Publications by authors named "Ekaterina Laukhtina"

76 Publications

The Value of Preoperative Plasma VEGF Levels in Urothelial Carcinoma of the Bladder Treated with Radical Cystectomy.

Eur Urol Focus 2021 Aug 25. Epub 2021 Aug 25.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Background: Elevated preoperative plasma levels of the angiogenesis-related marker VEGF have been associated with worse oncological outcomes in various malignancies.

Objective: To investigate the predictive/prognostic role of VEGF in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC).

Design, Setting, And Participants: VEGF plasma levels were measured preoperatively in 1036 patients with UCB who underwent RC.

Outcome Measurements And Statistical Analysis: The correlation between plasma VEGF levels and pathological and survival outcomes was assessed using logistic regression and Cox regression analyses. Discrimination was assessed using the concordance index (C index). The clinical net benefit was evaluated using decision curve analysis (DCA).

Results And Limitations: Patients with higher pretreatment plasma VEGF levels had poorer recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) according to log-rank tests (all p < 0.001). Higher VEGF levels were not independently associated with higher risk of lymph node metastasis, ≥pT3 disease, or non-organ-confined disease (all p > 0.05). Preoperative plasma VEGF levels were independently associated with RFS, CSS, and OS in preoperative and postoperative multivariable models. However, in all cases the C index increased by <0.02 and there was no improvement in net benefit on DCA. A limitation is that none of the patients received current elements of standard of care such as neoadjuvant chemotherapy.

Conclusions: Elevated plasma VEGF levels were associated with features of biologically and clinically aggressive disease such as worse survival outcomes among patients with UCB treated with RC. However, VEGF appears to have relatively limited incremental additive value in clinical use. Further study of VEGF for UCB prognostication is warranted before routine use in clinical algorithms.

Patient Summary: Currently available models for predicting outcomes in bladder cancer are less than optimal. A protein called vascular endothelial growth factor (VEGF), which is a marker of the formation of blood vessels (angiogenesis), may have a role in predicting survival outcomes in bladder cancer.

Take Home Message: Elevated plasma VEGF levels are associated with worse survival outcomes for patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy. VEGF could be used as a part of a biomarker panel to enhance tools currently used for risk stratification for patients with UCB.
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http://dx.doi.org/10.1016/j.euf.2021.08.006DOI Listing
August 2021

Survival Outcomes After Immediate Radical Cystectomy Versus Conservative Management with Bacillus Calmette-Guérin Among T1 High-grade Micropapillary Bladder Cancer Patients: Results from a Multicentre Collaboration.

Eur Urol Focus 2021 Aug 18. Epub 2021 Aug 18.

Department of Urology, Spedali Civili di Brescia, Brescia, Italy.

Background: Literature lacks clear evidence regarding the optimal treatment for non-muscle-invasive micropapillary bladder cancer (MPBC) due to its rarity and the presence of only small sample size and single-centre studies.

Objective: To assess cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and conservative management among T1 high-grade (HG) MPBC.

Design, Setting, And Participants: We retrospectively analysed a multicentre dataset including 119 T1 HG MPBC patients treated between 2005 and 2019 at 15 tertiary referral centres. The median follow-up time was 35 mo (interquartile range: 19-64).

Intervention: Patients underwent immediate RC versus conservative management with bacillus Calmette-Guérin.

Outcomes Measurements And Statistical Analysis: Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. Multivariable Cox analyses were performed to assess independent predictors of disease recurrence and disease progression after conservative management; covariates consisted of pure MPBC, concomitant lymphovascular invasion (LVI), and carcinoma in situ at initial diagnosis.

Results And Limitations: Immediate RC and conservative management were performed in 27% and 73% of patients, respectively. CSM and OM did not differ significantly among patient treated with immediate RC versus conservative management (Pepe-Mori test p = 0.5 and log-rank test p = 0.9, respectively). Overall, 66.7% and 34.5% of patients experienced disease recurrence and disease progression after conservative management, respectively. At multivariable Cox analyses, concomitant LVI was an independent predictor of disease recurrence (p = 0.01) and progression (p = 0.03), while pure MPBC was independently associated with disease progression (p = 0.03). The absence of a centralised re-review and the retrospective design represent the main limitations of our study.

Conclusions: Conservative management could achieve satisfactory results among T1 HG MPBC patients with neither pure MPBC nor LVI at initial diagnosis.

Patient Summary: Bacillus Calmette-Guérin seems to be an effective therapy for T1 micropapillary bladder cancer patients with neither pure micropapillary disease nor lymphovascular invasion at initial diagnosis.
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http://dx.doi.org/10.1016/j.euf.2021.07.015DOI Listing
August 2021

Adjuvant therapy with tyrosine kinase inhibitors for localized and locally advanced renal cell carcinoma: an updated systematic review and meta-analysis.

Urol Oncol 2021 Aug 14. Epub 2021 Aug 14.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: Tyrosine kinase inhibitors (TKIs) have been widely used in the management of patients with metastatic renal cell carcinoma (RCC). However, the use of systemic therapies in the adjuvant setting of localized and locally advanced RCC has shown conflicting results across the literature. Therefore, we aimed to conduct an updated systematic review and meta-analysis comparing the efficacy and safety of TKIs in the adjuvant setting for patients with localized and locally advanced RCC.

Materials And Methods: The MEDLINE and EMBASE databases were searched in December 2020 to identify phase III randomized controlled trials of patients receiving adjuvant therapies with TKI for RCC. Disease-free survival (DFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included treatment-related adverse events (TRAEs) of high and any grade.

Results: Five trials (S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our meta-analysis comprising 6,531 patients. The forest plot revealed that TKI therapy was associated with a significantly longer DFS compared to placebo (pooled HR: 0.88, 95% CI: 0.81-0.96, P= 0.004). The Cochrane's Q test (P = 0.51) and I2 test (I2 = 0%) revealed no significant heterogeneity. Adjuvant TKI was not associated with improved OS compared to placebo (pooled HR: 0.93, 95% CI: 0.83-1.04, P= 0.23). The Cochrane's Q test (P = 0.74) and I2 test (I2 = 0%) revealed no significant heterogeneity. The forest plot revealed that TKI therapy, compared to placebo, was associated with higher rates of high grade TRAEs (OR: 5.20, 95% CI: 4.10-6.59, P< 0.00001) as well as any grade TRAEs (OR: 3.85, 95% CI: 1.22-12.17, P= 0.02). The Cochrane's Q tests (P < 0.0001 and P < 0.00001, respectively) and I2 tests (I2 = 79% and I2 = 90%, respectively) revealed significant heterogeneity.

