Novel Delivery Systems and Pharmacotherapeutic Approaches for the Treatment of Non-muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Therapeutic options for patients with non-muscle-invasive bladder cancer (NMIBC) have traditionally been limited to intravesical immunotherapy or chemotherapy. A considerable number of new options have been investigated in recent years. Our aim was to review the efficacy and toxicity of novel therapeutic options (results already reported or currently under investigation) for patients with NMIBC. METHODS: We assessed the efficacy of various novel therapeutic options by examining key endpoints in diverse settings, including recurrence, progression, overall survival, disease-specific survival, and complete response. We identified the principal advantages and limitations for each option. Safety was predominantly evaluated as the incidence of grade ≥3 adverse events. Our investigation focused on evidence from scientific articles and congress abstracts published in English within the past 5 yr. KEY FINDINGS AND LIMITATIONS: To date, pembrolizumab, nadofaragene firadenovec, and the combination of BCG with N-803 have received US Food and Drug administration approval for the treatment of BCG-unresponsive carcinoma in situ of the bladder (with or without papillary tumours). Five phase 3 trials are recruiting BCG-naïve patients with high-risk NMIBC. There is increasing interest in an ablative rather than an adjuvant approach for patients with intermediate-risk NMIBC. CONCLUSIONS AND CLINICAL IMPLICATIONS: Novel drugs and device-assisted drug delivery systems are on the verge of changing the treatment of NMIBC. Novel intravesical options seem to have the same efficacy with fewer adverse events in comparison to systemic therapies. PATIENT SUMMARY: We reviewed new therapy options for non-muscle-invasive bladder cancer. Two agents (pembrolizumab and nadofaragene firadenovec) have been approved to date. Ongoing trials are assessing direct delivery of drugs in solution into the bladder. This route seems to have similar efficacy and fewer side effects than intravenous immunotherapy.

The Role of Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: Intravesical mitomycin C (MMC) instillations are recommended to prevent recurrence of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC); however, the optimal regimen and dose are uncertain. Our aim was to assess the effectiveness of adjuvant MMC and compare different MMC regimens in preventing recurrence. METHODS: We performed a comprehensive search in PubMed, Scopus, and Web of Science in November 2023 for studies investigating recurrence-free survival (RFS) among patients with IR-NMIBC who received adjuvant MMC. Prospective trials with different MMC regimens or other intravesical drugs as comparators were considered eligible. KEY FINDINGS AND LIMITATIONS: Overall, 14 studies were eligible for systematic review and 11 for meta-analysis of RFS. Estimates of 1-yr, 2-yr, and 5-yr RFS rates were 84% (95% confidence interval [CI] 79-89%), 75% (95% CI 68-82%), and 51% (95% CI 40-63%) for patients treated with MMC induction plus maintenance, and 88% (95% CI 83-94%), 78% (95% CI 67-89%), and 66% (95% CI 57-75%) for patients treated with bacillus Calmette-Guérin (BCG) maintenance, respectively. Estimates of 2-yr RFS rates for MMC maintenance regimens were 76% (95% CI 69-84%) for 40 mg MMC (2 studies) and 66% (95% CI 60-72%) for 30 mg MMC (4 studies). Among the studies included, BCG maintenance provided comparable 2-yr RFS to 40 mg MMC with maintenance (78% vs 76%). RFS did not differ by MMC maintenance duration (>1 yr vs 1 yr vs <1 yr). CONCLUSIONS AND CLINICAL IMPLICATIONS: MMC induction and maintenance regimens seem to provide short-term RFS rates equivalent to those for BCG maintenance in IR-NMIBC. For adjuvant induction and maintenance, 40 mg of MMC appears to be more effective in preventing recurrence than 30 mg. We did not observe an RFS benefit for longer maintenance regimens. PATIENT SUMMARY: For patients with intermediate-risk non-muscle-invasive bladder cancer, bladder treatments with a solution of a drug called mitomycin C (MMC) seem to be as effective as BCG (bacillus Calmette-Guérin) in preventing recurrence after tumor removal. Further trials are needed for stronger evidence on the best MMC dose and treatment time.

Clinical Validation of the Intermediate-risk Non-muscle-invasive Bladder Cancer Scoring System and Substratification Model Proposed by the International Bladder Cancer Group: A Multicenter Young Academic Urologists Urothelial Working Group Collaboration.

BACKGROUND AND OBJECTIVE: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) encompasses a broad spectrum of disease, with heterogeneous outcomes in terms of disease recurrence and progression. The International Bladder Cancer Group (IBCG) recently proposed an updated scoring model for IR substratification that is based on five key risk factors. Our aim was to provide a clinical validation of the IBCG scoring system and substratification model for IR NMIBC. METHODS: This was an international multicenter retrospective study. Patients diagnosed with IR NMIBC between 2012 and 2022 and treated with transurethral resection of the bladder and adjuvant intravesical chemotherapy were included. According to the presence or absence of risk factors, patients with IR NMIBC were further categorized in IR-low (no risk factors), IR-intermediate (1-2 risk factors), and IR-high (≥3 risk factors) groups. The 1-yr and 3-yr rates for recurrence-free survival (RFS) and progression-free survival (PFS) were evaluated for each subgroup. Cox regression analyses were used to compare oncological outcomes between the groups. KEY FINDINGS AND LIMITATIONS: Of the 677 patients with IR NMIBC included in the study, 231 (34%), 364 (54%), and 82 (12%) were categorized in the IR-low, IR-intermediate, and IR-high groups, respectively. There were significant differences in RFS and PFS rates between these groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: We provide the first clinical validation of the IBCG scoring system and model for substratification of IR NMIBC. PATIENT SUMMARY: Our study demonstrates that patients with intermediate-risk non-muscle-invasive bladder cancer can be correctly classified into three distinct subgroups according to their risk of both disease recurrence and progression. Our results support use of this scoring system in clinical practice.

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.

Improved Survival in Contemporary Community-Based Patients With Metastatic Clear-Cell Renal Cell Carcinoma Undergoing Active Treatment.

BACKGROUND: We hypothesized that the evolving treatment paradigms recommended based on phase III trials may have translated into improved overall survival (OS) in contemporary community-based patients with clear-cell metastatic renal cell carcinoma (ccmRCC) undergoing active treatment. PATIENTS AND METHODS: Within the SEER database, contemporary (2017-2020) and historical (2010-2016) patients with ccmRCC treated with either systemic therapy (ST), cytoreductive nephrectomy (CN), or both (ST+CN) were identified. Univariable and multivariable Cox-regression models were used. RESULTS: Overall, 993 (32%) contemporary versus 2,106 (68%) historical patients with ccmRCC were identified. Median OS was 41 months in contemporary versus 25 months in historical patients (Δ=16 months; P<.001). In multivariable Cox-regression analyses, contemporary membership was independently associated with lower overall mortality (hazard ratio [HR], 0.7; 95% CI, 0.6-0.8; P<.001). In patients treated with ST alone, median OS was 17 months in contemporary versus 10 months in historical patients (Δ=7 months; P<.001; multivariable HR, 0.7; P=.005). In patients treated with CN alone, median OS was not reached in contemporary versus 33 months in historical patients (Δ=not available; P<.001; multivariable HR, 0.7; P<.001). In patients treated with ST+CN, median OS was 38 months in contemporary versus 26 months in historical patients (Δ=12 months; P<.001; multivariable HR, 0.7; P=.003). CONCLUSIONS: Contemporary community-based patients with ccmRCC receiving active treatment clearly exhibited better survival than their historical counterparts, when examined as one group, as well as when examined as separate subgroups according to treatment type. Treatment advancements of phase III trials seem to be applied appropriately outside of centers of excellence.

Temporal Trends and Cancer-Specific Mortality in Nonmetastatic Muscle-Invasive Urothelial Carcinoma of the Urinary Bladder Treated With Trimodal Therapy.

INTRODUCTION: Trimodal therapy (TMT) is guideline-recommended for the management of organ confined urothelial carcinoma of urinary bladder (UCUB). However, temporal trends in TMT use and cancer-specific mortality free-survival (CSM-FS) between historical TMT versus contemporary TMT have not been assessed. We addressed this knowledge gap. MATERIAL AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2004-2020), we identified nonmetastatic UCUB patients with cT2-T4aN0-N2 treated with TMT, defined as the combination of transurethral resection of bladder tumor, chemotherapy and radiotherapy. Temporal trends described TMT use over time. Subsequently, patients were divided between historical (2004-2012) versus contemporary (2013-2020) cohorts. Survival analyses consisting of Kaplan-Meier plots and multivariable Cox regression (MCR) models addressed CSM-FS. Separate analyses addressed patients with organ confined (OC: cT2N0M0) versus nonorgan confined (NOC: cT3-4a and/or cN1-2) clinical stages. RESULTS: Of 4,097 assessable UCUB TMT patients, 1744 (43%) were treated in the historical period (2004-2012) versus 2353 (58%) in the contemporary period (2013-2020). TMT use increased over time in OC patients (EAPC:+3.4%, P < .001), as well as in NOC (EAPC:+2.7%, P < .001). In OC stage, median CSM-FS was 55.3% in historical versus 49.0% in contemporary patients (HR:0.75, P < .001). Similarly, in NOC stage, 5-year median CSM-FS was 43.0% in historical versus 32.8% in contemporary patients (HR:0.78, P = .01). CONCLUSION: TMT rates have increased over time in both OC and NOC patients. Contemporary TMT patients benefit of better cancer-specific survival. Interestingly, this benefit applies equally to OC and NOC TMT-treated patients.

The Potential Role of Urinary Microbiota in Bladder Carcinogenesis: A Systematic Review.

PURPOSE: The quantitative objective of the current systematic review was to identify the potential role of urinary microbiota in bladder cancer (BC) carcinogenesis, invasiveness, progression, and metastasis. MATERIALS AND METHODS: The proposed systematic review was conducted in accordance with critical review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, and the Joanna Briggs Institute (JBI) methodology for systematic reviews. The search strategy aimed to find both published and unpublished studies up to the January 2024. A JBI appraisal checklist was used to assess possible biases. RESULTS: This systematic review was centered on 27 studies comprising 926 BC patients. Overall, 412 control individuals were compared with BC patients. The most common sampling method was midstream urine collection. Regarding microbial alpha diversity, there was no statistically significant difference between cancerous and healthy samples (n = 8), recurrent and not recurrent (n = 1), responders versus non-responders(n = 1), tumor grades (n = 1), and collection methods (n = 1). However, five studies reported higher diversity in controls, and five other studies reported, conversely, high levels of alpha diversity in BC patients or recurrent cases. Furthermore, a responder (RE) to treatment and a non-muscle invasive bladder cancer (NMIBC) groups demonstrated significant difference with non-responder (NR) and muscle invasive bladder cancer (MIBC), respectively. In terms of beta-diversity, nine studies reported significant diversity between BC patients and controls, one article demonstrated difference between recurrent and not recurrent patients, a study reported significant difference in RE and NR groups whereas another showed opposite, and others (n = 4) did not find any difference between BC, controls, MIBC and NMIBC patients, or between tumor grades. One study reported a difference between the collection method and beta-diversity in males and another reported the difference in females. CONCLUSION: The included studies demonstrate that the composition of urinary microbiota is altered in patients with BC. However, the differentially enriched genera in the urine of these patients vary between studies, and there is too much heterogeneity across studies to make any reliable and valid conclusions. Furthermore, well-designed research is necessary to assess the role of microbiota in the carcinogenesis and progression of BC.

Defining oligometastatic state in uro-oncological cancers.

PURPOSE OF REVIEW: Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology. RECENT FINDINGS: Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor. SUMMARY: Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future.

Unmarried Status Effect on Stage at Presentation and Treatment Patterns in Non-Metastatic Upper Tract Urothelial Carcinoma Patients.

