Analysis of the immunological markers BTLA, TIM-3, and PD-L1 at the invasion front and tumor center in clear cell renal cell carcinoma.

PURPOSE: Immune checkpoint inhibitors (ICI) are then backbone in the therapy of metastatic renal cell carcinoma (RCC). The aim of this analysis was to explore the different expression of the ICI PD-L1, BTLA, and TIM-3 at the different tumor locations of the invasion front and the tumor center. METHODS: Large-area sections of the tumor center and invasion front of 44 stage pT1-4 clear cell RCCs were examined immunohistochemically using antibodies against BTLA, TIM-3, and PD-L1 and subsequently correlated with clinicopathologic data. RESULTS: TIM-3 was most strongly expressed at the invasion front (mean ± SD: 84.1 ± 46.6, p = 0.094). BTLA expression was highest in normal tissue, with weak staining in the tumor center and at the invasion front [110.2 vs. 18.6 (p < 0.001) vs. 32.2 (p = 0.248)]. PD-L1 was weakly expressed at the tumor center (n = 5/44) and at the invasion front (n = 5/44). Correlation with clinicopathological parameters revealed significantly higher BTLA expression in ≥ T3 tumors compared to T1/2 tumors (tumor center p = 0.009; invasion front p = 0.005). BTLA-positive tumors at the tumor center correlated with worse CSS (median 48.46 vs. 68.91 months, HR 4.43, p = 0.061). PD-L1 expression was associated with worse CSS (median 1.66 vs. 4.5 years, HR 1.63, p = 0.652). For TIM-3, there were no significant associations with clinicopathological parameters and survival. CONCLUSION: The present results show heterogeneous intratumoral and intertumoral expression of the investigated checkpoint receptors PD-L1, BTLA, and TIM-3. In the clinical practice tumor sampling should include different tumor locations, and multiple inhibition of different checkpoint receptors seems reasonable to increase the therapeutic success.

Ex vivo Study of Partial Bladder Resection in a Porcine ModelEx vivo Study of Partial Bladder Resection in a Porcine Model.

INTRODUCTION: Partial cystectomy aims to preserve bladder function, yet its urodynamic impacts remain unclear. We investigate these effects using an ex-vivo porcine model, evaluating bladder volume, compliance, and wall thickness, alongside with thermal damage after bi- and monopolar resection. METHODS: Within an artificial human pelvis, we conducted partial bladder wall resections (5 cm2, 10 cm2). Urodynamic tests and sonography assessed volume, compliance, and thickness changes. Traction force for catheter retrieval and thermal collagen destruction were measured. RESULTS: Bladder compliance decreased by 1.12 and 1.5 after 5 cm2 and 10 cm2 resections respectively, with volume reductions of 3-6% and 10-18%. Wall thickness decreased by 20% and 30% post-resection. Comparable thermal damage was observed with mono- and bipolar resection methods. CONCLUSION: Our study outlines urodynamic impacts and technical considerations of partial cystectomy, affirming its endoscopic feasibility while highlighting potential bladder dysfunction risks.

Interleukin-1ß/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer-An Exploratory Analysis of Clinical and Tumor Biological Significance.

Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1ß and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1ß, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal-Wallis tests, Chi-square tests or linear regression, dependent on the variable's category. Kaplan-Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1ß and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p < 0.005). IL-1ß was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1ß expression (p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1ß expression on RFS, CSS, and OS. The IL-1ß and IL-1ß/IL-1RA ratios were positively correlated to the AKT expression (p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1ß (p = 0.01). The overexpression of IL-1ß and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1ß protein expression. The observed link between the IL-1ß/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT.

Prospective Analysis of Versatility and User Satisfaction with a Novel Single-Use Cystoscope with Working Channel.

