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Biomedical Papers of the Medical... Sep 2021Cancer 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...
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.
Topics: Biomarkers, Tumor; CD24 Antigen; Carcinoma, Transitional Cell; Humans; Neoplastic Stem Cells; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 32424373
DOI: 10.5507/bp.2020.017 -
BMC Urology Dec 2022In this study we investigated the expression of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen...
BACKGROUND
In this study we investigated the expression of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) to analyze their potency as targets for the detection of lymph node (LN) metastases of urothelial carcinoma of the bladder.
METHODS
Antigen expression was determined in 40 samples with urothelial carcinoma and compared to 17 matched samples without metastases by immunohistochemistry. The total immunostaining score (TIS 0-12) was determined as the product of a proportion score (PS 0-4) and intensity score (IS 0-3).
RESULTS
VEGF expression was high in primary tumor and LN metastases (median TIS 8 in both) and VEGF expression was also seen in LNs without metastases (median TIS 6). EGFR expression was low in primary tumor and LN metastases (median TIS 3 and 2 respectively) and absent in LNs without metastases. PSMA expression was low in samples with urothelial carcinoma (median TIS 2).
CONCLUSION
VEGF shows moderate to high expression levels in both primary tumors and LN metastases and could be a candidate as a target agent for imaging modalities of urothelial carcinoma. EGFR and PSMA do show low staining levels in tumor tissue with urothelial carcinoma and do not seem suitable as target agents.
TRIAL REGISTRATION
The Medical Ethics Review Board of the University Medical Center Groningen approved this study on 14 December 2017 (METc UMCG 2017/639). Trial registration number (UMCG Research Register): 201700868.
Topics: Humans; Carcinoma, Transitional Cell; ErbB Receptors; Lymph Nodes; Lymphatic Metastasis; Urinary Bladder; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A
PubMed: 36581931
DOI: 10.1186/s12894-022-01157-7 -
Molecular Genetics and Genomics : MGG Nov 2022We sought to examine epigenetic inactivation of DNA damage repair (DDR) genes as prognostic and predictive biomarkers for urothelial bladder cancer (UBC) as there are...
We sought to examine epigenetic inactivation of DNA damage repair (DDR) genes as prognostic and predictive biomarkers for urothelial bladder cancer (UBC) as there are currently no reliable prognostic biomarkers that identify UBC patients who would benefit from chemotherapy. Genome-wide DNA methylome using the cancer genome atlas-bladder cancer (TCGA-BLCA) datasets (primary tumors = 374 and normal tissues = 37) was performed for 154 DDR genes. The most two significant differentially methylated genes, Retinoblastoma binding protein 8 (RBBP8) and MutS homologue 4 (MSH4), between primary tumors and normal tissues of TCGA-BLCA were validated by methylation-specific PCR (MSP) in UBC (n = 70) compared to normal tissues (n = 30). RBBP8 and MSH4 expression was measured using qRT-PCR. We developed a predictive model for therapeutic response based on the RBBP8- and MSH4-methylation along with patients' clinical features. Then, we assessed the prognostic significance of RBBP8 and MSH4. RBBP8- and MSH4 methylation and corresponding gene downregulation significantly associated with muscle-invasive phenotype, prolonged progression-free survival (PFS) and increased susceptibility to cisplatin chemotherapy in UBC. Promoter methylation of RBBP8 and MSH4 was positively correlated with each other and with their corresponding gene repression. The best machine-learning classification model predicted UBC patients' response to cisplatin-based chemotherapy with an accuracy of 90.05 ± 4.5%. Epigenetic inactivation of RBBP8 and MSH4 in UBC could sensitize patients to DNA-damaging agents. A predictive machine-learning modeling approach based on the clinical features along with RBBP8- and MSH4-methylation might be a promising tool for stratification of UBC responders from nonresponders to chemotherapy.
Topics: Humans; Urinary Bladder Neoplasms; Cisplatin; Prognosis; Urinary Bladder; Biomarkers, Tumor; Epigenesis, Genetic; DNA Repair; Retinoblastoma Binding Proteins; Carcinoma; DNA Methylation
PubMed: 36076047
DOI: 10.1007/s00438-022-01950-x -
Aging Apr 2023Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder...
Urinary bladder urothelial carcinoma (UBUC) encompasses about 90% of all bladder cancer cases, and the mainstream treatment is the transurethral resection of the bladder tumor followed by intravesical instillation. High rates of mortality, recurrence, and progression in bladder cancer have stimulated the search for alternative adjuvant therapies. The aim of this study was to investigate the potential of melatonin as adjuvant therapy in bladder cancer. Cell viability and clonogenic ability were assessed by an MTT assay and colony formation. Cell cycle and apoptosis analysis were performed by flow cytometry and Hoechst 33342 staining, while cell metastasis capacity was measured by wound healing and transwell assays. Potential mechanisms were investigated by an oncology array and verified via western blotting. The melatonin treatment significantly reduced T24 and UMUC3 bladder cancer cell proliferation and clonogenic ability. G1 arrest and sub-G1 accumulation in the T24 and UMUC3 cells led to cell proliferation suppression and cell death, and Hoechst 33342 staining further verified the apoptosis induction directly by melatonin. Moreover, melatonin weakened cell motility and invasiveness. Based on the oncology array results, we demonstrated that melatonin exerts its anti-cancer effect by down-regulating the HIF-1α and NF-κB pathways and downstream pathways, including Bcl-2, leading to cell cycle arrest and apoptosis induction in the UBUC cells. Overall, these findings support the potential of melatonin as adjuvant therapy in bladder cancer.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Melatonin; Urinary Bladder; Cell Line, Tumor; Cell Cycle Checkpoints; Cell Proliferation; Cell Cycle; Apoptosis; Cell Movement
PubMed: 37086261
DOI: 10.18632/aging.204673 -
International Braz J Urol : Official... 2021
Topics: Carcinoma; Cystectomy; Feasibility Studies; Fiducial Markers; Humans; Muscles; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 33047915
DOI: 10.1590/S1677-5538.IBJU.2019.0713.1 -
Medicine Jul 2020Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We... (Review)
Review
INTRODUCTION
Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We summarized the clinicopathological features, immunophenotype, diagnosis, and differential diagnosis of this type of bladder cancer, in order to improve the understanding of surgeons and pathologists.
PATIENT CONCERNS
An 83-year-old female presented with hematuria and frequent micturition, without odynuria, hypogastralgia, or fever.
DIAGNOSIS
The computed tomography scan demonstrated extensive tumors in the anterior wall of the bladder and a soft tissue shadow anterior to the sacrum. Cystoscopy showed massive wide-based tumors located on the anterior and lateral walls of the bladder, with no tumor involving the bladder neck. Multiple punch biopsies were performed, the histologic evaluation of which revealed a poorly differentiated invasive UCs with myxoid stroma.
INTERVENTIONS
The patient underwent a laparoscopic radical cystectomy and cutaneous ureterostomy.
OUTCOMES
The patient discharged without any complications. Histologic evaluation revealed an invasive UC; the most prominent feature was an abundant myxoid stroma that covered approximately 80% of the lesion and the tumor cells were arranged in cords, small nests, or a sheet-like structure. Immunohistochemically, the tumor cells were positive for CK19, CK20, VEGF, EGFR, p63, 34βE12, MUC1, GATA3, uroplakin3, and TopII (rate = 15%), while the Ki-67 proliferation index was 10%. The myxoid stroma in the mesenchyme stained positively with AB-PAS and colloidal iron, and some tumor cells stained positive for colloidal iron. Considering the histologic, histochemical, and immunohistochemical findings, a diagnosis of UC with abundant myxoid stroma was made. After surgery, the regular follow-up was continued in clinic, and there was no recurrence for 2 years.
CONCLUSION
Morbidity associated with UC with abundant myxoid stroma is very low. The diagnosis mainly depends on histopathological and immunohistochemical findings.
Topics: Aged, 80 and over; Biopsy; Carcinoma, Transitional Cell; Cystectomy; Cystoscopy; Diagnosis, Differential; Female; Humans; Immunophenotyping; Urinary Bladder; Urinary Bladder Neoplasms; Urologic Neoplasms; Urothelium
PubMed: 32664169
DOI: 10.1097/MD.0000000000021204 -
The Journal of Urology Feb 2022There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer.
Management Trends and Outcomes of Patients Undergoing Radical Cystectomy for Urothelial Carcinoma of the Bladder: Evolution of the University of Southern California Experience over 3,347 Cases.
PURPOSE
There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer.
MATERIALS AND METHODS
Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models.
RESULTS
In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001).
CONCLUSIONS
Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.
Topics: Academic Medical Centers; Aged; California; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cystectomy; Disease-Free Survival; Female; Humans; Lymph Node Excision; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prospective Studies; Retrospective Studies; Robotic Surgical Procedures; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 34994657
DOI: 10.1097/JU.0000000000002242 -
Clinics (Sao Paulo, Brazil) 2021Whole genome expression profiles allow the stratification of bladder urothelial carcinoma into basal and luminal subtypes which differ in histological patterns and...
Combined use of immunohistochemical markers of basal and luminal subtypes in urothelial carcinoma of the bladder: Association with clinicopathological features and outcomes.
OBJECTIVES
Whole genome expression profiles allow the stratification of bladder urothelial carcinoma into basal and luminal subtypes which differ in histological patterns and clinical behavior. Morpho-molecular studies have resulted in the discovery of immunohistochemical markers that might enable discrimination between these two major phenotypes of urothelial carcinoma.
METHODS
We used two combinations of immunohistochemical markers, i.e., cytokeratin (CK) 5 with CK20 and CK5 with GATA3, to distinguish subtypes, and investigated their association with clinicopathological features, presence of histological variants, and outcomes. Upon searching for tumor heterogeneity, we compared the findings of primary tumors with their matched lymph node metastases. We collected data from 183 patients who underwent cystectomy for high-grade muscle-invasive urothelial carcinoma, and representative areas from the tumors and from 76 lymph node metastasis were organized in tissue microarrays.
RESULTS
Basal immunohistochemical subtype (CK5 positive and CK20 negative, or CK5 positive and GATA3 negative) was associated with the squamous variant. The luminal immunohistochemical subtype (CK5 negative and CK20 positive, or CK5 negative and GATA3 positive) was associated with micropapillary and plasmacytoid variants. Remarkably, only moderate agreement was found between the immunohistochemical subtypes identified in bladder tumors and their lymph node metastasis. No significant difference in survival was observed when using either combination of the markers.
CONCLUSION
This study demonstrates that these three routinely used immunohistochemical markers could be used to stratify urothelial carcinomas of the bladder into basal and luminal subtypes, which are associated with several differences in clinicopathological features.
Topics: Biomarkers, Tumor; Carcinoma, Transitional Cell; Humans; Prognosis; Retrospective Studies; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 33909826
DOI: 10.6061/clinics/2021/e2587 -
Scientific Reports Apr 2023Recurrence and progression rates vary widely among different histological subtypes of bladder cancer (BC). Normal-appearing mucosa in non-muscle invasive bladder cancer...
Recurrence and progression rates vary widely among different histological subtypes of bladder cancer (BC). Normal-appearing mucosa in non-muscle invasive bladder cancer and muscle-invasive bladder cancer in cystoscopy and histopathology is a factor in staging and treatment. Telocytes (TCs) are spindle-shaped cells that connect with other cell types allowing communication though cytoskeletal signaling. They are involved in tissue regeneration and pathogenesis of diseases and cancer. In this study, 12 normal-appearing tissues from urinary bladder with BC, both invasive and non-invasive were evaluated in patients who had either trans-urethral resection of bladder tumor or cystectomy. In each case, cystoscopy, intraoperative inspection, and histopathology all confirmed the absence of cancerous elements. Five patients with neurogenic bladder were used as a control group. Immunohistochemistry revealed that c-Kit + cells were intensively distributed in bladder layers from BC samples, while they were seldom detected in the control group. Ultrastructural examination of reprocessed tissue showed an intense distribution of TCs and telopodes in the submucosa and between smooth muscle cells in BC. Telopodes were numerous, arborizing, and intercommunicating. Whereas TCs and telopodes were scarce in the neurogenic bladder. Also, cancerous tissue had the highest expression level of ezrin protein, and this level gradually decreased as we moved away from the tumor. Our finding of TCs number in normal-appearing tissues in conjunction with ezrin expression may compete invasiveness and possibly a trail to reduce recurrence rates.
Topics: Humans; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Telocytes; Neoplasm Invasiveness
PubMed: 37061568
DOI: 10.1038/s41598-023-33282-0 -
Cancer Medicine Nov 2022Given the low incidence of urachal carcinoma of the bladder (UCB), there is limited published data from contemporary population-based cohorts. This study aimed to...
BACKGROUND
Given the low incidence of urachal carcinoma of the bladder (UCB), there is limited published data from contemporary population-based cohorts. This study aimed to describe demographic, clinicopathological features, and survival outcomes of patients diagnosed with UCB.
METHODS
The National Cancer Database (2004-2016) was queried for UCB patients. Descriptive analyses characterized demographics and clinicopathologic features. We assessed 5-year overall survival (OS) rates of the entire cohort and subgroups of localized/locally advanced and metastatic disease. We utilized Cox proportional hazards models to assess the association between covariates of interest and all-cause mortality and to examine the impact of surgical technique and chemotherapy.
RESULTS
We identified 841 patients with UCB. The most common histologic subtype was non-mucinous adenocarcinoma (39.6%). Approximately 50% had ≥cT2 disease, and 14.3% were metastatic at diagnosis. Altogether, partial cystectomy (60%) was most performed, and lymph node dissection was performed in 377 patients (44.8%), with specific temporal increase in utilization over the study period (p < 0.001). Overall, median OS was 59 months, and 5-year OS was 49%. In patients with localized/locally advanced disease, we found no association between partial and radical cystectomy (Hazards ratio [HR] 1.75; 95% CI 0.72-4.3) as well as receipt of perioperative chemotherapy (HR 1.97, 95% CI 0.79-4.90) and outcomes. Lastly, receipt of systemic therapy was not associated with survival benefit (HR 0.785, 95% CI 0.37-1.65) in metastatic disease cohort.
CONCLUSION
This large population-based cohort provides insight into the surgical management and systemic therapy, without clear evidence on the association of chemotherapy and survival in the perioperative and metastatic setting.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder; Neoplasm Staging; Urinary Bladder Neoplasms; Cystectomy; Retrospective Studies
PubMed: 35509235
DOI: 10.1002/cam4.4786