Publications by authors named "Michael Rink"

216 Publications

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

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

Quality indicators for the management of high-risk upper tract urothelial carcinoma requiring radical nephroureterectomy.

Curr Opin Urol 2021 Jul;31(4):291-296

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

Purpose Of Review: The purpose of this article was to identify quality indicators for an optimized management of high-risk upper tract urothelial carcinoma (UTUC) requiring radical nephroureterectomy (RNU).

Recent Findings: RNU with bladder cuff resection is the standard treatment of high-risk UTUC. For the bladder cuff resection, two main approaches are accepted: transvesical and extravesical. Lymph node dissection following a dedicated template should be performed in all high-risk patients undergoing RNU as it improves tumour staging and possibly survival. Postoperative bladder instillation of single-dose chemotherapy should be administered after RNU to decrease the risk of intravesical tumour recurrence. Perioperative systemic chemotherapy should always be considered for advanced cancers. Although level-1 evidence is available for adjuvant platinum-based chemotherapy, neoadjuvant regimens are still being evaluated.

Summary: Optimal management of high-risk UTUC requires evidence-based reproducible quality indicators in order to allow guidance and frameworks for clinical practices. Adherence to quality indicators allows for the measurement and comparison of outcomes that are likely to improve prognosis. Based on the literature, we found four evidence-based accepted quality indicators that are easily implementable to improve the management of high-risk UTUC patients treated with RNU: adequate management of the distal ureter/ bladder cuff, template-based lymph node dissection, single-shot postoperative intravesical chemotherapy, and perioperative systemic treatment.
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http://dx.doi.org/10.1097/MOU.0000000000000895DOI Listing
July 2021

Accuracy of Transurethral Resection of the Bladder in Detecting Variant Histology of Bladder Cancer Compared with Radical Cystectomy.

Eur Urol Focus 2021 Apr 15. Epub 2021 Apr 15.

Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.

Background: Correct identification of variant histologies (VHs) of bladder cancer (BCa) at transurethral resection of the bladder (TURB) could drive the subsequent treatment.

Objective: To evaluate the concordance in detecting VHs between TURB and radical cystectomy (RC) specimens in BCa patients.

Design, Setting, And Participants: We retrospectively analyzed 1881 BCa patients who underwent TURB and subsequent RC at seven tertiary care centers between 1980 and 2018. VHs were classified as sarcomatoid, lymphoepithelioma-like, neuroendocrine, squamous, micropapillary, glandular, adenocarcinoma, nested, and other variants.

Outcome Measurements And Statistical Analysis: Concordance between TURB and RC was defined as the ability to achieve histological subtypes at TURB confirmed at RC specimen, and was expressed according to Cohen's kappa coefficient.

Results And Limitations: Of the patients, 14.6% and 21% were diagnosed with VH at TURB and RC specimens, respectively. The most common VHs at TURB were squamous, neuroendocrine, and micropapillary carcinoma (5.2%, 1.5%, and 1.5%, respectively). At RC, the most frequent VHs were squamous, micropapillary, and sarcomatoid carcinoma (7.2%, 3.0%, and 2.7%, respectively). The overall concordance in detecting VH was defined as slight concordance (coefficient: 0.18). Moderate concordance was found for neuroendocrine, adenocarcinoma, and squamous carcinoma (coefficient: 0.49, 0.47, and 0.41, respectively). Micropapillary, glandular, and other variants showed slight concordance (coefficient: 0.05, 0.17, and 0.12, respectively), while nested and sarcomatoid carcinoma showed fair concordance (coefficient: 0.32 and 0.26, respectively). Results may be limited by the absence of centralized pathological analysis.

Conclusions: A non-negligible percentage of patients were diagnosed with VH at both TURB and RC. TURB showed relatively low accuracy, ranging from poor to moderate, in detecting VHs. Our study underlines the need of additional diagnostic tools in order to identify VHs properly at precystectomy time and to improve patient survival outcomes.

Patient Summary: In this report, we underlined the low accuracy of transurethral resection of the bladder in detecting variant histologies and the need for additional diagnostic tools.
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http://dx.doi.org/10.1016/j.euf.2021.04.005DOI Listing
April 2021

Mismatch repair deficiency occurs very rarely in seminomas.

Transl Androl Urol 2021 Mar;10(3):1048-1055

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Dense tumor-associated lymphocyte infiltration is linked to mismatch repair (MMR) deficiency in colorectal and endometrial cancer. MMR deficiency is of high clinical importance as MMR deficient cancers tend to react favorably to treatment with immune checkpoint inhibitors. Strong lymphocytic infiltration is a morphological hallmark of seminomas. We thus asked whether seminomas may exhibit MMR deficiency at relevant frequency.

Methods: To screen for tumors with MMR deficiency, protein expression of MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry (IHC) on a tissue microarray (TMA) containing 574 seminomas.

Results: In total, 536 cases were evaluable resulting in 481 seminomas with unequivocally intact MMR protein expression. In 55 cancers, one or several IHC stains were equivocal and lacked detectable MMR protein in both tumor and stromal cells. Large section IHC analysis of all 55 equivocal cases demonstrated substantial staining issues due to improper fixation in 54 cases and identified one tumor with clear-cut MLH1 and PMS2 protein loss. This seminoma showed homogeneous loss of MLH1 and PMS2 in the entire tumor mass whereas minor adjacent foci of associated germ cell neoplasia in situ (GCNIS) were MMR intact. Polymerase chain reaction (PCR) analysis using the 5 microsatellite loci of the "Bethesda Panel" revealed instability in 1 of 4 interpretable loci ("MSI-low") and additional instability of the complex tetra-penta repeat locus MYCL1 in this tumor.

