Urothelial carcinoma is a tumor type featuring pronounced intertumoral heterogeneity and a high mutational and epigenetic load. The two major histopathological urothelial carcinoma types - the non-muscle-invasive and muscle-invasive urothelial carcinoma - markedly differ in terms of their respective typical mutational profiles and also by their probable cells of origin, that is, a urothelial basal cell for muscle-invasive carcinomas and a urothelial intermediate cell for at least a large part of non-muscle-invasive carcinomas. Both non-muscle-invasive and muscle-invasive urothelial carcinomas can be further classified into discrete intrinsic subtypes based on their typical transcriptomic profiles. Urothelial carcinogenesis shows a number of parallels to a urothelial regenerative response. Both of these processes seem to be dominated by specific stem cell populations. In the last years, the nature and location of urothelial stem cell(s) have been subject to many controversies, which now seem to be settled down, favoring the existence of a largely single urothelial stem cell type located among basal cells. Basal cell markers have also been amply used to identify urothelial carcinoma stem cells, especially in muscle-invasive disease, but they proved useful even in some non-muscle-invasive tumors. Analyses on molecular nature of urothelial carcinoma stem cells performed till now point to their great heterogeneity, both during the tumor development and upon intertumoral comparison, sexual dimorphism providing a special example of the latter. Moreover, urothelial cancer stem cells are endowed with intrinsic plasticity, whereby they can modulate their stemness in relation to other tumor-related traits, especially motility and invasiveness. Such transitional modulations suggest underlying epigenetic mechanisms and, even within this context, inter- and intratumoral heterogeneity becomes apparent. Multiple molecular aspects of urothelial cancer stem cell biology markedly influence therapeutic response, implying their knowledge as a prerequisite to improved therapies of this disease. At the same time, the notion of urothelial cancer stem cell heterogeneity implies that this therapeutic benefit would be most probably and most efficiently achieved within the context of individualized antitumor therapy.

• Klíčová slova
• COX-2, DNMT-1, Epigenetic plasticity, Epithelial-mesenchymal transition, Intrinsic subtypes, Lineage-depletion, Lineage-tracing, Muscle-invasive bladder cancer, Non-muscle-invasive bladder cancer, SOX-2, STAT-3, Sonic hedgehog, Stemness signaling pathway, Urothelial carcinoma, Urothelial carcinoma heterogeneity, Urothelial carcinoma sexual dimorphism, Urothelial carcinoma stem cells, Urothelial regenerative response, Urothelial stem cells, Urothelium, Wnt/β-catenin pathway, YAP-1,
• MeSH
• lidé MeSH
• nádorové kmenové buňky cytologie   MeSH
• nádory močového měchýře patologie   MeSH
• urotel patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: To test the effect of variant histology relative to urothelial histology on stage at presentation, cancer specific mortality (CSM), and overall mortality (OM) after chemotherapy use, in urethral cancer. MATERIALS AND METHODS: Within the Surveillance, Epidemiology and End Results (2004-2016) database, we identified 1,907 primary variant histology urethral cancer patients. Kaplan-Meier plots, Cox regression analyses, cumulative incidence-plots, multivariable competing-risks regression models and propensity score matching for patient and tumor characteristics were used. RESULTS: Of 1,907 eligible urethral cancer patients, urothelial histology affected 1,009 (52.9%) vs. squamous cell carcinoma (SCC) 455 (23.6%) vs. adenocarcinoma 278 (14.6%) vs. other histology 165 (8.7%) patients. Urothelial histological patients exhibited lower stages at presentation than SCC, adenocarcinoma or other histology patients. In urothelial histology patients, five-year CSM was 23.5% vs. 34.4% in SCC [Hazard Ratio (HR) 1.57] vs. 40.7% in adenocarcinoma (HR 1.69) vs. 43.4% in other histology (HR 1.99, p < 0.001). After matching in multivariate competing-risks regression models, variant histology exhibited 1.35-fold higher CSM than urothelial. Finally, in metastatic urethral cancer, lower OM was recorded after chemotherapy in general, including metastatic adenocarcinoma and other variant histology subtypes, except metastatic SCC. CONCLUSION: Adenocarcinoma, SCC and other histology subtypes affect fewer patients than urothelial histology. Presence of variant histology results in higher CSM. Finally, chemotherapy for metastatic urethral cancer improves survival in adenocarcinoma and other variant histology subtypes, but not in SCC.

