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Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response.We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS).Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P 0.001). CRP flare response was associated with prolonged PFS and OS (P 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P 0.001).CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

Cancers 14(3), 737 (2022). doi:10.3390/cancers14030737 special issue: "Special Issue "New Advances in Metastatic Prostate Cancer" / Special Issue Editor: Prof. Dr. Christian Thomas, Guest Editor", Published by MDPI, Basel

Despite perioperative advantages, robot-assisted surgery is associated with high costs. However, the lower morbidity of robotic surgery could lead to a lower nursing workload and cost savings. In this comparative cost analysis of open retroperitoneal versus robot-assisted transperitoneal partial nephrectomies (PN), these possible cost savings, including other cost factors, were quantified. Therefore, patient, tumor characteristics, and surgical results of all PN within two years at a tertiary referral center were retrospectively analyzed. The nursing effort was quantified by the local nursing staff regulation and INPULS® intensive care and performance-recording system. Out of 259 procedures, 76.4% were performed robotically. After propensity score matching, the median total nursing time (2407.8 vs. 1126.8 min, p < 0.001) and daily nursing effort (245.7 vs. 222.6 min, p = 0.025) were significantly lower after robotic surgery. This resulted in mean savings of EUR 186.48 in nursing costs per robotic case, in addition to savings of EUR 61.76 due to less frequent administrations of erythrocyte concentrates. These savings did not amortize the higher material costs for the robotic system, causing additional expenses of EUR 1311.98 per case. To conclude, the nursing effort after a robotic partial nephrectomy was significantly lower compared to open surgery; however, this previously unnoticed savings mechanism alone could not amortize the overall increased costs.

718 Background: Predictive markers for immune checkpoint inhibition (ICI) in renal cell carcinoma patients are still missing. Until now, mainly primary tumor tissues have been analyzed to identify reliable markers including PD-L1, although distant metastases represent the therapy targets. Taking into account putative heterogeneity between primary tumors and metastases as well as dynamic changes during tumor progression and treatment, markers from liquid biopsies seem to be more suitable. The aim of this study was to investigate the predictive value of PD-L1 in plasma and on extracellular vesicles (EV) from plasma in the Nivoswitch trial. Methods: Plasma samples at randomization were obtained from 39 patients who received 3 months of tyrosine kinase inhibitor (TKI) therapy followed by random allocation to Nivolumab (“switch arm”) or continued TKI therapy (control arm) and during treatment (day 30). PD-L1 concentration was quantified by ELISA. EVs were isolated by ultracentrifugation or by using a commercial kit. They were characterized by Western blotting using cell specific, EV-specific markers as well as PD-L1 antibody. The data was analyzed by Mann Whitney and Kruskal Wallis tests as well as Kaplan Meier estimates. Results: PD-L1 was detected in plasma and EVs in all patients. PD-L1 plasma concentration was similar between response categories both in the overall cohort and the control (TKI) arm. In contrast, PD-L1 concentration in the “switch arm” was significantly lower in patients with objective response compared to patients with stable (p=0.028) or progressive disease (p=0.008) at day 0, whereas no significant difference occurred at day 30. Plasma PD-L1 levels during treatment (day 30 compared to day 0) did not show an association with therapy response in both arms. A trend towards better OS was found in patients with lower PD-L1 irrespective of treatment arm, but not for PFS. PD-L1 was detected on plasma EVs both by Western blotting as well as by ELISA, although the concentrations were too low for statistical analysis. Conclusions: In this study, plasma PD-L1 concentration did not show strong associations with clinical outcomes which might be caused by the rather small sample size and inherent heterogeneity of treatment. However, PD-L1 concentrations may have prognostic value confirming published data on tumor tissues. PD-L1 is detectable on EVs from plasma. Further studies should investigate the potential of EVs as biomarkers as well as their functional role in therapy response, especially in ICI. Clinical trial information: NCT02959554 .

Simple Summary: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection. Abstract: There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.

INTRODUCTION AND OBJECTIVE:The interaction between cancer cells und cancer-associated fibroblasts (CAFs) plays an important role in the biology of prostate cancer (PCa) and seems to be also mediate...

Introduction: Non-coding RNAs (ncRNAs) are important regulators of cellular signaling in tumor-related processes. They can not only be detected in tumor tissues, but also in body fluids. ncRNAs are released into circulation as cell-free RNAs in at least two ways: bound to proteins like Ago2 or packed in extracellular vesicles (EV). Therefore, they have a great potential to serve as biomarkers in liquid biopsies. This review gives an overview of the current knowledge concerning ncRNAs and EVs as putative liquid biomarkers in urological tumor diseases.Areas covered: Literature was searched for ncRNAs including microRNA, long non-coding RNA, small interfering RNA, small nuclear RNA, small nucleolar RNA and PIWI-interacting RNA in blood (serum, plasma) and urine samples from urological tumor (urothelial, kidney, prostate, testicular germ cell, penile cancer) patients.Expert opinion: The data demonstrate an important potential of circulating non-coding RNAs as biomarkers in liquid biopsies for diagnosis and follow-up of patients with urological tumors. To translate these markers into clinical practice, independent and prospective validation, standardization of isolation and quantification techniques are inevitable. Another task is the development of predictive ncRNA biomarkers to overcome problems associated with tumor heterogeneity and to select patients individually for systemic therapies.

Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10-5 , P = 5×10-6 and P = 3.57×10-8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as "low" or "intermediate risk." We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.

Changes in miRNA expression of glomerular capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs. controls. A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes.