FGFR Inhibition in Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain. METHODS: Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer". An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review. KEY FINDINGS AND LIMITATIONS: Somatic FGFR3 alterations are found in up to 70% of low-grade non-muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC. CONCLUSIONS AND CLINICAL IMPLICATIONS: With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer.

The Importance of Being Grade 3: A Plea for a Three-tier Hybrid Classification System for Grade in Primary Non-muscle-invasive Bladder Cancer.

Grade is an important determinant of progression in non-muscle-invasive bladder cancer. Although the World Health Organization (WHO) 2004/2016 grading system is recommended, other systems such as WHO1973 and WHO1999 are still widely used. Recently, a hybrid (three-tier) system was proposed, separating WHO2004/2016 high grade (HG) into HG/grade 2 (G2) and HG/G3 while maintaining low grade. We assessed the prognostic performance of HG/G3 and HG/G2. Three independent cohorts with 9712 primary (first diagnosis) Ta-T1 bladder tumors were analyzed. Time to progression was analyzed with cumulative incidence functions and Cox regression models. Harrell's C-index was used to assess discrimination. Time to progression was significantly shorter for HG/G3 than for HG/G2 in multivariable analyses (cohort 1: hazard ratio [HR] = 1.92; cohort 2: HR = 2.51, and cohort 3: HR = 1.69). Corresponding progression risks at 5 yr were 18%, 20%, and 18% for HG/G3 versus 7.3%, 7.5%, and 9.3% for HG/G2, respectively. Cox models using hybrid grade performed better than models with WHO2004/2016 (all cohorts; p < 0.001). For the three cohorts, C-indices for WHO2004/2016 were 0.69, 0.62, and 0.75, while, for hybrid grade, C-indices were 0.74, 0.68, and 0.78, respectively. Subdividing the HG category into HG/G2 and HG/G3 stratifies time to progression and supports the recommendation to adopt the hybrid grading system for Ta/T1 bladder cancers.

The Prognostic Significance of Histological Subtypes in Patients with Muscle-Invasive Bladder Cancer: An Overview of the Current Literature.

Bladder cancer (BC) is the tenth most commonly diagnosed malignancy worldwide. In approximately 25% of cases, it presents as a muscle-invasive disease, requiring a radical treatment. Traditionally, the mainstay of treatment has been radical cystectomy (RC), but in the last decade, bladder-sparing treatments have been gaining growing interest. In particular, trimodal therapy (TMT) seems to yield survival results comparable to RC with less morbidity and better quality of life (QoL) outcomes. In this scenario, we aimed at shedding light on the role of the histological subtypes (HS) of BC and their prognostic significance in muscle-invasive BC (MIBC), treated either surgically or with TMT. We performed a narrative review to provide an overview of the current literature on this topic. When compared with patients diagnosed with conventional urothelial carcinoma (UC) of the same disease stage, survival did not appear to be significantly worse across the reports. But when sub-analyzed for separate subtype, some appeared to be independently associated with adverse survival outcomes such as the micropapillary, plasmacytoid, small-cell, and sarcomatoid subtypes, whereas others did not. Moreover, the optimal management remains to be defined, also depending on the therapeutic susceptibility of each histology. From this perspective, multi-disciplinary assessment alongside the routine inclusion of such entities in randomized clinical trials appears to be essential.

Multi-Center Assessment of Lymph-Node Density and Nodal-Stage to Predict Disease-Specific Survival in Patients with Bladder Cancer Treated by Radical Cystectomy.

BACKGROUND: Prognostic tools in pathological-node (pN) patients after radical cystectomy (RC) are needed. OBJECTIVES: To evaluate the prognostic impact of lymph node (LN)-density on disease-specific survival (DSS) in patients with bladder cancer (BC) undergoing RC with pelvic lymph node dissection. METHODS: We analyzed a multi-institutional cohort of 1169 patients treated with upfront RC for cT1-4aN0M0 urothelial BCat nine centers. LN-densitywas calculated as the ratio of the number of positive LNs×100% to the number of LNs removed. The optimal LN-density cut-off value was defined by creating a time-dependent receiver operating characteristic (ROC) curve in pN patients. Univariable and multivariable Cox' regression analyses were used to assess the effect of conventional Tumor Nodes Metastasis (TNM) nodal staging system, LN-density and other LN-related variables on DSS in the pN-positive cohort. RESULTS: Of the 1169 patients, 463 (39.6%) patients had LN-involvement. The area under the ROC curve was 0.60 and the cut-off for LN-density was set at 20%, 223 of the pN-positive patients (48.2%) had a LN-density ≥ 20%. In multivariable models, the number of LN-metastases (HR 1.03, p = 0.005) and LN-density, either as continuous (HR 1.01, p = 0.013) or as categorical variable (HR 1.37, p = 0.014), were independently associated with worse DSS, whereas pN-stage was not. CONCLUSIONS: LN-density ≥ 20% was an independent predictor of worse DSS in BC patients with LN-involvement at RC. The integration of LN-density and other LN-parameters rather than only conventional pN-stage may contribute to a more refined risk-stratification in BC patients with nodal involvement.

