Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients.

BACKGROUND: Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool. METHODS: Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80-20 splitting of the data set and 10-fold cross validation. To assess performance, R2, RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models. RESULTS: For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R2 = 0.12, RMSE = 25.40, sexual function: R2 = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/. CONCLUSION: The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.

Alteration of Cadherin 3 Expression and DNA Methylation in Association with Aggressive Renal Cell Carcinoma.

Cadherins (calcium-dependent adhesion proteins) are important in cellular adhesion and may play a role in the development and progression of renal cell carcinoma (RCC). This study investigated changes in cadherin 3 (CDH3; P-cadherin) mRNA expression, DNA methylation, and protein expression in RCC and compared the results with the histopathological and clinical characteristics of patients. The possible contribution of CDH3 to tumor cell invasiveness was tested in a functional assay using siRNA-based suppression of CDH3 expression and subsequent real-time impedance analysis using a Matrigel invasion model. Our analyses revealed a tumor-specific loss of CDH3 mRNA expression, CDH3 DNA hypermethylation, and loss of distal tubular and collecting duct CDH3 protein expression in RCC. A relatively higher methylation level in tumors was associated with a loss of cell differentiation and higher clinical stage. siRNA-induced suppression of CDH3 expression modulated the invasion characteristics of tumor cells in the impedance-based real-time cellular analysis. Our results indicate that loss of CDH3 expression is common in RCC and may contribute to the pathogenesis of a subset of RCC. Further studies to reveal the mechanisms of loss of expression and its effects on the invasive behavior of renal tumor cells are required.

Digital Rectal Examination Is Not a Useful Screening Test for Prostate Cancer.

BACKGROUND: Annual digital rectal examination (DRE) is recommended as a stand-alone screening test for prostate cancer (PCa) in Germany for 45+ yr olds. DRE diagnostic performance in men as young as 45 yr old has not been proved by a screening trial. OBJECTIVE: To determine DRE diagnostic performance in a screening trial. DESIGN, SETTING, AND PARTICIPANTS: This analysis was conducted within the multicentric, randomized PROBASE trial, which enrolled >46 000 men at age 45 to test risk-adapted prostate-specific antigen (PSA) screening for PCa. INTERVENTION: (1) DRE was analyzed as a one-time, stand-alone screening offer at age 45 in 6537 men in one arm of the trial and (2) PCa detection by DRE was evaluated at the time of PSA-screen-driven biopsies (N = 578). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: (1) True-/false-positive detection rates of DRE as compared with PSA screening and (2) DRE outcome at the time of a prostate biopsy were evaluated. RESULTS AND LIMITATIONS: (1) A prospective analysis of 57 men with suspicious DRE at age 45 revealed three PCa. Detection rate by DRE was 0.05% (three of 6537) as compared with a four-fold higher rate by PSA screening (48 of 23 301, 0.21%). The true-positive detection rate by DRE relative to screening by PSA was 0.22 (95% confidence interval [CI] = [0.07-0.72]) and the false-positive detection rate by DRE was 2.2 (95% CI = [1.50-3.17]). (2) Among PSA-screen-detected PCa cases, 86% had unsuspicious DRE (sensitivity relative to PSA was 14%), with the majority of these tumors (86%) located in the potentially accessible zones of the prostate as seen by magnetic resonance imaging. CONCLUSIONS: The performance of stand-alone DRE to screen for PCa is poor. DRE should not be recommended as a PCa screening test in young men. Furthermore, DRE does not improve the detection of PSA-screen-detected PCa. PATIENT SUMMARY: Our report demonstrated the poor diagnostic performance of digital rectal examination in the screening for prostate cancer in young men.

First experiences using transurethral ultrasound ablation (TULSA) as a promising focal approach to treat localized prostate cancer: a monocentric study.

PURPOSE: To share our experience using transurethral ultrasound ablation (TULSA) treatment for focal therapy of localized prostate cancer (PCa). MATERIALS AND METHODS: Between 10/2019 and 06/2021 TULSA treatment for localized PCa was performed in 22 men (mean age: 67 ± 7 years, mean initial PSA: 6.8 ± 2.1 ng/ml, ISUP 1 in n = 6, ISUP 2 in n = 14 and 2 patients with recurrence after previous radiotherapy). Patients were selected by an interdisciplinary team, taking clinical parameters, histopathology from targeted or systematic biopsies, mpMRI and patients preferences into consideration. Patients were thoroughly informed about alternative treatment options and that TULSA is an individual treatment approach. High-intensity ultrasound was applied using an ablation device placed in the prostatic urethra. Heat-development within the prostatic tissue was monitored using MR-thermometry. Challenges during the ablation procedure and follow-up of oncologic and functional outcome of at least 12 months after TULSA treatment were documented. RESULTS: No major adverse events were documented. In the 12 month follow-up period, no significant changes of urinary continence, irritative/obstructive voiding symptoms, bowel irritation or hormonal symptoms were reported according to the Expanded Prostate Cancer Index Composite (EPIC) score. Erectile function was significantly impaired 3-6 months (p < 0.01) and 9-12 months (p < 0.05) after TULSA. PSA values significantly decreased after therapy (2.1 ± 1.8 vs. 6.8 ± 2.1 ng/ml, p < 0.001). PCa recurrence rate was 23% (5/22 patients). CONCLUSION: Establishment of TULSA in clinical routine was unproblematic, short-term outcome seems to be encouraging. The risk of erectile function impairment requires elaborate information of the patient.

Spider silk erectile nerve reconstruction in robot-assisted radical prostatectomy: a first-in-men feasibility analysis.

PURPOSE: To investigate the safety and feasibility of spider silk interposition for erectile nerve reconstruction in patients undergoing robotic radical prostatectomy (RARP). METHODS: The major-ampullate-dragline from Nephila edulis was used for spider silk nerve reconstruction (SSNR). After removal of the prostate with either uni- or bilateral nerve-sparing, the spider silk was laid out on the site of the neurovascular bundles. Data analysis included inflammatory markers and patient reported outcomes. RESULTS: Six patients underwent RARP with SSNR. In 50% of the cases, only a unilateral nerve-sparing was performed, bilateral nerve-sparing could be performed in three patients. Placement of the spider silk conduit was uneventful, contact of the spider silk with the surrounding tissue was mostly sufficient for a stable connection with the proximal and distal ends of the dissected bundles. Inflammatory markers peaked until postoperative day 1 but stabilized until discharge without any need for antibiotic treatment throughout the hospital stay. One patient was readmitted due to a urinary tract infection. Three patients reported about erections sufficient for penetration after three months with a continuous improvement of erectile function both after bi- and unilateral nerve-sparing with SSNR up to the last follow-up after 18 months. CONCLUSION: In this analysis of the first RARP with SSNR, a simple intraoperative handling without major complications was demonstrated. While the series provides evidence that SSNR is safe and feasible, a prospective randomized trial with long-term follow-up is needed to identify further improvement in postoperative erectile function due to the spider silk-directed nerve regeneration.

Adherence to a risk-adapted screening strategy for prostate cancer: First results of the PROBASE trial.

PROBASE is a population-based, randomized trial of 46 495 German men recruited at age 45 to compare effects of risk-adapted prostate cancer (PCa) screening starting either immediately at age 45, or at a deferred age of 50 years. Based on prostate-specific antigen (PSA) levels, men are classified into risk groups with different screening intervals: low-risk (<1.5 ng/ml, 5-yearly screening), intermediate-risk (1.5-2.99 ng/ml, 2 yearly), and high risk (>3 ng/ml, recommendation for immediate biopsy). Over the first 6 years of study participation, attendance rates to scheduled screening visits varied from 70.5% to 79.4%, depending on the study arm and risk group allocation, in addition 11.2% to 25.4% of men reported self-initiated PSA tests outside the PROBASE protocol. 38.5% of participants had a history of digital rectal examination or PSA testing prior to recruitment to PROBASE, frequently associated with family history of PCa. These men showed higher rates (33% to 57%, depending on subgroups) of self-initiated PSA testing in-between PROBASE screening rounds. In the high-risk groups (both arms), the biopsy acceptance rate was 64% overall, but was higher among men with screening PSA ≥4 ng/ml (>71%) and with PIRADS ≥3 findings upon multiparameter magnetic resonance imaging (mpMRI) (>72%), compared with men with PSA ≥3 to 4 ng/ml (57%) or PIRADS score ≤ 2 (59%). Overall, PROBASE shows good acceptance of a risk-adapted PCa screening strategy in Germany. Implementation of such a strategy should be accompanied by a well-structured communication, to explain not only the benefits but also the harms of PSA screening.

Identification of a Novel Renal Metastasis Associated CpG-Based DNA Methylation Signature (RMAMS).

