Urothelial Carcinoma Of Urinary Bladder Research Articles

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions.

Simple SummaryUpper tract urothelial carcinoma (UTUC) represents 5 to 10% of urothelial carcinoma. Their mutational profile is different as compared to bladder urothelial carcinoma (UC). While immune checkpoint inhibitors are now part of the therapeutic landscape of urothelial carcinoma, data concerning their use in UTUC patient’s treatment remain scarce. The aim of this review is to summarize the available evidence and the biological rationale of using immune checkpoint inhibitors in high-grade UTUC. We reviewed the latest molecular characterization data and proposed an insight for future therapeutic strategies based on molecular alteration profiles.Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC.

High glycosyltransferase8 domain containing two protein levels contribute to poor prognosis in urothelial carcinoma.

To examine the expression levels of the glycosyltransferase8 domain containing protein2 and its clinical implications in urothelial carcinoma patients. Data mining, immunohistochemistry together with H-score calculation was carried out to evaluate the glycosyltransferase8 domain containing protein2 levels on tissue specimens from urothelial carcinoma patients, retrospectively. Correlations between glycosyltransferase8 domain containing protein2 H-score and imperative clinicopathological factors were measured. The indication of glycosyltransferase8 domain containing protein2 level on disease-specific and metastasis-free survivals were next analyzed. In upper tract urothelial carcinomas (n=340) and bladder urothelial carcinomas (n=295), 170 (50%) and 148 (50%) patients, respectively, were identified to have high glycosyltransferase8 domain containing protein2 expression. The glycosyltransferase8 domain containing protein2 levels were correlated to several clinicopathological characteristics and patient survival. Upregulation of the glycosyltransferase8 domain containing protein2 was correlated to primary tumor (P<0.001), nodal metastasis (P<0.001), histological grade (P<0.001), vascular invasion (P<0.001), perineural invasion (P<0.05) and mitotic rate (P<0.001). High glycosyltransferase8 domain containing protein2 levels independently predicted poor disease-specific survival (P=0.049) and metastasis-free survival (P=0.008) in upper tract urothelial carcinoma and urinary bladder urothelial carcinoma, respectively. Gene Ontology enrichment analysis additionally showed that multiple biological processes were enriched including "ECM organization" (Gene Ontology:0030198), "extracellular structure organization" (Gene Ontology:0043062), "biological adhesion" (Gene Ontology:0022610), "cell adhesion" (Gene Ontology:0007155), "collagen fibril organization" (Gene Ontology:0030199) and "vasculature development" (Gene Ontology:0001944). The present findings suggest that upregulation of the glycosyltransferase8 domain containing protein2 is an independent and disadvantageous prognosticator in urothelial carcinoma. High glycosyltransferase8 domain containing protein2 level might play a crucial role in progression of urothelial carcinoma.

Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer.

