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Background and Objective: Metastatic urothelial carcinoma (mUCa) ranks as the costliest cancer to treat per patient due to frequent interventions and expensive follow-ups. Investigating first-line therapies, combinations such as enfortumab vedotin + pembrolizumab (EV + P) and gemcitabine/cisplatin + nivolumab exhibit significant overall survival benefits compared with the standard treatment (SoC; gemcitabine/cisplatin). Here, we conducted a cost-effectiveness analysis for mUCa., Methods: We developed a Markov model from a payer perspective, filtering clinical data from the phase 3 Checkmate-901 and EV302/Keynote-A39 trials. Monte Carlo simulation was used to identify the optimal treatment from a socioeconomic perspective in Germany and the USA. Finally, we compared the incremental cost-effectiveness ratio (ICER) of each modality at different willingness-to-pay (WTP) thresholds., Key Findings and Limitations: At a lifetime horizon, SoC, gemcitabine/cisplatin + nivolumab, and EV + P were associated with average costs of €163 424 (USA: $458 006), €206 853 (USA: $597 802), and €401 170 (USA: $1 228 455), and gained quality-adjusted life years (QALYs) of 1.21, 1.71, and 2.31, respectively. The ICERs of the newer strategies were €87 340 (USA: $281 142; gemcitabine/cisplatin + nivolumab) and €216 140 (USA: $700 448; EV + P). At a commonly used WTP threshold of €/$100 000, gemcitabine/cisplatin + nivolumab would be the optimal strategy in Germany, while EV + P would require a price reduction of 46% (USA: 82%) to be cost effective., Conclusions and Clinical Implications: QALYs nearly double with EV + P compared with the current SoC; yet, current costs may not be justified from a strict socioeconomic perspective. Despite its lower oncological benefit, gemcitabine/cisplatin + nivolumab should be considered for first-line therapy due to favorable cost effectiveness, especially in Europe. Establishing individual risk factors is essential for optimizing therapeutic response and treatment costs in the future., Patient Summary: This report presents a cost-effectiveness analysis of emerging treatment options for metastatic urothelial carcinoma. The combination of enfortumab vedotin + pembrolizumab emerged as the most effective treatment; however, it also proved to be the costliest. From a purely socioeconomic standpoint, the combination of gemcitabine/cisplatin and nivolumab represents a cost-effective alternative at least in Germany., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC., Methods: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score., Results: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R 2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R 2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC., Conclusion: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Objective: In narrow anterior urethral strictures, the combined buccal mucosa graft (BMG) with pedicled penile skin flap (PSF) represents a well-known effective alternative to staged urethroplasty. We hypothesized that if the native urethral plate and adjacent corpus spongiosum were preserved, a narrower flap would be needed, and reinforced ventral stability could be achieved without compromising the surgical outcome., Methods: Twelve patients with narrow penile urethral strictures underwent single-stage augmentation urethroplasty using a combined technique. A BMG was quilted to the corpora cavernosa in a dorsal onlay approach, and a longitudinal ventral PSF was transposed ventrally and sutured to the scarred native urethral mucosa on one side and to the BMG on the other side to form a neourethra of triangular form. The preserved corpus spongiosum was wrapped and fixed around the flap ventrally., Results: The median age was 47 years (IQR 35-59), and the median stricture length was 5 cm (IQR 3, 8-7). The median surgical time was 205 min (IQR 172-236). The overall success rate (SR) was 91.7% without sacculation or diverticula formation after a median follow-up period of 38 months (IQR 33-40). Three transient fistulas healed through prolonged urinary diversion. Five patients (41.7%) reported postvoid dribbling following urethroplasty., Conclusion: Preservation of the native urethral plate is a valuable adjunct to the combination of graft and flap for single-stage augmentation urethroplasty for narrow urethral strictures, with satisfactory mid-term success and an acceptable complication rate., (© 2024 The Japanese Urological Association.)

Background: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients., Methods: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic., Results: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595)., Conclusions: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Prostate cancer (PCa) diagnosis and staging have evolved with the advent of 68Ga-Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). This study investigates the role of complementary systematic biopsies (SB) during PSMA-PET/CT-guided targeted prostate biopsies (PET-TB) for PCa detection, grading, and distribution. We address the uncertainty surrounding the necessity of SB in conjunction with PET-TB., Methods: We analyzed PCa grading and distribution in 30 men who underwent PET-TB and SB because of contraindication to magnetic resonance imaging or high clinical suspicion of PCa. Tumor distribution was assessed in relation to the PET-highlighted lesions. Standardized reporting schemes, encompassing SUV max , PRIMARY score, and miTNM classification, were evaluated., Results: 80% of patients were diagnosed with PCa, with 70% classified as clinically significant (csPCa). SB detected more csPCa cases than PET-TB, but the differences were not statistically significant. Discordant results were observed in 25% of cases, where SB outperformed PET-TB. Spatial analysis revealed that tumor-bearing cores from SB were often located in close proximity to the PET-highlighted region. Reporting schemes showed potential for csPCa detection with significantly increased SUV max in csPCA patients. Subsequent follow-up data underscored the importance of SB in precise PCa grading and staging., Conclusions: While PET-TB can simplify prostate biopsy and reduce invasiveness by core number, SB cannot be omitted yet due to potential PET-TB targeting errors. Factors such as limited spatial resolution and fusion inaccuracies contribute to the need for SB. Standardization in reporting schemes currently cannot compensate for targeting errors highlighting the need for refinement., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

Purpose: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC)., Methods: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro., Results: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG., Conclusion: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection., Methods: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality., Results: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60-0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82-0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups., Conclusion: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation., (© 2024. The Author(s).)

Purpose: Additive systematic biopsy (SB) contributes to prostate cancer (PCA) detection in MRI-targeted biopsy (TB). However, the reasons for this are not yet clear. We compared the performance of TB, SB and the combined approach (CB) in biopsy-naive men to determine the added value of SB for tumor grading and spatial tumor distribution., Methods: Two hundred and fifty-nine men with PI-RADS 3-5 graded lesions who underwent CB were enrolled. Data were prospectively collected, and cancer detection rates (CDR) were compared at patient and lesion level. Gleason grade up- and down-grading from biopsy to prostatectomy specimens (n = 56; 21.6%) were determined. Clinically significant cancer (csPCA) was defined as Gleason grade ≥ 2., Results: CDR by CB based on PI-RADS categories 3, 4 and 5 for PCA were 24%, 72% and 98% and 17%, 64% and 96% for csPCA. CB detected more PCA and csPCA than TB (p < 0.001). However, TB showed higher efficiency, defined as CDR per biopsy core, for PCA and csPCA in PI-RADS 4-5 rated patients (p < 0.001). Concordance between biopsy and prostatectomy grading was highest in CB with misdiagnosis of csPCA in 25% of men. TB missed cancer attributed to the index lesion in 10.2% and underestimated csPCA in 7%. In these cases, 76% of csPCA were detected and 85% were upgraded to csPCA by SB in adjacent sectors., Conclusion: SB cannot be safely abundant without increased diagnostic uncertainty. When TB missed csPCA, SB detected it close to the MRI-target lesion. Therefore, perifocal biopsies could potentially replace 12-core SB with increased efficiency in taking manageable risks., (© 2022. The Author(s).)

Purpose: The coronavirus disease 2019 (COVID-19) pandemic is disrupting urology health-care worldwide. Reduced emergency room visits resulting in adverse outcomes have most recently been reported in pediatrics and cardiology. We aimed to compare patients with emergency room visits for pyelonephritis in 2019 (pre-COVID-19 era) and within the first wave of pandemic in 2020 (COVID-19 era) with regard to the number of visits and severe adverse disease outcomes., Methods: We performed a retrospective multicentre study comparing characteristics and outcomes of patients with pyelonephritis, excluding patients with hydronephrosis due to stone disease, in 10 urology departments in Germany during a 1-month time frame in March and April in each 2019 and 2020., Results: The number of emergency room visits for pyelonephritis in the COVID-19 era was lower (44 patients, 37.0%) than in the pre-COVID-19 era (76 patients, 63.0%), reduction rate: 42.1% (p = 0.003). Severe adverse disease outcome was more frequent in the COVID-19 era (9/44 patients, 20.5%) than in the pre-COVID-19 era (5/76 patients, 6.6%, p = 0.046). In detail, 7 versus 3 patients needed monitoring (15.9 vs. 3.9%), 2 versus no patients needed intensive-care treatment (4.5 vs. 0%), 2 versus no patients needed drain placement (4.5 vs. 0%), 2 versus no patients had a nephrectomy (4.5 vs. 0%), and 2 versus 1 patient died (4.5 vs. 1.3%)., Conclusion: This report of collateral damage during CO-VID-19 showed that emergency room visits were decreased, and severe adverse disease outcomes were increased for patients with pyelonephritis in the COVID-19 era. Health authorities should set up information campaign programs actively encouraging patients to utilize emergency room services in case of severe symptoms specifically during the actual second wave of pandemic., (© 2021 S. Karger AG, Basel.)

