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Background: Different combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response., Methods: In this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan-Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias., Result: irAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan-Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE group (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE group, while it was not reached in the irAE group (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE group at the landmark time., Conclusion: The presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes. Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers., Competing Interests: Disclosure MS has nothing to disclose. LMK received fees for advisory roles and lectures from BMS, Ipsen, Merck Healthcare, MSD, Roche. MB received fees for advisory roles and lectures from AAA, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA-Pharma, Exelixis, Gilead, Ipsen, Janssen Cilag, Lilly, Merck Healthcare, MSD, Novartis, Pfizer, Roche, Sanofi and travel expenses from Astra Zeneca, Bayer, Janssen Cilag, Ipsen, Merck Healthcare. AJS has nothing to disclose. KT has nothing to disclose. KS received fees for advisory roles and lectures from AAA, Amgen, Apogepha, Astellas, AstraZeneca, Bayer, BMS, Eisai, EUSA-Pharma, Fosanis, Ipsen, Janssen Cilag, Merck Healthcare, MSD, Novartis, Pfizer, Roche and travel expenses from Sanofi-Aventis, Astra Zeneca, Astellas, Bayer, Janssen Cilag, Ipsen, Merck Healthcare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objective: Despite the proven effectiveness of organized PSA-based screening in reducing prostate cancer-related mortality, there is currently no program in Germany covered by statutory health insurance. In accordance with the EU Council Decision (2022/0290(NLE)), the German Society of Urology (DGU) has developed a concept for risk-adapted prostate cancer early detection., Materials and Methods: Based on a literature review of current screening studies, an algorithm for PSA-based prostate cancer early detection was developed., Results: Risk-adapted prostate cancer screening involves PSA testing in the age group of 45-70 years, followed by PSA-based individual risk stratification and stepwise expansion of diagnostics through magnetic resonance imaging (MRI) to biopsy. While initially up to 2.6 million men will undergo PSA testing, a reduction in these initial examinations to fewer than 200,000 men per year will occur from year four onwards., Conclusions: The presented algorithm provides clear recommendations for risk-adapted PSA-based early detection for prostate cancer for urologists and patients. The goal is to improve diagnosis of clinically significant prostate cancer, while reducing overdiagnosis and overtreatment., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Understanding stakeholders' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC., Materials and Methods: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified., Results: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public)., Conclusion: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Muscle-invasive bladder cancer (MIBC) is a highly heterogeneous and costly disease with significant morbidity and mortality. Understanding tumor histopathology leads to tailored therapies and improved outcomes. In this study, we employed a weakly supervised learning and neural architecture search to develop a data-driven scoring system. This system aimed to capture prognostic histopathological patterns observed in H&E-stained whole-slide images. We constructed and externally validated our scoring system using multi-institutional datasets with 653 whole-slide images. Additionally, we explored the association between our scoring system, seven histopathological features, and 126 molecular signatures. Through our analysis, we identified two distinct risk groups with varying prognoses, reflecting inherent differences in histopathological and molecular subtypes. The adjusted hazard ratio for overall mortality was 1.46 (95% CI 1.05-2.02; z: 2.23; p = 0.03), thus identifying two prognostic subgroups in high-grade MIBC. Furthermore, we observed an association between our novel digital biomarker and the squamous phenotype, subtypes of miRNA, mRNA, long non-coding RNA, DNA hypomethylation, and several gene mutations, including FGFR3 in MIBC. Our findings underscore the risk of confounding bias when reducing the complex biological and clinical behavior of tumors to a single mutation. Histopathological changes can only be fully captured through comprehensive multi-omics profiles. The introduction of our scoring system has the potential to enhance daily clinical decision making for MIBC. It facilitates shared decision making by offering comprehensive and precise risk stratification, treatment planning, and cost-effective preselection for expensive molecular characterization.

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 m 2 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/1.73m 2 (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 m 2 ) 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 m 2 ). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m 2 ), 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.

Purpose: While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort., Materials and Methods: We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival., Results: Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage ( P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins ( P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1)., Conclusions: In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

Background: Androgen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment., Methods: AR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment., Results: We revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility., Conclusion: We demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients., (© 2023. The Author(s).)

Introduction: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations., Methods: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board., Results: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guérin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists., Conclusions: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates., (© 2021 S. Karger AG, Basel.)