European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ)-A Summary of the 2024 Guidelines Update.

BACKGROUND AND OBJECTIVE: This publication represents a summary of the updated 2024 European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ. The information presented herein is limited to urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation. METHODS: For the 2024 guidelines on NMIBC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS: Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with NMIBC. The guidelines stress the importance of defining patients' risk stratification and treating them appropriately. CONCLUSIONS AND CLINICAL IMPLICATIONS: This overview of the 2024 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, prognostic factors, treatment, and follow-up of NMIBC. These guidelines are designed for effective integration into clinical practice.

Platinum-Based Chemotherapy Induces Opposing Effects on Immunotherapy Response-Related Spatial and Stromal Biomarkers in the Bladder Cancer Microenvironment.

PURPOSE: Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized. We aimed to investigate this modulation, focusing on potential clinical implications for immune checkpoint inhibitor response. EXPERIMENTAL DESIGN: We assessed immune cell densities, spatial relations, and tumor/stromal components from 116 patients with urothelial bladder cancer (paired data for 95 patients) before and after platinum-based chemotherapy. RESULTS: Several published biomarkers for immunotherapy response changed upon chemotherapy treatment. The intratumoral CD8+ T-cell percentage increased after treatment and was associated with increased TNFα-via-NF-κB signaling. The percentage of PDL1+ immune cells was higher after chemotherapy. An increase in chemo-induced changes that potentially inhibit an antitumor immune response was also observed, including increased fibroblast-based TGFß signaling and distances from immune cells to the nearest cancer cell. The latter two parameters correlated significantly in posttreatment samples, suggesting that TGFß signaling in fibroblasts may play a role in spatially separating immune cells from cancer cells. We examined specific chemotherapy regimens and found that treatment with methotrexate, vinblastine, doxorubicin, and cisplatin was associated with an increase in the macrophage cell percentage. Gemcitabine-containing chemotherapy was associated with upregulation of fibroblast TGFß signaling. CONCLUSIONS: The opposing effects of platinum-based chemotherapy on the immune cell composition and stromal context of the tumor-immune microenvironment may explain the inconsistent results of clinical trials investigating chemotherapy and immune checkpoint inhibitor combinations in bladder cancer.

Consistencies in Follow-up After Radical Cystectomy for Bladder Cancer: A Framework Based on Expert Practices Collaboratively Developed by the European Association of Urology Bladder Cancer Guideline Panels.

BACKGROUND AND OBJECTIVE: There is no standardized regimen for follow-up after radical cystectomy (RC) for bladder cancer (BC). To address this gap, we conducted a multicenter study involving urologist members from the European Association of Urology (EAU) bladder cancer guideline panels. Our objective was to identify consistent post-RC follow-up strategies and develop a practice-based framework based on expert opinion. METHODS: We surveyed 27 urologist members of the EAU guideline panels for non-muscle-invasive bladder cancer and muscle-invasive and metastatic bladder cancer using a pre-tested questionnaire with dichotomous responses. The survey inquired about follow-up strategies after RC and the use of risk-adapted strategies. Consistency was defined as >75% affirmative responses for follow-up practices commencing 3 mo after RC. Descriptive statistics were used for analysis. KEY FINDINGS AND LIMITATIONS: We received responses from 96% of the panel members, who provided data from 21 European hospitals. Risk-adapted follow-up is used in 53% of hospitals, with uniform criteria for high-risk (at least ≥pT3 or pN+) and low-risk ([y]pT0/a/1N0) cases. In the absence of agreement for risk-based follow up, a non-risk-adapted framework for follow-up was developed. Higher conformity was observed within the initial 3 yr, followed by a decline in subsequent follow-up. Follow-up was most frequent during the first year, including patient assessments, physical examinations, and laboratory tests. Computed tomography of the chest and abdomen/pelvis was the most common imaging modality, initially at least biannually, and then annually from years 2 to 5. There was a lack of consistency for continuing follow-up beyond 10 yr after RC. CONCLUSIONS AND CLINICAL IMPLICATIONS: This practice-based post-RC follow-up framework developed by EAU bladder cancer experts may serve as a valuable guide for urologists in the absence of prospective randomized studies. PATIENT SUMMARY: We asked urologists from the EAU bladder cancer guideline panels about their patient follow-up after surgical removal of the bladder for bladder cancer. We found that although urologists have varying approaches, there are also common follow-up practices across the panel. We created a practical follow-up framework that could be useful for urologists in their day-to-day practice.

Variation in Follow-Up after Radical Cystectomy for Bladder Cancer-An Inventory Roundtable and Literature Review.

Background: Follow-up after radical cystectomy (RC) for bladder cancer can be divided into oncological and functional surveillance. It remains unclear how follow-up after RC should ideally be scheduled. The aim of this report was to gain insight into the organization of follow-up after RC in Europe, for which we conducted a roundtable inventory within the EAU Young Academic Urologists Urothelial Cancer working group. Methods: An inventory semi-structured survey was performed among urologists of the EAU Young Academic Urologists Urothelial Cancer working group to describe the organization of follow-up. The surveys were analyzed using a deductive approach. Similarities and differences in follow-up after RC for bladder cancer were described. Results: The survey included 11 urologists from six different European countries. An institutional follow-up scheme was used by six (55%); three (27%) used a national or international guideline, and two (18%) indicated that there was no defined follow-up scheme. Major divergent aspects included the time points of follow-up, the frequency, and the end of follow-up. Six centers (55%) adopted a risk-adapted follow-up approach tailored to (varying) patient and tumor characteristics. Laboratory tests and CT scans were used in all cases; however, the intensity and frequency varied. Functional follow-up overlapped with oncological follow-up in terms of frequency and duration. Patient-reported outcome measures were only used by two (18%) urologists. Conclusions: Substantial variability exists across European centers regarding the follow-up after RC for bladder cancer. This highlights the need for an international analysis focusing on its organization and content as well as on opportunities to improve patients' needs during follow-up after RC.

Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) can achieve remarkable responses in urothelial cancer (UC), which may depend on tumor microenvironment (TME) characteristics. However, the relationship between the TME, usually characterized by immune cell density, and response to ICI is unclear. Here, we quantify the TME immune cell densities and spatial relationships (SRs) of 24 baseline UC samples, obtained before pre-operative combination ICI treatment, using multiplex immunofluorescence. We describe SRs by approximating the first nearest-neighbor distance distribution with a Weibull distribution and evaluate the association between TME metrics and ipilimumab+nivolumab response. Immune cell density does not discriminate between response groups. However, the Weibull SR metrics of CD8+ T cells or macrophages to their closest cancer cell positively associate with response. CD8+ T cells close to B cells are characteristic of non-response. We validate our SR response associations in a combination ICI cohort of head and neck tumors. Our data confirm that SRs, in contrast to density metrics, are strong biomarkers of response to pre-operative combination ICIs.

Simulation of the effects of molecular urine markers in follow-up of patients with high-risk non-muscle invasive bladder cancer.

A plethora of urine markers for the management of patients with bladder cancer has been developed and studied in the past. However, the clinical impact of urine testing on patient management remains obscure. The goal of this manuscript is to identify scenarios for the potential use of molecular urine markers in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. Information on the course of disease of patients with high-risk NMIBC and performance data of a point-of-care test (UBC rapid™), an MCM-5 directed ELISA (ADXBLADDER™), and 2 additional novel assays targeting alterations of mRNA expression and DNA methylation (Xpert bladder cancer monitor™, Epicheck™) were retrieved from high-quality trials and/or meta-analyses. In addition, the sensitivity of white light cystoscopy (WLC) and the impact of a urine marker result on the performance of WLC were estimated based on fluorescence cystoscopy data and information from the CeFub trial. This information was applied to different scenarios in patient follow-up and sensitivity, estimated number of cystoscopies, and the numbers needed to diagnose were calculated. The sensitivity of guideline-based regular follow-up (SOC) at 1 year was calculated at 96%. For different marker-supported strategies sensitivities ranging from 77% to 97.9% were estimated. Calculations suggest that several strategies are effective for the SOC. While for the SOC 24.6 WLCs were required to diagnose 1 tumor recurrence (NND), this NND dropped below 5 in some marker-supported strategies. Based on the results of this simulation, a marker-supported follow-up of patients with HR NMIBC is safe and offers the option to significantly reduce the number of WLCs. Further research focusing on prospective randomized trials is needed to finally find a way to implement urine markers into clinical decision-making.

Penile cancer care in the Netherlands: increased incidence, centralisation, and improved survival.

OBJECTIVE: To evaluate penile squamous cell carcinoma (PSCC) incidence and centralisation trends in the Netherlands over the past three decades, as well as the effect of centralisation of PSCC care on survival. PATIENTS AND METHODS: In the Netherlands PSCC care is largely centralised in one national centre of expertise (Netherlands Cancer Institute [NCI], Amsterdam). For this study, the Netherlands Cancer Registry, an independent nationwide cancer registry, provided per-patient data on age, clinical and pathological tumour staging, follow-up, and vital status. Patients with treatment at the NCI were identified and compared to patients who were treated at all other centres. The age-standardised incidence rate was calculated with the European Standard Population. The probability of death due to PSCC was estimated using the relative survival. Multivariable Cox regression analysis was performed to evaluate predictors of survival. RESULTS: A total of 3160 patients were diagnosed with PSCC between 1990 and 2020, showing a rising incidence (P < 0.001). Annual caseload increased at the NCI (1% in 1990, 65% in 2020) and decreased at other (regional) centres (99% to 35%). Despite a relatively high percentage of patients with T2-4 (64%) and N+ (33%) at the NCI, the 5-year relative survival was higher (86%, 95% confidence interval [CI] 82-91%) compared to regional centres (76%, 95% CI 73-80%, P < 0.001). Patients with a pathological T2 tumour were treated with glans-sparing treatment more often at the reference centre than at the regional centres (16% vs 5.0%, P < 0.001). After adjusting for age, histological grading, T-stage, presence of lymph node involvement and year of diagnosis, treatment at regional centres remained a predictor for worse survival (hazard ratio 1.22, 95% CI 1.05-1.39; P = 0.006). CONCLUSION: The incidence of PSCC in the Netherlands has been gradually increasing over the past three decades, with a noticeable trend towards centralisation of PSCC care and improved relative survival rate.

The Financial Burden of Guideline-recommended Cancer Medications for Metastatic Urothelial Carcinoma.

Bladder cancer is a significant global health concern owing to its prevalence, negative impact on quality of life, and high treatment costs. Treatment for metastatic urothelial carcinoma (mUC) traditionally relies on platinum-based chemotherapy regimens. However, clinical trial results have led to the approval of immune checkpoint inhibitors (ICIs) as viable treatment options. We assessed the escalating costs and economic viability of mUC treatment guidelines in Europe. We used a pragmatic approach that involved: (1) collection of the costs of the recommended medications in the five most populous European countries; (2) conversion of the costs into international dollars to account for differences in purchasing power parity among countries; (3) evaluation of the cost trends over time; and (4) comparison of the medication costs to World Health Organization thresholds. Introduction of ICIs in European guidelines substantially increased the cost of medications for mUC. Intriguingly, important differences across European countries emerged: the annual cost of medications was twofold higher in Italy than in France and the UK. Despite limitations, our study sheds light on the escalating costs and economic challenges of mUC treatment, and highlights the need for assessments of sustainable and cost-effective management approaches. PATIENT SUMMARY: We looked at the costs of treatments for metastatic bladder cancer and found that costs have been rising over time, especially with the introduction of new immune therapies, with notable differences among European countries. While these new treatments improve patient outcomes, they also come with a high price tag, which could strain health care budgets. Our results suggest that cost-effectiveness studies will be essential in determining the best and most sustainable treatment strategies in the future.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes.

BACKGROUND: Grading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. OBJECTIVE: To develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. DESIGN, SETTING, AND PARTICIPANTS: Tissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: GGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. RESULTS AND LIMITATIONS: Integration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. CONCLUSIONS: We propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. PATIENT SUMMARY: We developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

The Diagnostic Accuracy of Cystoscopy for Detecting Bladder Cancer in Adults Presenting with Haematuria: A Systematic Review from the European Association of Urology Guidelines Office.

CONTEXT: Haematuria can be macroscopic (visible haematuria [VH]) or microscopic (nonvisible haematuria [NVH]), and may be caused by a number of underlying aetiologies. Currently, in case of haematuria, cystoscopy is the standard diagnostic tool to screen the entire bladder for malignancy. OBJECTIVE: The objective of this systematic review is to determine the diagnostic test accuracy of cystoscopy (compared with other tests, eg, computed tomography, urine biomarkers, and urine cytology) for detecting bladder cancer in adults. EVIDENCE ACQUISITION: A systematic review of the literature was performed according to the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension for diagnostic test accuracy studies' checklist. The MEDLINE, Embase, Cochrane CENTRAL, and Cochrane CDSR databases (via Ovid) were searched up to July 13, 2022. The population comprises patients presenting with either VH or NVH, without previous urological cancers. Two reviewers independently screened all articles, searched reference lists of retrieved articles, and performed data extraction. The risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). EVIDENCE SYNTHESIS: Overall, nine studies were included in the qualitative analysis. Seven out of nine included trials covered the use of cystoscopy in comparison with radiological imaging. Overall, sensitivity of cystoscopy ranged from 87% to 100%, specificity from 64% to 100%, positive predictive value from 79% to 98%, and negative predictive values between 98% and 100%. Two trials compared enhanced or air cystoscopy versus conventional cystoscopy. Overall sensitivity of conventional white light cystoscopy ranged from 47% to 100% and specificity from 93.4% to 100%. CONCLUSIONS: The true accuracy of cystoscopy for the detection of bladder cancer within the context of haematuria has not been studied extensively, resulting in inconsistent data regarding its performance for patients with haematuria. In comparison with imaging modalities, a few trials have prospectively assessed the diagnostic performance of cystoscopy, confirming very high accuracy for cystoscopy, exceeding the diagnostic value of any other imaging test. PATIENT SUMMARY: Evidence of tests for detecting bladder cancer in adults presenting with haematuria (blood in urine) was reviewed. The most common test used was cystoscopy, which remains the current standard for diagnosing bladder cancer.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 1: Comparison of Bladder Cancer Grading System Performance.

Grade is a key prognostic factor in determining progression in nonmuscle invasive papillary urothelial carcinomas. The 2 most common grading methods in use worldwide are the World Health Organization (WHO) 2004 and 1973 schemes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland on current issues in bladder cancer and tasked working group 1 to make recommendations for future iterations of bladder cancer grading. For this purpose, the ISUP developed in collaboration with the European Association of Urology a 10-question survey for their memberships to understand the current use of grading schemes by pathologists and urologists and to ascertain the areas of potential improvements. An additional survey was circulated to the ISUP membership for their opinion on interobserver variability in grading, reporting of urine cytology, and challenges encountered in grade assignment. Comprehensive literature reviews were performed on bladder cancer grading prognosis and interobserver variability along with The Paris System for urine cytology. There are notable differences in practice patterns between North American and European pathologists in terms of used grading scheme and diagnosis of papillary urothelial neoplasm of low malignant potential. Areas of common ground include difficulty in grade assignment, a desire to improve grading criteria, and a move towards subclassifying high-grade urothelial carcinomas. The surveys and in-person voting demonstrated a strong preference to refine current grading into a 3-tier scheme with the division of WHO 2004 high grade into clinically relevant categories. More variable opinions were voiced regarding the use of papillary urothelial carcinoma with low malignant potential.

The effect of cisplatin-based neoadjuvant chemotherapy on the renal function of patients undergoing radical cystectomy.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m2 reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m2 (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m2) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m2). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m2), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year.

BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets.

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.

Considering the Effects of Modern Point-of-Care Urine Biomarker Assays in Follow-Up of Patients with High-Risk Non-muscle-Invasive Bladder Cancer.

BACKGROUND: Although a plethora of urine markers for diagnosis and follow-up of patients with bladder cancer (BC) has been developed and studied, the clinical impact of urine testing on patient management remains unclear. The goal of this manuscript is to identify scenarios for a potential use of modern point-of-care (POC) urine marker assays in the follow-up of patients with high-risk non-muscle-invasive BC (NMIBC) and estimate potential risks and benefits. METHODS: To permit comparison between different assays, the results of 5 different POC assays studied in a recent prospective multicenter study including 127 patients with suspicious cystoscopy undergoing TURB were used for this simulation. For the current standard of care (SOC), a "marker-enforced" procedure, and a combined strategy sensitivity (Se), estimated number of cystoscopies, and the numbers needed to diagnose (NND) over a 1-year follow-up period were calculated. RESULTS: For regular cystoscopy (SOC), a Se of 91.7% and a NND of 42.2 repetitive office cystoscopies (WLCs) for 1 recurrent tumor at 1 year were calculated. For the "marker-enforced" strategy, marker sensitivities between 94.7% and 97.1% were observed. The "combined" strategy yielded for markers with a Se exceeding 50% an overall Se at 1 year similar or superior to the current SOC. Savings regarding the number of cystoscopies in the "marker-enforced" strategy vs. the SOC were small, while, depending on the marker, up to 45% of all cystoscopies may be saved using the "combined" strategy. CONCLUSIONS: Based on the results of this simulation, a marker-supported follow-up of patients with high-risk (HR) NMIBC is safe and offers options to significantly reduce the number of cystoscopies without compromising the Se. Further research focusing on prospective randomized trials is needed to finally find a way to include marker results into clinical decision-making.