Conclusions: The findings of our analyses suggest an improved DFS in patients with localized and locally advanced RCC receiving adjuvant TKI as compared to placebo; however, this did not translate into any significant OS benefit. Additionally, TKI therapy led to significant toxicity. Adjuvant TKI does not seem to offer a satisfactory risk and/orbenefit balance for all patients. Select patients with very poor prognosis may be considered in a shared decision-making process with the patient. With the successful arrival of immune-based therapies in RCC, these may allow a more favorable risk/benefit profile.
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http://dx.doi.org/10.1016/j.urolonc.2021.07.022DOI Listing
August 2021

Androgen receptor axis-targeted agents for non-metastatic castration-resistant prostate cancer impact on overall survival and safety profile: an updated systematic review and meta-analysis.

Minerva Urol Nephrol 2021 Jul 26. Epub 2021 Jul 26.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Introduction: The management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with the development of androgen receptor axis-targeted (ARAT) agents. The updated results with final overall survival (OS) data of the phase III PROSPER, SPARTAN, and ARAMIS trials have recently been reported. Therefore, we performed an updated meta-analysis and network meta-analysis to indirectly compare the efficacy and safety of currently available treatments.

Evidence Acquisition: Multiple databases were searched for articles published before January 2021. Studies that compared OS and adverse events (AEs) in patients with nmCRPC were considered eligible.

Evidence Synthesis: Three studies (n=4,117) met our eligibility criteria. Formal network meta-analyses were conducted. ARAT agent is associated with significantly longer OS compared to placebo (pooled hazard ratio (HR): 0.74, 95% confidence interval (CI): 0.65-0.83, P<0.001), with similar results shown for patients with both N1 and N0 disease (pooled HR 0.61 and pooled HR 0.76, respectively). In the network meta-analysis, apalutamide, darolutamide, and enzalutamide were more effective than placebo, with similar efficacies in terms of OS. For AEs (including any AEs, grade 3 or grade 4 AEs, grade 5 AEs, serious AEs, and AEs leading to treatment discontinuation), darolutamide was shown to be likely well tolerated. Quality-of-life was preserved in treatment arms irrespective of the drug.

Conclusions: All three ARAT agents are efficacious options for the treatment of nmCRPC, whereas darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.
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http://dx.doi.org/10.23736/S2724-6051.21.04431-1DOI Listing
July 2021

The Efficacy and Safety of Relugolix Compared with Degarelix in Advanced Prostate Cancer Patients: A Network Meta-analysis of Randomized Trials.

Eur Urol Oncol 2021 Jul 20. Epub 2021 Jul 20.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Special Surgery, Jordan University Hospital, the University of Jordan, Amman, Jordan; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Context: Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients.

Objective: This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix.

Evidence Acquisition: A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis.

Evidence Synthesis: Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses.

Conclusions: We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available.

Patient Summary: We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.
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http://dx.doi.org/10.1016/j.euo.2021.07.002DOI Listing
July 2021

Incidence, risk factors and outcomes of urethral recurrence after radical cystectomy for bladder cancer: A systematic review and meta-analysis.

Urol Oncol 2021 Jul 12. Epub 2021 Jul 12.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

We aimed to conduct a systematic review and meta-analysis assessing the incidence and risk factors of urethral recurrence (UR) as well as summarizing data on survival outcomes in patients with UR after radical cystectomy (RC) for bladder cancer. The MEDLINE and EMBASE databases were searched in February 2021 for studies of patients with UR after RC. Incidence and risk factors of UR were the primary endpoints. The secondary endpoint was survival outcomes in patients who experienced UR. Twenty-one studies, comprising 9,435 patients, were included in the quantitative synthesis. Orthotopic neobladder (ONB) diversion was associated with a decreased probability of UR compared to non-ONB (pooled OR: 0.44, 95% CI: 0.31-0.61, P < 0.001) and male patients had a significantly higher risk of UR compared to female patients (pooled OR: 3.16, 95% CI: 1.83-5.47, P < 0.001). Among risk factors, prostatic urethral or prostatic stromal involvement (pooled HR: 5.44, 95% CI: 3.58-8.26, P < 0.001; pooled HR: 5.90, 95% CI: 1.82-19.17, P = 0.003, respectively) and tumor multifocality (pooled HR: 2.97, 95% CI: 2.05-4.29, P < 0.001) were associated with worse urethral recurrence-free survival. Neither tumor stage (P = 0.63) nor CIS (P = 0.72) were associated with worse urethral recurrence-free survival. Patients with UR had a 5-year CSS that varied from 47% to 63% and an OS - from 40% to 74%; UR did not appear to be related to worse survival outcomes. Male patients treated with non-ONB diversion as well as patients with prostatic involvement and tumor multifocality seem to be at the highest risk of UR after RC. Risk-adjusted standardized surveillance protocols should be developed into clinical practice after RC.
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http://dx.doi.org/10.1016/j.urolonc.2021.06.009DOI Listing
July 2021

Bladder perforation during transurethral resection of the bladder: a comprehensive algorithm for diagnosis, management and follow up.

Minerva Urol Nephrol 2021 Jul 15. Epub 2021 Jul 15.

Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.

Introduction: Despite bladder perforation (BP) is a frequent complication during transurethral resection of bladder (TURB) for bladder cancer (BCa), literature lacks systematic reviews focusing on this issue. We aimed to investigate incidence, diagnosis, therapy, and prognosis after BP during TURB for BCa; therapy was distinguished between conservative (without the need for bladder repair) and surgical management (requiring bladder wall closure).

Evidence Acquisition: A systematic search was conducted up to April 2021 using PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science to identify articles focusing on incidence, detection, management, or survival outcomes after iatrogenic BP. The selection of articles followed the Preferred Reporting Items for Systematic Review and Meta-Analyses process.

Evidence Synthesis: We included 41 studies, involving 21,174 patients. Overall, 521 patients experienced BP during TURB for BCa, with a mean incidence of 2.4%, up to 58.3% when post-operative cystography is routinely performed after all TURB procedures. Risk factors were low body mass index (BMI) (p=0.01), resection depth (p=0.006 and p=0.03), and low surgical experience (p=0.006). Extraperitoneal BP (68.5%) were treated conservatively in 97.5% of patients; intraperitoneal BP were managed with surgical bladder closure in 56% of cases. Overall, three immediate BP-related deaths were recorded due to septic complications. Extravesical tumour seeding was observed after 6 intraperitoneal and 1 extraperitoneal BP (median time: 6.2 months). Intraperitoneal BP (p=0.0003) and bladder closure (p<0.001) were found as independent predictors of extravesical tumour recurrence.

Conclusions: BP is more frequent than expected when proper diagnosis is routinely performed after all TURB procedures. Risk factors include low BMI, resection depth, and unexperienced surgeon. The risk of sepsis after BP suggests empirical antibiotic prophylaxis after BP.
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http://dx.doi.org/10.23736/S2724-6051.21.04436-0DOI Listing
July 2021

Prognostic value of the pre-operative serum albumin to globulin ratio in patients with non-metastatic prostate cancer undergoing radical prostatectomy.