• Klíčová slova
• adenocarcinoma, chemotherapy, metastatic urethral cancer, mortality, non-urothelial, squamous cell carcinoma, urethral cancer, variant histology,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause another type of kidney fibrosis with malignant transformation of the urothelium, called Balkan Endemic Nephropathy (BEN). The compound predominantly responsible for the nephropathy and urothelial cancer of AA, is aristolochic acid I (AAI) which is a genotoxic mutagen after metabolic activation The activation pathway involves reduction of the nitro group to a cyclic N-acylnitrenium ion that can form covalent DNA adducts. These specific DNA adducts have been detected in experimental animals exposed to AAI, and in urothelial tissues from AAN patients. In rodent tumours induced by AAI, 7-(deoxyadenosin-N(6)-yl)aristolactam I was the most abundant DNA adduct formed and associated with activation of ras oncogenes through a characteristic transversion mutation. Such A:T-->T:A mutations have been identified in TP53 of urothelial tumour DNA of an AAN patient and in several patients suffering from BEN along with specific AA-DNA adducts. Understanding which enzymes are involved in AAI activation to species forming DNA adducts and/or detoxification to its O-demethylated metabolite aristolochic acid Ia (AAIa) is important in order to assess susceptibility to this carcinogen. METHODS AND RESULTS: A literature search. CONCLUSIONS: The most important human enzymes activating AAI by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 (CYP) 1A2 and renal microsomal NADPH:CYP reductase as well as cyclooxygenase which is highly expressed in urothelial tissue. However, the contribution of most of these enzymes to the development of AAN and BEN diseases is still unclear. Hepatic CYP enzymes were found to detoxify AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of the 1A subfamily seem to play a major role in this process in mouse liver. Likewise, among human CYP enzymes, CYP1A1 and 1A2 were found to be the most efficient enzymes participating in AAI oxidation to AAIa in vitro. Nevertheless, which CYPs are the most important in this process in both animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AAI to species responsible for induction of urothelial cancer in humans remains still to be resolved.

• MeSH
• adukty DNA metabolismus   MeSH
• aktivace enzymů MeSH
• biotransformace MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• kyseliny aristolochové farmakokinetika   toxicita   MeSH
• ledviny účinky léků   MeSH
• lidé MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa metabolismus   MeSH
• nemoci ledvin chemicky indukované   MeSH
• urologické nádory chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adukty DNA MeSH
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• kyseliny aristolochové MeSH
• NADPH-cytochrom c-reduktasa MeSH

Cancer stem cells are defined as a self-renewing and self-protecting subpopulation of cancer cells able to differentiate into morphologically and functionally diverse cancer cells with a limited lifespan. To purify cancer stem cells, two basic approaches can be applied, the marker-based approach employing various more of less-specific cell surface marker molecules and a marker-free approach largely based on various self-protection mechanisms. Within the context of urothelial carcinoma, both methods could find use. The cell surface markers have been mainly derived from the urothelial basal cell, a probable cell of origin of muscle-invasive urothelial carcinoma, with CD14, CD44, CD90, and 67LR representing successful examples of this strategy. The marker-free approaches involve side population sorting, for which a detailed protocol is provided, as well as the Aldefluor assay, which rely on a specific overexpression of efflux pumps or the detoxification enzyme aldehyde dehydrogenase, respectively, in stem cells. These assays have been applied to both non-muscle-invasive and muscle-invasive bladder cancer samples and cell lines. Urothelial carcinoma stem cells feature a pronounced heterogeneity as to their molecular stemness mechanisms. Several aspects of urothelial cancer stem cell biology could enter translational development rather soon, e.g., a specific CD44+-derived gene expression signature able to identify non-muscle-invasive bladder cancer patients with a high risk of progression, or deciphering a mechanism responsible for repopulating activity of urothelial carcinoma stem cells within the context of therapeutic resistance.

• Klíčová slova
• Cancer stem cells, Drug resistance, Side population, Urothelial carcinoma, Urothelial carcinoma cells of origin, Urothelial carcinoma stem cell markers, Urothelial regeneration, Urothelium stem cells,
• MeSH
• biologické markery MeSH
• heterografty MeSH
• imunofenotypizace MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• nádorové biomarkery MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• průtoková cytometrie MeSH
• separace buněk metody   MeSH
• testy nádorových kmenových buněk MeSH
• urologické nádory metabolismus   patologie   MeSH
• urotel cytologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• nádorové biomarkery MeSH