Purpose: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine-carboplatin (gem-carbo) versus gemcitabine-cisplatin (gem-cis)., Methods: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem-carbo or gem-cis followed by RC., Results: We included 747 patients treated with gem-carbo (n = 147) or gem-cis (n = 600). Patients treated with gem-carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem-carbo and gem-cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61-1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85-1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93-1.96]; p = 0.11). Median OS of patients treated with gem-carbo and gem-cis was 28.6 months (95%CI 18.1-39.1) and 45.1 months (95%CI 32.7-57.6) (p = 0.18), respectively. Median CSS of patients treated with gem-carbo and gem-cis was 28.8 months (95%CI 9.8-47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences., Conclusion: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem-carbo and that survival outcomes seem comparable to gem-cis provided patients are able to receive ≥ 3 cycles and undergo RC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: For many years, the standard treatment of metastatic, hormone-sensitive prostatic carcinoma (mHSPC) was androgen deprivation therapy (ADT) alone. By lowering the testosterone level into the castration range, ADT deprives the tumor of a key growth factor., Methods: For this article, we evaluated the treatment recommendations contained in national and international guidelines (German S3 guidelines and those of the European Society for Medical Oncology [ESMO], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN]), as well as pertinent publications revealed by a PubMed search and the congress abstracts of the ESMO and of the American Society of Clinical Oncology [ASCO]., Results: The past few years have witnessed fundamental changes in the treatment of mHSPC. Treatment intensification with docetaxel or with the new drugs directed against the androgen receptor signal pathway (abiraterone, apalutamide and enzalutamide) has been found to lower mortality by 19-40% and is now an integral component of first-line therapy. Relevant new findings have also been obtained with threefold combinations of ADT, docetaxel, and abiraterone or darolutamide. For patients with a light tumor burden, local radiotherapy of the primary tumor improves the probability of survival at 3 years by 8% (45.4 versus 49.1 months, difference 3.6 months; 95% confidence interval, 1.0 to 6.2 months)., Conclusion: The treatment of mHSPC is constantly changing. Phase III trials that are now in the recruitment stage, as well as our continually improving understanding of the underlying molecular-pathological mechanisms, will be altering the treatment landscape still further in the years to come.

Perioperative management of anticoagulation in patients receiving long-term anticoagulation or platelet aggregation inhibitors requires an individual consideration of competing risks. If the risk for bleeding is low, anticoagulation can often be continued. If it is necessary to pause anticoagulation, the necessity and dosage of bridging must be determined based on the individual risk of thromboembolism. Only patients with a high risk of thromboembolism should receive bridging in the full therapeutic dosage. The timing of pausing anticoagulation depends on the risk of bleeding from the urological intervention and the renal function of the patient. Platelet aggregation inhibitors should not be discontinued in the first month after coronary stent implantation, especially after acute coronary syndrome., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Biomarker in metastatic castration resistant prostate cancer (mCRPC) treatment are rare. We aimed to compare the clinical value of circulating tumor cells (CTCs) and androgen receptor splice variant 7 (AR-V7) as biomarker in mCRPC patients undergoing androgen receptor-targeted agent (ARTA) treatment. Overall cohort (65 patients) was stratified regarding either CTC or AR-V7 status followed by further sub-stratification of the respective other marker. Subsequently, prostate specific antigen (PSA) response, progression free survival (PFS) and overall survival (OS)) of subgroups was compared. CTCs and AR-V7 were detected in 54 (83%) and 33 (61%) patients, respectively. All AR-V7 + were CTC +. We detected PSA response in all subgroups. For PFS and OS, biomarker stratification revealed differences between all subgroups. Interestingly, no significant differences of AR-V7 transcript copy numbers were detected between responding and non-responding patients. Additionally, multivariable analysis revealed no independent prognostic value of AR-V7 positivity. Both biomarkers show clinical value in prognosticating clinical outcome. Nonetheless, AR-V7 stratification underestimates the heterogenous subgroup of CTC - and CTC + patient, the latter requiring more intense clinical surveillance. Additionally, AR-V7 level does not correlate with clinical response. Thus, the value of AR-V7 as a clinical biomarker must be considered skeptically., (© 2022. The Author(s).)