Simple SummaryApproximately 70% of all bladder cancer is diagnosed as non-muscle invasive bladder cancer and can be treated by transurethral resection of the bladder tumor, followed by intravesical instillation chemotherapy. Bacille Calmette-Guérin (BCG) is the first-line agent for intravesical instillation, but its accessibility has been limited for years due to a BCG shortage. Here, our aim was to evaluate the therapeutic role of intravesical instillation of azacitidine, a DNA methyltransferase inhibitor, in bladder cancer. Cell model experiments showed that azacitidine inhibited TNFR1 downstream pathways to downregulate HIF-1α, claspin, and survivin. Concomitant upregulation of the TRAIL R2 pathway by azacitidine ultimately drove the tumor cells to apoptosis. Rats with genotoxic carcinogen-induced bladder cancer showed a significantly reduced in vivo tumor burden after intravesical instillation of azacitidine. These findings might support further clinical trials of azacitidine in bladder cancer.Azacitidine, an inhibitor of DNA methylation, shows therapeutic effects against several malignancies by inducing apoptosis and inhibiting tumor cell proliferation. However, the anti-tumor effects of azacitidine on urinary bladder urothelial carcinoma (UBUC), especially following intravesical instillation (IVI), are not established. Here, UBUC cell lines were used to analyze the in vitro therapeutic effects of azacitidine. Potential signaling pathways were investigated by antibody arrays and Western blotting. The N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat UBUC model was used for in vivo quantitative analysis of tumor burden. Azacitidine significantly inhibited DNMT expression in UBUC cell lines and reduced cell viability and clonogenic activity, as determined by MTT and colony formation assays, while also inducing significant cytotoxic effects in the form of increased sub-G1 and Annexin V-PI populations (all p < 0.05). Antibody arrays confirmed the in vitro suppression of TNF-R1 and the induction of TRAIL-R2 and their downstream signaling molecules. TNF-R1 suppression reduced claspin and survivin expression, while TRAIL-R2 activation induced cytochrome C and caspase 3 expression. Rats with BBN-induced bladder cancer had a significantly reduced tumor burden and Ki67 index following IVI of azacitidine (p < 0.01). Our study provides evidence for a reduction in BBN-induced bladder cancer by IVI of azacitidine through alterations in the TRAIL-R2 and TNF-R1 signaling pathways. These findings might provide new insights for further clinical trials.

EMP2 induces cytostasis and apoptosis via the TGFβ/SMAD/SP1 axis and recruitment of P2RX7 in urinary bladder urothelial carcinoma.

Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease, and its high recurrence rates impose a heavy clinical burden. The objective of this study was to identify signaling pathways downstream of epithelial membrane protein 2 (EMP2), which induces cytostasis and apoptosis in UBUC. A series of in vitro and in vivo assays using different UBUC-derived cell lines and mouse xenograft models were performed, respectively. In addition, primary UBUC specimens were evaluated by immunohistochemistry. Exogenous expression of EMP2 in J82 UBUC cells significantly decreased DNA replication and altered the expression levels of several TGFβ signaling-related proteins. EMP2 knockdown in BFTC905 UBUC cells resulted in opposite effects. EMP2-dysregulated cell cycle progression was found to be mediated by the TGFβ/TGFBR1/SP1 family member SMAD. EMP2 or purinergic receptorP2X7 (P2RX7) gene expression upregulation induced apoptosis via both intrinsic and extrinsic pathways. In 242 UBUC patient samples, P2RX7 protein levels were found to be significantly and positively correlatedwith EMP2 protein levels. Low P2RX7 levels conferred poor disease-specific and metastasis-free survival rates, and significantly decreased apoptotic cell rates. EMP2 was found to physically interact with P2RX7. In the presence of a P2RX7 agonist, BzATP, overexpression of both EMP2 and P2RX7 significantly increased apoptotic cell rates compared to overexpression of EMP2 or P2RX7 alone. EMP2 induces cytostasis via the TGFβ/SMAD/SP1 axis and recruits P2RX7 to enhance apoptosis in UBUC. Our data provide new insights that may be employed for the design of UBUC targeting therapies.

Significance of Vascular Endothelial Growth Factor Expression in the Bladder Urothelial Carcinoma and Its Association with Tumor Grade and Invasiveness

Background & Objective: Vascular Endothelial Growth Factor (VEGF) is one of the newer molecular markers that acts as a central mediator of tumor angiogenesis and is essential for tumor growth, progression, and metastasis. So anti-angiogenic drugs can be used as anticancer therapy. Treatments with anti-VEGF (Bevacizumab) therapy have been proved to improve relapse-free survival in many tumors. Urinary bladder tumor has become emerging cancer globally among elderly individuals. So, the identification and development of novel biomarkers for effective treatment of urinary bladder carcinoma is essential. The present study aimed to investigate the immunohistochemical expression of VEGF in urothelial carcinoma of urinary bladder and to assess its association with tumor grade and muscle invasiveness.Methods: This cross-sectional study was conducted in the Department of Pathology, Chittagong Medical College, Chattogram from September 2018 to August 2020. Fifty-six formalin-fixed paraffin-embedded tissue blocks of urinary bladder carcinoma were prepared for both histopathological and immunohistochemical examination. Each slide was evaluated by at least two pathologists.Results: Weak to strong positive expression of VEGF were observed in 52 cases (92.86%). The proportion of tumors positive for VEGF expression was higher among patients with high grade and non-muscle invasive bladder carcinoma. Conclusion: We found that VEGF expression has a significant association with tumor grade and an inverse association with muscle invasion. These findings may be useful for selecting the subset of patients likely to respond to anti-VEGF targeted therapy.