Conclusions: In summary, one single seminoma with MMR deficiency, characterized by protein loss of MLH1 and PMS2, was identified among 536 interpretable seminomas (0.19%). MMR deficiency is not a relevant determinant of lymphocyte influx in seminoma.
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http://dx.doi.org/10.21037/tau-20-1355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039613PMC
March 2021

Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer.

Int Urol Nephrol 2021 Apr 1. Epub 2021 Apr 1.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome.

Methods: We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8 cytotoxic cells.

Result: At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8 lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8 cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280).

Conclusions: These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.
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http://dx.doi.org/10.1007/s11255-021-02841-7DOI Listing
April 2021

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Future Oncol 2021 Jun 16;17(18):2325-2338. Epub 2021 Mar 16.

University Hospital Muenster, 48149, Muenster, Germany.

Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1020DOI Listing
June 2021

Y-chromosome loss is frequent in male renal tumors.

Ann Transl Med 2021 Feb;9(3):209

Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52 D-20246 Hamburg, Germany.

Background: Loss of the Y-chromosome is a common event in different tumor types but its prevalence and clinical relevance in renal cell tumors is still not understood.

Methods: It was the aim of this study to estimate the frequency and clinical relevance of Y-loss in kidney neoplasms. A cohort of 1,252 male renal tumors was analyzed in a tissue microarray format by fluorescence in-situ hybridization (FISH).

Results: Y-loss was found in 47% of tumors. The frequency of this alteration varied markedly between kidney tumor subtypes. Y-loss was most prevalent in papillary renal cell carcinoma (RCC) (77%) followed by chromophobe RCC (60%), oncocytoma (51%), clear cell RCC (39%) and clear cell (tubulo)papillary RCC (19%). Y-loss was linked to higher patient age and smaller tumor size at diagnosis. Mean age (95% CI) was 65 (64-66) years in patients with Y-loss in their tumor compared to 60 (58-61) years in patients without Y-loss (P<0.0001). Significant correlations between Y-loss and tumor phenotype were found only for papillary carcinomas (P=0.002), especially for type 1 (P=0.03).

Conclusions: Y-loss is present in different histologic subtypes of renal neoplasm. The highest frequency is in papillary RCC, where it may represent a potentially relevant prognostic biomarker suggesting favorable disease outcome.
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http://dx.doi.org/10.21037/atm-20-3061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940894PMC
February 2021

A panel of systemic inflammatory response biomarkers for outcome prediction in patients treated with radical cystectomy for urothelial carcinoma.

BJU Int 2021 Mar 1. Epub 2021 Mar 1.

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

Objectives: To determine the predictive and prognostic value of a panel of systemic inflammatory response (SIR) biomarkers relative to established clinicopathological variables in order to improve patient selection and facilitate more efficient delivery of peri-operative systemic therapy.

Materials And Methods: The preoperative serum levels of a panel of SIR biomarkers, including albumin-globulin ratio, neutrophil-lymphocyte ratio, De Ritis ratio, monocyte-lymphocyte ratio and modified Glasgow prognostic score were assessed in 4199 patients treated with radical cystectomy for clinically non-metastatic urothelial carcinoma of the bladder. Patients were randomly divided into a training and a testing cohort. A machine-learning-based variable selection approach (least absolute shrinkage and selection operator regression) was used for the fitting of several multivariable predictive and prognostic models. The outcomes of interest included prediction of upstaging to carcinoma invading bladder muscle (MIBC), lymph node involvement, pT3/4 disease, cancer-specific survival (CSS) and recurrence-free survival (RFS). The discriminatory ability of each model was either quantified by area under the receiver-operating curves or by the C-index. After validation and calibration of each model, a nomogram was created and decision-curve analysis was used to evaluate the clinical net benefit.

Results: For all outcome variables, at least one SIR biomarker was selected by the machine-learning process to be of high discriminative power during the fitting of the models. In the testing cohort, model performance evaluation for preoperative prediction of lymph node metastasis, ≥pT3 disease and upstaging to MIBC showed a 200-fold bootstrap-corrected area under the curve of 67.3%, 73% and 65.8%, respectively. For postoperative prognosis of CSS and RFS, a 200-fold bootstrap corrected C-index of 73.3% and 72.2%, respectively, was found. However, even the most predictive combinations of SIR biomarkers only marginally increased the discriminative ability of the respective model in comparison to established clinicopathological variables.

Conclusion: While our machine-learning approach for fitting of the models with the highest discriminative ability incorporated several previously validated SIR biomarkers, these failed to improve the discriminative ability of the models to a clinically meaningful degree. While the prognostic and predictive value of such cheap and readily available biomarkers warrants further evaluation in the age of immunotherapy, additional novel biomarkers are still needed to improve risk stratification.
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http://dx.doi.org/10.1111/bju.15379DOI Listing
March 2021

Predictive value of De Ritis ratio in metastatic renal cell carcinoma treated with tyrosine-kinase inhibitors.

World J Urol 2021 Mar 1. Epub 2021 Mar 1.

Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Background: Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid tumors.

Objective: To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI).

Methods: Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden's J. We used multiple strata for DRR, performed descriptive, Kaplan-Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS).

Results: Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (p = 0.01). There was no difference in PFS (p > 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42; p = 0.03), DRR ≥ 1.1(HR 1.44; p = 0.02), ≥ 1.8 (HR 1.56; p = 0.03), ≥ 1.9 (HR 1.59; p = 0.02) and ≥ 2.0 (HR 1.63; p = 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78; p = 0.02), ≥ 1.1 (HR 1.81; p = 0.01) and above median (HR 1.88; p = 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54; p = 0.029) and DRR ≥ 1.1 (HR 1.53; p = 0.029) were associated with OS in multivariable analyses.

Conclusion: There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups.
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http://dx.doi.org/10.1007/s00345-021-03628-2DOI Listing
March 2021

A Systematic Review and Scoping Analysis of Smoking Cessation after a Urological Cancer Diagnosis.

J Urol 2021 May 12;205(5):1275-1285. Epub 2021 Feb 12.

Department of Urology, New York University Grossman School of Medicine, New York, New York.

Purpose: Smoking cessation after a urological cancer diagnosis significantly benefits patients. It is not well known how often patients quit after diagnosis or how urologists intervene to support patients' smoking cessation efforts. We examined rates of smoking cessation after diagnosis among patients with urological cancers, and assessed how often patients are given advice and support to quit smoking in the urology setting.

Materials And Methods: Following PRISMA guidelines, a systematic review was conducted of the available studies on smoking cessation after a urological cancer diagnosis during April 2020 by a trained medical librarian using the MEDLINE®, PsycInfo®, Embase® and Cochrane Central databases. Studies were included based on 3 independent reviews and if they met a priori inclusion/exclusion criteria. In total, 2,568 records were identified, 31 of which were included for final analysis.

Results: Four studies (587 patients) reported outcomes related to the prospective implementation of a smoking cessation program with patient-level quit rates ranging from 3.2% to 47.3%. A total of 21 studies (3,669 patients) reported outcomes of passive (no directed, active intervention) smoking cessation after the diagnosis of a urological cancer with widely varying quit rates. In general, the quality of included studies was poor. There was no standardization of the measurement or timing of outcomes, and few studies included validated survey instruments or biochemical confirmation of cessation. A total of 17 studies included data on whether patients received advice to quit smoking after diagnosis. The proportion of patients in each study who were told to quit ranged from 2.8% to 78.3%.

Conclusions: There are few smoking cessation interventions that have been prospectively implemented and reported in the urology literature, and studies on quit rates after diagnosis are limited. The paucity of quality data and lack of smoking cessation interventions being used in routine urological oncology care underscores the need for more rigorous study and implementation of evidence-based practices in this area.
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http://dx.doi.org/10.1097/JU.0000000000001641DOI Listing
May 2021

Prognostic value of albumin to globulin ratio in non-muscle-invasive bladder cancer.

World J Urol 2021 Jan 26. Epub 2021 Jan 26.

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

Purpose: To investigate the prognostic value of preoperative serum albumin to globulin ratio (AGR) in patients with non-muscle-invasive bladder cancer (NMIBC) treated with transurethral resection of bladder tumor (TURB) with or without intravesical therapy (IVT).

Materials And Methods: We retrospectively reviewed 1,096 consecutive patients with NMIBC. Levels of albumin and globulin were obtained before TURB and used to calculate the preoperative AGR level. Multivariable Cox regression analyses were performed to assess the prognostic effect of preoperative AGR on oncologic outcomes. Subgroup analyses were performed in patients based on the European Association of Urology (EAU) risk groups for NMIBC.

Results: Low AGR levels were observed in 389 (35.5%) patients. The median follow-up was 63.7 months (IQR 25.3-111). On multivariable Cox regression analysis, low AGR was associated with increased risk of progression to muscle-invasive BCa (MIBC) (HR 1.81, 95% CI 1.22-2.68, P = 0.003). The addition of AGR only minimally improved the discrimination ability of a base model that included established clinicopathologic features (C-index = 0.7354 vs. C-index = 0.7162). Low preoperative AGR was not significantly associated with the risk of disease recurrence (P = 0.31). In subgroup analyses based on patients' EAU risk groups, low preoperative AGR was not associated with recurrence-free survival (RFS) (P = 0.59) or progression-free survival (PFS) (P = 0.22) in any of the risk groups. Additionally, in patients treated with Bacillus Calmette-Guerin (BCG) for intermediate- or high-risk NMIBC, low AGR failed to predict disease recurrence or progression.

Conclusion: Preoperative serum AGR levels independently predicted the risk of disease progression in patients with NMIBC. However, it was not found to be associated with either RFS or PFS in NMIBC patients based on their EAU risk group. This marker seems to have a limited role in NMIBC at the present time. However, further research is needed to investigate this marker in combination with other systemic inflammatory markers to help improve prediction in this heterogeneous group of patients.
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http://dx.doi.org/10.1007/s00345-020-03586-1DOI Listing
January 2021

p63 expression in human tumors and normal tissues: a tissue microarray study on 10,200 tumors.

Biomark Res 2021 Jan 25;9(1). Epub 2021 Jan 25.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting.

Methods: To comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed.

Results: p63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96-100%), thymic tumors (100%), urothelial carcinomas (81-100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81-100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p < 0.0001 each) and poor survival (p < 0.0001) and might reflect clinically relevant tumor dedifferentiation.

Conclusion: The high prevalence of p63 expression in specific tumor types makes p63 immunohistochemistry a suitable diagnostic tool. Loss of p63 expression might constitute a feature of aggressive cancers.
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http://dx.doi.org/10.1186/s40364-021-00260-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830855PMC
January 2021

Copy number variations in primary tumor, serum and lymph node metastasis of bladder cancer patients treated with radical cystectomy.

Sci Rep 2020 12 9;10(1):21562. Epub 2020 Dec 9.

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

The aim of the present study was to analyze copy number variations (CNV) of multiple oncogenes and tumor suppressor genes in genomic DNA from primary tumor tissue, lymph node metastasis and cell-free DNA (cfDNA) from serum of 72 urothelial carcinoma of bladder (UCB) patients treated with radical cystectomy (RC), using multiplex ligation-dependent probe amplification (MLPA). We hypothesized that primary tumor and lymph node metastasis show similar CNV profiles, and CNV are more present in lymph node metastasis compared to primary tumor tissue. Samples from 43 (59.7%) patients could be analyzed. In total, 35 (83%), 26 (68%) and 8 (42%) patients had CNV in primary tumor, serum and lymph node metastasis, respectively. MYC, CCND1, ERBB2 and CCNE1 displayed the most frequent amplifications. In particular, CNV in ERBB2 was associated with aggressive tumor characteristics. CNV in both ERBB2 and TOP2A were risk factors for disease recurrence. The current findings show that CNV are present in various oncogenes and tumor suppressor genes in genomic DNA from primary tumor, lymph node metastasis and cfDNA from serum. CNV were more present in genomic DNA from primary tumor tissue compared to cfDNA from serum and genomic DNA from lymph node metastasis. Patients with CNV in ERBB2 and TOP2A are at increased risk for disease recurrence following RC. Further studies are necessary to validate, whether these genes may represent promising candidates for targeted-therapy.
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http://dx.doi.org/10.1038/s41598-020-75869-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725833PMC
December 2020

Impact of preoperative serum albumin-globulin ratio on disease outcome after radical cystectomy for urothelial carcinoma of the bladder.

Urol Oncol 2021 Apr 11;39(4):235.e5-235.e14. Epub 2020 Nov 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University Hospital of Tours, Tours, France.

Introduction: The Albumin-Globulin Ratio (AGR; albumin/total protein - albumin) has been associated with oncological outcome in various malignancies. However, its role in urothelial carcinoma of the bladder (UCB) has not been clearly established. In this study, we assessed the association of preoperative AGR (pAGR) with survival in patients who underwent radical cystectomy (RC) for UCB.

Material And Methods: We conducted a retrospective analysis of an established multicenter database of 4.335 patients who were treated with RC for UCB. The cohort was divided into 2 groups according to the pAGR status. Binominal logistic regression as well as uni- and multivariable Cox regression analyses were used. The predictive value of the models was assessed by calculating receiver operating characteristics curves and concordance-indices (C-Index). The additional clinical value was assessed using the decision curve analysis (DCA).

Results: Overall, 1.670 patients (38.5%) had a low pAGR. On multivariable logistic regression analyses, low pAGR was associated with an increased risk of ≥pT3 disease at RC (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.01-1.31, P= 0.04). On multivariable Cox regression analyses, low pAGR remained associated with worse recurrence-free survival (RFS, HR 1.24, 95% CI 1.1-1.37, P< 0.001), cancer-specific survival (CSS, HR 1.23, 95% CI 1.1-1.38, P< 0.001) and overall survival (OS, HR 1.17, 95% CI 1.07-1.28, P< 0.001). The addition of pAGR to multiple prognostic models that were respectively fitted for clinical and postoperative variables did not improve the predictive accuracy.

Conclusion: pAGR status is an independent predictor of ≥pT3 disease, therefore it could help identify patients who have a higher likelihood to benefit from neoadjuvant systemic therapy. While pAGR was independently associated with RFS, CSS, and OS, it did not improve the predictive accuracy and clinical value beyond obtained by information already available. The predictive value of this biomarker in the age of immunotherapy needs further evaluation.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.005DOI Listing
April 2021

Impact of Smoking Habit on Perioperative Morbidity in Patients Treated with Radical Cystectomy for Urothelial Bladder Cancer: A Systematic Review and Meta-analysis.

Eur Urol Oncol 2020 Nov 4. Epub 2020 Nov 4.

Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland. Electronic address:

Context: Smoking habit at the time of surgery is associated with higher perioperative complications and mortality across different types of surgeries. In recent years, several studies have attempted to explore the influence of smoking on perioperative outcomes following radical cystectomy (RC) for urothelial bladder cancer (UBC) with contradictory results.

Objective: To systematically investigate and meta-analyze the association between smoking habit and perioperative morbidity and mortality in UBC patients treated with RC.

Evidence Acquisition: A systematic review of the literature published between January 2000 and January 2020 investigating the impact of smoking habit on perioperative outcomes of patients treated with RC for UBC was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement and the Cochrane Handbook for Systematic Reviews of Interventions.

Evidence Synthesis: Overall, 27 articles involving 27 854 patients were included in the systematic review, and of these, 11 studies were included in the meta-analysis. The studies included showed a moderate to high risk of bias. Smoking status (smokers vs nonsmokers) was significantly associated with the onset of major postoperative complications (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.51-2.32; I = 0%), infections (HR 1.34, 95% CI 1.02-1.72; I = 66.2%), and mortality (HR 1.84, 95% CI 1.14-2.98; I = 4.9%).

Conclusions: Smoking status at the time of RC is associated with increased risk for major postoperative complications, infections, and mortality. These results suggest the need for strict postoperative monitoring in smokers due to the increased risk of experiencing adverse events and underline the need for intensive smoking cessation interventions in the preoperative setting.

Patient Summary: In this study, we reviewed the impact of smoking habit on perioperative outcomes following radical cystectomy (RC). Based on the available data, the impact of smoking on morbidity and mortality after RC is significant and relevant; as such, every effort should be made in the preoperative setting to encourage smoking cessation.
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http://dx.doi.org/10.1016/j.euo.2020.10.006DOI Listing
November 2020

Learning benefits of live surgery and semi-live surgery in urology-informing the debate with results from the International Meeting of Reconstructive Urology (IMORU) VIII.

World J Urol 2020 Nov 2. Epub 2020 Nov 2.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: To analyze the perceived learning opportunities of participants of the International Meeting on Reconstructive Urology (IMORU) VIII for both live surgery demonstrations (LSD) and semi-live surgery demonstrations (SLSD). Safety and educational efficacy of LSD and SLSD at live surgery events (LSE) have been debated extensively, however, objective data comparing learning benefits are missing.

Methods: We conducted a detailed survey, which employed the Kirkpatrick model, a well-established assessment method of training models, to investigate participants preferences as well as the learning benefit of LSE. Furthermore, we employed an audience response system and the Objective Structured Assessment of Technical Skills (OSATS), a well-established assessment method of surgery skills, to let our participants rate the perceived learning opportunity of LSD and SLSD.

Results: Of 229 participants at the IMORU VIII, 39.7% returned our questionnaires. 90% stated that they prefer LSD. On all levels of Kirkpatrick's training evaluation model, the IMORU received high ratings, suggesting a high learning benefit. For the assessment of OSATS, a total of 23 surgical cases were evaluable. For all six utilized items, LSD scored significantly better ratings than SLSD.

Conclusion: Our study suggests that there is still a rationale for LSD, as participants attributed a statistically significant higher learning benefit to LSD over SLDS. Evaluation of the survey showed that for LSE such as the IMORU VIII, a high learning benefit can be expected. Considering that most of our participants are active surgeons with high caseloads, their opinion on the educational value of LSE is of high relevance.
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http://dx.doi.org/10.1007/s00345-020-03506-3DOI Listing
November 2020

The Impact of Circulating Tumor Cells on Venous Thromboembolism and Cardiovascular Events in Bladder Cancer Patients Treated with Radical Cystectomy.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Department of Urology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.

Background: Cancer is a relevant risk factor for venous thromboembolism (VTE). Circulating tumor cells (CTC) are associated with an increased risk of VTE in breast cancer. In addition, circulating cell-free nucleic acids have been associated with cardiovascular events (CVE).

Objective: To investigate the association of CTC status and the risk of VTE as well as CVE in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC).

Methods: We collected data of 189 UCB patients treated with RC at our institution. Blood samples were acquired preoperatively and analyzed for CTC using the CellSearch system. Thirty-day postoperative complications were extracted from digital charts and graded according to the Clavien-Dindo classification (CDC). Moreover, each patient's individual Comprehensive Complication Index (CCI) was calculated.

Results: CTC were present in 43 patients (22.8%). Overall, six patients experienced VTE (3.2%) and eight patients (4.2%) experienced CVE. There was no association of VTE or CVE according to CTC status. In total, 168 patients (89%) experienced a total of 801 complications, of which the majority was classified as "minor" (CDC grade ≤ IIIa; 79%). There was no association between CTC status and any grade of a complication or CCI. Presence of CTC was associated with more aggressive clinicopathological UCB features.

Conclusions: The overall rate of VTE and CVE was low in our study. Presence of CTC was neither associated with an increased risk of VTE nor CVE in UCB patients treated with RC. According to this study, CTC are not a qualified biomarker for individualized thromboprophylaxis management in these patients.
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http://dx.doi.org/10.3390/jcm9113478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692134PMC
October 2020

Longitudinal Evaluation of Perineogenital Pain and Postoperative Complications After One-stage Buccal Mucosal Graft Urethroplasty: A Secondary Analysis of a Randomized Controlled Trial.

Eur Urol Focus 2020 Oct 14. Epub 2020 Oct 14.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Little is known about patient-reported intensity and quality of pain at the receiver site as well as postoperative complications following one-stage buccal mucosal graft urethroplasty (BMGU).

Objective: To evaluate perineogenital pain intensity and quality as well as short-term complications after BMGU, and to describe the impact of pain and complications on stricture recurrence.

Design, Setting, And Participants: A secondary analysis of a randomized controlled trial including 135 patients, who underwent BMGU from 2014 to 2015, was performed.

Intervention: One-stage BMGU.

Outcome Measurements And Statistical Analysis: Patient-reported perineogenital pain was assessed by the Numeric Pain Rating Scale and the Short-form McGill Pain Questionnaire preoperatively and at 1, 5, and 21 d, and 3, 6, and 12 mo postoperatively. Complications were assessed by the Clavien-Dindo classification and the Comprehensive Complication Index. Pain and complications were compared according to stricture recurrence.