INTRODUCTION: In the present study, a prospective systematic assessment of the clinical utility of the Ambu® aScopeTM 4 Cysto Reverse Deflection with regard to image quality, maneuverability, and navigation in an outpatient and inpatient setting was performed. MATERIALS AND METHODS: A prospective multicenter study was performed for evaluation of the instrument during routine cystoscopy. We evaluated the clinical performance of the instruments using a standardized user questionnaire in different categories including image quality, treatment success, imaging of all areas of the urinary bladder, quality of navigation, flexibility of the endoscope, and satisfaction with the device. Statistical analyses were performed by SPSS using the Kruskal-Wallis and Wilcoxon-Mann-Whitney tests. A p value of p ≤ 0.05 was defined as statistically significant. RESULTS: A total of 200 cystoscopies were performed, and the questionnaire response rate was 100%. The image quality was rated as very good in 65.5% (n = 131), good in 30.5% (n = 61), and neutral in 4% (n = 8) of cases. The criteria for poor or very poor were not mentioned. The characteristic "treatment success based on image quality" was also evaluated as very good in 49% (n = 98) and good in 50.5% (n = 101). The analysis revealed a very good or good overall impression of the examiners in all cases. Replacement of the cystoscope was not necessary during any of the examinations. However, in 3 cases, technical difficulties were documented. Further analysis of the data showed that physicians with less professional experience rated the visualization of the urinary bladder (p = 0.007) and the treatment success with regard to image quality significantly worse (p = 0.007). CONCLUSION: The Ambu® aScope™ 4 Cysto Reverse Deflection shows high satisfaction values among users in clinical routine. In analogy to other studies with flexible endoscopes, urologists with more professional experience show higher satisfaction values than examiners with less training in flexible endoscopy.

Uterine allograft removal by total laparoscopic hysterectomy after successful cesarean delivery in a living-donor uterus recipient with uterovaginal agenesis (MRKHS).

PURPOSE: To limit the burden of long-term immunosuppression (IS) after uterus transplantation (UTx), removal of the uterine allograft is indicated after maximum two pregnancies. Hitherto this has required graft hysterectomy by laparotomy. Our objective was to demonstrate, as a proof of concept, the feasibility of less traumatic transplantectomy by total laparoscopic hysterectomy (TLH). PATIENT: A 37-year-old woman with uterovaginal agenesis due to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) who had undergone neovaginoplasty at age 19 years prior to living-donor (LD) UTx in 10/2019 at age 35 years gave birth to a healthy boy by primary cesarean section in 06/2021. During pregnancy, she developed impaired renal function, with bilateral hydronephrosis, necessitating early allograft removal in 09/2021 to prevent chronic kidney disease, particularly during a potential second pregnancy. METHODS: Transplantectomy by TLH essentially followed standard TLH procedures. We paid meticulous attention to removing as much donor tissue as possible to prevent postoperative complications from residual donor tissue after stopping IS, as well as long-term vascular damage. RESULTS: TLH was performed successfully without the need to convert to open surgery. Surgical time was 90 min with minimal blood loss. No major complications occurred intra- or postoperatively and during the subsequent 9-month follow-up period. Kidney function normalized. CONCLUSIONS: To our knowledge, we report the first successful TLH-based removal of a uterine allograft in a primipara after LD UTx, thus demonstrating the feasibility of TLH in uterus recipients with MRKHS.

Differential Expression and Clinical Relevance of C-X-C Motif Chemokine Receptor 4 (CXCR4) in Renal Cell Carcinomas, Benign Renal Tumors, and Metastases.

C-X-C Motif Chemokine Receptor 4 (CXCR4) is part of the human chemokine system and involved in progression and metastasis in renal cell carcinoma (RCC). However, the role of CXCR4 protein expression in RCC remains controversial. In particular, data regarding the subcellular distribution of CXCR4 in RCC and RCC metastasis as well as CXCR4 expression in renal tumors of variant histology are limited. The aim of the present study was the evaluation of the differential CXCR4 expression in RCC primary tumor and metastatic tissue as well as in variant renal histologies. In addition, the prognostic capacity of CXCR4 expression in organ-confined clear cell RCC (ccRCC) was evaluated. Three independent renal tumor cohorts (primary ccRCC cohort n1 = 64; cohort of various histological entities n2 = 146; metastatic RCC tissue cohort n3 = 92) were evaluated using tissue microarrays (TMA). After immunohistochemical staining for CXCR4, nuclear and cytoplasmic expression patterns were evaluated. CXCR4 expression was correlated with validated pathologic prognosticators, clinical data, and overall and cancer-specific survival. Positive cytoplasmic staining was observed in 98% of the benign and 38.9% of the malignant samples. Nuclear staining was positive for 94.1% of the benign samples and 83% of the malignant samples. The median cytoplasmic expression score was found to be higher in benign tissue than in ccRCC (130.00 vs. 0.00); median nuclear expression score analysis indicated the opposite (56.0 vs. 71.0). Within malignant subtypes, the highest expression score was seen in papillary renal cell carcinomas (cytoplasmic: 117.50, nuclear: 41.50). Within benign renal tumors, high cytoplasmic and nuclear CXCR4 expression scores were seen for oncocytomas (cytoplasmic: 100.00, nuclear: 31.00). Expression scores in RCC metastasis ranked between benign renal tissue and ccRCC in cytoplasmic and nuclear expression. Cytoplasmic CXCR4 expression was identified as a prognostic factor for OS and CSS (p = 0.042; p = 0.019). Multivariate analysis including clinicopathological parameters did not reveal an independent prognostic character of CXCR4 expression. CXCR4 expression differs significantly within benign lesions and renal neoplasms. Cytoplasmic and nuclear expression of CXCR4 could be detected across all RCC subtypes. The prognostic value of CXCR4 in ccRCC was confirmed in univariate analysis.