Clinicopathological Significance of Estrogen Receptor β and Estrogen Synthesizing/Metabolizing Enzymes in Urothelial Carcinoma of Urinary Bladder.

Sex-specific differences in the incidence of urinary bladder carcinomas are well known, and the possible involvement of sex steroids has been proposed. We previously reported the association of the loss of androgen receptors and androgen-producing enzymes with tumor progression of urinary bladder cancer patients. Clinically, the selective estrogen receptor modulators (SERMs) were reported to suppress the progression of these tumors but the status of estrogen receptors (ERs) has not been well studied in patients with bladder urinary cancer. Moreover, not only ERs but also estrogen-related enzymes, such as aromatase, steroid sulfatase (STS), and estrogen sulfotransferase (EST), have been reported in the biological/clinical behavior of various hormone-dependent carcinomas but not studied in urinary bladder carcinoma. Therefore, in this study, we immunolocalized ERs as well as estrogen metabolizing enzymes in urinary bladder carcinoma and performed immunoblotting and cell proliferation assays using the bladder urothelial carcinoma cell line, T24. The results revealed that the loss of STS and aromatase was significantly correlated with advanced stages of the carcinoma. In vitro studies also revealed that T24 cell proliferation rates were significantly ameliorated after treatment with estradiol or diarylpropionitrile (DPN). EST and aromatase were also significantly correlated with the nuclear grade of the carcinoma. The results of our present study, for the first time, demonstrated that biologically active estrogens that bind to ERs could suppress tumor progression and the inactive ones could promote its progression and the potential clinical utility of SERM treatment in selective patients with urinary bladder carcinoma.

Correlation of Human Epidermal Growth Factor Receptor (Her2-neu) Marker with the Grades of Urothelial Carcinoma

Background: Urothelial carcinoma is the common carcinoma of urothelium. Its incidence is high in developed countries but itsoccurrence is increasing in developing countries like Pakistan with mortality rate of 3.8/100,000 in males and 1/100,000 in females.HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family.Amplification or over-expression ofthis oncogene has been shown to play an important role in the development and progression urothelial carcinoma.Objective: To evaluate the relationship between HER2/NEU expression and grades of urothelial carcinoma bladderMaterial and Methods: This was a cross-sectional descriptive study for the period of six months from January to June, 2017conducted at Pathology section Rehman Medical Institute Peshawar. After approval from university Ethical board 63 cases wereselected by purposive sampling.The Tissue samples from diagnosed cases of urothelial carcinoma of urinary bladder were included.Cases of urothelial carcinoma from other sites were excluded. Paraffin embedded tissue blocks were cut and sections stained byH&amp;E to evaluate histopathological features and tumor grades. Immunohistochemical expression of HER2 was determinedapplying standard techniques of immunohistochemistry.Results: Out of total 63 cases, 47 were males and 16 were female with a mean age of 60.7 years (range 14-90 years). There were38 High grade, 23 Low grade and 2 cases of PUNLMP. 36 cases were positive for HER2 expression in which 26(72.2%) were Highgrade, 9(25%) of Low grade and 1(2.7%) of PUNLMP. High grade was more common in HER2 positive cases and this relationshipwas significant (p&lt;.05). Among positive 36 cases, 19 cases of +3 score were High grade, 05 in Low grade and 01 in PUNLMP whilescore 2+ was in 07 cases of High grade and 04 were in Low grade. The relationship of HER2 score was not significantly related tograde of tumor (p&gt;.05)Conclusion: HER2 is highly expressed in high grades of urothelial carcinoma bladder and this relationship between HER2expression and tumor grades is statistically significant.Keywords: HER2, Urothelial carcinoma, Grades, Immunohistochemistry

Clinical Predictors of Histological Grade of Urothelial Carcinoma of Urinary Bladder before First-Time Transurethral Resection of the Bladder Tumor (Turbt)

Background: Early diagnosis and prompt treatment can save lives of the patients with bladder cancer. The confirmatory test for grade of the disease is histopathological examination after transurethral resection. But if the grade of the tumor can be predicted at the time of presentation from size and number of tumors seen by ultrasonographic imaging, clinician can counsel the patient beforehand and also arrange rapid treatment to save life. Objective: To assess the size and number of tumors as clinical predictors of histological grade of urothelial carcinoma of urinary bladder before first-time transurethral resection of the bladder tumor (TURBT). Methods: This cross-sectional study was conducted in the Department of Urology, National Institute of Kidney Diseases &amp; Urology (NIKDU), Dhaka, Bangladesh from January 2020 to April 2020. Fifty patients were enrolled in this study. Size and number of the tumor was determined by preoperative ultrasonography of urinary bladder. Histopathological examination was used to determine the grade of the tumor after TURBT. Statistical analysis was performed using SPSS version 22.0. Results: Mean age of the study subjects was 52.04 ± 18.37 years within the range of 22–95 years. Males (56.0%) were predominant than females (44.0%). Male to female ratio was 1.27:1. Mean number of tumor was 1.28 ± 0.64 (1-3) and mean tumor size was 3.54 ± 1.47 cm (1-7). High grade tumor was 26 (52.0%) and low grade tumor was 24 (48.0%). There was no significant association of tumor grading with number of tumor in this study. High grade tumor was significantly higher among the study subjects with tumor size &gt;3.5 cm. Area under curve (AUC) of tumor number and tumor size was 0.558 and 0.827 respectively in prediction of tumor grading. Sensitivity, specificity, PPV, NPV and accuracy of tumor number (at cut of value 3) was 15.4%, 95.8%, 80.0%, 51.1% and 54.0% respectively. Sensitivity, specificity, PPV, NPV and accuracy of tumor size (at cut of value 3.5 cm) was 90.5%, 76.3%, 80.9%, 87.9% and 83.7% respectively. Overall Sensitivity, specificity, PPV, NPV and accuracy of tumor size was better than tumor number in prediction of tumor grading. Conclusion: According to this study finding, it can be concluded that the grade of newly diagnosed bladder tumors can be predicted with high accuracy using tumor size

Comparison between 1973 and 2004/2016 WHO grading systems in patients with Ta urothelial carcinoma of urinary bladder

AimsTo compare the 1973 WHO and the 2004/2016 WHO grading systems in patients with urothelial carcinoma of urinary bladder (UCUB), since no consensus has been made which classification should supersede...

ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of SKP2 at Both Transcriptional and Post-Translational Levels.

The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G2/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial–mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed S-phase kinase associated protein 2 (SKP2) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for SKP2 transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.

Comprehensive Gene Expression Analyses of Immunohistochemically Defined Subgroups of Muscle-Invasive Urinary Bladder Urothelial Carcinoma.

A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.

Prediction of Grade of Urothelial Carcinoma of Urinary Bladder from the Size and Number of Tumors at First Presentation

Prediction of Grade of Urothelial Carcinoma of Urinary Bladder from the Size and Number of Tumors at First Presentation

Significance of Vascular Endothelial Growth Factor Expression in the Bladder Urothelial Carcinoma and Its Association with Tumor Grade and Invasiveness.