Int J Clin Oncol 2021 Sep 28;26(9):1729-1735. Epub 2021 Jun 28.

Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: To evaluate the potential predictive value of the preoperative serum albumin to globulin ratio (AGR) for oncological outcomes in patients treated with radical prostatectomy (RP) for clinically non-metastatic prostate cancer (PCa).

Methods: Pre-operative AGR was assessed in a multi-institutional cohort of 6041 patients treated with RP. Logistic regression analyses were performed to assess the association of the AGR with advanced disease. We performed Cox regression analyses to determine the relationship between AGR and biochemical recurrence (BCR).

Results: The optimal cut-off value was determined to be 1.31 according to receiver operating curve analysis. Compared to patients with a higher AGR, those with a lower preoperative AGR had worse BCR-free survival (P < 0.01) in the Kaplan-Meier analysis. Pre- and post-operative multivariable models that adjusted for the effects of established clinicopathologic features, confirmed its independent association with BCR [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.31-1.75, P < 0.01, HR 1.55, 95% CI 1.34-1.79, P < 0.01, respectively]. However, the addition of AGR to established prognostic models did not improve their discrimination.

Conclusion: While AGR is significantly associated with BCR, in the present study, the clinical impact of AGR was not large enough to affect patient management. Longer follow-up is necessary to observe the true effect of AGR.
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http://dx.doi.org/10.1007/s10147-021-01952-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364901PMC
September 2021

Prognostic Impact of Preoperative Plasma Levels of Urokinase Plasminogen Activator Proteins on Disease Outcomes after Radical Cystectomy.

J Urol 2021 Jun 28:101097JU0000000000001936. Epub 2021 Jun 28.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: We sought to validate the association of plasma levels of urokinase-type plasminogen activator (uPA), its soluble receptor (SuPAR) and its inhibitor (PAI-one) with oncologic outcomes in a large cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

Materials And Methods: We collected preoperative blood samples from 1,036 consecutive patients treated with RC for UCB. Plasma specimens were assessed for levels of uPA, SuPAR and PAI-one. Retrospective logistic and Cox regression analyses were performed to assess their correlation with clinical outcomes. The additional clinical net benefit provided by the biomarkers was evaluated using decision curve analysis.

Results: Preoperative plasma uPA, SuPAR and PAI-one levels were significantly elevated in patients harboring adverse pathological features. Higher levels of all biomarkers were independently associated with an increased risk of lymph node metastasis; uPA levels were also independently associated with ≥pT3 disease. Preoperative uPA and SuPAR were independently associated with recurrence-free and cancer-specific survival. The addition of these biomarkers to standard pre-treatment and post-treatment models improved the discriminatory power for prediction of lymph node metastasis, ≥pT3 disease, and recurrence-free and cancer-specific survival by a prognostically significant margin.

Conclusions: We confirmed that elevated preoperative plasma levels of uPA, SuPAR and PAI-one are associated with features of aggressive disease and worse survival outcomes in patients treated with RC for UCB. These biomarkers hold potential in identifying patients who are likely to benefit from intensified/multimodal therapy. They also demonstrated the ability to improve the discriminatory power of predictive/prognostic models, thus refining personalized clinical decision-making.
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http://dx.doi.org/10.1097/JU.0000000000001936DOI Listing
June 2021

Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis.

BJU Int 2021 Jun 25. Epub 2021 Jun 25.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Objectives: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel.

Methods: Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible.

Results: Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS.

Conclusions: All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.
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http://dx.doi.org/10.1111/bju.15507DOI Listing
June 2021

Differences in oncological and toxicity outcomes between programmed cell death-1 and programmed cell death ligand-1 inhibitors in metastatic renal cell carcinoma: A systematic review and meta-analysis.

Cancer Treat Rev 2021 Sep 12;99:102242. Epub 2021 Jun 12.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Background: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients.

Methods: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events.

Results: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy.

Conclusions: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.
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http://dx.doi.org/10.1016/j.ctrv.2021.102242DOI Listing
September 2021

Intracorporeal versus extracorporeal urinary diversion in robot-assisted radical cystectomy: a systematic review and meta-analysis.

Int J Clin Oncol 2021 Sep 19;26(9):1587-1599. Epub 2021 Jun 19.

Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

This systematic review and meta-analysis aimed to assess and compare the perioperative and oncological outcomes of intracorporeal (ICUD) and extracorporeal (ECUD) urinary diversion following robot-assisted radical cystectomy (RARC). A systematic literature search of articles was performed in PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. We included studies that compared patients who underwent RARC with ICUD to those with ECUD. Twelve studies including 3067 patients met the eligibility criteria. There were no significant differences between ICUD and ECUD in overall and major complications, regardless of the period (short-term [≤ 30 days] or mid-term [> 30 days]). Subgroup analyses demonstrated that ICUD performed by high-volume centers exhibited a significantly reduced risk of major complications (short-term: OR 0.57, 95% CI 0.37-0.86, p = 0.008, mid-term: OR 0.66, 95% CI 0.46-0.94, p = 0.02). Patients who underwent ICUD had lower estimated blood loss (MD -102.3 ml, 95% CI - 132.8 to - 71.8, p < 0.00001), less likely to receive blood transfusion rates (OR 0.36, 95% CI 0.20-0.62, p = 0.00003); and these findings were consistent in subgroup analyses by low-volume centers (MD-121.6 ml, 95% CI - 160.9 to - 82.3, p < 0.00001 and OR 0.36, 95% CI 0.20-0.62, p = 0.00003, respectively). ICUD had a higher lymph node yield (MD 3.68, 95% CI 0.80-6.56, p = 0.01). Patients receiving ICUD provided comparable complications, superior perioperative outcomes, and similar oncological outcomes compared with ECUD. Centralization of patients may contribute to a reduction of postoperative complications, while maintaining the advantages.
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http://dx.doi.org/10.1007/s10147-021-01972-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364906PMC
September 2021

Prognostic value of the systemic immune-inflammation index in non-muscle invasive bladder cancer.

World J Urol 2021 Jun 18. Epub 2021 Jun 18.

Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: We assessed the prognostic value of systemic immune-inflammation index (SII) to refine risk stratification of the heterogeneous spectrum of patients with non-muscle-invasive bladder cancer (NMIBC) METHODS: In this multi-institutional cohort, preoperative blood-based SII was retrospectively assessed in 1117 patients with NMIBC who underwent transurethral resection of bladder (TURB) between 1996 and 2007. The optimal cut-off value of SII was determined as 580 using the best Youden index. Cox regression analyses were performed. The concordance index (C-index) and decision curve analysis (DCA) were used to assess the discrimination of the predictive models.