Results And Limitations: At a mean follow-up of 21±15 mo, 29 patients (21%) had stricture recurrence. Pain intensity as well as sensory and affective pain quality decreased over time, reaching a minimum at 6 mo. Postoperative complications at days 5 (95% of patients) and 21 (27% of patients) were predominantly "minor" (Clavien-Dindo classification grade≤IIIa). Neither patient-reported perineogenital pain nor cumulative morbidity burden was different between patients with and those without stricture recurrence (all p ≥ 0.05).

Conclusions: Perineogenital pain is frequent after BMGU, but pain intensity and quality decrease over time. The same holds true for postoperative complications, which are frequent but mostly present as minor events. Current findings allow for thorough preoperative patient counseling regarding the expected perineogenital pain intensity and quality over time as well as complications following BMGU.

Patient Summary: In this study, we looked at pain intensity and pain quality as well as complications following buccal mucosal graft urethroplasty. We found that pain in the perineogenital region is frequent, but pain intensity and quality decrease over time. Similarly, postoperative complications are frequent, but mainly present as minor events.
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http://dx.doi.org/10.1016/j.euf.2020.09.018DOI Listing
October 2020

Diagnostic challenges and treatment strategies in the management of upper-tract urothelial carcinoma.

Turk J Urol 2021 Feb 9;47(Supp. 1):S33-S44. Epub 2020 Oct 9.

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

Upper-tract urothelial carcinoma (UTUC) is a rare disease, posing many challenges for the treating physician due to the lack of strong evidence-based recommendations. However, novel molecular discoveries and a better understanding of the clinical behavior of the disease lead to a continuous evolution of therapeutic landscape in UTUC. The aim of the review is to provide a comprehensive update of the current diagnostic modalities and treatment strategies in UTUC with a special focus on recent developments and challenges. A comprehensive literature search including relevant articles up to August 2020 was performed using the MEDLINE/PubMed database. Despite several technological improvements, accurate staging and outcome prediction remain major challenges and hamper appropriate risk stratification. Kidney-sparing surgery can be offered in low risk UTUC; however, physician and patient must be aware of the high rate of recurrence and risk of progression due to tumor biology and understaging. The value and efficacy of intracavitary therapy in patients with UTUC remains unclear due to the lack of high-quality data. In high-risk diseases, radical nephroureterectomy with bladder cuff excision and template lymph node dissection is the standard of care. Perioperative systemic chemotherapy is today accepted as a novel standard for advanced cancers. In metastatic or unresectable disease, the therapeutic landscape is rapidly changing due to several novel agents, such as checkpoint inhibitors. While several diagnostic and treatment challenges remain, progress in endoscopic technology and molecular knowledge have ushered a new age in personalized management of UTUC. Novel accurate molecular and imaging biomarkers are, however, still needed to guide decision making as tissue acquisition remains suboptimal. Next generation sequencing and novel agents are promising to rapidly improve patient outcomes.
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http://dx.doi.org/10.5152/tud.2020.20392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057353PMC
February 2021

Assessing the Outcome of Holmium Laser Enucleation of the Prostate by Age, Prostate Volume, and a History of Blood Thinning Agents: Report from a Single-Center Series of >1800 Consecutive Cases.

J Endourol 2021 May 29;35(5):639-646. Epub 2021 Jan 29.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

To assess perioperative outcomes of holmium laser enucleation of the prostate (HoLEP) in a real-world scenario and with a focus on demanding patient factors, such as large prostate size, advanced patient age, and anticoagulation therapy (AT). We retrospectively analyzed HoLEP procedures at our institution between 2010 and 2016. After stratification by prostate volume, age, and AT, perioperative and early voiding characteristics were compared. A multivariable regression model was employed to identify predictors of prolonged time of catheterization (defined as being above group's median). The study cohort consisted of 1816 men with a median age of 71 years (interquartile range [IQR]: 66-76), a median prostate volume of 80 mL (IQR: 58-105), and American Society of Anesthesiologists score ≥3 in 618 men (34%). Median time of enucleation and morcellation was 43 minutes (IQR: 31-60) and 10 minutes (IQR: 6-18), respectively. Perioperative blood transfusions were administered in 44 (2.4%) cases, severe postoperative complications (Clavien-Dindo grade ≥3b) occurred in 61 (3.3%) cases. The median time of catheterization was 2 days (IQR: 2-2), with prolonged catheterization occurring in 277 (15%) cases. After adjustment, large prostates (fourth volume quartile [106-280 mL]) (odds ratio [OR]: 1.8, 95% confidence interval [CI]: 1.3-2.6,  = 0.001), therapeutic low-molecular-weight heparin bridging regimen (OR: 2.2, 95% CI: 1.4-3.6,  = 0.037), low-dose acetylsalicylic acid (OR: 1.5, 95% CI: 1.0-2.2,  = 0.015), and a history of direct oral anticoagulation (OR: 2.3, 95% CI: 1.2-4.0,  = 0.022), but not patient age, were independently associated with prolonged catheterization. We confirm HoLEP as safe and efficient; however, patients with large prostates and patients with a history of AT are at risk of prolonged catheterization.
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http://dx.doi.org/10.1089/end.2020.0605DOI Listing
May 2021

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry.

Future Oncol 2020 Dec 6;16(35):2939-2948. Epub 2020 Oct 6.

Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany.

Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0548DOI Listing
December 2020

Incidence and outcome of salvage cystectomy after bladder sparing therapy for muscle invasive bladder cancer: a systematic review and meta-analysis.

World J Urol 2020 Sep 29. Epub 2020 Sep 29.

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

Objective: We conducted a systematic review and meta-analysis to assess the available literature regarding the surgical and oncologic outcomes of patients undergoing salvage radical cystectomy (SV-RC) for recurrence or failure of bladder sparing therapy (BST) for muscle-invasive bladder cancer (MIBC).

Methods: We searched MEDLINE (PubMed), EMBASE and Google Scholar databases in May 2020. We included all studies of patients with ≥ cT2N0/xM0 bladder cancer that were eligible for all treatment modalities at the time of treatment decision who underwent BST including radiotherapy (RTX). A meta-analysis was conducted to calculate the pooled rate of several variables associated with an increased need for SV-RC. Study quality and risk of bias were assessed using MINORS criteria.

Results: 73 studies comprising 9110 patients were eligible for the meta-analysis. Weighted mean follow-up time was 61.1 months (range 12-144). The pooled rate of non-response to BST and local recurrence after BST, the two primary reasons for SV-RC, was 15.5% and 28.7%, respectively. The pooled rate of SV-RC was 19.2% for studies with a follow-up longer than 5 years. Only three studies provided a thorough report of complication rates after SV-RC. The overall complication rate ranged between 67 and 72% with a 30-day mortality rate of 0-8.8%. The pooled rates of 5 and 10-year disease-free survival after SV-RC were 54.3% and 45.6%, respectively.

Conclusion: Approximately one-fifth of patients treated with BST with a curative intent eventually require SV-RC. This procedure carries a proportionally high rate of complications and is usually accompanied by an incontinent urinary diversion.
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http://dx.doi.org/10.1007/s00345-020-03436-0DOI Listing
September 2020

The association of cigarette smoking and pathological response to neoadjuvant platinum-based chemotherapy in patients undergoing treatment for urinary bladder cancer - A prospective European multicenter observational study of the EAU Young Academic Urologists (YAU) urothelial carcinoma working group.

Surg Oncol 2020 Sep 30;34:312-317. Epub 2020 Jun 30.

Department of Urology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address:

Objective: To prospectively study the impact of smoking on pathological response to neoadjuvant chemotherapy (NAC) in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

Materials & Methods: We collected standard clinicopathological variables, including smoking status (never, former, current) in patients undergoing NAC and RC for UCB at 12 European tertiary care centers between 12/2013-12/2015. Clinicopathological variables were compared according to smoking status. Multivariable logistic regression models were built to assess the association of smoking status and a) complete (no residual disease), b) partial (residual, non-muscle invasive disease), c) no pathological response (residual muscle invasive or lymph node positive disease). Kaplan-Meier and Cox regression analyses were employed to study the impact of response to NAC on survival.

Results And Limitations: Our final cohort consisted of 167 NAC patients with a median follow-up of 15 months (interquartile range (IQR) 9-26 months) of whom 48 (29%), 69 (41%), and 50 (30%) where never, former, and current smokers, respectively. Smoking was significantly associated with advanced age (p = 0.013), worse ECOG performance status (p = 0.049), and decreased pathological response to NAC (p = 0.045). On multivariable logistic regression analyses, former and current smoking status was significantly associated with lower odds of complete pathological response (odds ratio (OR) 0.37, 95% confidence interval (CI) 0.16-0.87, p = 0.023, and OR 0.34, 95% CI 0.13-0.85, p = 0.021), while current smoking status was significantly associated with a greater likelihood of no pathological response (OR 2.49, 95% CI 1.02-6.06, p = 0.045). Response to NAC was confirmed as powerful predictor of survival.

Conclusions: Smoking status is adversely associated with pathological response to NAC. Smokers should be informed about these adverse effects, counseled regarding smoking cessation, and possibly be considered for immunotherpeutics as they may be more effective in smokers.
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http://dx.doi.org/10.1016/j.suronc.2020.06.006DOI Listing
September 2020

Pathomics in urology.

Curr Opin Urol 2020 11;30(6):823-831

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

Purpose Of Review: Pathomics, the fusion of digitalized pathology and artificial intelligence, is currently changing the landscape of medical pathology and biologic disease classification. In this review, we give an overview of Pathomics and summarize its most relevant applications in urology.

Recent Findings: There is a steady rise in the number of studies employing Pathomics, and especially deep learning, in urology. In prostate cancer, several algorithms have been developed for the automatic differentiation between benign and malignant lesions and to differentiate Gleason scores. Furthermore, several applications have been developed for the automatic cancer cell detection in urine and for tumor assessment in renal cancer. Despite the explosion in research, Pathomics is not fully ready yet for widespread clinical application.

Summary: In prostate cancer and other urologic pathologies, Pathomics is avidly being researched with commercial applications on the close horizon. Pathomics is set to improve the accuracy, speed, reliability, cost-effectiveness and generalizability of pathology, especially in uro-oncology.
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http://dx.doi.org/10.1097/MOU.0000000000000813DOI Listing
November 2020

Retrograde ejaculation after holmium laser enucleation of the prostate (HoLEP)-Impact on sexual function and evaluation of patient bother using validated questionnaires.

Andrology 2020 11 31;8(6):1779-1786. Epub 2020 Aug 31.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: A vast body of literature has focused on erectile function after Holmium Laser Enucleation of the Prostate (HoLEP). Interestingly, retrograde ejaculation (RE), despite its frequency has sparsely been investigated.

Objectives: To study patient perception and impact of RE on sexuality following HoLEP.

Materials And Methods: We retrospectively analyzed 2,131 patients undergoing HoLEP 2006-2015 at our institution. Patients were followed via standardized questionnaires namely International Index of Erectile Function (IIEF) as well as Male Sexual Health Questionnaire Ejaculatory Short Form (MSHQ-EjD-SF). Exclusion criteria were missing/follow-up <6 months, missing data on MSHQ-EjD-SF and IIEF score, resulting in 535 assessable patients. Multivariable logistic regression was employed to identify independent predictors of satisfaction with overall sex life (IIEF question 13).

Results: Median follow-up was 50 months (IQR: 30-78). Overall, 495 (92.5%) patients reported RE. Patients differed significantly with respect to age (P = .036), IPSS at follow-up (P = .01), and erectile function (P < .001), whereas no other statistically significant differences were observed. In multivariable logistic regression analyses, presence of RE was not independently associated with satisfaction with overall sex life (OR: 2.7, 95% CI: 0.70-10.5, P = .1). However, in the cohort of patients exhibiting RE, patients who stated "feeling bothered by RE" had lower satisfaction with overall sex life (OR: 0.23, 95% CI: 0.13-0.38, P < .001). Bother by RE varied according to erectile function and did not impact overall satisfaction in men with superior erectile function.

Conclusions: RE is a very common event after HoLEP but in this retrospective analysis was not associated with overall satisfaction with sex life. Contrary, satisfaction with sex life is impaired in patients who feel bothered by RE. Proper patient selection will pose key to identify patients in which RE bother will offset the benefits of LUTS relief.
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http://dx.doi.org/10.1111/andr.12887DOI Listing
November 2020

Primary Ta high grade bladder tumors: Determination of the risk of progression.

Urol Oncol 2021 02 7;39(2):132.e7-132.e11. Epub 2020 Aug 7.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Departments 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; European Association of Urology Research Foundation, Arnhem, Netherlands; Karl Landsteiner Institute, Vienna, Austria. Electronic address:

Purpose: TaG3 bladder cancer is an under-investigated disease and because of its rarity it is commonly studies together with T1G3 disease. We sought to exclusively study TaG3 disease and to determine the factors associated with disease progression.

Material And Method: We retrospectively studied patients with primary TaG3 bladder cancer. Progression to ≥pT1 and pT2 were analyzed using Cox and competing-risk regression analyses.

Results: Of 3,505 consecutive patients with nonmuscle invasive bladder cancer, 285 patients had primary TaG3 without concomitant carcinoma in-situ. Progression to ≥pT1 occurred in 21 patients (7.4%). In a multivariable competing-risk regression analysis, intravesical Bacillus Calmette-Guerin (BCG) was significantly associated with a lower risk of progression to ≥pT1 (HR 0.23, 95%CI 0.08-0.64, P = 0.005). Recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥pT1 (HR 7.81, 95%CI 2.50-24.44, P < 0.001). Progression to ≥T2 was observed in 9 patients (3.2%). In univariable competing-risk regression analyses, intravesical BCG was significantly associated with a lower risk of progression to ≥pT2 (HR 0.11, 95%CI 0.04-0.47, P = 0.003). On the other hand, recurrence in the first year of diagnosis was significantly associated with an increased risk of stage progression to ≥T2 (HR 7.12, 95%CI 1.50-33.77, P = 0.013). In a subgroup of 199 patients who were treated with BCG, there was no statistically significant association between tumor recurrence in the 1 year of diagnosis and stage progression to ≥pT1 (P = 0.14) or ≥pT2(P = 0.19).

Conclusion: Patients with TaG3 bladder cancer are considered high risk but if appropriately treated with BCG that risk is considerably mitigated. Our data support that TaG3 without concomitant carcinoma in-situ should not be considered as aggressive as T1G3 as it has a lower risk of progression to muscle-invasive bladder cancer. Recurrence in the first year after diagnosis is the strongest predictor of progression to muscle-invasive bladder cancer.
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http://dx.doi.org/10.1016/j.urolonc.2020.07.017DOI Listing
February 2021

Pathogen-induced tissue-resident memory T17 (T17) cells amplify autoimmune kidney disease.

Sci Immunol 2020 08;5(50)

III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (T) cells persist in peripheral organs and provide immune protection against reinfection. However, whether T cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4 T cells with a T17 signature (termed T17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal T17 cells were induced by pathogens infecting the kidney, such as , , and uropathogenic , and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney T17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced T17 cells have a previously unrecognized function in aggravating autoimmune disease.
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http://dx.doi.org/10.1126/sciimmunol.aba4163DOI Listing
August 2020

Prevalence of APC and PTEN Alterations in Urachal Cancer.

Pathol Oncol Res 2020 Oct 4;26(4):2773-2781. Epub 2020 Aug 4.

Department of Urology, Semmelweis University, Budapest, 1082, Hungary.

Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.
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http://dx.doi.org/10.1007/s12253-020-00872-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471184PMC
October 2020