Background & Objective:Vascular Endothelial Growth Factor (VEGF) is one of the newer molecular markers that acts as a central mediator of tumor angiogenesis and is essential for tumor growth, progression, and metastasis. So anti-angiogenic drugs can be used as anticancer therapy. Treatments with anti-VEGF (Bevacizumab) therapy have been proved to improve relapse-free survival in many tumors. Urinary bladder tumor has become emerging cancer globally among elderly individuals. So, the identification and development of novel biomarkers for effective treatment of urinary bladder carcinoma is essential. The present study aimed to investigate the immunohistochemical expression of VEGF in urothelial carcinoma of urinary bladder and to assess its association with tumor grade and muscle invasiveness.Methods:This cross-sectional study was conducted in the Department of Pathology, Chittagong Medical College, Chattogram from September 2018 to August 2020. Fifty-six formalin-fixed paraffin-embedded tissue blocks of urinary bladder carcinoma were prepared for both histopathological and immunohistochemical examination. Each slide was evaluated by at least two pathologists.Results:Weak to strong positive expression of VEGF were observed in 52 cases (92.86%). The proportion of tumors positive for VEGF expression was higher among patients with high grade and non-muscle invasive bladder carcinoma. Conclusion:We found that VEGF expression has a significant association with tumor grade and an inverse association with muscle invasion. These findings may be useful for selecting the subset of patients likely to respond to anti-VEGF targeted therapy.

Immunohistochemical expression of β-Catenin in urinary bladder urothelial carcinoma

Background: Bladder cancer is the ninth common cancer in the world, the third common cancer among men in the Arabic and Western Asian countries. In Egypt, UC has become the most frequent type with its incidence rising from 16% to 65.8%. Tumor grade and stage have been shown to have a strong correlation with tumor recurrence and progression to invasive bladder cancer. Β-catenin functions as part of the E-cadherin/β-catenin complex and plays a role in cell-to-cell adhesion and Wnt/β-catenin pathways have been reported to regulate urothelial homeostasis and carcinogenesis. Several studies have assessed the role of β-catenin and malignant transformation, as well as tumor progression. Objectives: Evaluation of the expression of β-catenin in urothelial bladder carcinoma and its correlation with other clinicopathological parameters of prognostic importance.Patients and methods: 50 specimens; either transurethral resection (TUR) or cystectomy will be Formalin fixed and paraffin-embedded and tissue sections will be examined histopathologically by routine HE strong in 5/23 (27.8%), moderate in 6/23 (42.9%), mild in 9/23 (60%) and not expressed in 3/23 (100%) of cases.Conclusions: Expression of β-catenin increases with increasing grades of the tumor and also it showed an increase in expression by the presence of invasion.

PD-L1 Expression in Muscle-Invasive Urinary Bladder Urothelial Carcinoma According to Basal/Squamous-Like Phenotype.

Urothelial carcinoma (UC) is the most common histologic type of urinary bladder cancer, and muscle-invasive UC shows aggressive behaviors. Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockades have been approved as standard treatments for patients with advanced stage UC. A total of 166 muscle-invasive urinary bladder cancer (MIBC) patients, who underwent transurethral resection of the bladder or cystectomy from 2004 to 2010 were included. We evaluated PD-L1 expression by the SP142 and SP263 assays and classified the cases “positive” or “negative” according to the manufacturer’s recommendations. We performed immunohistochemistry (IHC) for cytokeratin (CK) 5/6, CK14, GATA3, FOXA1, and CK20 and classified samples as Basal-Squamous-like (BASQ) or non-BASQ subtype. The overall concordance rate for PD-L1 expression is 91.6% (152/166) (kappa = 0.732). The SP142 assay showed 15.1% positivity; the SP263 assay showed 23.5%. The high positivity in the SP142 and SP263 assay was significantly correlated with positive CK5/6, CK14 expression, negative GATA3, FOXA1, and CK20 expression. Classification according to IHC expression resulted in 12.0% (20/166) of samples being classified as BASQ subtype and 88.0% (146/166) of samples being classified as non-BASQ subtype. High positivity in the SP142 and SP263 assay was significantly correlated with the BASQ subtype (p < 0.001, both). Our study is the first to analyze the association of immunohistochemically defined BASQ and non-BASQ subtypes with two PD-L1 assays in MIBC. In conclusion, we revealed that a high PD-L1 positive rate in all PD-L1 assays was significantly associated with the BASQ-subtype, and these results suggest that the BASQ classification may be important to apply the PD-1/PD-L1 blockades in MIBC.