Approximately 21% of patients with renal cell cancer (RCC) present with synchronous metastatic disease at the time of diagnosis, and metachronous metastatic disease occurs in 20-50% of cases within 5 years. Recent advances in adjuvant treatment of aggressive RCC following surgery suggest that biomarker-based prediction of risk for distant metastasis could improve patient selection. Biometrical analysis of TCGA-KIRC data identified candidate loci in the NK6 homeobox 2 gene (NKX6-2) that are hypermethylated in primary metastatic RCC. Analyses of NKX6-2 DNA methylation in three gene regions including a total of 16 CpG sites in 154 tumor-adjacent normal tissue, 189 RCC, and 194 metastatic tissue samples from 95 metastasized RCC patients revealed highly significant tumor-specific, primary metastatic-specific, and metastatic tissue-specific hypermethylation of NKX6-2. Combined CpG site methylation data for NKX6-2 and metastasis-associated genes (INA, NHLH2, and THBS4) demonstrated similarity between metastatic tissues and metastatic primary RCC tissues. The random forest method and evaluation of an unknown test cohort of tissues using receiver operator characteristic curve analysis revealed that metastatic tissues can be differentiated by a median area under the curve of 0.86 (p = 1.7 × 10-8-7.5 × 10-3) in 1000 random runs. Analysis of variable importance demonstrated an above median contribution for decision-making of at least one CpG site in each of the genes, suggesting superior informativity for sites annotated to NHLH2 and NKX6-2. Thus, DNA methylation of NKX6-2 is associated with the metastatic state of RCC tissues and contributes to a four-gene-based statistical predictor of tumoral and metastatic renal tissues.

Combination of PI-RADS score and mRNA urine test-A novel scoring system for improved detection of prostate cancer.

Available tests to detect clinically significant prostate cancer frequently lead to overdiagnosis and overtreatment. Our study assessed the feasibility of combining a urinary biomarker-based risk score (SelectMDx®) and multiparametric MRI outcomes in order to identify patients with prostate cancer on prostate biopsy with increased accuracy and reliability. Samples of 74 men with suspicion of prostate cancer and available multiparametric MRI were analysed in a prospective cross-sectional study design. First-voided urine for determination of HOXC6 and DLX1 mRNA levels was collected after digital rectal examination and prior to MRI/ultrasound fusion-guided prostate biopsy. All multiparametric MRI images were centrally reviewed by two experienced radiologists blinded for urine test results and biopsy outcome. The PI-RADS v2 was used. SelectMDx® score, PI-RADS and Gleason Sore were obtained. Associations between Gleason Score, PI-RADS scores and SelectMDx® were assessed using ANOVA and t-test. Sensitivity and specificity were assessed and evaluated as area-under-the-curve of the receiver operating characteristic. Upon biopsy, 59.5% of patients were diagnosed with prostate cancer, whereby 40.6% had high-grade prostate cancer (GS ≥ 7a). SelectMDx® scores were significantly higher for patients with positive biopsy findings (49.07 ± 25.99% vs. 22.00 ± 26.43%; p < 0.001). SelectMDx® scores increased with higher PI-RADS scores. Combining SelectMDx®, history of prior biopsy with benign histology and PI-RADS scores into a novel scoring system led to significant prostate cancer detection rates with tiered detection rate of 39%, 58%, 81% and 100% for Gleason grade group II, III, IV, and V, respectively. The area-under-the-curve for our novel sum score in receiver operating characteristic analysis was 0.84. The synergistic combination of two non-invasive tests into a sum score with increased sensitivity may help avoiding unnecessary biopsies for initial prostate cancer diagnosis. For confirmation, further prospective studies with larger sample sizes and univariate and multivariate regression analyses and decision curve analyses are required.

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes.

Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70−0.88, p < 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001−0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p < 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.

First experiences and results after cryoablation of prostate cancer with histopathological evaluation and imaging-based follow-up.

Aim: To share our experience after 28 cryoablation treatments for prostate cancer (PCa) with histopathology, clinical data and MRI as the follow-up methods. Methods: Clinical follow-up comprised prostate-specific antigen (PSA)-measurements, PSA-density and quality of life-parameters. multi-parametric (mp)MRI pre- and post-cryoablation were retrospectively re-analyzed in 23 cases using Likert scores. Follow-up-histopathology was performed via MRI/ultrasound fusion-guided and/or systematic biopsy. Receiver operating characteristic curve analysis was performed. Results: 17 PCa (61%) were diagnosed within 12-month post-cryotherapy (infield and out-of-field disease). PSA levels and PSA density were not significantly different between patients with or without PCa recurrence. mpMRI can characterize the decrease in prostate volume and necrosis. Area under the curve for the detection of PCa was 81% (global Likert scores), 74-87% (T2), 78% (diffusion weighted imaging) and 57-78% (dynamic contrast enhanced imaging; Youden-selected cutoff ≥3). Conclusion: Besides histopathological evaluation and control biopsy, MRI might have the potential to accurately detect PCa after cryotherapy. Clinical data and interdisciplinary communication are required for efficient monitoring after cryoablation treatments for PCa.

A randomized trial of risk-adapted screening for prostate cancer in young men-Results of the first screening round of the PROBASE trial.

There is no generally accepted screening strategy for prostate cancer (PCa). From February 2014 to December 2019 a randomized trial (PROBASE) recruited 46 642 men at age 45 to determine the efficacy of risk-adapted prostate-specific antigen-based (PSA) screening, starting at either 45 or 50 years. PSA tests are used to classify participants into a low (<1.5 ng/mL), intermediate (1.5-2.99 ng/mL) or high (≥3 ng/mL) risk group. In cases of confirmed PSA values ≥3 ng/mL participants are recommended a prostate biopsy with multiparametric magnetic resonance imaging (mpMRI). Half of the participants (N = 23 341) were offered PSA screening immediately at age 45; the other half (N = 23 301) were offered digital rectal examination (DRE) with delayed PSA screening at age 50. Of 23 301 participants who accepted baseline PSA testing in the immediate screening arm, 89.2% fell into the low, 9.3% into intermediate, and 1.5% (N = 344) into the high risk group. Repeat PSA measurement confirmed high-risk status for 186 men (0.8%), of whom 120 (64.5%) underwent a biopsy. A total of 48 PCas was detected (overall prevalence 0.2%), of which 15 had International Society of Uropathology (ISUP) grade 1, 29 had ISUP 2 and only 4 had ISUP ≥3 cancers. In the delayed screening arm, 23 194 participants were enrolled and 6537 underwent a DRE with 57 suspicious findings, two of which showed PCa (both ISUP 1; detection rate 0.03%). In conclusion, the prevalence of screen-detected aggressive (ISUP ≥3) PCa in 45-year-old men is very low. DRE did not turn out effective for early detection of PCa.

Predictors for the utilization of social service counseling by prostate cancer patients.

PURPOSE: Social service counseling (SSC) is an important instrument to support cancer patients, for example, regarding legal support, or rehabilitation. Several countries have established on-site SSC in routine care. Previous analyses have shown that SSC utilization varies across cancer centers. This analysis investigates patient and center-level predictors that explain variations in SSC utilization between centers. METHODS: Logistic multilevel analysis was performed with data from 19,865 prostate cancer patients from 102 prostate cancer centers in Germany and Switzerland. Data was collected within an observational study between July 2016 and June 2020 using survey (online and paper) and tumor documentation. RESULTS: The intraclass correlation coefficient for the null model implies that 51% of variance in SSC utilization is attributable to the center a patient is treated in. Patients aged 80 years and older, with higher education, private insurance, without comorbidities, localized intermediate risk, and undergoing androgen deprivation therapy before study inclusion were less likely to utilize SSC. Undergoing primary radiotherapy, active surveillance, or watchful waiting as compared to prostatectomy was associated with a lower likelihood of SSC utilization. Significant negative predictors at the center level were university hospital, center's location in Switzerland, and a short period of certification. CONCLUSION: The results show that patient and center characteristics contribute to explaining the variance in SSC utilization in prostate cancer centers to a large extent. The findings may indicate different organizational processes in the countries included and barriers in the sectoral structure of the healthcare system. In-depth analyses of processes within cancer centers may provide further insights into the reasons for variance in SSC utilization.

Comparison of PD-L1 Scores in Primary Kidney Tumors Versus Accompanying Venous Tumor Thrombi: Retrospective, Comparative, Monocentric Study in Treatment-Naive Patients.

INTRODUCTION: Renal cell carcinoma (RCC), an immunogenic tumor, is the most common form of kidney cancer worldwide. Immune checkpoint inhibitors (ICIs) play an important role in the treatment of metastatic RCC. Programmed death-ligand (PD-L1) has already been proposed as a possible prognosticator for ICIs effectiveness. To elucidate the feasible role of ICIs in neoadjuvant settings, we have assessed the most common PD-L1 expression modalities [tumor proportion score (TPS), combined positivity score (CPS) and inflammatory cell (IC) score] in primary tumors (PTs) and venous tumor thrombi (VTT) in first diagnosed, previously untreated RCC patients with accompanying VTT. METHODS: Between January 1999 and December 2016, 71 patients with a first diagnosed, untreated, locally advanced RCC (aRCC) (≥ pT3a) underwent surgery in Hanover Medical School (MHH). PD-L1 expression was examined separately in PTs and VTT using the CPS, IC score and TPS. We also considered the age at the time of the initial surgery and gender as probable influencing factors. By using a cutoff value of 1 (1%), PD-L1 expression levels in PTs and VTT were assessed to enable the determination of any frequency differences. RESULTS: Positive scores for PTs were shown by 54 (CPS), 53 (IC score) and 34 (TPS) patients, whereas in VTT, positive scores were evaluated for a total of 50 (CPS), 47 (IC-score) and 36 (TPS) patients. No statistically significant differences were obtained between the PD-L1 expression immunoscores for PTs and VTT. The covariates age at the time of the initial surgery and gender could not be statistically proven to influence the differences in PD-L1 expression between the VTT and PTs. CONCLUSION: To the best of our knowledge, this research is the largest study to investigate PD-L1 expression in PTs and VTT in 71 cases. It could have relevance for the future development of neoadjuvant immunotherapy options, particularly in aRCC with VTT.

DNA methylation of tumor associated calcium signal transducer 2 (TACSTD2) loci shows association with clinically aggressive renal cell cancers.

BACKGROUND: DNA methylation is frequently observed in the development and progression of many human tumors as well as renal cell cancer (RCC). Tumor Associated Calcium Signal Transducer 2 (TACSTD2) participates in cell cycle progression through MAPK signalling pathway activation. Moreover, tumor-specific hypermethylation and association with aggressive cancer characteristics has been found for lung adenocarcinoma, hepatocellular carcinoma and cholangiocarcinoma. Whether TACSTD2 is tumor specifically hypermethylated in RCC or shows association of methylation with adverse clinicopathological parameters and survival of patients has not been investigated at yet. METHODS: Quantitative methylation-specific PCR (qMSP) analysis of a locus in the intron 1 region of TACSTD2 gene was carried out in a cross-sectional study of 127 paired RCC and normal samples. In silico analysis of TACSTD2 methylation in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset of 280 patients served as validation cohort. Statistical analyses were carried out using the two-sided paired t-test for matched tumor and normal sample comparisons, logistic regression for subgroup comparisons, Cox regression for analysis of recurrence free survival (RFS) and Pearson correlation analysis for correlation of TACSTD2 methylation and TACSTD2 mRNA in KIRC data. RESULTS: Higher methylation levels in RCC were significantly associated with advanced disease (p < 0.001), high tumor stage (p = 0.003), tumor differentiation (p = 0.033) and presence of lymph node (p = 0.021) or distant metastases (p = 0.008). TACSTD2 hypermethylation was associated with a shorter RFS of patients and demonstrate statistical independency from clinical parameters as state of metastasis, tumor stage, grade and state of advanced disease. In silico validation using TCGA KIRC data also demonstrated association of TACSTD2 loci with adverse clinicopathology and shortened RFS of patients. In addition, in silico analyses of TCGA KIRC data showed an inverse correlation between DNA methylation levels of TACSTD2 and mRNA expression. CONCLUSIONS: Our results suggest an association between TACSTD2 methylation and disease progression and clinical course of RCC.

DNA Methylation in INA, NHLH2, and THBS4 Is Associated with Metastatic Disease in Renal Cell Carcinoma.

The detection of DNA methylation in primary tumor tissues could be relevant for early stratification of aggressive renal cell carcinomas (RCCs) as a basis for future personalized adjuvant therapy. Methylated TCGA KIRC based candidate CpG loci in INA, NHLH2, and THBS4 that are possibly associated with RCC metastasis were evaluated by pyrosequencing in 154 paired normal adjacent and primary tumor tissues, as well as in 202 metastatic tissues. Statistical analysis was carried out by bivariate logistic regression for group comparisons, log rank survival analysis, and unsupervised and supervised analysis for the classification of tumors. Increased methylation of INA, NHLH2, and THBS4 loci were significantly associated with distant metastasis in primary tumors (p < 0.05), tissue-specific hypermethylation in metastatic (p = 7.88 × 10-8, 5.57 × 10-10, 2.06 × 10-7) and tumor tissues (p = 3.72 × 10-24, 3.17 × 10-13, 1.58 × 10-19), and shortened progression free survival in patients (p = 0.03). Combined use of CpG site-specific methylation permits the discrimination of tissues with metastatic disease and reveals a significant contribution of CpG sites in all genes to the statistical classification model. Thus, metastasis in RCC is significantly associated with methylation alterations in INA, NHLH2, and THBS4 loci, providing independent information for the potential early detection of aggressive renal cancers as a rationale for stratifying patients to adjuvant therapies.

