This study aimed to evaluate the diagnostic and prognostic roles of GATA3 immunohistochemistry in urothelial carcinoma (UC) through a meta-analysis. We investigated GATA3 immunohistochemical expression rates and performed a subgroup analysis based on tumor site, study location, and histological subtypes. The overall survival rates of patients with GATA3-positive and negative UC were compared. The estimated GATA3 expression rate was 0.748 (95% confidence interval [CI]: 0.704–0.787). GATA3 expression rates in the urinary bladder and urinary tract were 0.775 (95% CI: 0.727–0.818) and 0.614 (95% CI: 0.426–0.774), respectively. The GATA expression rates of noninvasive and invasive UCs were 0.965 (95% CI: 0.938–0.980) and 0.644 (95% CI: 0.581–0.702), respectively. In invasive UCs, there was a significant difference in GATA3 expression between non-muscular invasion and muscular invasion subgroups (0.937, 95% CI: 0.883–0.967 vs. 0.753, 95% CI: 0.645–0.836). GATA3 expression was the highest in the microcytic subtype among the histologic subtypes (0.952, 95% CI: 0.724–0.993). There was a significant correlation between GATA3 expression and better prognosis (hazard ratio: 0.402, 95% CI: 0.311–0.521). Taken together, GATA3 expression significantly correlated with low-stage and better prognosis in UC. GATA3 expression is highly variable across histological subtypes and it is careful interpreting GATA3 expression.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

Background Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who previously received platinum-based chemotherapy and immune checkpoint inhibitors. The EV-301 phase III trial demonstrated a significantly improved overall survival and response rates compared with standard chemotherapy. However, more data, especially from larger real-world studies, are needed to assess its effectiveness in Japanese patients. Methods A total of 6,007 urothelial cancer patients treated with pembrolizumab as second-line treatment were analyzed. Among them, 619 patients received enfortumab vedotin after pembrolizumab, while 394 received docetaxel or paclitaxel after pembrolizumab. Results The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p=0.013, hazard ratio: 0.71). In the multivariate analysis, enfortumab vedotin induction was an independent risk factor for the overall survival (p=0.013, hazard ratio: 0.70). There were no significant differences in the cancer-specific survival. Conclusions Enfortumab vedotin prolonged the overall survival in Japanese patients with advanced or metastatic urothelial carcinoma compared with paclitaxel or docetaxel after pembrolizumab treatment.

Background: The incidence of intravesical recurrence (IVR) following radical nephroureterectomy (RNU) is reported in up to 50% of patients with upper tract urothelial carcinoma (UTUC). It was suggested that preoperative diagnostic ureteroscopy (URS) could increase the IVR rate after RNU, however, the available data are often conflicting. Thus, in this systematic review and meta-analysis we sought to synthesize that available data for the impact of pre-RNU URS for UTUC on IVR and other oncological outcomes; Materials and methods: A systematic literature search of the PubMed, Embase and Cochrane Library databases was performed in June 2020. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CI) were conducted. The primary endpoint was intravesical recurrence-free survival (IVRFS), with the secondary endpoints being cancer-specific survival (CSS), overall survival (OS), and metastasis-free survival (MFS); Results: Among a total of 5489 patients included in the sixteen selected papers, 2387 (43.4%) underwent diagnostic URS before RNU and 3102 (56.6%) did not. Pre-RNU diagnostic URS was significantly associated with worse IVRFS after RNU (HR=1.44, 95% CI: 1.29-1.61, p<0.001) than RNU alone. However, subgroup analysis including patients without biopsy during URS revealed no significant impact of diagnostic URS on IVRFS (HR=1.28, 95% CI: 0.90-1.80, p=0.16). The results of other analyses showed no significant differences in CSS (HR=0.94, p=0.63), OS (HR: 0.94, p=0.56), and MFS (HR: 0.91, p=0.37) between patients who underwent URS before RNU and those who did not. Conclusions: The results of this meta-analysis confirm that diagnostic URS prior to RNU is significantly associated with worse IVRFS, albeit with no concurrent impact on the other long-term survival outcomes. Our results indicate that URS has a negative impact on IVRFS only when combined with endoscopic biopsy. Future studies are warranted to assess the role of immediate postoperative intravesical chemotherapy in patients undergoing biopsy during URS for suspected UTUC.

Urinary cytology is a useful, essential diagnostic method in routine urological clinical practice. Liquid-based cytology (LBC) for urothelial carcinoma screening is commonly used in the routine clinical cytodiagnosis because of its high cell collection rate. Since conventional screening processes by cytoscreeners and cytopathologists using microscopes is limited in terms of human resources, it is important to integrate new deep learning methods that can automatically and rapidly diagnose a large amount of specimens without delay. The goal of this study was to investigate the use of deep learning models for the classification of urine LBC whole-slide images (WSIs) into neoplastic and non-neoplastic (negative). We trained deep learning models using 786 WSIs by transfer learning, fully supervised, and weakly supervised learning approaches. We evaluated the trained models on two test sets (equal and clinical balance) with a combined total of 750 WSIs, achieving ROC-AUCs for WSI diagnosis in the range of 0.984-0.990 by the best model, demonstrating the promising potential use of our model for aiding urine cytodiagnostic processes.

This study aimed to evaluate the diagnostic roles of various immunohistochemical markers in urothelial carcinoma in situ (uCIS) through a meta-analysis and review of diagnostic test accuracy. Immunohistochemical markers CK20, CD44, AMACR, and p53 were evaluated in the present study. We analyzed the expression rates of immunohistochemical markers and compared their diagnostic accuracies. The estimated expression rates were 0.803 (95% confidence interval [CI]: 0.726–0.862), 0.142 (95% CI: 0.033–0.449), 0.824 (95% CI: 0.720–0.895), and 0.600 (95% CI: 0.510–0.683) for CK20, CD44, AMACR, and p53, respectively. In the comparison between uCIS and reactive/normal urothelium, the expression of CK20, AMACR, and p53 in uCIS was significantly higher than in reactive/normal urothelium. CD44 showed significantly lower expression in uCIS than in the reactive/normal urothelium. Among the markers, AMACR had the highest sensitivity, specificity, and diagnostic odds ratio. The AUC on SROC was the highest for CK20. In conclusion, immunohistochemical markers, such as CK20, CD44, AMACR, and p53, can be useful in differentiating uCIS from reactive/normal urothelium.

We performed urine cytology analysis of a pharmacologically induced diuresis for diagnostics of upper tract urothelial carcinoma. To evaluate the diagnostic value of cytology of pharmacologically forced diuresis, a first cohort of 77 consecutive patients with primary upper tract urothelial carcinoma treated with radical surgery was enrolled. To evaluate pharmacologically forced diuresis cytology as follow-up procedure, a second cohort of 1250 patients who underwent radical cystectomy for bladder cancer was selected. In the first cohort, sensitivity of cytology of pharmacologically forced diuresis in patients with invasive, high-grade, low-grade, and concomitant carcinoma in situ was 8%, 9%, 0% and 14%, respectively. In the second cohort, cytology of pharmacologically forced diuresis was positive in 30/689 (4.3%) of patients, in whom upper urinary tract recurrence was present in 21/30 (70%) and urethral recurrence in 8/30 (26%) of cases. As a follow-up tool, cytology of pharmacologically forced diuresis showed a sensitivity, specificity, and positive and negative predictive value of 60%, 99%, 70% and 98%, respectively. Summarized, as diagnostic tool, sensitivity of cytology of pharmacologically forced diuresis is slightly better in patients with invasive upper tract urothelial carcinoma and concomitant carcinoma in situ. As follow-up method, positive cytology of pharmacologically forced diuresis is strongly related to cancer recurrence and can reveal urethral recurrence. cytology of pharmacologically forced diuresis might be useful in patients with contraindications for imaging or with difficult endoscopic access to the upper urinary tract.