Results: Overall, 309 (28%) patients had high SII. On multivariable analyses, high SII was significantly associated with worse PFS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.23-2.77; P = 0.003) and CSS (HR 2.53; 95% CI 1.42-4.48; P = 0.001). Subgroup analyses, according to the European Association of Urology guidelines, demonstrated the main prognostic impact of high SII, with regards to PFS (HR 3.39; 95%CI 1.57-7.31; P = 0.002) and CSS (HR 4.93; 95% CI 1.70-14.3; P = 0.005), in patients with intermediate-risk group; addition of SII to the standard predictive model improved its discrimination ability both on C-index (6% and 12%, respectively) and DCA. In exploratory intergroup analyses of patients with intermediate-risk, the improved discrimination ability was retained the prediction of PFS and CSS.

Conclusion: Preoperative SII seems to identify NMIBC patients who have a worse disease and prognosis. Such easily available and cheap standard biomarkers may help refine the decision-making process regarding adjuvant treatment in patients with intermediate-risk NMIBC.
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http://dx.doi.org/10.1007/s00345-021-03740-3DOI Listing
June 2021

Accuracy of Frozen Section Analysis of Urethral and Ureteral Margins During Radical Cystectomy for Bladder Cancer: A Systematic Review and Diagnostic Meta-Analysis.

Eur Urol Focus 2021 Jun 11. Epub 2021 Jun 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Context: The question of the ability of frozen section analysis (FSA) to accurately detect malignant pathology intraoperatively has been discussed for many decades.

Objective: We aimed to conduct a systematic review and meta-analysis assessing the diagnostic estimates of FSA of the urethral and ureteral margins in patients treated with radical cystectomy (RC) for bladder cancer (BCa).

Evidence Acquisition: The MEDLINE and EMBASE databases were searched in February 2021 for studies analyzing the association between FSA and the final urethral and ureteral margin status in patients treated with RC for BCa. The primary endpoint was the value of pathologic detection of urethral and ureteral malignant involvement with FSA during RC compared with the final margin status. We included studies that provided true positive, true negative, false positive, and false negative values for FSA, which allowed us to calculate the diagnostic estimates.

Evidence Synthesis: Fourteen studies, comprising 8208 patients, were included in the quantitative synthesis. Forest plots revealed that the pooled sensitivity and specificity for FSA of urethral margins during RC were 0.83 (95% confidence interval [CI] 0.38-0.97) and 0.95 (95% CI 0.91-0.97), respectively. While for the FSA of ureteral margins, the pooled sensitivity and specificity were 0.77 (95% CI 0.67-0.84) and 0.97 (95% CI 0.95-0.98), respectively. Calculated diagnostic odds ratios indicated high FSA effectiveness, and patients with a positive urethral or ureteral margin at final pathology are over 100 times more likely to have positive FSA than patients without margin involvement at final pathology. Area under the curves of 96.6% and 96.7% were reached for FSA detection of urethral and ureteral tumor involvement, respectively.

Conclusions: Intraoperative FSA demonstrated high diagnostic performance in detecting both urethral and ureteral malignant involvement at the time of RC for BCa. FSA of both urethral and ureteral margins during RC is accurate enough to be of great value in the routine management of BCa patients treated with RC. While its specificity was great to guide intraoperative decision-making, its sensitivity remains suboptimal yet.

Patient Summary: We believe that the frozen section analysis of both urethral and ureteral margins during radical cystectomy should be considered more often in urologic practice, until quality of life-based cost-effectiveness studies can identify patients within each institution who are unlikely to benefit from it.
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http://dx.doi.org/10.1016/j.euf.2021.05.010DOI Listing
June 2021

Prognostic Impact of Different Gleason Patterns on Biopsy Within Grade Group 4 Prostate Cancer.

Ann Surg Oncol 2021 Jun 11. Epub 2021 Jun 11.

Department of Urology, Medical University of Vienna, Vienna, Austria.

Background: Grade group (GG) 4 prostate cancer (PC) is considered a single entity; however, there are questions regarding prognostic heterogeneity. This study assessed the prognostic differences among various Gleason scores (GSs) classified as GG 4 PC on biopsy before radical prostatectomy (RP).

Methods: We conducted a multicenter retrospective study, and a total of 1791 patients (GS 3 + 5: 190; GS 4 + 4: 1557; and GS 5 + 3: 44) with biopsy GG 4 were included for analysis. Biochemical recurrence (BCR)-free survival, cancer-specific survival, and overall survival were analyzed using the Kaplan-Meier method and the log-rank test. Logistic regression analysis was performed to identify factors associated with high-risk surgical pathologic features. Cox regression models were used to analyze time-dependent oncologic endpoints.

Results: Over a median follow-up of 75 months, 750 patients (41.9%) experienced BCR, 146 (8.2%) died of any causes, and 57 (3.2%) died of PC. Biopsy GS 5 + 3 was associated with significantly higher rates of GS upgrading in RP specimens than GS 3 + 5 and GS 4 + 4. On multivariable analysis adjusted for clinicopathologic features, different GSs within GG 4 were significantly associated with BCR (p = 0.03) but not PC-specific or all-cause mortality. Study limitations include the lack of central pathological specimen evaluation.

Conclusions: Patients with GG 4 at biopsy exhibited some limited biological and clinical heterogeneity. Specifically, GS 5 + 3 had an increased risk of GS upgrading. This can help individualize patients' counseling and encourage further study to refine biopsy specimen-based GG classification.
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http://dx.doi.org/10.1245/s10434-021-10257-xDOI Listing
June 2021

Impact of systemic Immune-inflammation Index on oncologic outcomes in patients treated with radical prostatectomy for clinically nonmetastatic prostate cancer.

Urol Oncol 2021 Jun 8. Epub 2021 Jun 8.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Department of Urology, Weill Cornell Medical College, New York, NY USA; Department of Urology, University of Texas Southwestern, Dallas, TX USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address:

Purpose: To evaluate the predictive and prognostic value of the Systemic Immune-inflammation Index (SII) in a large cohort of patients treated with radical prostatectomy (RP) for clinically non-metastatic prostate cancer (PCa).

Methods: We retrospectively analyzed our multicenter database comprising 6,039 consecutive patients. The optimal preoperative SII cut-off value was assessed with the Youden index calculated on a time-dependent receiver operating characteristic (ROC) curve. Logistic regression and Cox regression analyses were used to investigate the association of SII with pathologic features and biochemical recurrence (BCR), respectively. The discriminatory ability of the models was evaluated by calculating the concordance-indices (C-Index). The clinical benefit of the implementation of SII in clinical decision making was assessed using decision curve analysis (DCA).