The regulation of FGF23 under physiological and pathophysiological conditions.

Fibroblast growth factor 23 (FGF23) is an important bone hormone that regulates phosphate homeostasis in the kidney along with active vitamin D (1,25(OH)2D3) and parathyroid hormone (PTH). Endocrine effects of FGF23 depend, at least in part, on αKlotho functioning as a co-receptor whereas further paracrine effects in other tissues are αKlotho-independent. Regulation of FGF23 production is complex under both, physiological and pathophysiological conditions. Physiological regulators of FGF23 include, but are not limited to, 1,25(OH)2D3, PTH, dietary phosphorus intake, and further intracellular and extracellular factors, kinases, cytokines, and hormones. Moreover, several acute and chronic diseases including chronic kidney disease (CKD) or further cardiovascular disorders are characterized by early rises in the plasma FGF23 level pointing to further mechanisms effective in the regulation of FGF23 under pathophysiological conditions. Therefore, FGF23 also serves as a prognostic marker in several diseases. Our review aims to comprehensively summarize the regulation of FGF23 in health and disease.

Prognostic impact of complete metastasectomy in metastatic renal cell carcinoma in the era of immuno-oncology-based combination therapies.

PURPOSE: Complete metastasectomy of renal cell carcinoma (RCC) is receding into the past due to the progress of immuno-oncology-based combinations (IO) in systemic therapy. The prognostic impact of curative intended complete metastasectomy vs. immediate IO-based therapy or tyrosine kinase inhibition (TKI) on progression-free survival (PFS) and cancer-specific survival (CSS) was investigated in the first-line setting. METHODS: 205 patients with synchronous or metachronous metastasis received complete metastasectomy (n = 80) or systemic therapy (n = 125, TKI: 87, TKI-IO: 13, IO-IO: 25) as first-line therapy. The prognostic impact of these therapies was assessed using Cox regression and Kaplan-Meier analyses. RESULTS: First-line complete metastasectomy significantly improved CSS compared to both TKI monotherapy (6.1 vs. 2.6 years, HR 0.45, p < 0.001) and IO-based combination therapy (IO-IO/TKI-IO, 6.1 vs. 3.5 years, HR 0.28, p = 0.007). Repetitive complete metastasectomy without ever receiving systemic therapy vs. systemic therapy in first-line significantly prolonged CSS (11.3 vs. 3.1 years, HR 0.34, p = 0.002). First-line complete metastasectomy and subsequent systemic therapy at tumor progression was associated with a significant CSS benefit vs. systemic therapy (5.8 vs. 3.1 years, HR 0.53, p = 0.003), also compared to IO-based combinations (5.8 vs. 3.5 years, HR 0.30, p = 0.017). Median PFS was improved by IO-based therapy compared to TKI monotherapy in the first-line setting (HR 0.61, p = 0.05), with maximal benefit of the TKI-IO combination vs. TKI monotherapy (HR 0.27, p = 0.01), as well as compared to PFS of complete metastasectomy (HR 0.34, p = 0.035). CONCLUSION: Despite the progress of IO-based combination therapies in first line, complete metastasectomy remains an integral part of the multimodality treatment of metastatic RCC.

Head-to-head comparison of biparametric versus multiparametric MRI of the prostate before robot-assisted transperineal fusion prostate biopsy.

