Muscle-invasive Bladder Tumors Research Articles

Latrophilin-3 as a downstream effector of the androgen receptor induces bladder cancer progression

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.

Nucleocytoplasmic β-catenin expression contributes to neuroendocrine differentiation in muscle invasive bladder cancer.

Bladder cancers are heterogeneous in nature, showing diverse molecular profiles and histopathological characteristics, which pose challenges for diagnosis and treatment. However, understanding the molecular basis of such heterogeneity has remained elusive. This study aimed to elucidate the molecular landscape of neuroendocrine-like bladder tumors, focusing on the involvement of β-catenin localization. Analyzing the transcriptome data and benefiting from the molecular classification tool, we undertook an in-depth analysis of muscle-invasive bladder cancers to uncover the molecular characteristics of the neuroendocrine-like differentiation. The study explored the contribution of transcription factors and chromatin remodeling complexes to neuroendocrine differentiation in bladder cancer. The study revealed a significant correlation between β-catenin localization and neuroendocrine differentiation in muscle-invasive bladder tumors, highlighting the molecular complexity of neuroendocrine-like tumors. Enrichment of YY1 transcription factor, E2F family members, and Polycomb repressive complex components in β-catenin-positive tumors suggest their potential contribution to neuroendocrine phenotypes. Our findings contribute valuable insights into the molecular complexity of neuroendocrine-like bladder tumors. By identifying potential therapeutic targets and refining diagnostic strategies, this study advances our understanding of endocrinology in the context of bladder cancer. Further investigations into the functional implications of these molecular relationships are warranted to enhance our knowledge and guide future therapeutic interventions.

Bladder tumor ablation with 980-nm and 980-/1470-nm diode lasers: a retrospective study

Abstract Purpose This study evaluated the safety and feasibility of ablation of both non-muscle invasive and muscle invasive bladder tumors using single- and dual-wavelength diode lasers (980 nm and 980/1470 nm). Methods We retrospectively examined 151 patients with bladder tumors of any type from 2009 to 2021 who underwent V-LABT (visual laser ablation of bladder tumor) with both single- and dual-wavelength diode lasers at Shalamar Hospital Lahore, Pakistan. All procedures were performed by the same surgeon. Shalamar Medical and Dental College review board approved this retrospective cohort study (IRB No. -623-2023). The collected clinical data were consolidated into a single group, encompassing various variables such as the patients’ age, tumor size, number of tumors, tumor location, tumor grade, ablation duration, postoperative catheterization time, bladder discomfort, obturator nerve reflex, intraoperative and postoperative complications, and recurrence of tumors at the ablation sites. The patients were monitored for a minimum of 12 months to observe recurrence at the ablation sites through cystoscopy performed postoperatively every three months. The data were analyzed using Chi-square test, and p value < 0.05 was considered significant. Results The average age of the 151 patients was found to be 64.72 ± 13.85 years. The size of the tumors was 4.88 ± 2.16 cm, with 48/151 (31.7%) patients having tumors larger than 3 cm. Among the cases studied, 117/151 (77.4%) patients had a single tumor, while the remaining patients had multiple tumors ranging in size from 5 to 7 cm in aggregate. Ablation took 1.57 ± 0.73 h to complete on average. None of the patients required a conversion to TURBT in 151 patients. No obturator reflexes or bladder perforations were observed in any case. Postoperatively, histopathology results showed 53/151 (35%) and 92/151 (60.9%) high- and low-grade tumors. The average catheterization duration was 6.58 ± 1.47 days. Tumors located on difficult sites, such as the anterior wall, lateral wall, and bladder neck, were ablated with ease. There was no recurrence seen on previously tumor ablated sites till 12-month follow-up. Conclusion Ablation of bladder tumors of any type using single- or dual-wavelength diode laser (980 nm and 980/1470 nm) is safe and feasible. These lasers possess the capability to effectively ablate/coagulate bladder tumors in challenging anatomical locations including diverticular tumors with minimal difficulty.

Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation.

Bladder cancer is one of the most common cancer types worldwide. Generally, research relies on invasive sampling strategies. Here, we generate bladder cancer organoids directly from urine (urinoids). In this project, we establish 12 urinoid lines from 22 patients with non-muscle and muscle-invasive bladder tumours, with an efficiency of 55%. The histopathological features of the urinoids accurately resemble those of the original bladder tumours. Genetically, there is a high concordance of single nucleotide polymorphisms (92.56%) and insertions & deletions (91.54%) between urinoids and original tumours from patient 4. Furthermore, these urinoids show sensitivity to bladder cancer drugs, similar to their tissue-derived organoid counterparts. Genetic analysis of longitudinally generated tumoroids and urinoids from one patient receiving systemic immunotherapy, identify alterations that may guide the choice for second-line therapy. Successful treatment adaptation was subsequently demonstrated in the urinoid setting. Therefore, urinoids can advance precision medicine in bladder cancer as a non-invasive platform for tumour pathogenesis, longitudinal drug-response monitoring, and therapy adaptation.

Interobserver agreement for the Vesical Imaging-Reporting and Data System (VI-RADS) in differentiating non-muscle-invasive and muscle-invasive urinary bladder tumors

BackgroundBladder cancer is the most common tumor of the genitourinary tract. Transitional cell carcinoma is divided into two categories: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). In spite of the high recurrence rate, NMIBC has good prognosis, while MIBC has poor prognosis due to local organ invasion and metastases. Mp-MRI shows better tumor detection and staging. The aim of this study is to validate VI-RADS in detecting MIBC and assessing interobserver agreement and impact of reader's experience.ResultsAt cutoff value of VI-RADS score ≥ 3, the VI-RADS showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 96.8%,83.3%, 93.8%, 90.9%, and 93%, respectively, for reader 1, 93.5%, 91.7%, 84.6%, and 93% for reader 2, and 96.8%,83.3%, 93.8%, 90.9%, and 93% for reader 3. The interobserver agreement between individual readers was excellent among the three readers.ConclusionsVesical imaging-reporting and data system (VI-RADS) is a good method showing satisfactory sensitivity, specificity, and diagnostic value for detecting detrusor muscle invasion.

Pilot study on quantifying the epithelial/mesenchymal hybrid state in the non-muscle invasive and muscle invasive bladder tumors: A promising marker of diagnosis and prognosis

BackgroundManifestation of epithelial-to-mesenchymal transition (EMT) program in tumor cells is associated with the occurrence of multiple intermediate phenotypic states namely epithelial (E), mesenchymal (M) and hybrid E/M across the epithelial-mesenchymal spectrum and these states exhibit different invasive properties. Understanding the cellular and molecular mechanisms defining the E/M hybrid state of the cells during bladder tumor development may significantly aid in the identification of novel diagnostic and prognostic markers. Materials and methodsThe present study is taken up to identify hybrid E/M score based on the immunohistochemical localization and surface expressions of epithelial proteins [E-cadherin and Beta-catenin] and mesenchymal marker proteins [N-cadherin and Vimentin] on formalin fixed paraffin embedded tumor sections of the prospective series of 99 non-muscle invasive bladder cancer (NMIBC) and 87 muscle invasive bladder cancer (MIBC) patients. E/M score was then statistically examined with patients’ demographics to assess its potential in the diagnosis and prognosis of UCB patients. ResultsAmong the E (E-cadherinhigh, β-cateninhigh), hybrid E/M (E-cadherinlow, β-cateninlow, N- cadherinhigh and Vimentinhigh) and M (N-cadherinhigh and Vimentinhigh) phenotypes, E/M phenotype was observed to be more prevalent in MIBC compared to E phenotype in NMIBC subtype. The current study reports the statistical association of tumor stage and tumor grade with the hybrid E/M state of urothelial tumor cells across both the subtypes. Hybrid E/M phenotype in MIBC patients was significantly shown to lower the overall survival time period compared to NMIBC patients. This supports the contribution of hybrid E/M state of tumor cells to the.aggressiveness of the disease. ConclusionsCharacterizing the hybrid E/M state instead of all or none phenotype becomes an imperative to understand the dynamics of EMT and MET in the tumor pathophysiology of NMIBC and MIBC subtypes, and could contribute to better patient stratification and therapeutic strategies.