Background: The European Association of Urology risk stratification dichotomizes patients with upper tract urothelial carcinoma (UTUC) into two risk categories., Objective: To evaluate the predictive value of a new classification to better risk stratify patients eligible for kidney-sparing surgery (KSS)., Design, Setting, and Participants: This was a retrospective study including 1214 patients from 21 centers who underwent ureterorenoscopy (URS) with biopsy followed by radical nephroureterectomy (RNU) for nonmetastatic UTUC between 2000 and 2017., Outcome Measurements and Statistical Analysis: A multivariate logistic regression analysis identified predictors of muscle invasion (≥pT2) at RNU. The Youden index was used to identify cutoff points., Results and Limitations: A total of 811 patients (67%) were male and the median age was 71 yr (interquartile range 63-77). The presence of non-organ-confined disease on preoperative imaging (p < 0.0001), sessile tumor (p < 0.0001), hydronephrosis (p = 0.0003), high-grade cytology (p = 0.0043), or biopsy (p = 0.0174) and higher age at diagnosis (p = 0.029) were independently associated with ≥pT2 at RNU. Tumor size was significantly associated with ≥pT2 disease only in univariate analysis with a cutoff of 2 cm. Tumor size and all significant categorical variables defined the high-risk category. Tumor multifocality and a history of radical cystectomy help to dichotomize between low-risk and intermediate-risk categories. The odds ratio for muscle invasion were 5.5 (95% confidence interval [CI] 1.3-24.0; p = 0.023) for intermediate risk versus low risk, and 12.7 (95% CI 3.0-54.5; p = 0.0006) for high risk versus low risk. Limitations include the retrospective design and selection bias (all patients underwent RNU)., Conclusions: Patients with low-risk UTUC represent ideal candidates for KSS, while some patients with intermediate-risk UTUC may also be considered. This classification needs further prospective validation and may help stratification in clinical trial design., Patient Summary: We investigated factors predicting stage 2 or greater cancer of the upper urinary tract at the time of surgery for ureter and kidney removal and designed a new risk stratification. Patients with low or intermediate risk may be eligible for kidney-sparing surgery with close follow-up. Our classification scheme needs further validation based on cancer outcomes., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC)., Materials and Methods: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age., Results: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype., Conclusions: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age., (© 2021. The Author(s).)

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome., Objective: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium., Design, Setting, and Participants: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC., Outcome Measurements and Statistical Analysis: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility., Results and Limitations: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology., Conclusions: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy., Patient Summary: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability., (Copyright © 2020. Published by Elsevier B.V.)

Background: Several groups have proposed features to identify low-risk patients who may benefit from endoscopic kidney-sparing surgery in upper tract urothelial carcinoma (UTUC)., Objective: To evaluate standard risk stratification features, develop an optimal model to identify ≥pT2/N+ stage at radical nephroureterectomy (RNU), and compare it with the existing unvalidated models., Design, Setting, and Participants: This was a collaborative retrospective study that included 1214 patients who underwent ureterorenoscopy with biopsy followed by RNU for nonmetastatic UTUC between 2000 and 2017., Outcome Measurements and Statistical Analysis: We performed multiple imputation of chained equations for missing data and multivariable logistic regression analysis with a stepwise selection algorithm to create the optimal predictive model. The area under the curve and a decision curve analysis were used to compare the models., Results and Limitations: Overall, 659 (54.3%) and 555 (45.7%) patients had ≤pT1N0/Nx and ≥pT2/N+ disease, respectively. In the multivariable logistic regression analysis of our model, age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.0-1.03, p = 0.013), high-grade biopsy (OR 1.81, 95% CI 1.37-2.40, p < 0.001), biopsy cT1+ staging (OR 3.23, 95% CI 1.93-5.41, p < 0.001), preoperative hydronephrosis (OR 1.37 95% CI 1.04-1.80, p = 0.024), tumor size (OR 1.09, 95% CI 1.01-1.17, p = 0.029), invasion on imaging (OR 5.10, 95% CI 3.32-7.81, p < 0.001), and sessile architecture (OR 2.31, 95% CI 1.58-3.36, p < 0.001) were significantly associated with ≥pT2/pN+ disease. Compared with the existing models, our model had the highest performance accuracy (75% vs 66-71%) and an additional clinical net reduction (four per 100 patients)., Conclusions: Our proposed risk-stratification model predicts the risk of harboring ≥pT2/N+ UTUC with reliable accuracy and a clinical net benefit outperforming the current risk-stratification models., Patient Summary: We developed a risk stratification model to better identify patients for endoscopic kidney-sparing surgery in upper tract urothelial carcinoma., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In bone metastatic castration-resistant prostate cancer (bmCRPC) treated with Enzalutamide commonly used prostate-specific antigen (PSA) can be misleading since initial PSA-flares may occur. In other therapies, bouncing of alkaline phosphatase (ALP-bouncing) was shown to be a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) is usually associated with better outcome. We evaluated the prognostic ability of ALP-bouncing, LDH, PSA, and the combination of these markers after initiation of Enzalutamide., Methods: Eighty-nine patients with bmCRPC and dynamic changes of PSA, LDH and ALP were analyzed. ALP-bouncing, an increase after therapy start followed by a decline below baseline during the first 8 weeks, LDH-normalization and PSA-decline were analyzed regarding their association with survival using Kaplan-Meier analyses and uni- and multivariate (UV and MV) Cox-regression models., Results: In Kaplan-Meier analysis a PSA-decline >50%, LDH-normalization and ALP-bouncing were associated with longer median progression-free survival (PFS) with 7 [95% confidence interval (CI): 4.2-9.8] vs. 3 (2.3-3.7) months for PSA-decline (log-rank P<0.01), 6 (4.1-8) vs. 2 (1.2-2.8) for LDH-normalization (P<0.01) and 8 (0-16.3) vs. 3 (1.9-4.1) for ALP-bouncing (P=0.01). Analysis of overall survival (OS) showed similar, not for all parameters significant, results with 17 (11.7-22.3) vs. 12 (7.0-17.1) months for PSA (P=0.35), 17 (13.2-20.8) vs. 7 (5.8-8.2) for LDH-normalization (P<0.01) and 19 (7.9-30.1) vs. 12 (7.7-16.3) for ALP-bouncing (P=0.32). In UV analysis, ALP-bouncing [hazard ratio (HR): 0.5 (0.3-1.0); P=0.02], PSA-decline >50% [HR: 0.5 (0.3-0.7); P<0.01] and LDH-normalization [HR: 0.4 (0.2-0.6); P<0.01] were significantly associated with longer PFS. For OS, LDH-normalization significantly prognosticated longer survival [HR: 0.4 (0.2-0.6); P<0.01]. In MV analysis, LDH-normalization was associated with a trend towards better OS [HR: 0.5 (0.2-1.1); P=0.09]. Comparing ALP-bouncing, LDH-normalization and PSA-decline with a PSA-decline alone, Kaplan-Meier analysis showed significantly longer PFS [11 (0.2-21.8) vs. 4 (0-8.6); P=0.01] and OS [20 (17.7-22.3) vs. 8 (0.3-15.7); P=0.02] in favor of the group presenting with the beneficial dynamics of all three markers. In UV analysis, the presence of favorable changes in the three markers was significantly associated with longer PFS [HR: 0.2 (0.1-0.7); P<0.01] and OS [HR: 0.3 (0.1-0.8); P=0.02]., Conclusions: ALP-bouncing and LDH-normalization may add to identification of bmCRPC-patients with favorable prognosis under Enzalutamide., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-1117). The series “Management of Advanced Genitourinary Malignancies” was commissioned by the editorial office without any funding or sponsorship. Dr. KS reports other from Astellas, during the conduct of the study; personal fees from Janssen, non-financial support from Astellas, non-financial support from Bayer, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Novartis, personal fees from EUSApharm, personal fees from Amgen, personal fees from Ipsen, personal fees from Merck, personal fees from MSD, personal fees from BMS, personal fees from Eisai, outside the submitted work. Dr. KR reports personal fees from Bayer Healthcare, personal fees from AAA, personal fees from ABX, personal fees from Janssen Cielag, personal fees from AMGEN, outside the submitted work. Dr. AS reports grants from Astellas, during the conduct of the study; other from Myriad, other from German Cancer Aid, other from Philips Healthcare, other from Proteomedix, personal fees from Janssen, personal fees from Ipsen, outside the submitted work. In addition, Dr. AS has a patent characterization of primary tumors (039PCT0735) issued. Dr. MB reports personal fees from Astellas, during the conduct of the study; grants and personal fees from Janssen, personal fees from Astellas, personal fees from Bayer, personal fees from AstraZeneca, personal fees from Sanofi, personal fees from Pfizer, personal fees from Novartis, personal fees from EUSApharm, personal fees from Amgen, personal fees from Ipsen, personal fees from Merck, personal fees from MSD, personal fees from BMS, personal fees from Eisai, personal fees from ABX, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Translational Andrology and Urology. All rights reserved.)