Results: Patients with high preoperative SII (≥ 620) were more likely to have adverse clinicopathologic features. On multivariable logistic regression analysis, high preoperative SII was independently associated with extracapsular extension (odds ratio [OR] 1.16, P = 0.041), non-organ confined disease (OR 1.18, P = 0.022), and upgrading at RP (OR 1.23, P < 0.001). We built two Cox regression models including preoperative and postoperative variables. In the preoperative multivariable model, high preoperative SII was associated with BCR (hazard ratio [HR] 1.34, 95% CI 1.15-1.55, P < 0.001). In the postoperative multivariable model, SII was not associated with BCR (P = 0.078). The addition of SII to established models did not improve their discriminatory ability nor did it increase the clinical net benefit on DCA.

Conclusion: In men treated with RP for clinically nonmetastatic PCa, high preoperative SII was statistically associated with an increased risk of adverse pathologic features at RP as well as BCR. However, it did not improve the predictive accuracy and clinical value beyond that obtained by current predictive and prognostic models. SII together with a panel of complementary biomarkers is praised to help guide decision-making in clinically nonmetastatic PCa.
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http://dx.doi.org/10.1016/j.urolonc.2021.05.002DOI Listing
June 2021

Impact of the preoperative modified glasgow prognostic score on disease outcome after radical cystectomy for urothelial carcinoma of the bladder.

Minerva Urol Nephrol 2021 Jun 11. Epub 2021 Jun 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria -

Background: To investigate the predictive and prognostic value of the preoperative modified Glasgow Prognostic Score (mGPS) in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC).

Methods: We conducted a retrospective analysis of an established multicenter database consisting of 4,335 patients who were treated with RC +/- adjuvant chemotherapy for UCB between 1979 and 2012. The mGPS of each patient was calculated on the basis of preoperative serum C-reactive protein and albumin. Uni- and multivariable logistic and Cox regression analyses were performed. The discriminatory ability of the models was assessed by calculating the area under receiver operating characteristics curves (AUC) and concordance-indices (C-Index). The additional clinical net-benefit was assessed using the decision curve analysis (DCA).

Results: A mGPS of 0, 1, and 2 was observed in 3,158 (72.8%), 1,020 (23.5%), and 157 (3.6%) patients, respectively. On multivariable logistic regression analyses, mGPS of 1 or 2 were associated with an increased risk of pT3/4 disease at RC (OR 1.25, p=0.004 and OR 2.58, p<0.001, respectively) and/or lymph node metastasis (OR 1.7, p<0.001 and OR 3.9, p<0.001, respectively). Addition of the mGPS to a predictive model based on preoperatively available variables improved its accuracy for prediction of lymph node metastasis (change of AUC +3.7%, p<0.001). On multivariable Cox regression analyses, mGPS of 1 or 2 remained associated with worse recurrence-free survival (HR 1.14, p=0.03 and HR 1.89 p<0.001, respectively), cancer-specific survival (HR 1.16, p=0.032 and HR 2.1, p<0.001, respectively) and overall survival (HR 1.5, p=0.007 and HR 1.92 p<0.001, respectively) compared to mGPS of 0. The additional discriminatory ability of the mGPS for prognosis of survival outcomes in separate models that included either established pre- or postoperative variables did not improve the C-Index by a prognostically relevant degree (change of C-Index <2% for all models). On DCA, the inclusion of the mGPS did not meaningfully improve the net-benefit for clinical decision-making regarding survival outcomes.

Conclusions: We confirmed that an elevated mGPS is an independent risk factor for non-organ confined disease and poor survival outcomes in patients with UCB undergoing RC. However, the mGPS showed little value in improving the discriminatory ability of predictive and prognostic models that relied on either pre- or postoperative clinicopathological variables. The discriminatory ability of this biomarker in the age of immunotherapy warrants further evaluation.
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http://dx.doi.org/10.23736/S2724-6051.21.04216-6DOI Listing
June 2021

Adverse events of the second-line treatment for patients with locally advanced or metastatic urothelial carcinoma of the bladder: network meta-analysis.

Immunotherapy 2021 Aug 3;13(11):917-929. Epub 2021 Jun 3.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, 1090, Austria.

We aimed to compare the mortality rates related to adverse events (AEs) and discontinuation of treatment due to toxicity as well as all AEs of currently used regimens of second-line treatment strategies for advanced or metastatic urothelial carcinoma of the bladder. The MEDLINE and EMBASE databases were searched for articles according to the PRISMA extension statement for network meta-analysis. Five trials comprising 2205 patients met our eligibility criteria. It is highly likely that immunotherapy, as single regimen, has the lowest rates of motor and sensory neuropathies, constipation, abdominal pain, alopecia, decreased appetite, vomiting and febrile neutropenia. Immunotherapy, in combination regimen, has the lowest rates of anemia and fatigue. Immunotherapy, especially as single regimen, demonstrated the highest favorable tolerability to most AEs.
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http://dx.doi.org/10.2217/imt-2020-0305DOI Listing
August 2021

Current application of the enhanced recovery after surgery protocol for patients undergoing radical cystectomy: lessons learned from European excellence centers.

World J Urol 2021 Jun 2. Epub 2021 Jun 2.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: There is no consensus on which items of Enhanced Recovery After Surgery (ERAS) should and should not be implemented in radical cystectomy (RC). The aim of this study is to report current practices across European high-volume RC centers involved in ERAS.

Methods: Based on the recommendations of the ERAS society, we developed a survey with 17 questions that were validated by the Young Academic Urologists-urothelial group. The survey was distributed to European expert centers that implement ERAS for RC. Only one answer per-center was allowed to keep a representative overview of the different centers.

Results: 70 surgeons fulfilled the eligibility criteria. Of note, 28.6% of surgeons do not work with a referent anesthesiologist and 25% have not yet assessed the implementation of ERAS in their center. Avoiding bowel preparation, thromboprophylaxis, and removal of the nasogastric tube were widely implemented (> 90%application). On the other hand, preoperative carbohydrate loading, opioid-sparing anesthesia, and audits were less likely to be applied. Common barriers to ERAS implementation were difficulty in changing habits (55%), followed by a lack of communication across surgeons and anesthesiologist (33%). Responders found that performing a regular audit (14%), opioid-sparing anesthesia (14%) and early mobilization (13%) were the most difficult items to implement.

Conclusion: In this survey, we identified the ERAS items most and less commonly applied. Collaboration with anesthesiologists as well as regular audits remain a challenge for ERAS implementation. These results support the need to uniform ERAS for RC patients and develop strategies to help departments implement ERAS.
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http://dx.doi.org/10.1007/s00345-021-03746-xDOI Listing
June 2021

The role of lymph node dissection in salvage radical prostatectomy for patients with radiation recurrent prostate cancer.