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

• Klíčová slova
• Adjuvant chemotherapy, Bladder cancer, Carboplatin, Nodal metastasis, Radical cystectomy, Urothelial cancer,
• MeSH
• adjuvantní chemoterapie MeSH
• cystektomie metody   MeSH
• karboplatina terapeutické užití   MeSH
• karcinom z přechodných buněk * farmakoterapie   chirurgie   MeSH
• lidé MeSH
• nádory močového měchýře * farmakoterapie   chirurgie   MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• karboplatina MeSH

CONTEXT: Smoking habit at the time of surgery is associated with higher perioperative complications and mortality across different types of surgeries. In recent years, several studies have attempted to explore the influence of smoking on perioperative outcomes following radical cystectomy (RC) for urothelial bladder cancer (UBC) with contradictory results. OBJECTIVE: To systematically investigate and meta-analyze the association between smoking habit and perioperative morbidity and mortality in UBC patients treated with RC. EVIDENCE ACQUISITION: A systematic review of the literature published between January 2000 and January 2020 investigating the impact of smoking habit on perioperative outcomes of patients treated with RC for UBC was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement and the Cochrane Handbook for Systematic Reviews of Interventions. EVIDENCE SYNTHESIS: Overall, 27 articles involving 27 854 patients were included in the systematic review, and of these, 11 studies were included in the meta-analysis. The studies included showed a moderate to high risk of bias. Smoking status (smokers vs nonsmokers) was significantly associated with the onset of major postoperative complications (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.51-2.32; I2 = 0%), infections (HR 1.34, 95% CI 1.02-1.72; I2 = 66.2%), and mortality (HR 1.84, 95% CI 1.14-2.98; I2 = 4.9%). CONCLUSIONS: Smoking status at the time of RC is associated with increased risk for major postoperative complications, infections, and mortality. These results suggest the need for strict postoperative monitoring in smokers due to the increased risk of experiencing adverse events and underline the need for intensive smoking cessation interventions in the preoperative setting. PATIENT SUMMARY: In this study, we reviewed the impact of smoking habit on perioperative outcomes following radical cystectomy (RC). Based on the available data, the impact of smoking on morbidity and mortality after RC is significant and relevant; as such, every effort should be made in the preoperative setting to encourage smoking cessation.

• Klíčová slova
• Complication, Infection, Outcome, Perioperative mortality, Radical cystectomy, Smoking exposure, Urothelial bladder cancer,
• MeSH
• cystektomie škodlivé účinky   MeSH
• karcinom z přechodných buněk * MeSH
• kouření škodlivé účinky   MeSH
• lidé MeSH
• morbidita MeSH
• nádory močového měchýře * epidemiologie   chirurgie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH

BACKGROUND: Cancer stem cells (CSC) and their role in tumorigenesis of various solid tumors have been studied in past decades. Urothelial CSC were first identified 10 years ago and subsequent studies have been performed with the aim to identify reliable markers of CSC. So far, a few studies have investigated a relationship between CSC markers expression in urothelial carcinoma tissue and histopathological characteristics of the tumor. METHODS: In our study, we evaluated an immunoexpression of the CSC markers CD24, CD44, CD66 and CD133 in tissue sections of urothelial carcinoma (all tumor grades and stages were included), urothelial carcinoma in situ and non-neoplastic urothelium, totally 218 specimens were enrolled. RESULTS: All studied molecules were expressed either in tumor tissue and non-neoplastic urothelium. Urothelial carcinomas of higher tumor grade and stage expressed molecules CD24 and CD133 significantly more frequently whereas molecules CD44 and CD66 did not show significant association with tumor histopathological features. CONCLUSIONS: Our results showed that studied molecules are not suitable for direct detection of CSC in urothelial carcinoma tissue sections, but an expression of molecules CD24 and CD133 is significantly related to urothelial carcinoma grade and stage, which are both important prognostic indicators and therefore an expression of these markers might have a potential prognostic value.

• Klíčová slova
• cancer stem cells, immunohistochemistry, markers, urothelial carcinoma,
• MeSH
• antigen CD24 MeSH
• karcinom z přechodných buněk * MeSH
• lidé MeSH
• močový měchýř MeSH
• nádorové biomarkery MeSH
• nádorové kmenové buňky MeSH
• nádory močového měchýře * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen CD24 MeSH
• nádorové biomarkery MeSH

Ingestion of aristolochic acid (AA) is associated with the development of AA-nephropathy and Balkan endemic nephropathy, which are characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. Understanding which enzymes are involved in AA activation and/or detoxification is important in assessing susceptibility to AA. Xiao et al. demonstrate that hepatic cytochrome P450s in mice detoxicate AA and thereby protect kidney from injury. The relative contribution of enzymes activating AA to induce urothelial cancer in humans remains to be resolved.

• MeSH
• játra enzymologie   MeSH
• karcinogeny metabolismus   toxicita   MeSH
• kyseliny aristolochové metabolismus   toxicita   MeSH
• metabolická inaktivace MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa genetika   metabolismus   MeSH
• nemoci ledvin chemicky indukované   enzymologie   MeSH
• urologické nádory chemicky indukované   enzymologie   MeSH
• urotel MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• Názvy látek
• aristolochic acid I MeSH Prohlížeč
• karcinogeny MeSH
• kyseliny aristolochové MeSH
• NADPH-cytochrom c-reduktasa MeSH

OBJECTIVE: The aim of the study was to investigate differences in the stage at presentation and cancer-specific mortality (CSM) between rural area (RA) and urban area (UA) residence status in nonmetastatic upper urinary tract urothelial carcinoma (UTUC) patients. METHODS: Newly diagnosed T1-3N0M0 UTUC patients with available residence status were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2016). Propensity score (PS) matching (1 RA vs. 3 UA) accounted for age (interval ≤2 years), T stage (exact matching: T1, T2, and T3), and tumor grade (exact matching: high grade, low grade/unknown). Cumulative incidence plots and multivariable competing risk regression models focused on CSM, after adjustment for other-cause mortality. RESULTS: Of 6,012 patients, 125 (2.1%) resided in RAs and 5,887 (97.9%) in UAs. RA patients were younger than UA patients (median age 72 vs. 75 years, p = 0.03). No differences were recorded in tumor location, T stage, tumor grade, or surgical treatment between RA and UA patients. After 1:3 PS matching, 125 RA patients and 375 UA patients were assessable. At 5 years of follow-up, CSM rates were 26.7 versus 15.7% according to RA versus UA, respectively. After additional multivariable adjustment for age, sex, tumor location, and surgical treatment, RA remained an independent predictor of higher CSM (hazard ratio 1.75, p = 0.02). CONCLUSIONS: Despite no differences in cancer characteristics, UTUC patients in RA are at higher risk of CSM than their UA counterparts. This suggests suboptimal care delivery and compliance as possible causes. Complex and/or rare disease should be centralized to expert centers, which are often in UAs.

• Klíčová slova
• Cancer-specific survival, North American population, Residence status, SEER database, Upper urinary tract urothelial carcinoma,
• MeSH
• karcinom z přechodných buněk mortalita   patologie   MeSH
• ledvinná pánvička * MeSH
• lidé MeSH
• nádory ledvin mortalita   patologie   MeSH
• nádory močovodu mortalita   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• zdraví ve městech MeSH
• zdraví venkovských oblastí MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Spojené státy americké MeSH

Radical nephroureterectomy (RNU) with bladder cuff excision is a standard of care in patients with high-risk upper tract urothelial carcinoma (UTUC). Although several recommendations and guidelines on the delayed treatment of urologic cancers exist, the evidence on UTUC is scarce and ambiguous. The present systematic review aimed to summarize the available evidence on the survival outcomes after deferred RNU in patients with UTUC. A systematic literature search of the three electronic databases (PubMed, Embase, and Cochrane Library) was conducted until 30 April 2022. Studies were found eligible if they reported the oncological outcomes of patients treated with deferred RNU compared to the control group, including those patients treated with RNU without delay. Primary endpoints were cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS). In total, we identified seven eligible studies enrolling 5639 patients. Significant heterogeneity in the definition of "deferred RNU" was found across the included studies. Three out of five studies reporting CSS showed that deferring RNU was associated with worse CSS. Furthermore, three out of four studies reporting OS found a negative impact of delay in RNU on OS. One out of three studies reporting RFS found a negative influence of delayed RNU on RFS. While most studies reported a 3 month interval as a significant threshold for RNU delay, some subgroup analyses showed that a safe delay for RNU was less than 1 month in patients with ureteral tumors (UT) or less than 2 months in patients with hydronephrosis. In conclusion, long surgical waiting time for RNU (especially more than 3 months after UTUC diagnosis) could be considered as an important risk factor having a negative impact on oncological outcomes in patients with UTUC; however, the results of the particular studies are still inconsistent. The safe delay for RNU might be shorter in specific subsets of high-risk patients, such as those with UT and/or hydronephrosis at the time of diagnosis. High-quality additional studies are required to establish evidence for valid recommendations.

• Klíčová slova
• deferred, delay, oncological outcomes, radical nephroureterectomy, upper tract urothelial carcinoma,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH