cancer at 3 times the rate of women. However, women present with advanced disease and have poorer survival, suggesting delays in bladder cancer diagnosis. Hematuria is the presenting symptom in most cases. We assessed gender differences in hematuria evaluation in older adults with bladder cancer.
Materials and methods:
Using the SEER (Surveillance, Epidemiology and End Results) cancer registry linked with Medicare claims we identified Medicare beneficiaries 66 years old or older diagnosed with bladder cancer between 2000 and 2007 with a claim for hematuria in the year before diagnosis. We examined the impact of gender, and demographic and clinical factors on time from initial hematuria claim to urology visit and on time from initial hematuria claim to hematuria evaluation, including cystoscopy, upper urinary tract imaging and urine cytology.
Results:
Of 35,646 patients with a hematuria claim in the year preceding bladder cancer diagnosis 97% had a urology visit claim. Mean time to urology visit was 27 days (range 0 to 377). Time to urology visit was longer for women than for men (adjusted HR 0.9, 95% CI 0.87-0.92). Women were more likely to undergo delayed (after greater than 30 days) hematuria evaluation (adjusted OR 1.13, 95% CI 1.07-1.21).
Conclusions:
We observed longer time to a urology visit for women than for men presenting with hematuria. These findings may explain stage differences in bladder cancer diagnosis and inform efforts to decrease gender disparities in bladder cancer stage and outcomes.
In 2008, urothelial carcinoma of the bladder (UCB) was the 8th most common cause of death in Germany. An increasing body of evidence suggests differences in the presentation and prognosis of UCB between genders. Large population-based and multi-institutional studies have found a higher incidence of UCB in men, while women treated with radical cystectomy (RC) have shown unfavorable outcomes compared to their male counterparts. Indeed, it is important to note that UCB incidence and outcomes have regional and country-specific variability. These distinct country and gender-specific differences must be considered in patient counseling, treatment decisions, and UCB management. This review summarizes the contemporary literature regarding the impact of gender on UCB outcomes, focusing on patients treated with RC in Germany. We evaluated the most current literature regarding gender-specific differences in UCB incidence, treatment patterns, and oncological outcomes, including pathological stage distribution and survival.
Objectives
To characterize and measure different components of preoperative delays experienced by bladder cancer patients before radical cystectomy in the province of Quebec, Canada and to identify predictors of long wait times.Methods
We conducted a retrospective cohort study using data of patients who underwent radical cystectomy for bladder cancer from 2000 to 2009 in Quebec. The cohort was obtained with the linkage of two health provincial databases: the RAMQ database (data on medical services dispensed to Quebec residents), and the ISQ database (demographic data on births and deaths). For the entire cohort, we determined several components of delay from first medical visit related to bladder cancer symptoms until radical cystectomy. Predictors of long delays were analysed using logistic regression.ResultsWe analyzed a total of 2778 patients who met inclusion criteria. Median urologist referral delay was 32 days. Median delays between first urologist visit and radical cystectomy and from TURBT to surgery were 90 days and 46 days, respectively. Median overall delay was 116 days. All components of delay progressively increased from the decade of 1990 to the 2000's. Male sex was a protective factor for several components of delay, which suggests that gender-related variations may exist in the continuum of care for bladder cancer (OR= 0.67, 95%CI: 0.50-0.89 for overall delay). Patient's age and gender were associated with delayed urologist referral, delayed time to TURBT, and long overall wait time. Factors related to the health system were associated with long cystoscopy delays.Conclusion
Median preoperative delays among patients with bladder cancer have been increasing and remain unacceptably long. Patient's age, gender, and type of hospital facility were associated with long wait times.
Introduction
Controversial findings regarding gender-specific oncological outcomes of urothelial carcinoma of the bladder (UCB) have recently been reported. The aim of this study was to analyze gender-specific outcomes using a stage-adjusted approach in a homogenous, contemporary radical cystectomy (RC) cohort.
Material and methods
We prospectively collected data of 517 UCB patients treated with RC and pelvic lymphadenectomy without neoadjuvant chemotherapy at our institution between 1996 and 2010. Stage-adjusted uni- and multivariable Cox regression models analyzed the association of gender with disease recurrence, cancer-specific mortality and overall survival.
Results
In total, 398 (77%) patients were male and 119 (23%) were female. Compared to men, women were more likely to have advanced tumor stages (p = 0.017), nodal metastasis (p = 0.047) and received more frequently adjuvant chemotherapy (p = 0.009). At a median follow-up of 44 months, there was no statistical difference in disease recurrence, cancer-specific mortality and overall survival between both genders when analyzed as a group. In stage-adjusted analyses, only women with non-invasive UCB were more likely to die of UCB compared to the male counterparts (p = 0.013). In gender-specific multivariable analyses that adjusted for standard clinico-pathologic features, pathologic tumor stage was an independent predictor for disease recurrence (p-values ≤0.047) and cancer-specific mortality (p-values ≤0.049), respectively.
Conclusion
Women present with more aggressive tumor biologic features at RC, however this did not translate into inferior outcomes compared to men in stage-specific analyses in our cohort. Tumor stage is the most important factor influencing the course of disease in both genders. Validation of our findings is warranted in a larger cohort.
Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.
Women have disproportionately higher mortality rates relative to incidence for bladder cancer. Multiple etiologies have been proposed, including delayed diagnosis and treatment. Guidelines recommend ruling out malignancy in men and women presenting with hematuria. This study sought to determine the difference in timing from presentation with hematuria to diagnosis of bladder cancer in women versus men.
This is a retrospective population-based study examining the timing from presentation with hematuria to diagnosis of bladder cancer, based on data from the MarketScan databases, which include enrollees of more than 100 health insurance plans of approximately 40 large US employers from 2004 through 2010. All study patients presented with hematuria and were subsequently diagnosed with bladder cancer. The primary outcome measure was number of days between initial presentation with hematuria and diagnosis of bladder cancer by sex.
A total of 5416 men and 2233 women met inclusion criteria. Mean days from initial hematuria claim to bladder cancer claim was significantly longer in women (85.4 versus 73.6 days, P < .001), and the proportion of women with >6 month delay in bladder cancer diagnosis was significantly higher (17.3% versus 14.1%, P < .001). Women were more likely to be diagnosed with urinary tract infection (odds ratio = 2.32, 95% confidence interval = 2.07-2.59) and less likely to undergo abdominal or pelvic imaging (odds ratio = 0.80, 95% confidence interval = 0.71-0.89).
Both men and women experience significant delays between presentation with hematuria and diagnosis of bladder cancer, with longer delays for women. This may be partly responsible for the sex-based discrepancy in outcomes associated with bladder cancer. Cancer 2014;120:555-661. © 2013 American Cancer Society.
To determine the association of gender with outcome after radical cystectomy for patients with bladder cancer.
An observational cohort study was conducted using retrospectively collected data from 11 centers on patients with advanced bladder cancer treated with radical cystectomy. The association of gender with disease recurrence and cancer-specific mortality was examined using a competing risk analysis.
The study comprised 4296 patients, including 890 women (21%). The median follow-up duration was 31.5 months for all patients. Disease recurred in 1430 patients (33.9%) (36.8% of women and 33.1% of men) at a median of 11 months after surgery. Death from any cause was observed in 46.0% of men and 50.1% of women. Cancer-specific death was observed in 33.0% of women and 27.2% of men. Multivariable regression with competing risk found that female gender was associated with an increased risk for disease recurrence and cancer-specific mortality (hazard ratio, 1.27; 95% confidence interval, 1.108-1.465; P = .007) compared with male gender. Important limitations include the inability to account for additional potential confounders, such as differences in environmental exposures, treatment selection, and histologic subtypes between men and women.
Our analysis identified female gender as a poor-risk feature for patients undergoing radical cystectomy. This adverse prognostic factor was independent of standard clinical and pathologic features and competing risk from non-cancer-related death.
Previous studies have reported substantial worldwide regional variations in bladder cancer (BCa) incidence and mortality.
To describe contemporary international variations in BCa incidence and mortality rates and trends using the most recent data from the International Agency for Research on Cancer (IARC).