The metabolic syndrome is associated with the risk of urothelial carcinoma from a health examination database.

The metabolic syndrome was associated with bladder cancer in the previous studies. However, there have no large-scale cohort studies to elucidate the relationship between metabolic syndromes and urothelial carcinoma including urinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC). We analyze a population-based cohort study by using physical examination data and diagnosis of UC from the Taiwan Cancer Registry Database. Differences in demographic and clinical characteristics among UTUC and non-UTUC groups, UBUC and non-UBUC groups were compared. Odds ratios (ORs) for determining risk factors were estimated through the multiple logistic regression model. A total of 557,063 records for 211,319 participants which consisted of 31 UTUC and 309 UBUC met the eligibility criteria in this study. Our results showed that female are more likely to develop UTUC than male. As opposed to UTUC, male are more likely to develop UBUC than female. It also showed that participants smoked or chewed betel quid daily are more likely to develop UBUC. Age and estimated glomerular filtration rate (eGFR) are significantly increased the risk of developing UTUC. The association between the eGFR and risk of UTUC is stronger (P < 0.001) for eGFR < 45 (vs. eGFR ≥ 75, OR = 6.795; 95% CI 2.901-15.917). Metabolic syndrome is related to higher risk of UBUC incidence [OR was 1.373 (95% CI 1.104-1.707)]. There was a significant relationship between the incidence of UBUC and metabolic syndrome. Renal function impairment presents higher risk in both UBUC and UTUC development.

Correlation between immunohistochemical expression of Ki-67and P63 and aggressiveness of urinary bladder urothelial carcinoma

ABSTRACT Urothelial carcinoma is the most common urinary malignancy with a wide proportion of cancer morbidity and mortality. The aim of the present study is to evaluate Ki-67 and p63 immunoexpression and their correlation with grade and stage of bladder urothelial carcinoma. Fifty cases of bladder urothelial carcinoma were investigated and were submitted to immunohistochemical staining for p63 and Ki-67, which were assessed qualitatively and quantitatively. A high percentage of p63 immunoexpression showed a significant association with low-grade tumors (P < .05), while Ki-67 mean percentage of expression was higher in high-grade tumors, advanced stage and multiple tumors compared to low grade, early-stage and single tumors without statistical association. Furthermore, the mean percentage of p63 was higher in urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma with an absence of statistical significance. P63 could help in the identification of bladder tumors with squamous differentiation since identifying these cases is important regarding prognostic and therapeutic aspects. Ki 67 seems to be associated with features of bladder tumor progression as multiplicity, high grade and advanced stage.

Prognostic Utility of FBLN2 Expression in Patients With Urothelial Carcinoma.

Background: Abnormal extracellular matrix (ECM) remodeling plays an essential role in urothelial carcinoma (UC) invasiveness and metastasis. Focusing on the ECM structural constituent (GO: 0005201), we recognized a significant upregulation of the fibulin 2 gene (FBLN2) during UC progression in a published UC transcriptome (GSE31684). Thus, we aimed to investigate the roles of FBLN2 expression and its prognostic value in upper urinary tract UC (UTUC) and urinary bladder UC (UBUC) in our large, well-characterized cohort.Patients and Methods: Clinicopathological data and formalin-fixed paraffin-embedded UC tissues were analyzed retrospectively. We determined FBLN2 expression using immunohistochemical staining assessed by H-scores. FBLN2 expression correlated with clinicopathological features and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS). Statistical analyses were performed using Pearson's chi-square test, Kaplan–Meier estimates of DSS and MFS, and the Cox proportional hazards model. We used Ingenuity Pathway Analysis (IPA) to clarify the functional significance of dysregulated FBLN2 in UC.Results: Data from 295 UBUC and 340 UTUC patients were available for the final evaluation. Pearson's chi-square test showed that high FBLN2 immunoexpression significantly correlated with adverse pathologic variables, such as advanced pathologic tumor stage, high histological grade, perineural invasion, vascular invasion, lymph node metastasis, and increased mitotic rate (all p < 0.05). Kaplan–Meier analysis demonstrated associations of high FBLN2 expression with worse DSS (p < 0.001) and MFS (p < 0.001). Furthermore, multivariate analysis identified high FBLN2 expression as an independent predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.306, p = 0.014; in UTUC, 2.561, p = 0.012] and MFS (HR in UBUC, 2.493, p = 0.001; in UTUC, 2.837, p = 0.001). IPA demonstrated that multiple signaling pathways were enriched, including the oxidative phosphorylation, mitochondrial dysfunction, and regulation of the epithelial–mesenchymal transition pathways.Conclusion: High FBLN2 expression was associated with adverse pathologic features and worse oncological outcomes and may serve as a prognostic biomarker for UC.