Outcome of radical cystectomy in remote area of Pakistan: Recep Tayyip Erdogan Hospital, Muzaffargarh (IHHN)

Background: Radical cystectomy with bilateral pelvic lymphadenectomy is the standard treatment for high grade/ muscle invasive urinary bladder tumor. Continent or incontinent urinary diversion is the part of this major operation. High volume centers perform routinely but low volume centers do less frequent. It might be because of availability of equipment and trained surgeon in remote area of Pakistan. Objectives: to assess the results of radical cystectomy at a low-volume center for high-grade muscle-invasive bladder tumours. For patients aged 50 to 75, this involves evaluating surgical complications, overall survival, and the absence of tumour recurrence throughout a one-year follow-up period. Study design: A Retrospective StudyDuration and place of study: Recep Tayyip Erdogan hospital, Muzaffargarh from October 2018 to August 2022 Methods: total Cases from both genders and 50 to 75 years old with High grade/ Muscle invasive urinary bladder carcinoma, incomplete resection during TURBT due to high volume of mass (irresistible) included. Performa designed for collection of information. All the patients underwent same procedure by same urologist. Patients were followed for one year after surgery. Results: All participants were followed for one year. 33.3% patients had paralytic ileus (CDC I), 13.3% had wound infection (CDC I) and 6.7% had urinary leakage (CDC IIIb). There was 86.6% overall survival rate. 6.7% lost to follow up. Mean operative time was 308 ±95 minutes. There was no recurrence noted throughout the study period. Conclusion: Good operative results can also achieve at low volume centers. High level of surveillance and expertise help to achieve better outcomes in remote. Keywords: cystectomy, radical cystectomy, bladder tumor, ileal conduit

Nadofaragene firadenovec: a breakthrough in the field of bladder oncology

Muscle-invasive bladder tumors pose a grave mortality risk due to their propensity for distant metastases. The therapeutic spectrum for such tumors encompasses surgery, chemotherapy, and radiation, tailored to the cancer’s severity. In the context of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), a novel treatment has emerged as a beacon of hope. Nadofaragene firadenovec, a pioneering gene therapy, has gained worldwide approval for combating this condition, marking a watershed moment in bladder cancer therapy. Nadofaragene firadenovec is ingeniously designed to address high-risk BCG-unresponsive NMIBC, particularly carcinoma in situ (CIS) with or without papillary tumors, in adult patients. Rooted in a vector DNA, this therapy encodes interferon (IFN)-2b, which imparts urothelial cells with the ability to generate IFN-2b. The resulting cascade of events triggers a multifaceted assault on cancer, characterized by its immunostimulatory, antiangiogenic, and apoptotic effects. The therapeutic efficacy of nadofaragene firadenovec rests on its capacity to exploit the transformed urothelial cells to deliver these targeted anticancer activities. The evolutionary trajectory of nadofaragene firadenovec culminated in its monumental approval in December 2022 by the United States, signifying a pivotal juncture in the field. Notably, a segment of patients, approximately 30%, prove refractory to BCG treatment. For these individuals, alternative therapeutic avenues are imperative. Presently, the landscape for patients with non-muscle invasive bladder cancer lacks a definitive, enduring solution. Against this backdrop, the introduction of nadofaragene firadenovec heralds a momentous stride toward the global availability of an authorized therapeutic intervention.

Determination of expression level of AP1S1, CDK9, FIGF and HDAC11 genes in bladder tumors for aggressive phenotype characterization

Bladder cancer holds a steady 10th place among oncological diseases. Follow-up and timely diagnosis of recurrence and progression of bladder cancer are still based on regular but outdated cystoscopy followed by cytological examination. To reduce the number of cystoscopy procedures, new and reliable biomarkers for predicting tumor behavior must be developed. The aim of this study was to confirm our previous results that demonstrated overexpression of AP1S1, CDK9, FIGF and HDAC11 in muscle-invasive bladder cancer. The project management was performed using iterative flexible project work (Flexible Methodology for Innovative Projects in Scientific Organizations, FMIPSO). Gene expression analysis of the AP1S1, CDK9, FIGF and HDAC11 genes was evaluated in 39 newly collected non-invasive and muscle-invasive bladder tumors. Differential gene expression was calculated using the ΔΔCt method with GPDH as a housekeeping gene. The 4,0-fold change in gene expression was used as a cutoff to determine up- or down-regulation compared to the negative control. Our results demonstrate the involvement of the FIGF, CDK9 and HDAC11 in tumor progression and their potential use as candidate biomarkers to characterize invasive tumor phenotype and muscle progression, as well as potentially reduce the number of cystoscopies. We used FMIPSO to be able to achieve the results at the optimum level of efficiency and control of the project with all possible constraints in scientific organizations.

Role of En Bloc Resection in Staging of Non-Muscle Invasive Bladder Urothelial Carcinoma

Background Among cancers affecting both sexes, bladder cancer ranks as the fourth most prevalent cancer globally, and in the top 5 in prevalence in individual countries of all income levels and all regions enbloc resection approach of bladder tumors has a great effect in staging bladder tumors that help in early management of bladder tumors. Objective to review systematically studies whether en bloc resection of non-muscle invasive bladder cancer (NMIBC) could improve the identification of muscularis mucosa (MM) and muscle properia. Patients and Methods We searched PubMed, Google scholar search engine, Cochrane database of systematic reviews, EMBASE and science Direct, using the following Keywords “bladder tumors, enbloc resection, transurethral resection,”. The mentioned databases were searched for studies published during the last five years Results Total number of patients in included studies was 1940 of which 955 (49.2%) underwent en bloc resection and 985(50.8%) underwent conventional TURBT. after analyzing available data, en bloc resection has superiority in less recurrence rate and less hospital stay and higher in staging rate. Data Sources Medline databases (PubMed, Medscape, ScienceDirect. EMF-Portal) and all materials available in the Internet till 2022. Data Extraction If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, and adequate information and defined assessment measures. Conclusion In our review, ERBT show that it is an effective approach with some advantages over cTURBT regarding the treatment of NMIBC. This review revealed that hospitalization time and staging rate are superior in patients treated with ERBT than cTURBT, and complication rate and 24-month recurrence rate were also lower using ERBT. Accumulating evidence indicates that ERBT improves the quality of the surgical specimens and decreases the ReTUR frequency. Based on the previous evidence we recommend that, ERBT should be adapted by more surgeons in the treatment of non muscle invasive bladder tumors.

Robot based Transurethral Bladder Tumor Resection with automatic detection of tumor cells

Thehandiness, perception, and risks of bladder wall perforation with Transurethral Bladder Tumor Resection (TBRD) have been challenging to process and diagnose due to muscle-invasive bladder tumors. Survey shows in the medical sector, TBTR is usually collected via a rigid resectoscope. Further, the deficiencies in mobility are increased when tumors in the bladder neck area are established. A TBTR Endoscopic Robotic System (ERS) is designed to overcome these limitations. This paper describes the challenges of designing, modeling, and controlling the first TBTR in the robot framework. A Master-Slave robot consists of a continuous cross-sectional robot that can control the ablation, the grasp, and fiber optics with a micro-snake-continuous robot. The strategy for limited telemanipulation, based on redundancy, is consistent with the degree of limitation where the robot experiences are transurethral. The Deep Learning assisted Multi-Scale Feature Fusion Algorithm (MSFFA) has been used to track hundreds of cells with a fully automated and efficient system. Finally, a retracing algorithm combines historical data from matching objects. The results are promising and show that the proposed approach is consistent with the other established methods, which means that potential applications are likely to exist in biomedical engineering.

Transurethral resection of bladder tumors (TURBT)

Die transurethrale Resektion von Blasengewebe (TUR-B) ist für die Diagnostik und Therapie bei Blasentumoren indiziert. Diese werden fragmentiert mittels diathermaler Schlinge abgetragen. Der Wundgrund wird zur Blutstillung koaguliert. Zu achten ist auf eine ausreichende Schnitttiefe, sodass die Detrusormuskulatur erfasst ist. Postoperativ kann zur Rezidivprophylaxe eine intravesikale Single-shot-Chemotherapie verabreicht werden. Methoden zur verbesserten Tumorvisualisation (insbesondere photodynamische Diagnostik) helfen, besonders bei multilokulärem Befund oder Carcinoma in situ (CIS) bessere Detektionsraten zu erreichen sowie das Rezidiv- und Progressionsrisiko zu senken. In Abhängigkeit von der Histologie ergibt sich das weitere Vorgehen: bei nicht muskelinvasivem Blasenkarzinom Nachsorge, adjuvante Instillationstherapie mittels Chemotherapie oder Bacillus Calmette-Guérin (BCG), die Nachresektion („second look TUR-B“), die Frühzystektomie oder bei muskelinvasivem Blasenkarzinom die Zystektomie oder (onkologisch nachrangig) die trimodale Therapie mit erneuter TUR‑B, Radiotherapie und Chemotherapie. Mögliche Komplikationen im Rahmen der TUR‑B sind v. a. Nachblutung mit Blasentamponade, extra- oder intraperitoneale Blasenperforation oder Infektionen des Urogenitaltrakts.

Bladder tumor ILC1s undergo Th17‐like differentiation in human bladder cancer

PurposeHuman innate lymphoid cells (hILCs) are lineage‐negative immune cells that do not express rearranged adaptive antigen receptors. Natural killer (NK) cells are hILCs that contribute to cancer defense. The role of non‐NK hILCs in cancer is unclear. Our study aimed to characterize non‐NK hILCs in bladder cancer.Experimental designMass cytometry was used to characterize intratumoral non‐NK hILCs based on 35 parameters, including receptors, cytokines, and transcription factors from 21 muscle‐invasive bladder tumors. Model‐based clustering was performed on t‐distributed stochastic neighbor embedding (t‐SNE) coordinates of hILCs, and the association of hILCs with tumor stage was analyzed.ResultsMost frequent among intratumoral non‐NK hILCs were hILC1s, which were increased in higher compared with lower stage tumors. Intratumoral hILC1s were marked by Th17‐like phenotype with high RORγt, IL‐17, and IL‐22 compared to Th1 differentiation markers, including Tbet, perforin, and IFN‐γ. Compared with intratumoral hILC2s and hILC3s, hILC1s also had lower expression of activation markers (NKp30, NKp46, and CD69) and increased expression of exhaustion molecules (PD‐1 and Tim3). Unsupervised clustering identified nine clusters of bladder hILCs, which were not defined by the primary hILC subtypes 1–3. hILC1s featured in all the nine clusters indicating that intratumoral hILC1s displayed the highest phenotypic heterogeneity among all hILCs.ConclusionshILC1s are increased in higher stage tumors among patients with muscle‐invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17‐like differentiation, identifying them as potential targets for immunotherapy.

Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression.

To study the progression of bladder cancer from non-muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. SIGNIFICANCE: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

Vesical Imaging-Reporting and Data System (VI-RADS®): Initial experience in the classification of muscle-invasive bladder cancer

ObjectiveTo analyze the diagnostic accuracy of the VI-RADS® system in the differentiation of non-muscle-invasive bladder tumors (NMIBT) from muscle-invasive bladder tumors (MIBT) in suspicious cystoscopic findings without prior transurethral resection (TUR) evaluated by radiologists with no prior experience in its use. Material and methodsRetrospective study carried out with 18 patients with suspicious lesions in cystoscopy. All of them underwent MRI of the bladder. Two radiologists with no prior experience in the use of the VI-RADS® system evaluated the results. All patients underwent TUR of the suspicious lesions after MRI. The sensitivity and specificity of the system were analyzed for VI-RADS® values ​​≥3 or VI-RADS® ≥4, as well as the Cohen’s kappa coefficient between both radiologists. ResultsThe mean values ​​of sensitivity and specificity of both radiologists considering both the VI-RADS® ≥3 or VI-RADS® ≥4 values were 91.7% and 87.5%, respectively. The kappa coefficient considering the VI-RADS® ≥3 as positive, was 0.551 (P < .05), while considering the VI-RADS® ≥4 as positive, it was 0.571 (P < .05). ConclusionThe VI-RADS® system presents excellent sensitivity ​​ (91.7%) and specificity (87.5%) values in the classification of MIBT performed by radiologists with no prior experience in its use, with a moderate interobserver agreement.

Vesical Imaging-Reporting and Data System (VI-RADS®): experiencia inicial en la clasificación del cáncer de vejiga músculo-infiltrante

Objectiveto analyze the diagnostic accuracy of the VI-RADS® system in the differentiation of non-muscle-invasive bladder tumors (NMIBT from muscle-invasive bladder tumors (MIBT in suspicious cystoscopic findings without prior transurethral resection (TUR evaluated by radiologists with no prior experience in its use. Material and methodsretrospective study carried out with 18 patients with suspicious lesions in cystoscopy. All of them underwent MRI of the bladder. Two radiologists with no prior experience in the use of the VI-RADS® system evaluated the results. All patients underwent TUR of the suspicious lesions after MRI. The sensitivity and specificity of the system were analyzed for VI-RADS® values ≥ 3 or VI-RADS® ≥ 4, as well as the Cohen's kappa coefficient between both radiologists. Resultsthe mean values of sensitivity and specificity of both radiologists considering both the VI-RADS® ≥ 3 or VI-RADS® ≥ 4 values were 91.7% and 87.5%, respectively. The kappa coefficient considering the VI-RADS® ≥ 3 as positive, was 0.551 (P<.05), while considering the VI-RADS® ≥ 4 as positive, it was 0.571 (P<.05). ConclusionThe VI--RADS® system presents excellent sensitivity (91.7% and specificity (87.5% values in the classification of MIBT performed by radiologists with no prior experience in its use, with a moderate interobserver agreement.

Prognostic Value of the WHO1973 and WHO2004/2016 Classification Systems for Grade in Primary Ta/T1 Non–muscle-invasive Bladder Cancer: A Multicenter European Association of Urology Non–muscle-invasive Bladder Cancer Guidelines Panel Study

BackgroundIn the current European Association of Urology (EAU) non–muscle-invasive bladder cancer (NMIBC) guideline, two classification systems for grade are advocated: WHO1973 and WHO2004/2016. ObjectiveTo compare the prognostic value of these WHO systems. Design, setting, and participantsIndividual patient data for 5145 primary Ta/T1 NMIBC patients from 17 centers were collected between 1990 and 2019. The median follow-up was 3.9 yr. Outcome measurements and statistical analysisUnivariate and multivariable analyses of WHO1973 and WHO2004/2016 stratified by center were performed for time to recurrence, progression (primary endpoint), cystectomy, and duration of survival, taking into account age, concomitant carcinoma in situ, gender, multiplicity, tumor size, initial treatment, and tumor stage. Harrell’s concordance (C-index) was used for prognostic accuracy of classification systems. Results and limitationsThe median age was 68 yr; 3292 (64%) patients had Ta tumors. Neither classification system was prognostic for recurrence. For a four-tier combination of both WHO systems, progression at 5-yr follow-up was 1.4% in low-grade (LG)/G1, 3.8% in LG/G2, 7.7% in high grade (HG)/G2, and 18.8% in HG/G3 (log-rank, p < 0.001). In multivariable analyses with WHO1973 and WHO2004/2016 as independent variables, WHO1973 was a significant prognosticator of progression (p < 0.001), whereas WHO2004/2016 was not anymore (p = 0.067). C-indices for WHO1973, WHO2004, and the WHO systems combined for progression were 0.71, 0.67, and 0.73, respectively. Prognostic analyses for cystectomy and survival showed results similar to those for progression. ConclusionsIn this large prognostic factor study, both classification systems were prognostic for progression but not for recurrence. For progression, the prognostic value of WHO1973 was higher than that of WHO 2004/2016. The four-tier combination (LG/G1, LG/G2, HG/G2, and HG/G3) of both WHO systems proved to be superior, as it divides G2 patients into two subgroups (LG and HG) with different prognoses. Hence, the current EAU-NMIBC guideline recommendation to use both WHO classification systems remains correct. Patient summaryAt present, two classification systems are used in parallel to grade non–muscle-invasive bladder tumors. Our data on a large number of patients showed that the older classification system (WHO1973) performed better in terms of assessing progression than the more recent (WHO2004/2016) one. Nevertheless, we conclude that the current guideline recommendation for the use of both classification systems remains correct, since this has the advantage of dividing the large group of WHO1973 G2 patients into two subgroups (low and high grade) with different prognoses.

Risk factors and outcomes of myocardial injury after non-cardiac surgery in high-risk patients who underwent radical cystectomy.

Radical cystectomy is considered the standard treatment for patients with muscle-invasive bladder tumors and has high postoperative complication rates among urological surgeries. High-risk patients, defined as those ≥45 years of age with history of coronary artery disease, stroke, or peripheral artery disease or those ≥65 years of age, can have a higher incidence of cardiac complications. Therefore, we evaluated the incidence, risk factors, and outcomes of myocardial injury after non-cardiac surgery (MINS) in high-risk patients who underwent radical cystectomy.This retrospective observational study analyzed 248 high-risk patients who underwent radical cystectomy. MINS was defined as serum troponin I concentration ≥0.04 mg/L within postoperative 3 days. The risk factors for MINS were evaluated by multivariate logistic regression analysis. Postoperative outcomes were evaluated. The 1-year survival after radical cystectomy was also compared between patients who developed MINS (MINS group) and those who did not (non-MINS group) by Kaplan–Meier analysis.MINS occurred in 35 patients (14.1%). Multivariate logistic regression analysis showed that early diastolic transmitral filling velocity (E)/early diastolic septal mitral annular velocity (E’) ratio (odds ratio = 1.102, 95% confidence interval [1.009–1.203], P = .031) and large volume blood transfusion (odds ratio = 2.745, 95% confidence interval [1.131–6.664], P = .026) were significantly associated with MINS in high-risk patients who underwent radical cystectomy. Major adverse cardiac events and 1-year mortality were significantly higher in the MINS group than in the non-MINS group (17.1% vs 6.1%, P = .035; 28.6% vs 12.7%, P = .021, respectively). Kaplan–Meier analysis showed significantly lower 1-year survival in the MINS group than in the non-MINS group (P = .010).MINS occurred in 14.1% of patients. High E/E’ ratio and large volume blood transfusion were risk factors for MINS in high-risk patients who underwent radical cystectomy. Postoperative major adverse cardiac events and 1-year mortality were significantly higher in the MINS group than in the non-MINS group. Preoperative evaluation of risk factors for MINS may provide useful information to detect cardiovascular complications after radical cystectomy in high-risk patients.

Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer

Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

Comparison of Outcomes Between Radical Radiotherapy and Radical Cystectomy in Muscle Invasive Bladder Cancer in a Cancer Specialized Unit of a Developing Country.

IntroductionRadical cystectomy (RC) is the current standard of care for treating muscle-invasive bladder cancer (MIBC), however bladder preservation by offering radical radiotherapy (RT) is gaining interest for improving the quality of life while maintaining a reasonable oncological outcome. In this study, we have compared outcomes of the two treatment options.Materials and methodsThis is a 10-year retrospective cohort study that included all patients who were treated for histologically proven muscle-invasive bladder cancer in the department of uro-oncology at Shaukat Khanum Memorial Cancer Hospital and Research Centre from January 2005 to January 2015. Data was analysed using Statistical Product and Service Solutions (SPSS), version 21 (IBM Corp., Armonk, NY). The primary end point of our study was to calculate the three- and five-year disease-free survival (DFS) and overall survival (OS).ResultsA total of 230 patients were included in the study with male gender predominating (88%). The mean and standard deviation for age was 58.32+11.128. Radical cystectomy was performed in 119 patients while 111 received RT. Clinically, 34% had stage 2 disease, while 66 % had stage 3 cancer. The median follow-up duration was 41 months (range: 2-155). During follow-up 57.4% of patients showed no recurrence. Local recurrence was found in 9.6% patients and distant metastasis in 32.2%. The three-year DFS of RC was 63% and that of RT was 57% while the five-year DFS for RC and RT were 60% and 49%, respectively (p=0.196). The three-year OS of RC was 64% and that for RT was 58%. On further analysis the five-year OS of RC was 53% and that for RT was 50% (p=0.98). Upon stage-based comparisons, we found no statistically significant difference between the three- and five-year DFS and OS of stage 2 and stage 3 when treated with either modality.ConclusionMost studies favor RC and consider it as the gold standard treatment for muscle-invasive bladder tumor treatment. The current study reveals that bladder preservation approach by chemo radiotherapy is a viable treatment option, having comparable oncological outcomes with patients receiving radical cystectomy, and can be offered to patients having muscle-invasive urothelial bladder cancer.