Estimated 2008 BCa incidence and mortality rates for each country by sex were obtained from GLOBOCAN. Recent trends in incidence for 43 countries and in mortality for 64 countries were assessed by join-point model using data from the IARC's Cancer Incidence in Five Continents and from the World Health Organisation's mortality database, respectively.
The highest incidence rates for both men and women are found in Europe, the United States, and Egypt, and the lowest rates are found in sub-Saharan Africa, Asia, and South America. Mortality rates are highest in parts of Europe and northern Africa and lowest in Asia, Central America, and middle Africa. Incidence rates among men decreased in 11 of 43 countries (46 registries) (North America, western and northern Europe), remained stable in 20, and increased in 12 countries (southern, central, and eastern Europe). Among women, incidence rates decreased in 10 countries, stabilised in 22 countries, and increased in 12 countries. Mortality rates among men decreased in 32 of 65 countries (throughout all world regions except Central and South America), stabilised in 30 countries, and increased in 3 (Romania, Slovenia, and Cuba). Among women, mortality rates decreased in 24 countries, remained stable in 36 countries, and increased in 5 countries (central and eastern Europe).
Incidence and mortality rates in general decreased in most Western countries but increased in some eastern European and developing countries. These patterns in part may reflect differences in the stage and extent of the tobacco epidemic, changes in coding practices, prevalence of schistosomiasis (Africa), and occupational exposure.
To evaluate the association of gender with survival following radical cystectomy (RC) for patients with pT4 bladder cancer.
We reviewed our institutional registry of 2,088 patients treated with RC between 1980 and 2005 to identify 128 with pT4 tumors, including 91 males and 37 females. Survival was estimated using the Kaplan-Meier method and compared with log-rank test. Cox hazard regression models were used to analyze the association of clinicopathologic demographics, including gender, with outcome.
A total of 7 women and 30 men with pT4 tumor received perioperative chemotherapy. Median postoperative follow-up was 10.5 years, during which time 27 patients experienced local recurrence (LR) and 120 died, including 90 who died from bladder cancer. Women with pT4 tumor trended to have higher 5-year LR-free survival (72 vs. 59 %; p = 0.83), cancer-specific survival (31 vs. 17 %; p = 0.50), and overall survival (19 vs. 11 %; p = 0.33), although these differences did not reach statistical significance. On multivariate analysis, moreover, gender was not significantly associated with LR (HR 0.96; p = 0.93), cancer-specific mortality (HR 1.05; p = 0.87), or all-cause mortality (ACM) (HR 1.14; p = 0.58). Instead, poor ECOG performance status and pN+ disease were associated with an increased risk of ACM, while removal of a greater number of lymph nodes was associated with decreased ACM.
We did not find gender-specific disparities in survival following RC for pT4 bladder cancer. Prognosis was instead driven by patient performance status and lymph node status.
The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.
To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).
Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.
Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).
Female patients were older at the time of RC (p=0.033) and had higher rates of pathologic stage T3/T4 disease (p<0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p=0.022 and p=0.11, respectively). Female gender was an independent predictor for CSM (p=0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).
We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.
The oncological basis behind the observation that females experience worse outcomes following radical cystectomy for urothelial carcinoma of the bladder (UCB) is unclear. This study was aimed at examining the sole effect of gender on postcystectomy UCB outcomes and identifying potential factors that may explain the poor prognosis in females using a balanced case-control approach.
A review of 2,567 patients with UCB who underwent radical cystectomy identified 414 females ("cases") who were matched 1:1 for demographic, tumor, and treatment characteristics with 414 male counterparts ("controls"). Cases were also compared with an independent male UCB cohort (n = 1,166). Differences between females vs. matched control and independent male patients with UCB were analyzed. Recurrence-free survival, cancer-specific survival, and overall survival were compared by univariable and multivariable Cox regression models.
Median follow-up for cases, controls, and independent control cohort was 12.2, 8.6, and 13.5 years, respectively. Females were matched to male controls for tumor and nodal stages (P = 1.00), lymphovascular invasion and surgical margin status, age, prior intravesical treatment, and neoadjuvant and adjuvant chemotherapy administration (P = 0.61-1.00). Cases were also balanced with controls for grade, p53 status, nodal yield, American Society of Anesthesiologists score, presence of hydronephrosis, and times to diagnosis and cystectomy (P≥0.14). When thus matched, outcomes between females and males were not different (P≥0.34). However, when compared with an independent unmatched male control cohort, females had significantly poorer outcomes (P≤0.006). In this comparison, females presented with higher tumor (P<0.001) and nodal (P = 0.049) stages and a lesser proportion received precystectomy intravesical therapy (P = 0.032).
Females have similar UCB outcomes to males when matched for demographic, clinicopathologic, and management characteristics. However, they present with more advanced tumors, thus explaining the observation of poor outcomes.
It has long been known that bladder cancer (BC) incidence is approximately four-fold higher in men than in women in the United States, and a similar disparity also exists in other countries. The reason for this phenomenon is not known, which impedes progress in BC prevention. However, BC incidence is also significantly higher in male animals than in their female counterparts after treatment with aromatic amines, which are principal human bladder carcinogens. These animal studies and related studies in the context of available human data provide significant insight into what may drive the excessive BC risk in men, which is the focus of this article. The carcinogenicity and biotransformation of bladder carcinogens as well as the impact of sex hormones on these processes are discussed, highlighting the novel concept that the gender disparity in BC risk may result primarily from the interplay of androgen, estrogen, and liver, with the liver functioning via its metabolic enzymes as the main decider of bladder exposure to carcinogens in the urine and the male and female hormones exerting opposing effects on carcinogenesis in the bladder and likely also on liver enzymes handling bladder carcinogens. The findings may facilitate further investigation into the mechanism of gender disparity in BC risk and may also have important implications for BC prevention.
To analyze whether ereferral is associated with decreased time to completion of hematuria workup.
We included 100 individuals referred to Olive View-UCLA Medical Center for urologic consultation for hematuria. Half were referred before implementation of ereferral, and half were referred after the system was implemented. We performed bivariate analysis to assess correlations of baseline subject sociodemographic and clinical characteristics with ereferral status. We also created a multivariate linear regression model for log days to completion of hematuria workup, with ereferral as the main predictor and subject sociodemographic and clinical characteristics as covariates.
Excluding cases with an infectious cause, the mean number of days from urinalysis documenting hematuria to completed hematuria workup was 404 days before ereferral and 192 days after implementation of ereferral (median 239 vs 170; 2-sample median P = .0013). Upper tract imaging was obtained at a median of 76 days after initial positive urinalysis in the absence of infection, 122 days before ereferral, and 41 days after implementation of ereferral (2-sample median P = .1114). In all cases, lower tract evaluation was completed after upper tract imaging. Our multivariable model evaluating factors associated with time to hematuria workup demonstrated that ereferral use was independently associated with shorter time to hematuria workup (P = .006).
Electronic consultations can significantly shorten the time to work-up of hematuria in the safety net.
In the United States, among patients diagnosed with bladder cancer (BC), women have increased disease-specific mortality compared with men. The main objective of this study was to determine whether this pattern is also present in other countries. For comparison, similar analyses were performed for kidney cancer (KC).
Data for this study were obtained from the GLOBOCAN 2008 database. A total of 49 countries with available information on BC and KC incidence and mortality were included in the analysis, representing all major geographic regions except Africa. For each country, we computed the sex-specific ratio of the total number of deaths from a given cancer to the total number of diagnoses in the year 2008 (the mortality-to-incidence ratio [MIR]). The relative MIR was computed for each country as a ratio of MIR in women to MIR in men. A relative MIR of more than 1 would indicate that the number of cancer-specific deaths relative to the number of cancer-specific diagnoses is greater in women than in men.
For BC, the relative MIRs were significantly more than 1 in 26 countries (53%), significantly less than 1 in 2 countries (4%), and not significantly different from 1 in 21 countries (43%). The median relative MIR was 1.21 (interquartile range: 1.04-1.41). For KC, the relative MIRs were significantly more than 1 in 4 countries (8%), significantly less than 1 in 3 countries (6%), and not significantly different from 1 in 42 countries (86%). The median relative MIR was 1.00 (interquartile range: 0.94-1.06).
Among BC patients, increased disease-specific mortality in women compared with men appears to be a common (although not a universal) phenomenon. This pattern may potentially be explained by differences between the sexes in the biology of disease, time to diagnosis, treatment decisions, and other factors. In contrast, among KC patients, no significant differences in disease-specific mortality were seen between the 2 sexes in the overwhelming majority of the countries.
Purpose:
To describe the role of sex steroid-dependent growth of muscle-invasive bladder cancer (MIBC) and the role of single-nucleotide polymorphisms (SNP) located on chromosome 8q24 as a molecular explanation for gender-specific differences in the incidence and outcome of MIBC.
Methods:
A detailed, non-systematic analysis was performed for articles and reviews investigating the role of sex steroids in the development and progression of MIBC between 2000 and 2012.
Results:
Localized MIBCs overexpress the androgen receptor (AR), whereas in lymph node-positive stages, loss of AR expression has been found. High-risk SNPs of genes on chromosome 8q24, that is, the rs2294008 of prostate stem cell antigen (PSCA) gene, have been linked with increased susceptibility for MIBC. The PSCA gene possesses an androgen-responsive element (ARE) in its promoter region. Recent studies suggest that loss of AR responsiveness to the PSCA promoter may result in the induction of an androgen-independent mechanism, that is, the insulin-like growth factor-binding protein 2 signalling pathway-a key event in the development of hormone-independent prostate cancer-and this may increase the metastatic potential. In females, it can be hypothesized that due to the altered androgen levels, these mechanisms may be initiated earlier during tumor progression in females and result in inferior survival compared to males.
Conclusion:
Muscle-invasive bladder cancer (MIBC) is a sex steroid-dependent tumor. AREs in the promoter region of high-risk genes may drive tumor progression and result in loss of androgen responsiveness, which eventually leads to the activation of androgen-independent processes forming the metastatic potential. The determination of the AR status in cystectomy specimens additionally offers new adjuvant approaches after cystectomy.
Unlabelled:
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Urothelial carcinoma of the bladder (UCB) is more prevalent in men than women; however, in women the tumour stage is generally more advanced at the time of the diagnosis and the prognosis is worse. Possible explanations include anatomical, genetic and socio-economic factors. The study shows that clinical symptoms before the first-time diagnosis of UCB did not differ between the sexes, while primary care and referral patterns did. Women were more likely to receive symptomatic treatment or therapies for alleged UTIs without further investigation or referral to urological evaluation. The study highlights the fact that there may be a diagnostic delay in women which could contribute to the gender-dependent disparities in stage distribution and prognosis of UCB.
Objective:
To evaluate gender-dependent disparities regarding clinical symptoms, referral patterns or treatments before diagnosis of urothelial carcinoma of the bladder (UCB).
Patients and methods:
A consecutive series of patients with newly diagnosed UCB completed a questionnaire at the time of admission for elective transurethral resection of a bladder tumour (TURBT). The questionnaire surveyed the presence of haematuria, dysuria, urgency and bladder pain as well as the number of consultations and treatments before urological evaluation. Tumour characteristics, clinical symptoms, treatments and referrals were compared between men and women in the patient series.
Results:
In men (n = 130) the distribution of tumour stages was pTa 62.3%, pT1 23.1% and pT ≥ 2 12.3%. The respective percentages in women (n = 38) were pTa 57.9%, pT1 23.7% and pT ≥ 2 18.4% (P > 0.05). The prevalence of clinical symptoms in men vs women was as follows: gross haematuria 65 vs 68%, dysuria 32 vs 44%, urgency 61 vs 47%, and nocturia 57 vs 66%, respectively (P > 0.05). A total of 78% of men vs 55% of women directly consulted a urologist (P < 0.05). Symptomatic treatment for voiding disorders/pain was given without further evaluation to 19% of men vs 47% of women 1 year before the diagnosis of UCB (P < 0.05). A total of 3.8% of men vs 15.8% of women received three or more treatments for urinary tract infections (UTIs) within the same time period (P < 0.05).
Conclusions:
In the present study there were no gender-related differences in clinical symptoms of UCB, but women were more likely to be treated for voiding complaints or alleged UTIs without further evaluation or referral to urology than men. Gender-dependent disparities in referral patterns exist and might delay definitive diagnosis of UCB in women.
The incidence of bladder cancer among women is at least one third to one fourth that observed among men in many countries. Even after accounting for known risk factors, the reason for this gender disparity remains unexplained. We conducted a comprehensive evaluation of reproductive factors and exogenous hormone use with a primary focus on menopausal hormone therapy use and risk of bladder cancer in women in the NIH-AARP Diet and Health Study. Reproductive and hormonal factors were ascertained on the baseline questionnaire in 1995-1996 among 201,492 females who were followed until December 31, 2006. During follow-up, 651 cases of bladder cancer were diagnosed. A subset of women provided detailed information on use of MHT in a second questionnaire in 1996-1997. In this analysis, 127,361 females were followed through June 30, 2002 and 198 incident bladder cancer cases were identified. Cox proportional hazard models, adjusted for smoking status, cigarettes per day, and body mass index using age as the time metric, were used to obtain hazard ratios (HRs). A reduced risk was observed among parous women (HR=0.76; 95% CI 0.62-0.93) and women who reported late age at menarche (≥15 years) (HR=0.57; 95% CI 0.39-0.84). Women who reported ever using estrogen and progestin therapy had a decreased risk (HR=0.53; 95% CI: 0.34-0.83) compared to women who did not report MHT use. No association was observed for estrogen only users (HR=0.82; 95% CI: 0.58-1.15). Our results suggest a putative role for sex hormones in the etiology of bladder cancer among women. © 2013 Wiley Periodicals, Inc.
Background:
Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated.
Objectives:
The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC).
Methods:
This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79).
Results:
Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men.
Conclusions:
After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.
Purpose:
An increasing body of evidence suggests gender differences in the presentation and prognosis of bladder cancer. We aimed to assess the impact of gender on outcomes in patients with primary T1 high-grade (HG) urothelial carcinoma of the bladder (UCB).
Methods:
We retrospectively analysed the data from 916 patients with primary T1HG UCB from 7 tertiary care centres. Patients were treated with transurethral resection of the bladder with or without intravesical instillation therapy (IVT). Univariable and multivariable Cox regression analyses assessed the effect of gender on outcomes.
Results:
Within a median follow-up of 42.8 months, 365 (39.8 %) patients experienced disease recurrence, 104 (11.4 %) progression, 59 (6.4 %) cancer-specific mortality and 190 (20.7 %) mortality of any cause. Overall, 634 (69.2 %) patients received IVT of which 234 (25.5 %) received BCG therapy. Female gender (n = 190, 20.7 %) was associated with higher risk of disease recurrence (HR:1.359;1.071-1.724, p = 0.012) in all patients and in a subgroup of patients treated with BCG therapy (HR:1.717;1.101-2.677, p = 0.017). There was no difference between genders with regard to disease progression, cancer-specific mortality and any-cause mortality. In multivariable analyses that adjusted for the effects of concomitant carcinoma in situ (CIS), tumour size, number of tumours, and IVT, gender remained an independent predictor for disease recurrence (p = 0.026) when analysed in all patients, but not in the subgroup of BCG treated patients (p = 0.093).
Conclusions:
In patients with T1HG UCB, female gender is associated with higher risk of disease recurrence, but not with disease progression. This gender disparity may be due to differences in care and/or biology of UCB.
Background:
To determine whether patients found to have hematuria by their primary care physicians are evaluated according to best practice policy.
Materials and methods:
The University of Texas Southwestern Medical Center maintains institutional outpatient electronic medical records (EMR) that are used by all providers in all specialties. We conducted an Institutional Review Board approved observational study of patients found to have more than 5 red blood cells/high power field between March 2009 and February 2010.
Results:
There were 449 patients of whom the majority were female (82%), Caucasian (39%), with microscopic hematuria (MH) (85%). Almost 58% of patients were initially symptomatic with urinary symptoms or pain. Evaluation for the source of hematuria was limited and included imaging (35.6%), cystoscopy (9%, and cytology (7.3%). Only 36% of men and 8% of women were referred to a urologist. No abnormality was found in 32% and 51% of patients with gross hematuria and MH, respectively (P = 0.004). There were 4 bladder tumors and 1 renal mass detected. Male gender, ethnicity and gross (vs. microscopic) hematuria were associated with higher rate of urological referral. Advanced age, smoking, provider practice type, and the presence of urinary symptoms were not associated with an increase rate of urological referral. No additional cancers were diagnosed with 29-month follow-up.
Conclusions:
While urinalysis remains a common diagnostic tool, most cases of both microscopic and gross hematuria are not fully evaluated according to guidelines. Use of cystoscopy, cytology, and upper tract imaging is limited. Further studies will be needed to determine the extent of the problem and impact on morbidity and survival.
Purpose:
The purpose of this guideline is to provide a clinical framework for the diagnosis, evaluation and follow-up of asymptomatic microhematuria.
Materials and methods:
A systematic literature review using the MEDLINE® database was conducted to identify peer reviewed publications relevant to the definition, diagnosis, evaluation and follow-up for AMH. The review yielded 191 evidence-based articles, and these publications were used to create the majority of the guideline statements. There was insufficient evidence-based data for certain concepts; therefore, clinical principles and consensus expert opinions were used for portions of the guideline statements.
Results:
Guideline statements are provided for diagnosis, evaluation and follow-up. The panel identified multiphasic computed tomography as the preferred imaging technique and developed guideline statements for persistent or recurrent AMH as well as follow-up.
Conclusions:
AMH is only diagnosed by microscopy; a dipstick reading suggestive of hematuria should not lead to imaging or further investigation without confirmation of three or greater red blood cells per high power field. The evaluation and follow-up algorithm and guidelines provide a systematic approach to the patient with AMH. All patients 35 years or older should undergo cystoscopy, and upper urinary tract imaging is indicated in all adults with AMH in the absence of known benign causation. The imaging modalities and physical evaluation techniques are evolving, and these guidelines will need to be updated as the effectiveness of these become available. Please visit the AUA website at http://www.auanet.org/content/media/asymptomatic_microhematuria_guideline.pdf to view this guideline in its entirety.
Bladder cancer is the fifth most common type of cancer in the USA, with over 70,000 new cases diagnosed each year. Treatment often involves invasive surgical therapies, as chemotherapy alone is often ineffective and associated with high recurrence rates. Identification of estrogen receptor-β (ERβ) in up to 75 % of urinary tumors raises the question of whether this receptor could be targeted to effectively treat bladder cancer. In this study, a panel of five bladder cancer cell lines representing a variety of disease stage and grades were treated with the antiestrogens 4-hydroxytamoxifen, raloxifene, or the pure antagonist ICI 182,780. All cell lines were ERβ positive while only a few expressed estrogen receptor-α (ERα). Notably, all but the TCCSUP cell line were growth inhibited 20-100 % by at least two antiestrogens. Using RT4 cells, we demonstrate that growth inhibition by raloxifene is ER dependent and either ERα or ERβ can mediate this response. Activation of caspase-3 and its effector poly-ADP ribose polymerase (PARP) demonstrate that raloxifene-induced growth inhibition is in part the result of increased apoptosis; this PARP cleavage was ER dependent. Moreover, changes in the expression of cell cycle genes indicate that cell proliferation is also affected. Specifically, raloxifene treatment results in the stabilization of p27 protein, likely via the downregulation of S-phase kinase-associated protein (SKP2). Expression of the negative cell cycle regulator B-cell translocation gene (BTG2) is also increased, while cyclin D1 transcription is reduced. These results indicate that antiestrogens may be useful therapeutics in the treatment of bladder cancer by targeting ER and inhibiting growth via multiple mechanisms.
Context:
Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease.
Objective:
To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors.
Evidence acquisition:
A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected.
Evidence synthesis:
UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence.
Conclusions:
UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported.
What's known on the subject? and What does the study add?
Steroid hormone receptor signals have been implicated in bladder tumourigenesis and tumour progression. The expression of androgen and/or oestrogen receptors has been assessed in bladder cancer, leading to conflicting data of expression levels and their relationship to histopathological characteristics of the tumours. We simultaneously analyze three receptors in non-neoplastic bladder tissues as well as in primary and metastatic bladder tumour specimens. Our data demonstrate that the expression status correlates with tumour grades/stages and patients’ outcomes.