Androgen receptor expression in the urinary bladder urothelial carcinoma and its relation to known prognostic factors

Objective: The current study was carried out to assess the prognostic value of androgen receptor expression in urothelial carcinoma of the bladder and correlate it to the disease outcome.Methods: Histologically confirmed cases of bladder urothelial carcinoma were studied. Clinical, pathological, and radiological data were collected. Paraffin embedded tissue sections were submitted for hematoxylin and eosin staining, as well as immunohistochemical staining for androgen receptor in tumor cells.Results: Nuclear androgen receptor expression was positive in 75% of the studied histopathological specimens. Additionally, a significant positive association between androgen receptor expression and tumor grade, muscle invasion &amp; tumor size were noticed.Conclusions: There is a significant association between large tumor size, high grade, deep invasion, and expression of Androgen receptor in urothelial bladder carcinoma. Antiandrogen could be an effective chemo preventive or therapeutic approach in treatment of urothelial bladder carcinoma.

Immunohistochemical expression of receptors for luteinizing hormone-releasing hormone (LHRHR) in muscle-invasive Urothelial carcinoma of urinary bladder: a potential predictive marker for targeted cytotoxic LHRH hybrid analogs

BackgroundRecurrent disease following failed chemotherapy for muscle-invasive urothelial carcinoma (UC) has no universally accepted treatment guidelines. Receptors for luteinizing hormone-releasing hormone (LHRHR) have recently been identified in urothelial cancer cell lines as well as tissue samples. These receptors can be used as target for cytotoxic hybrid analogs of LHRH. The aim of this study was to determine the frequency of LHRHR expression in muscle invasive UC by immunohistochemistry.MethodsFifty-two cases, including TURBTs (31) and cystectomies (21), with at least muscle invasive UC were retrieved. Of 52 patients, 41 (78.8%) were male and 11 (21.1%) were female, with age ranging from 50 to 84 years. Immunohistochemical staining for LHRHR antibody (N-20, Santa Cruz, 1:50) was performed using the LSAB method. Membranous and/or granular cytoplasmic staining was considered as a positive reaction. Scoring was based on the percentage of positive tumor cells; negative (no staining), 1+ (1–25%), 2+ (26–50%), 3+ (51–75%), 4+ (> 75%).ResultsOf 52 UC cases, 32 (61%) were AJCC stage T2, 17 (33%) were T3, and 3 (6%) were T4. Of 52 cases, 30 (58%) were positive and 22 (42%) were negative for LHRHR. Of the 30 positive cases, 16 (53%) were scored 1+, 7 (23%) 2+, 5 (17%) 3+ and 2 (7%) 4 + .ConclusionsMore than half of the cases expressed LHRHR. Two-thirds of cases demonstrated focal (< 50%) immunoreactivity, which may cause false negative results in limited tissue samples. Immunohistochemical expression of LHRHR in UC can be a predictive marker for potential efficacy of LHRH cytotoxic hybrid analogs.