Prostate 2021 Aug 31;81(11):765-771. Epub 2021 May 31.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: To examine the effect of lymph node dissection on the outcomes of patients who underwent salvage radical prostatectomy (SRP).

Material And Methods: We retrospectively reviewed data from radiation-recurrent patients with prostate cancer (PCa) who underwent SRP from 2000-2016. None of the patients had clinical lymph node involvement before SRP. The effect of the number of removed lymph nodes (RLNs) and the number of positive lymph nodes (PLNs) on biochemical recurrence (BCR)-free survival, metastases free survival, and overall survival (OS) was tested in multivariable Cox regression analyses.

Results: About 334 patients underwent SRP and pelvic lymph node dissection (PLND). Lymph node involvement was associated with increased risk of BCR (p < .001), metastasis (p < .001), and overall mortality (p = .006). In a multivariable Cox regression analysis, an increased number of RLNs significantly lowered the risk of BCR (hazard ratio [HR] 0.96, p = .01). In patients with positive lymph nodes, a higher number of RLNs and a lower number of PLNs were associated with improved freedom from BCR (HR 0.89, p = .001 and HR 1.34, p = .008, respectively). At a median follow-up of 23.9 months (interquartile range, 4.7-37.7), neither the number of RLNs nor the number of PLNs were associated with OS (p = .69 and p = .34, respectively).

Conclusion: Pathologic lymph node involvement increased the risk of BCR, metastasis and overall mortality in radiation-recurrent PCa patients undergoing SRP. The risk of BCR decreased steadily with a higher number of RLNs during SRP. Further research is needed to support this conclusion and develop a precise therapeutic adjuvant strategy based on the number of RLNs and PLNs.
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http://dx.doi.org/10.1002/pros.24173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361975PMC
August 2021

Accuracy and Clinical Utility of a Tumor Grade- and Stage-based Predictive Model in Localized Upper Tract Urothelial Carcinoma.

Eur Urol Focus 2021 May 27. Epub 2021 May 27.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; European Association of Urology Research Foundation, Arnhem, The Netherlands. Electronic address:

Background: Among various clinicopathologic factors used to identify low-risk upper tract urothelial carcinoma (UTUC), tumor grade and stage are of utmost importance. The clinical value added by inclusion of other risk factors remains unproven.

Objective: To assess the performance of a tumor grade- and stage-based (GS) model to identify patients with UTUC for whom kidney-sparing surgery (KSS) could be attempted.

Design, Setting, And Participants: In this international study, we reviewed the medical records of 1240 patients with UTUC who underwent radical nephroureterectomy. Complete data needed for risk stratification according to the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines were available for 560 patients.

Outcome Measurements And Statistical Analysis: Univariable and multivariable logistic regression analyses were performed to determine if risk factors were associated with the presence of localized UTUC. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the GS, EAU, and NCCN models in predicting pathologic stage were calculated.

Results And Limitations: Overall, 198 patients (35%) had clinically low-grade, noninvasive tumors, and 283 (51%) had ≤pT1disease. On multivariable analyses, none of the EAU and NCCN risk factors were associated with the presence of non-muscle-invasive UTUC among patients with low-grade and low-stage UTUC. The GS model exhibited the highest accuracy, sensitivity, and negative predictive value among all three models. According to the GS, EAU, and NCCN models, the proportion of patients eligible for KSS was 35%, 6%, and 4%, respectively. Decision curve analysis revealed that the net benefit of the three models was similar within the clinically reasonable range of probability thresholds.

Conclusions: The GS model showed favorable predictive accuracy and identified a greater number of KSS-eligible patients than the EAU and NCCN models. A decision-making algorithm that weighs the benefits of avoiding unnecessary kidney loss against the risk of undertreatment in case of advanced carcinoma is necessary for individualized treatment for UTUC patients.

Patient Summary: We assessed the ability of three models to predict low-grade, low-stage disease in patients with cancer of the upper urinary tract. No risk factors other than grade assessed on biopsy and stage assessed from scans were associated with better prediction of localized cancer. A model based on grade and stage may help to identify patients who could benefit from kidney-sparing treatment of their cancer.
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http://dx.doi.org/10.1016/j.euf.2021.05.002DOI Listing
May 2021

Oncologic impact of delaying radical prostatectomy in men with intermediate- and high-risk prostate cancer: a systematic review.

World J Urol 2021 May 28. Epub 2021 May 28.

Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: To summarize the available evidence on the survival and pathologic outcomes after deferred radical prostatectomy (RP) in men with intermediate- and high-risk prostate cancer (PCa).

Methods: The PubMed database and Web of Science were searched in November 2020 according to the PRISMA statement. Studies were deemed eligible if they reported the survival and pathologic outcomes of patients treated with deferred RP for intermediate- and high-risk PCa compared to the control group including those patients treated with RP without delay.

Results: Overall, nineteen studies met our eligibility criteria. We found a significant heterogeneity across the studies in terms of definitions for delay and outcomes, as well as in patients' baseline clinicopathologic features. According to the currently available literature, deferred RP does not seem to affect oncological survival outcomes, such as prostate cancer-specific mortality and metastasis-free survival, in patients with intermediate- or high-risk PCa. However, the impact of deferred RP on biochemical recurrence rates remains controversial. There is no clear association of deferring RP with any of the features of aggressive disease such as pathologic upgrading, upstaging, positive surgical margins, extracapsular extension, seminal vesicle invasion, and lymph node invasion. Deferred RP was not associated with the need for secondary treatments.

Conclusions: Owing to the different definitions of a delayed RP, it is hard to make a consensus regarding the safe delay time. However, the current data suggest that deferring RP in patients with intermediate- and high-risk PCa for at least around 3 months is generally safe, as it does not lead to adverse pathologic outcomes, biochemical recurrence, the need for secondary therapy, or worse oncological survival outcomes.
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http://dx.doi.org/10.1007/s00345-021-03703-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160557PMC
May 2021

Impact of preoperative plasma levels of interleukin 6 and interleukin 6 soluble receptor on disease outcomes after radical cystectomy for bladder cancer.

Cancer Immunol Immunother 2021 May 23. Epub 2021 May 23.

Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: Preoperative plasma levels of Interleukin 6 (IL6) and its soluble receptor (IL6sR) have previously been associated with oncologic outcomes in urothelial carcinoma of the bladder (UCB); however, external validation in patients treated with radical cystectomy (RC) for UCB is missing.

Patients/methods: We prospectively collected preoperative plasma from 1,036 consecutive patients at two institutes. These plasma specimens were assessed for levels of IL6 and IL6sR. Logistic and Cox regression analyses were used to assess the correlation of plasma levels with pathologic and survival outcomes. The additional clinical net benefits of preoperative IL6 and IL6sR were evaluated using decision curve analysis (DCA).