Objective: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC)., Methods: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses., Results: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77)., Conclusion: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Background: People with urothelial carcinoma of the bladder are at risk for recurrence and progression following transurethral resection of a bladder tumour (TURBT). Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) are commonly used, competing forms of intravesical therapy for intermediate- or high-risk non-muscle invasive (Ta and T1) urothelial bladder cancer but their relative merits are somewhat uncertain., Objectives: To assess the effects of BCG intravesical therapy compared to MMC intravesical therapy for treating intermediate- and high-risk Ta and T1 bladder cancer in adults., Search Methods: We performed a systematic literature search in multiple databases (CENTRAL, MEDLINE, Embase, Web of Science, Scopus, LILACS), as well as in two clinical trial registries. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The latest search was conducted in September 2019., Selection Criteria: We included randomised controlled trials (RCTs) that compared intravesical BCG with intravesical MMC therapy for non-muscle invasive urothelial bladder cancer., Data Collection and Analysis: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated the quality of evidence according to GRADE per outcome. In the meta-analyses, we used the random-effects model., Main Results: We identified 12 RCTs comparing BCG versus MMC in participants with intermediate- and high-risk non-muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low-certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non-fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low-certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low-certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low-certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size., Authors' Conclusions: Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: Based on data retrieved from a comprehensive multicenter database, we externally validated a published postoperative nomogram for the prediction of disease-specific survival (DSS) in patients with papillary renal cell carcinoma (papRCC)., Methods: A multicenter database containing data of 2325 patients with surgically treated papRCC was used as validation cohort. After exclusion of patients with missing data and patients included in the development cohort, 1372 patients were included in the final analysis. DSS-probabilities according to the nomogram were calculated and compared to actual DSS-probabilities. Subsequently, calibration plots and decision curve analyses were applied., Results: The median follow-up was 38 months (IQR 11.8-80.7). Median DSS was not reached. The c-index of the nomogram was 0.71 (95% CI 0.60-0.83). A sensitivity analysis including only patients operated after 1998 delivered a c-index of 0.84 (95% CI 0.77-0.92). Calibration plots showed slight underestimation of nomogram-predicted DSS in probability ranges below 90%: median nomogram-predicted 5-year DSS in the range below 90% was 55% (IQR 20-80), but the median actual 5-year DSS in the same group was 58% (95% CI 52-65). Decision-curve analysis showed a positive net-benefit for probability ranges between a DSS probability of 5% and 85%., Conclusions: The nomogram performance was satisfactory for almost all DSS probabilities; hence it can be recommended for application in clinical routine and for counseling of patients with papRCC.

Urothelial carcinoma of the bladder (UCB) is a very heterogeneous disease and divided into invasive and non-invasive disease. In non-muscle-invasive bladder cancer (NMIBC), recurrence after transurethral resection or instillation-therapy, and progression to invasive disease are issues of concern. In muscle-invasive bladder cancer (MIBC), systemic recurrence after radical treatment is a pressing problem, as the available therapies in this setting are of limited efficacy. For both entities there are only few clinicopathological prognostic biomarkers to identify subgroups at risk to aid in decision making to whom to offer early radical cystectomy in case of NMIBC or neoadjuvant/adjuvant chemotherapy in case of MIBC to improve outcomes. Despite advances in surgery and intravesical therapy, up to 30% of NMIBC-patients suffer progression to MIBC. After cystectomy around 50% of MIBC patients suffer local or systemic recurrence and subsequently succumb to the disease. Standard features, like pathological staging and grading, are not sufficient to identify patients at risk beyond doubt. Recent advances in molecular diagnostics in combination with standard pathological features could be used to improve risk stratification of patients, guide treatment plans and ultimately improve outcomes. Immunohistochemical (IHC) analysis can detect altered regulatory pathway-products. Until now a plethora of prognostic IHC-biomarkers has been reported on in UCB, but only few have been validated and no biomarker is in routine use or recommended by guidelines. In this review we discuss the prognostic potential of the most promising IHC-biomarkers in NMIBC and MIBC with a focus on prognostication of recurrence and stage progression in NMIBC as well as recurrence-free, cancer-specific and overall survival in MIBC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC., Methods: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression., Results: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02)., Conclusion: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies., Methods: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05., Results: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS., Conclusions: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.