To defer or not to defer? A German longitudinal multicentric assessment of clinical practice in urology during the COVID-19 pandemic.

INTRODUCTION: After the outbreak of COVID-19 unprecedented changes in the healthcare systems worldwide were necessary resulting in a reduction of urological capacities with postponements of consultations and surgeries. MATERIAL AND METHODS: An email was sent to 66 urological hospitals with focus on robotic surgery (RS) including a link to a questionnaire (e.g. bed/staff capacity, surgical caseload, protection measures during RS) that covered three time points: a representative baseline week prior to COVID-19, the week of March 16th-22nd and April 20th-26th 2020. The results were evaluated using descriptive analyses. RESULTS: 27 out of 66 questionnaires were analyzed (response rate: 41%). We found a decrease of 11% in hospital beds and 25% in OR capacity with equal reductions for endourological, open and robotic procedures. Primary surgical treatment of urolithiasis and benign prostate syndrome (BPS) but also of testicular and penile cancer dropped by at least 50% while the decrease of surgeries for prostate, renal and urothelial cancer (TUR-B and cystectomies) ranged from 15 to 37%. The use of personal protection equipment (PPE), screening of staff and patients and protection during RS was unevenly distributed in the different centers-however, the number of COVID-19 patients and urologists did not reach double digits. CONCLUSION: The German urological landscape has changed since the outbreak of COVID-19 with a significant shift of high priority surgeries but also continuation of elective surgical treatments. While screening and staff protection is employed heterogeneously, the number of infected German urologists stays low.

Checkpoint Inhibition for Metastatic Urothelial Carcinoma After Chemotherapy-Real-World Clinical Impressions and Comparative Review of the Literature.

Background: The introduction of checkpoint inhibitors is a long-awaited new option for a urothelial cancer with a poor prognosis. Apart from clinical studies, the data on real world experience is scarce. Methods: Patients for monotherapy with either Atezolizumab, Nivolumab or Pembrolizumab after chemotherapy were included. Adverse events and immune related adverse events as well as survival data and imaging analyses were recorded in a prospectively designed multi-center data base. Duration of response, progression free survival (PFS), and overall survival (OS) were estimated with the Kaplan-Meier method. Results: A total of 28 patients were included. The median follow-up was 8.0 (range, 0.7-41.7) months. Median PFS was 5.8 (95% CI, 2.3-NA) months. Median OS for all patients was 10.0 (95% CI, 8.0-NA) months. The overall response rate (ORR) was 21.4% (6 out of 28 patients). Adverse events were recorded in 20 (71.4%) of patients. Higher grade adverse events (≥Grade 3) were present in 11 (39.3%) patients. No therapy related deaths occurred during the observation period. A total of 13 (46.4%) patients had adverse events that were considered to be immune related. The most commonly affected organ was the thyroid gland with 21.4% of events. Conclusion: Our real-world clinical series confirms an objective response for about every fifth patient, promising OS and a low incidence for severe adverse events (≥Grade 3).

Age-, tumor-, and metastatic tissue-associated DNA hypermethylation of a T-box brain 1 locus in human kidney tissue.

BACKGROUND: While a considerable number of tumor-specific hypermethylated loci have been identified in renal cell cancer (RCC), DNA methylation of loci showing successive increases in normal, tumoral, and metastatic tissues could point to genes with high relevance both for the process of tumor development and progression. Here, we report that DNA methylation of a locus in a genomic region corresponding to the 3'UTR of the transcription factor T-box brain 1 (TBR1) mRNA accumulates in normal renal tissues with age and possibly increased body mass index. Moreover, a further tissue-specific increase of methylation was observed for tumor and metastatic tissue samples. RESULTS: Biometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3'UTR TBR1 mRNA. To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing. Statistical evaluation demonstrated age-dependent methylation in normal tissue (R = 0.72, p < 2 × 10-16), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10-19) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10-6). CONCLUSIONS: Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.