The Mediator complex, a multi-subunit protein complex, plays an integral role in regulating transcription. Genetic alterations of the mediator subunit 15 (MED15) in separate tumor entities have been described previously. However, till now, not much is known about the role of MED15 in urothelial bladder cancer (BCa). Using cBioPortal, database analysis was executed for the mRNA expression and survival analysis of MED15 in BCa. Immunohistochemistry (IHC) analysis against MED15 was performed on tissue microarrays with 18 benign, 126 BCa, and 38 metastases samples. The intensity evaluation was performed using a staining intensity score from 0 to 3 and associated with clinicopathological data. The BCa cell lines T24 and TCCSUP were used for the functional investigation. After the MED15 knockdown by small interfering (si)RNA, cell proliferation, migration and invasion were investigated. On the mRNA level, only a low number of alterations (2%) was found for MED15 in BCa. Due to the small count of events, there were no significant differences or tendencies in survival. For IHC, MED15 was found to have a higher expression in non-muscle invasive BCa compared with benign and muscle invasive BCa. For survival analysis, no significant differences between samples with or without overexpression of MED15 were found. In the functional analysis, proliferation, migration, and invasion were significantly reduced in BCa-cells following the transient siRNA-mediated MED15 knockdown. In summary, MED15 appears to play a role in the tumor parameters proliferation, migration, and invasion in BCa, but further investigations are necessary.

Background: The mediator complex consists of 33 subunits and plays a central role in transcription. Studies have already described the involvement of individual subunits, especially in carcinogenesis. With regard to the subunit MED30, this has, so far, only been confirmed in gastric and breast carcinoma. The role of MED30 in urological tumours is unknown., Materials and Methods: First, a database analysis using cBioPortal was performed for the mRNA expression and survival analysis of MED30 in clear cell renal cell carcinoma (ccRCC) and papillary RCC (pRCC). The immunohistochemical analysis (IHC) against MED30 was performed on tissue microarrays (TMA), with benign, ccRCC, pRCC samples, and ccRCC-metastases. Intensity evaluation was performed using the IRS (Immunoreactive Score). The ccRCC cell lines ACHN and A-498 were used for the functional investigation of proliferation, migration, and invasion after the knockdown of MED30 by siRNA., Results: In a database analysis by cBioPortal, it was shown that mRNA overexpression of MED30 in the pRCC was significantly associated with a poorer overall survival and progression-free survival. In the IHC, pRCC showed the highest level of MED30 expression, unfortunately without significant results in the survival analysis. The knockdown of MED30 resulted in a significant decrease in proliferation, migration, and invasion in ccRCC., Conclusion: In summary, MED30 seems to be involved in the progression of the RCC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/objective: MED15 is a part of the multiprotein Mediator complex which is involved in the transcription of polymerase (Pol) II-dependent genes. Several studies in this field have reported altered expressions of distinct subunits in human malignancy. However, the role of MED15 in renal cell carcinoma (RCC) has not be investigated yet., Methods: First, we performed an RNA expression and survival analysis of MED15 in RCC by using the database cBioPortal. To confirm these data on the protein level, we executed immunohistochemical (IHC) staining against MED15 on a tissue microarray containing 184 samples of the most common subtypes of the tumour at the various stages. Further, we performed functional analysis including proliferation, migration, and invasion assays on the RCC cell lines A-498 and ACHN following the siRNA-mediated MED15 knockdown., Results: On the mRNA level, higher expression of MED15 was associated with worse patient survival rates. IHC staining validated this tendency, unfortunately the results were not significant. However, supporting this tendency, in vitro-assays showed a significant decrease in proliferation, migration, and invasion after knockdown of MED15., Conclusion: The research concludes that MED15 does seem to play a tumour promoting role in the progression and metastatic spread of renal cell carcinoma.

Background/aim: The Mediator complex is a key regulator of gene transcription, and several studies have demonstrated altered expression of particular subunits in diverse human diseases, especially cancer. To date, nothing is known about the role of MED30 in bladder cancer., Materials and Methods: We, therefore, performed an RNA expression and survival analysis of the subunit MED30 in 537 samples of bladder cancer by using the database cBioPortal. To validate these data on the protein level, we practiced immunohistochemical staining against MED30 on a tissue microarray containing 210 samples of all tumour stages and performed survival analyses. For functional analysis, the siRNA-mediated knockdown of MED30 was performed in the cell lines T24 and TCCSUP followed by proliferation, migration, and invasion assays., Results: On the mRNA and protein levels, higher expression of MED30 is associated with better patient survival. In accordance with this, advanced T- and N-stages showed lower expression of MED30. In contrast, knockdown of MED30 led to reduction of the tumour parameters proliferation, migration, and invasion in the BCa cell lines., Conclusion: MED30 appears to be integrated in the progression of the urothelial tumour in the bladder., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)