Results: Median IL6 and IL6sR plasma levels were significantly higher in patients with adverse pathologic features. Elevated biomarker levels were independently associated with an increased risk for lymph node metastasis and ≥ pT3 disease. Both biomarkers were independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The addition to, respectively, fitted pre- and postoperative prognostic models improved the predictive accuracy for lymph node metastasis, ≥ pT3 disease, RFS and CSS on DCA.

Interpretation: We confirmed that elevated preoperative plasma levels of IL6 and IL6sR levels are associated with worse oncological disease survival in patients treated with RC for UCB in a large multicenter study. Both biomarkers hold potential in identifying patients with adverse pathological features that may benefit from intensified/multimodal therapy and warrant inclusion into predictive/prognostic models. They demonstrated the ability to improve the discriminatory power of such models and thus guide clinical decision making.
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http://dx.doi.org/10.1007/s00262-021-02953-0DOI Listing
May 2021

Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer Progression During Active Surveillance: A Systematic Review and Meta-analysis.

Eur Urol 2021 May 18. Epub 2021 May 18.

Department of Urology, La Croix du Sud Hospital, Quint Fonsegrives, France.

Context: Although magnetic resonance imaging (MRI) is broadly implemented into active surveillance (AS) protocols, data on the reliability of serial MRI in order to help guide follow-up biopsy are inconclusive.

Objective: To assess the diagnostic estimates of serial prostate MRI for prostate cancer (PCa) progression during AS.

Evidence Acquisition: We systematically searched PubMed, Scopus, and Web of Science databases to select studies analyzing the association between changes on serial prostate MRI and PCa progression during AS. We included studies that provided data for MRI progression, which allowed us to calculate diagnostic estimates. We compared Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) accuracy with institution-specific definitions.

Evidence Synthesis: We included 15 studies with 2240 patients. Six used PRECISE criteria and nine institution-specific definitions of MRI progression. The pooled PCa progression rate, which included histological progression to Gleason grade ≥2, was 27%. The pooled sensitivity and specificity were 0.59 (95% confidence interval [CI] 0.44-0.73) and 0.75 (95% CI 0.66-0.84) respectively. There was significant heterogeneity between included studies. Depending on PCa progression prevalence, the pooled negative predictive value for serial prostate MRI ranged from 0.81 (95% CI 0.73-0.88) to 0.88 (95% CI 0.83-0.93) and the pooled positive predictive value ranged from 0.37 (95% CI 0.24-0.54) to 0.50 (95% CI 0.36-0.66). There were no significant differences in the pooled sensitivity (p = 0.37) and specificity (p = 0.74) of PRECISE and institution-specific schemes.

Conclusions: Serial MRI still should not be considered a sole factor for excluding PCa progression during AS, and changes on MRI are not accurate enough to indicate PCa progression. There was a nonsignificant trend toward improved diagnostic estimates of PRECISE recommendations. These findings highlight the need to further define the optimal triggers and timing of biopsy during AS, as well as the need for optimizing the quality, interpretation, and reporting of serial prostate MRI.

Patient Summary: Our study suggests that serial prostate magnetic resonance imaging (MRI) alone in patients on active surveillance is not accurate enough to reliably rule out or rule in prostate cancer progression. Other clinical factors and biomarkers along with serial MRI are required to safely tailor the intensity of follow-up biopsies.
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http://dx.doi.org/10.1016/j.eururo.2021.05.001DOI Listing
May 2021

Role of systemic immune-inflammation index in patients treated with salvage radical prostatectomy.

World J Urol 2021 May 17. Epub 2021 May 17.

Department of Urology, Comprehensive Cancer Center, Medical University Vienna, Vienna General Hospital, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: To examine the predictive and prognostic value of preoperative Systemic Immune-inflammation Index (SII) in patients with radio-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP).

Materials And Methods: This multicenter retrospective study included 214 patients with radio-recurrent PCa, treated with SRP between 2007 and 2015. SII was measured preoperatively (neutrophils × platelets/lymphocytes) and the cohort was stratified using optimal cut-off. Uni- and multivariable logistic and Cox regression analyses were performed to evaluate the predictive and prognostic value of SII as a preoperative biomarker.

Results: A total of 81 patients had high preoperative SII (≥ 730). On multivariable logistic regression modeling, high SII was predictive for lymph node metastases (OR 3.32, 95% CI 1.45-7.90, p = 0.005), and non-organ confined disease (OR 2.55, 95% CI 1.33-4.97, p = 0.005). In preoperative regression analysis, high preoperative SII was an independent prognostic factor for cancer-specific survival (CSS; HR 10.7, 95% CI 1.12-103, p = 0.039) and overall survival (OS; HR 8.57, 95% CI 2.70-27.2, p < 0.001). Similarly, in postoperative multivariable models, SII was associated with worse CSS (HR 22.11, 95% CI 1.23-398.12, p = 0.036) and OS (HR 5.98, 95% CI 1.67-21.44, p = 0.006). Notably, the addition of SII to preoperative reference models improved the C-index for the prognosis of CSS (89.5 vs. 80.5) and OS (85.1 vs 77.1).

Conclusions: In radio-recurrent PCa patients, high SII was associated with adverse pathological features at SRP and survival after SRP. Preoperative SII could help identify patients who might benefit from novel imaging modalities, multimodal therapy or a closer posttreatment surveillance.
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http://dx.doi.org/10.1007/s00345-021-03715-4DOI Listing
May 2021

The prognostic value of sarcopenia in patients with prostate cancer: a systematic review.

Curr Opin Urol 2021 07;31(4):315-323

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: Sarcopenia is known to affect perioperative and oncologic outcomes in patients with different urological malignancies. Nevertheless, the use of pretreatment sarcopenia as a predictor of clinical outcomes in patients with prostate cancer is still poorly studied. Therefore, we aimed to conduct a systematic review summarizing the available evidence and identifying the prognostic value of sarcopenia in prostate cancer patients.

Recent Findings: Sarcopenia was not predictive of biochemical recurrence in patients treated with radical prostatectomy. However, it was associated with worse long-term survival outcomes as well as the likelihood of developing postoperative complications after radical prostatectomy. In the context of radiotherapy, sarcopenia was a predictive factor for overall survival. In patients with hormone-sensitive prostate cancer treated with androgen deprivation, sarcopenia was associated with overall and cancer-specific survival. In patients with castration-resistant prostate cancer, sarcopenia was associated with poorer tolerance to docetaxel-based chemotherapy.