BACKGROUND: Unmarried status has been associated with higher proportions of locally advanced stage and lower treatment dose intensification rates in several urological and non-urological malignancies. However, no previous investigators focused on the association between unmarried status and advanced stage (T3-4N0-2) at presentation and lower nephroureterectomy (RNU) and systemic therapy (ST) rates in non-metastatic upper tract urothelial carcinoma (UTUC) patients. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database 2000-2020, all non-metastatic UTUC patients were identified. Multivariable logistic regression models (LRMs) tested for differences in stage at presentation and treatment (RNU and ST) according to marital status (married vs unmarried), in a sex-specific fashion. RESULTS: Of all 8544 non-metastatic UTUC patients, 4748 (56%) were male vs 3190 (44%) were female. Of all 4748 male UTUC patients, 1191 (25%) were unmarried. Of all 3190 female UTUC patients, 1608 (50%) were unmarried. In multivariable LRMs predicting RNU, unmarried status was an independent predictor of lower RNU rates in male (Odds Ratio [OR]: 0.56; P < .001), but not in female (OR: 0.81; P = .1) non-metastatic UTUC patients. In multivariable LRMs predicting ST exposure, unmarried status was an independent predictor of lower ST rates in both male (OR:0.73; P = .03) and female (OR:0.64; P < .001) UTUC patients. In multivariable LRMs predicting locally advanced stage (T3-4N0-2), unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male (OR: 0.95; P = .5) or female (OR: 0.99; P = .9) UTUC patients. CONCLUSIONS: Unmarried male UTUC patients appear at risk of less being able to access RNU, relative to their married counterparts. Moreover, unmarried UTUC patients appear to less benefit from ST, regardless of sex. Conversely, unmarried status was not associated with an increased risk of locally advanced stage at presentation in either male or female UTUC patients.

Female non-obstetric urogenital fistula repair: long-term patient-reported outcomes and a scoping literature review.

OBJECTIVE: To investigate long-term and patient-reported outcomes, including sexual function, in women undergoing urogenital fistula (UGF) repair, addressing the lack of such data in Western countries, where fistulas often result from iatrogenic causes. PATIENTS AND METHODS: We conducted a retrospective analysis at a tertiary referral centre (2010-2023), classifying fistulas based on World Health Organisation criteria and evaluating surgical approaches, aetiology, and characteristics. Both objective (fistula closure, reintervention rates) and subjective outcomes (validated questionnaires) were assessed. A scoping review of patient-reported outcome measures in UGF repair was also performed. RESULTS: The study included 50 patients: 17 (34%) underwent transvaginal and 33 (66%) transabdominal surgery. History of hysterectomy was present in 36 patients (72%). The median (interquartile range [IQR]) operating time was 130 (88-148) min. Fistula closure was achieved in 94% of cases at a median (IQR) follow-up of 50 (16-91) months and reached 100% after three redo fistula repairs. Seven patients (14%) underwent reinterventions for stress urinary incontinence after transvaginal repair (autologous fascial slings). Patient-reported outcomes showed median (IQR) scores on the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS) of 5 (3-7) for filling symptoms, 1 (0-2) for voiding symptoms and 4.5 (1-9) for incontinence symptoms. The median (IQR) score on the ICIQ Female Sexual Matters Associated with Lower Urinary Tract Symptoms Module (ICIQ-FLUTSsex) was 3 (1-5). The median (IQR) ICIQ Satisfaction (ICIQ-S) outcome score and overall satisfaction with surgery item score was 22 (18.5-23.5) and 10 (8.5-10), respectively. Higher scores indicate higher symptom burden and treatment satisfaction, respectively. Our scoping review included 1784 women, revealing mixed aetiology and methodological and aetiological heterogeneity, thus complicating cross-study comparisons. CONCLUSIONS: Urogenital fistula repair at a specialised centre leads to excellent outcomes and high satisfaction. Patients with urethrovaginal fistulas are at increased risk of stress urinary incontinence, possibly due to the original trauma site of the fistula.

Sarcomatoid Dedifferentiation as a Predictor of Cancer-Specific Mortality in Surgically Treated Localized Renal Cell Carcinoma.

BACKGROUND: In contemporary surgically treated patients with localized high-grade (G3 or G4) clear-cell renal cell carcinoma (ccRCC), it is not known whether presence of sarcomatoid dedifferentiation is an independent predictor and/or an effect modifier, when cancer-specific mortality (CSM) represents an endpoint. METHODS: Within the Surveillance, Epidemiology, and End Results database, all surgically treated localized high-grade ccRCC patients treated between 2010 and 2020 were identified. Univariable and multivariable Cox-regression models were used. RESULTS: In 18,853 surgically treated localized high-grade (G3 or G4) ccRCC patients, 5-year CSM-free survival was 87% (62% vs. 88% with vs. without sarcomatoid dedifferentiation, p < 0.001). Presence of sarcomatoid dedifferentiation was an independent predictor of higher CSM (hazard ratio [HR] 1.8, p < 0.001). In univariable survival analyses predicting CSM, presence versus absence of sarcomatoid dedifferentiation in G3 versus G4 yielded the following hazard ratios: HR 1.0 in absent sarcomatoid dedifferentiation in G3; HR 2.7 (p < 0.001) in absent sarcomatoid dedifferentiation in G4; HR 3.9 (p < 0.001) in present sarcomatoid dedifferentiation in G3; HR 5.1 (p < 0.001) in present sarcomatoid dedifferentiation in G4. Finally, in multivariable Cox-regression analyses, the interaction terms defining present versus absent sarcomatoid dedifferentiation in G3 versus G4 represented independent predictors of higher CSM. CONCLUSIONS: In contemporary surgically treated patients with localized high-grade ccRCC, sarcomatoid dedifferentiation is not only an independent multivariable predictor of higher CSM, but also interacts with tumor grade and results in even better ability to predict CSM.

Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

A systematic review and meta-analysis to evaluate the diagnostic accuracy of PSMA PET/CT in the initial staging of prostate cancer.

BACKGROUND: Positron Emission Tomography-Computed Tomography using Prostate-Specific Membrane Antigen (PSMA PET/CT) is notable for its superior sensitivity and specificity in detecting recurrent PCa and is under investigation for its potential in pre-treatment staging. Despite its established efficacy in nodal and metastasis staging in trial setting, its role in primary staging awaits fuller validation due to limited evidence on oncologic outcomes. This systematic review and meta-analysis aims to appraise the diagnostic accuracy of PSMA PET/CT compared to CI for comprehensive PCa staging. METHODS: Medline, Scopus and Web of science databases were searched till March 2023. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify eligible studies. Primary outcomes were specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of PSMA PET/CT for local, nodal and metastatic staging in PCa patients. Due to the unavailability of data, a meta-analysis was feasible only for detection of seminal vesicles invasion (SVI) and LNI. RESULTS: A total of 49 studies, comprising 3876 patients, were included. Of these, 6 investigated accuracy of PSMA PET/CT in detection of SVI. Pooled sensitivity, specificity, PPV and NPV were 42.29% (95%CI: 29.85-55.78%), 87.59% (95%CI: 77.10%-93.67%), 93.39% (95%CI: 74.95%-98.52%) and 86.60% (95%CI: 58.83%-96.69%), respectively. Heterogeneity analysis revealed significant variability for PPV and NPV. 18 studies investigated PSMA PET/CT accuracy in detection of LNI. Aggregate sensitivity, specificity, PPV and NPV were 43.63% (95%CI: 34.19-53.56%), 85.55% (95%CI: 75.95%-91.74%), 67.47% (95%CI: 52.42%-79.6%) and 83.61% (95%CI: 79.19%-87.24%). No significant heterogeneity was found between studies. CONCLUSIONS: The present systematic review and meta-analysis highlights PSMA PET-CT effectiveness in detecting SVI and its good accuracy in LNI compared to CI. Nonetheless, it also reveals a lack of high-quality research on its performance in clinical T staging, extraprostatic extension and distant metastasis evaluation, emphasizing the need for further rigorous studies.

Clofarabine Has a Superior Therapeutic Window as compared to Gemcitabine in Preclinical Bladder Cancer Models.

Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. PATIENT SUMMARY: We compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.

Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis.

Importance: Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway. Objective: To systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)-based screening with systematic biopsy strategies. Data Sources: PubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023). Study Selection: Randomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening. Data Extraction: Number of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted. Main Outcomes and Measures: The primary outcome was csPCa detection rate. Secondary outcomes included clinical insignificant PCa detection rate, biopsy indication rates, and the positive predictive value for the detection of csPCa. Data Synthesis: The generalized mixed-effect approach with pooled odds ratios (ORs) and random-effect models was used to compare the MRI-based and PSA-only screening strategies. Separate analyses were performed based on the timing of MRI (primary/sequential after a PSA test) and cutoff (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3 or ≥4) for biopsy indication. Results: Data were synthesized from 80 114 men from 12 studies. Compared with standard PSA-based screening, the MRI pathway (sequential screening, PI-RADS score ≥3 cutoff for biopsy) was associated with higher odds of csPCa when tests results were positive (OR, 4.15; 95% CI, 2.93-5.88; P ≤ .001), decreased odds of biopsies (OR, 0.28; 95% CI, 0.22-0.36; P ≤ .001), and insignificant cancers detected (OR, 0.34; 95% CI, 0.23-0.49; P = .002) without significant differences in the detection of csPCa (OR, 1.02; 95% CI, 0.75-1.37; P = .86). Implementing a PI-RADS score of 4 or greater threshold for biopsy selection was associated with a further reduction in the odds of detecting insignificant PCa (OR, 0.23; 95% CI, 0.05-0.97; P = .048) and biopsies performed (OR, 0.19; 95% CI, 0.09-0.38; P = .01) without differences in csPCa detection (OR, 0.85; 95% CI, 0.49-1.45; P = .22). Conclusion and relevance: The results of this systematic review and meta-analysis suggest that integrating MRI in PCa screening pathways is associated with a reduced number of unnecessary biopsies and overdiagnosis of insignificant PCa while maintaining csPCa detection as compared with PSA-only screening.

Advances in preclinical assessment of therapeutic targets for bladder cancer precision medicine.

PURPOSE OF REVIEW: Bladder cancer incidence is on the rise, and until recently, there has been little to no change in treatment regimens over the last 40 years. Hence, it is imperative to work on strategies and approaches to untangle the complexity of intra- and inter-tumour heterogeneity of bladder cancer with the aim of improving patient-specific care and treatment outcomes. The focus of this review is therefore to highlight novel targets, advances, and therapy approaches for bladder cancer patients. RECENT FINDINGS: The success of combining an antibody-drug conjugate (ADC) with immunotherapy has been recently hailed as a game changer in treating bladder cancer patients. Hence, interest in other ADCs as a treatment option is also rife. Furthermore, strategies to overcome chemoresistance to standard therapy have been described recently. In addition, other studies showed that targeting genomic alterations (e.g. mutations in FGFR3 , DNA damage repair genes and loss of the Y chromosome) could also be helpful as prognostic and treatment stratification biomarkers. The use of single-cell RNA sequencing approaches has allowed better characterisation of the tumour microenvironment and subsequent identification of novel targets. Functional precision medicine could be another avenue to improve and guide personalized treatment options. SUMMARY: Several novel preclinical targets and treatment options have been described recently. The validation of these advances will lead to the development and implementation of robust personalized treatment regimens for bladder cancer patients.

Preclinical models for bladder cancer therapy research.

PURPOSE OF REVIEW: Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major challenge for the development of novel therapeutics. Preclinical models that closely mimic in vivo tumours and reflect their diverse biology are indispensable for the identification of therapies with specific activity in various BC subtypes. In this review, we summarize efforts and progress made in this context during the last 24 months. RECENT FINDINGS: In recent years, one main focus was laid on the development of patient-derived BC models. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) were demonstrated to widely recapitulate the molecular and histopathological characteristics, as well as the drug response profiles of the corresponding tumours of origin. These models, thus, represent promising tools for drug development and personalized medicine. Besides PDXs, syngenic in vivo models are of growing importance. Since these models are generated using immunocompetent hosts, they can, amongst others, be used to develop novel immunotherapeutics and to evaluate the impact of the immune system on drug response and resistance. SUMMARY: In the past two years, various in vivo and in vitro models closely recapitulating the biology and heterogeneity of human bladder tumours were developed.

Recent contributions of single-cell and spatial profiling to the understanding of bladder cancer.

PURPOSE OF REVIEW: Current risk stratification and treatment decision-making for bladder cancer informed by histopathology as well as molecular diagnostics face limitations. This review summarizes recent advancements in single-cell and spatial omics methodologies for understanding bladder cancer biology and their potential impact on development of novel therapeutic strategies. RECENT FINDINGS: Single-cell RNA sequencing and spatial omics techniques offer unprecedented insights into various aspects of tumor microenvironment (TME), bladder cancer heterogeneity, cancer stemness, and cellular plasticity. Studies have identified multiple malignant cell subpopulations within tumors, revealing diverse transcriptional states and clonal evolution. Additionally, intratumor heterogeneity has been linked to tumor progression and therapeutic response. Immune cell composition analysis has revealed immunosuppressive features in the TME, impacting treatment response. Furthermore, studies have elucidated the role of cancer-associated fibroblasts and endothelial cells in shaping the tumor immune landscape and response to therapy. SUMMARY: Single-cell and spatial omics technologies have revolutionized our understanding of bladder cancer biology, uncovering previously unseen complexities. These methodologies provide valuable insights into tumor heterogeneity and microenvironmental interactions, with implications for therapeutic development. However, challenges remain in translating research findings into clinical practice and implementing personalized treatment strategies. Continued interdisciplinary collaboration and innovation are essential for overcoming these challenges and leveraging the full potential of single-cell and spatial omics in improving bladder cancer diagnosis and treatment.

Impact of Preoperative Plasma Potassium Levels on Oncological Outcomes, Major Complications, and 30-Day Mortality in Bladder Cancer Patients Undergoing Radical Cystectomy.

INTRODUCTION AND OBJECTIVES: We examined the impact of preoperative plasma potassium levels (PPLs) on outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB), hypothesizing that potassium imbalances might influence outcomes. PATIENTS AND METHODS: In this retrospective study, 501 UCB patients undergoing RC from 2009 to 2017 at a tertiary center were analyzed. Blood samples collected a week prior to surgery defined normal and abnormal PPL based on institutional standards. We assessed overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), postoperative complications, 30-day mortality, and non-organ confined disease. Kaplan-Meier estimates, Cox proportional hazards, logistic regression, and decision curve analyses (DCA) were employed. RESULTS: 63 (13%) patients had abnormal preoperative PPLs, with 50 (10%) elevated and 13 (2.5%) decreased. In a 59 months median follow-up, 152 (31%) had disease recurrence, 197 (39%) died from any cause, and 119 (24%) from UCB. Multivariable cox regression analyses adjusting for perioperative parameters demonstrated abnormal PPL was associated with worse OS (HR=1.9, P=0.009), CSS (HR=2.8, P<0.001) and RFS (HR=2.1; P=0.007). Elevated preoperative PPLs also demonstrated significant associations with adverse outcomes in OS, CSS, and RFS (all P<0.05). In multivariable logistic regression analyses, abnormal and elevated PPLs were not associated with 30-day mortality, major 30-day postoperative complications, positive nodal disease, pT3/4 stage, and non-organ confined disease (all P>0.05). CONCLUSION: Abnormal and elevated preoperative PPLs correlate with adverse oncologic outcomes in UCB patients treated with RC. Pending external validation, preoperative PPLs might be a cost-effective, easily obtainable supplemental biomarker for enriching accuracy of outcome prediction in this highly variable maladie.