The operative aspect of radical prostatectomy has changed dramatically in the past 200 years as significant technological advances have been made, particularly during the past 50 years. The work of Dr. Walsh in the late 1970 s and early 1980 s led to a significant reduction in surgical morbidity and is considered an important milestone of radical prostatectomy, as is the introduction of minimally-invasive (robotic-assisted) surgical techniques. Yet there is no absolute gold standard regarding surgical approaches. Innovative tools, e. g. the addition of "augmented reality", are currently under investigation. This review article for the anniversary issue of "Der Urologe" aims to cover the milestones of the evolution of this "signature" surgery in the field of urology., Competing Interests: Die Autoren geben keine Interessenkonflikte an., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Therapy resistance remains a serious dilemma in metastatic castration-resistant prostate cancer (mCRPC) with primary or secondary resistance frequently occurring against any given therapy. Available prognostic models for Abiraterone Acetate (AA) are specifically designed for either pre- or post-chemotherapy settings and mostly based on trial datasets not necessarily reflecting real-life. Results: A score of 0-2 (low-risk) is associated with an OS-probability of 80.0% (95%CI: 71.3-90.6) and 50.5% (95%CI: 38.7-66.0) after 1 and 2 years while a score of 3-4 (high risk) is associated with an OS-probability of 35.3% (95%CI: 22.3-55.8) and 5.7% (95%CI: 1.5-21.8), respectively. The bootstrapping survival analysis of the scoring-system revealed a median c-index of 0.80 (IQR: 0.79-0.82). Material and Methods: We developed a scoring-system using four real-life parameters 117 mCRPC patients treated with AA either pre- or post-chemotherapy. These parameters were evaluated using COX regression analysis. The scoring-system consists of binary-categorized parameters; when any of these exceeds the given cut-off, one point is added up to a final score ranging between 0-4 points. The final score was stratified by a median threshold of 2 into low- and high-risk groups. We evaluated the discriminative ability of our scoring-system using concordance probability (C-index) and Kaplan-Meier-analysis and applied a 100-times bootstrap for survival analysis. Conclusions: Our study introduces a novel prognostic scoring-system for OS of real-life mCRPC patients receiving AA treatment irrespective of the line of therapy. The scoring-system is simple and can be easily utilized based on PSA and LDH values, neutrophil to lymphocyte ratio, and ECOG performance status., Competing Interests: CONFLICTS OF INTEREST MB: received personal fees from Janssen, Astellas, and Sanofi within the scope of this manuscript. AJS: received personal fees from Janssen and Astellas within the scope of this manuscript. JS: received personal fees from Janssen within the scope of this manuscript. LMK: received personal fees from Janssen, Astellas, and Sanofi within the scope of this manuscript. KS, LF, YW, OE: reports no conflict of interest within the scope of this manuscript.

Objectives: To develop and externally validate a model that quantifies the likelihood that a pathologically node-negative patient with clear cell renal cell carcinoma (cRCC) has, indeed, no lymph node metastasis (LNM)., Patients and Methods: Data from 1389 patients treated with radical nephrectomy (RN) and lymph node dissection (LND) were analyzed. For external validation, we used data from 2270 patients in the Surveillance, Epidemiology and End Results (SEER) database. We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathological nodal staging score (pNSS), which represents the probability that a patient is correctly staged as node negative as a function of the number of examined lymph nodes (LNs)., Results: The mean and median number of LNs removed were 7.0 and 5.0 (standard deviation, SD 6.6; interquartile range, IQR 7.0) in the development cohort and 5.6 and 2.0 (SD 8.6, IQR 5.0) in the validation cohort, respectively. The probability of missing a positive LN decreased with increasing number of LNs examined. In both the validation and the development cohort, the number of LNs needed for correctly staging a patient as node negative increased with higher pathological tumor stage and Fuhrman grade., Conclusions: The number of examined LNs needed for adequate nodal staging in cRCC depends on pathological tumor stage and Fuhrman grade. We developed here and then externally validated a pNSS, which could help to refine patient counseling, decision-making regarding risk-stratified surveillance regimens and inclusion criteria for clinical trials of adjuvant therapy.