Summary: Most studies found sarcopenia to be a predictor for worse perioperative and oncologic outcomes in patients treated with radical surgery, radiotherapy, or systemic therapy for prostate cancer. However, there is significant heterogeneity across the studies in terms of sarcopenia definition. For a better understanding of the prognostic value of sarcopenia in patients with prostate cancer, large-scale prospective studies are needed.
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http://dx.doi.org/10.1097/MOU.0000000000000885DOI Listing
July 2021

Association between male infertility and prostate cancer: a systematic review and meta-analysis.

Curr Opin Urol 2021 07;31(4):346-353

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: Male infertility has been shown to be associated with different maladies. The present systematic review and meta-analysis aimed to summarize the available evidence on the association between male infertility or childlessness and prostate cancer.

Recent Findings: The PubMed, Web of Science, and Scopus databases were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies were deemed eligible if they compared males with known infertility or childlessness to the control group including fertile males with regards to the diagnosis of prostate cancer. Overall, ten studies met our eligibility criteria. Three studies found that infertility was associated with higher risk of prostate cancer, four studies - with a reduced risk of prostate cancer, and three studies found no association. The forest plot revealed that infertility was not associated with prostate cancer (odds ratio [OR]: 1.26, 95% confidence interval [CI] 0.63-2.54; P = 0.5). Infertility was not associated with high (OR: 1.44, 95% CI 0.54-3.83; P = 0.5) or low (OR: 0.99, 95% CI 0.43-2.27; P = 0.9) grade prostate cancer.

Summary: Infertility or childlessness were not associated with the risk of prostate cancer. The significant heterogeneity between the included studies supports the need for more granular research to guide/fine tune early detection guidelines based on fertility.
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http://dx.doi.org/10.1097/MOU.0000000000000886DOI Listing
July 2021

First-line immune-checkpoint inhibitor combination therapy for chemotherapy-eligible patients with metastatic urothelial carcinoma: A systematic review and meta-analysis.

Eur J Cancer 2021 Jul 4;151:35-48. Epub 2021 May 4.

Department of Urology, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Research Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; European Association of Urology Research Foundation, Arnhem, Netherlands. Electronic address:

Introduction: Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC.

Methods: Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC.

Results: Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76-0.94, P = 0.002; HR: 0.80, 95% CI: 0.71-0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12-1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31-2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone.

Conclusions: Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished.
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http://dx.doi.org/10.1016/j.ejca.2021.03.049DOI Listing
July 2021

Prognostic blood-based biomarkers in patients treated with neoadjuvant chemotherapy for urothelial carcinoma of the bladder: A systematic review.

Urol Oncol 2021 08 19;39(8):471-479. Epub 2021 Apr 19.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan; The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan; Department of Urology, Weill Cornell Medical College, New York, NY,; Department of Urology, University of Texas Southwestern, Dallas, TX; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria. Electronic address:

Purpose: The present systematic review aimed to identify prognostic values of blood-based biomarkers in patients treated with neoadjuvant chemotherapy (NAC) for urothelial carcinoma of the bladder (UCB).

Material And Methods: The PubMed, Web of Science, and Scopus databases were searched in August 2020 according to the PRISMA statement. Studies were deemed eligible if they compared oncological outcomes in patients treated with NAC for UCB with and without pretreatment laboratory abnormalities.

Results: Overall, ten studies, including 966 patients who underwent NAC, met our eligibility criteria. Six studies provided data on pretreatment neutrophil to lymphocyte ratio (NLR) with contradicting results on its association with pathologic response (PR) and complete pathologic response (pCR); some studies reported a strong association between a high level of pretreatment NLR and worse survival outcomes. Two studies reported that higher pretreatment platelet-lymphocyte ratio (PLR) is associated with a lower likelihood of achieving PR and/or pCR, while lymphocyte count alone had the opposite association. One study reported a negative association between pretreatment blood-based myeloid-derived suppressors cells and pCR. Patients who experienced a remission have been reported to have higher level of lymphocyte subsets (CD3+, CD4+, CD57+ cells, the ratio of CD4+/CD8+) compared to those who had progression. One study found that low pretreatment blood-based human chorionic gonadotrophin b subunit (hCGβ) was associated with improved overall survival (OS). High levels of epithelial tumor markers (CA-125, CA 19-9) were also associated with worse OS and recurrence-free survival in the NAC setting.

Conclusion: Current evidence suggests that several readily available, easy measurable blood-based biomarkers hold promise to improve our selection of UCB patients who are likely benefit from NAC. However, their role as an adjunct to established histopathologic characteristics for clinical decision-making requires further validation along the biomarker phased approach.
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http://dx.doi.org/10.1016/j.urolonc.2021.03.005DOI Listing
August 2021

Detection of Urothelial Bladder Cancer Based on Urine and Tissue Telomerase Activity Measured by Novel RT-TRAP-2PCR Method.

J Clin Med 2021 Mar 4;10(5). Epub 2021 Mar 4.

Institute for Urology and Reproductive Health, Sechenov University, 119435 Moscow, Russia.

Purpose: To assess the diagnostic performance of urine telomerase activity (TA) in detecting bladder cancer (BCa) using the modified Telomeric Repeat Amplification Protocol (TRAP) and the Real Time Telomeric Repeat Amplification Protocol with double Polymerase Chain Reaction (RT-TRAP-2PCR).

Methods: In this case-control study, matching urine (in the pre- and post-surgical period) and tissue samples from 68 patients with BCa were assessed for TA. As a control, 45 urine samples were examined from non-BCa patients. TA levels were measured using TRAP and RT-TRAP-2 PCR methods.

Results: Preoperative urinary TA was elevated in 64 (94.1%) of the 68 BCa patients. Urine TA was undetectable in 44 control patients, while TA was detected in one patient with histologically verified cystitis. Sensitivity for BCa detection of 94.1% and specificity of 97.8% were observed for urinary TA, while tissue TA had 100% sensitivity and 97.8% specificity. Both urine and tissue TA levels were not significantly higher in patients with muscle-invasive disease compared to those with non-muscle invasive BCa ( > 0.05). Urine and tissue TA levels were not associated with higher tumor grade, stage, and number of tumors ( > 0.05). However, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm ( = 0.02 and = 0.01, respectively). During the first postoperative year, 17 BCa patients experienced disease recurrence, and urinary TA was present in 14 (82.4%) of these patients. The sensitivity and specificity of urinary TA levels for BCa recurrence in patients with non-muscle invasive bladder cancer (NMIBC) during follow-up were 82% and 94.4%, respectively.

Conclusions: This pilot study demonstrates a high diagnostic performance of urinary and tissue TA levels measured by a new RT-TRAP-2PCR method for detecting and monitoring BCa. Additionally, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm; however, higher TA levels failed for significant correlation with advanced tumor stage and grade. Our study could serve as a benchmark for the evaluation of novel biomarkers using the RT-TRAP-2PCR method.
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http://dx.doi.org/10.3390/jcm10051055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961950PMC
March 2021
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