Background: Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC) and inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1ß and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. Design, Setting, and Participants: The study included two independent cohorts of n=92 and n=102 patients who underwent radical cystectomy for BC. Specimen from BC and benign urothelium (n=22 and n=39) were processed to a tissue microarray and immunohistochemically stained for IL-1ß, IL-1RA, AKT and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. Outcome measurements and statistical analysis: Association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Results: Both, IL-1ß and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p<0.005). IL-1ß was associated with vascular invasion (210 vs. 183, p<0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). Survival analysis revealed favorable RFS, CSS, and OS in case of high IL-1ß expression (p<0.02, <0.03 and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1ß expression on RFS, CSS and OS. IL-1ß and IL-1ß/IL-1RA ratio were positively correlated to AKT expression (p<0.05 and <0.01, respectively). Additionally, high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p=0.01). Conclusions: Overexpression of IL-1ß and IL-1RA is frequently found in BC, with a prognostic significance observed for IL-1ß protein expression. The observed link between the IL-1ß / IL-1RA axis and AKT signaling may indicate possible autophagy activation processes beside the known tumor-promoting effects of AKT.

Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, indicates patient frailty and impaired physical function. Sarcopenia can be caused by multiple factors, including advanced age, lack of exercise, poor nutritional status, inflammatory diseases, endocrine diseases, and malignancies. Recently, growing evidence has indicated the importance of sarcopenia in the management of patients with various cancers. Sarcopenia is associated with not only higher rates of treatment-related complications but also worse prognosis in cancer-bearing patients. In this article, we conducted a systematic literature review regarding the significance of sarcopenia as a prognostic biomarker of bladder cancer. We also reviewed recent studies focusing on the prognostic role of changes in skeletal muscle mass during the course of treatment in bladder cancer patients.

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neo-plasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched Pubmed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors, and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further pre-clinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

Inflammation is widely acknowledged as a significant characteristic of cancer, playing a substantial function in both the initiation and advancement of cancers. In this research, we planned to investigate the comparison among pan-immune inflammation markers and other well-known markers (systemic immune inflammation index and neutrophil to lymphocyte ratio) to predict prognosis in individuals treated with radical cystectomy for bladder cancer. Methods: In this retrospective analysis, we focused on preoperative PIV, systemic immune inflammation index (SII), and neutrophil-lymphocyte ratio (NLR) in 193 individuals managed with radical cystectomy for bladder cancer between January 2016 and November 2022. Multivariable logistic regression assessments were perfomred to assess the predictive capabilities of PIV, SII, and NLR for infiltration of lymph nodes (N), aggressive tumor stage (pT3/pT4), and any non-organ limited disease at the time of RC. Multivariable Cox regression analyses were conducted to assess the predictive impact of PIV on Relapse-free survival (RFS), Cancer-specific survival (CSS), and Overall survival (OS). Results: Our individuals were divided into high PIV and low PIV cohorts using the optimal cut-off value (340.96 x 109/ L) based on receiver operating characteristic curve analysis for relapse-free survival. In multivariable preoperative logistic regression models, only SII and PIV correlated with the infiltration of lymph nodes, aggressive disease, and any non-organ confined disease. In multivariable Cox regression models considering presurgical clinicopathological variables, an higher PIV was associated with diminished RFS (p = 0.017) and OS (p = 0.029). In addition, in multivariable Cox regression models for postoperative outcomes, a high PIV correlated with both RFS ( p = 0.034) and OS ( p= 0.048). Conclusions: Our study suggests that PIV and SII are two very similar markers that may serve as an independent and significant predictor of aggressive disease and worse survival impacts on individuals undergoing radical cystectomy for bladder neoplasm.

Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have favorable prognosis and quality of life with preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting clinical outcomes of chemoradiation-based BPT. Biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both chemoradiation response and prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients.

Carboxypeptidase A4 (CPA4) has shown the potential possibility as a biomarker in the early diagnosis for certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via TIMER2，STRING and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA+GETx database. The connection between CPA44 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan-Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared to matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that overexpression of CPA4 is linked with shorter OS, DSF, PFI, and increased diagnostic potential using Kaplan-Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes, while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.

Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in natural killer (NK) cells because they are important, but often overlooked anti-cancer lymphocytes.

Background: Micro-RNAs (miRNA) are emerging as biomarkers in the detection and prognosis of cancers due to their inherent stability and resilience. Methods: To summarize evidence regarding urinary miRNA (umiRNAs) role in the detection, prognosis and therapeutic management of urological cancers, we performed a systematic review of the most important scientific databases using the following keywords: (urinary mir-na)AND(prostate cancer); (urinary mirna)AND(bladder cancer); (urinary mirna)AND(renal cancer); (urinary mirna)AND(testicular cancer); (urinary mirna)AND(urothelial cancer). Results: Of all, 1364 articles were initially selected. Only original studies in the English language on human specimens were considered for inclusion in our systematic review. Thus, a convenient sample of 60 original articles was identified. Urinary miRNA (UmiRNAs) are downregulated in prostate cancers and may serve as potential non-invasive molecular biomarkers. Several umiR-NAs have been identified as diagnostic biomarkers of urothelial carcinoma and bladder cancer (BCa), allowing to discriminate malignant from non-malignant forms of haematuria. UmiRNAs could serve as therapeutic targets or recurrence markers of non-muscle invasive BCa and could predict the aggressivity and prognosis of muscle-invasive BCa. In renal cell carcinoma, miRNAs have been identified as predictors of tumour detection, aggressiveness, and progression to metastasis. Conclusion: umiRNAs could play an important role in the diagnosis, prognosis, and therapy of urological cancers.

Nowadays molecular research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and tumor cells. Signal transducer and activator of transcription 3 (STAT3) belongs to the family of latent cytoplasmic transcription factors called STATs which comprises seven members: STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. Those proteins play important role in cytokine-activated gene expression by transducing signals from the cell membrane to the nucleus. Abnormal prolonged activation results in tumorigenesis, metastasis, cell proliferation, invasion, migration and angiogenesis. Inhibition of this transcription factor inhibits previously mentioned effects in cancer cells whereas normal cells are not affected. Hence STAT3 might be a viable target for cancer therapy.

Patients with pT1 high-grade (HG) bladder cancer (BC) and a very high risk of progression might benefit from immediate radical cystectomy (RC), but this option remains controversial. Validation of a standardized method to evaluate the extent of lamina propria (LP) invasion (with recognized prognostic value) in transurethral resections (TURBT) specimens is still needed. The Rete Oncologica Lombarda (ROL) system showed a high predictive value for progression after TURBT in recent retrospective studies. Our aim was to validate ROL system on a large mono-institutional prospective series of primary urothelial carcinomas. From 2016 to 2020, we adopted ROL for all patients with pT1 HG BC on TURBT. We employed a 1.0-mm threshold to stratify tumors in ROL1 and ROL2. A total of 222 pT1HGBC were analyzed. Median age was 74 years, with male predominance (73.8%). ROL was feasible in all cases: 91 cases were ROL1 (41%) and 131 ROL2 (59%). At a median follow up of 26.9 months (IQR 13.8-40.6), we registered 80 recurrences and 40 progressions. ROL was a significant predictor of tumor progression at both univariable (HR 3.53; CI 95% 1.56 – 7.99; p<0.01) and multivariable (HR 2.90; CI 95% 1.25 – 6.75; p=0.01) Cox regression analyses. At Kaplan-Meier estimates, ROL showed correlation with both PFS (p=0.0012) and RFS (p=0.0167). Our results confirmed the strong predictive value of ROL for progression on a large prospective series. We encourage the application of ROL for reporting the extent of LP invasion, substaging T1 HG BC, and improving risk tables for urological decision making.