PURPOSE: Prostate biparametric magnetic resonance imaging (bpMRI) including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) might be an alternative to multiparametric MRI (mpMRI, including dynamic contrast imaging, DCE) to detect and guide targeted biopsy in patients with suspected prostate cancer (PCa). However, there is no upgrading peripheral zone PI-RADS 3 to PI-RADS 4 without DCE in bpMRI. The aim of this study was to evaluate bpMRI against mpMRI in biopsy-naïve men with elevated prostate-specific antigen (PSA) scheduled for robot-assisted-transperineal fusion-prostate biopsy (RA-TB). METHODS: Retrospective single-center-study of 563 biopsy-naïve men (from 01/2015 to 09/2018, mean PSA 9.7 ± 6.5 ng/mL) with PI-RADSv2.1 conform mpMRI at 3 T before RA-TB. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥ 2 in any core. Two experienced readers independently evaluated images according to PI-RADSv2.1 criteria (separate readings for bpMRI and mpMRI sequences, 6-month interval). Reference standard was histology from RA-TB. RESULTS: PI-RADS 2 was scored in 5.1% of cases (3.4% cancer/3.4% csPCa), PI-RADS 3 in 16.9% (32.6%/3.2%), PI-RADS 4 in 57.6% (66.1%/58.3%) and PI-RADS 5 in 20.4% of cases (79.1%/74.8%). For mpMRI/bpMRI test comparison, sensitivity was 99.0%/97.1% (p < 0.001), specificity 47.5%/61.2% (p < 0.001), PPV 69.5%/75.1% (p < 0.001) and NPV 97.6%/94.6% (n.s.). csPCa was considered gold standard. 35 cases without cancer were upgraded to PI-RADS 4 (mpMRI) and six PI-RADS 3 cases with csPCa were not upgraded (bpMRI). CONCLUSION: In patients planned for RA-TB with elevated PSA and clinical suspicion for PCa, specificity was higher in bpMRI vs. mpMRI, which could solve constrains regarding time and contrast agent.

Versatility and clinical effectiveness of a synthetic sealing hemostatic patch as alternative to parenchyma suturing in laparoscopic partial nephrectomy.

BACKGROUND: Improvements in laparoscopic partial nephrectomy (LPN) in order to minimize perioperative warm ischemia time (WIT), complications, and consequently patient outcome are desirable. Veriset™ is a ready-to-use hemostatic patch of absorbable oxidized cellulose and hydrogel components that has earlier been implemented in vascular and hepatic surgery. We report our experience using this device in LPN. METHODS: Patients with a solitary malignant renal mass suspicious for renal cancer underwent LPN with either the use of Veriset™ hemostatic patch (n = 40) or conventional suture technique (n = 40). Patient characteristics, operation time and WIT, postoperative course and complications were recorded retrospectively. Tumor complexity was calculated according to the R.E.N.A.L. score. Outcome was determined according to the "trifecta" criteria (negative surgical margin, WIT < 25 min, no complications within 30 days). RESULTS: No significant differences with regard to clinical parameters and median R.E.N.A.L. score (6) were observed between both groups. Operation time (mean 127.1 min vs. 162. 8 min; p = 0.001) and WIT were both lower in the Veriset™ group (14.6 min vs. 20.6 min; p = 0.01). No differences in surgical margins (p = 0.602) and overall complication rates at 30 (p = 0.599) and 90 days (p = 0.611) postoperatively were noticed. The surgical outcome according to "trifecta" was achieved in 65% of patients using Veriset™ and in 57.5% of patients by suture closure, respectively. CONCLUSION: The hemostatic Veriset™ patch can successfully be implemented in LPN. Handling and application appear favorable, thereby reducing operation time and WIT. The present results suggest that the device may represent an alternative to parenchyma suturing in LPN.

Robotic Transrectal Computed Tomographic Ultrasound with Artificial Neural Network Analysis: First Validation and Comparison with MRI-Guided Biopsies and Radical Prostatectomy.

INTRODUCTION: There is still a lack of availability of high-quality multiparametric magnetic resonance imaging (mpMRI) interpreted by experienced uro-radiologists to rule out clinically significant PC (csPC). Consequently, we developed a new imaging method based on computed tomographic ultrasound (US) supported by artificial neural network analysis (ANNA). METHODS: Two hundred and two consecutive patients with visible mpMRI lesions were scanned and recorded by robotic CT-US during mpMRI-TRUS biopsy. Only significant index lesions (ISUP ≥2) verified by whole-mount pathology were retrospectively analyzed. Their visibility was reevaluated by 2 blinded investigators by grayscale US and ANNA. RESULTS: In the cohort, csPC was detected in 105 cases (52%) by mpMRI-TRUS biopsy. Whole-mount histology was available in 44 cases (36%). In this subgroup, mean PSA level was 8.6 ng/mL, mean prostate volume was 33 cm3, and mean tumor volume was 0.5 cm3. Median PI-RADS and ISUP of index lesions were 4 and 3, respectively. Index lesions were visible in grayscale US and ANNA in 25 cases (57%) and 30 cases (68%), respectively. Combining CT-US-ANNA, we detected index lesions in 35 patients (80%). CONCLUSIONS: The first results of multiparametric CT-US-ANNA imaging showed promising detection rates in patients with csPC. US imaging with ANNA has the potential to complement PC diagnosis.

Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.

The prognostic value of fat invasion and tumor expansion in the hilar veins in pT3a renal cell carcinoma.

PURPOSE: The 7th TNM classification summarizes renal cell carcinoma (RCC) with perirenal (PFI) and/or sinus fat invasion (SFI) as well as hilar vein involvement (RVI) as pT3a tumors. In this study, we aimed to determine the prognostic value of fat invasion (FI) in the different compartments and RVI for medium-term cancer-specific-survival (CSS) in pT3a RCC. MATERIALS AND METHODS: Patients with pT3a RCC were identified using an institutional database. All original pathological reports were reclassified according to the 7th TNM edition. The prognostic value of FI as well as divided into PFI, SFI, combined PFI + SFI, and RVI for CSS was assessed using univariate and multivariate Cox-regression analysis. Survival was estimated using the Kaplan-Meier method. RESULTS: Median follow-up in 184 pT3a tumors was 38 months. FI was detectable in 153 patients (32.7% PFI, 45.1% SFI, 22.2% PFI + SFI), 31 patients showed RVI alone. Combined PFI + SFI increased the risk of cancer-related death compared to PFI (HR 3.11, p < 0.01), SFI (HR 1.84, p = 0.023) or sole RVI (HR 2.12, p = 0.025). In multivariate analysis, a combined PFI + SFI vs. PFI or SFI as the only compartment involved was confirmed as independent prognostic factor (HR 1.83, p = 0.029). Patients with FI and simultaneous RVI had significantly shorter CSS (HR 2.63, p < 0.01). In an unweighted model, the difference between patients with combined PFI + SFI and RVI and those with PFI alone was highest (HR 4.01, p = 0.029). CONCLUSIONS: These results underline the subdivision of pT3a RCC depending on the location of FI and RVI for patient stratification.

Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?

PURPOSE: The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size. METHODS: Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated. RESULTS: Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05). CONCLUSION: No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.

Enzalutamide plus androgen-deprivation therapy in hormone-sensitive prostate cancer: new perspectives from a current Phase III clinical trial.

Prostate cancer is a major health issue with an incidence of 1,100,000 worldwide. Eventually, 20-40% of curatively treated patients will face a biochemical recurrence. Lately, the treatment options in metastasized hormone sensitive prostate cancer (mHSPC) were rapidly evolving after years of stagnation. Encouraging results in clinical trials of combination treatment of androgen deprivation therapy with either chemotherapy or second-generation hormonal treatment indicate a paradigm shift in this clinical scenario. In the light of this, the current review is focusing on the concept and initial results of the Phase III (ARCHES) trial investigating enzalutamide plus androgen deprivation therapy in mHSPC. Moreover, a comprehensive appraisal of the expanding landscape of systemic therapies for mHSPC is provided.

Age-Adapted Prostate Cancer Gene 3 Score Interpretation - Suggestions for Clinical Use.

BACKGROUND: The prostate cancer antigen 3 (PCA3) gene urine assay is established for biopsy decision in case of prostate cancer (PC) suspicion. Recent findings pointed to an age dependence of PCA3, with putative impact on test interpretation. However, to date no experience has been reported with regard to the extent age might modify the score in certain age ranges. Therefore, the aim of the present study was to re-evaluate the age dependency and, moreover, give suggestions for interpretation of the PCA3 score in dependence of patient's age in daily routine. METHODS: The study comprised 684 patients before prostate biopsy or prostatectomy. Post-massage voided urine samples were assessed by PCA3 measurement. PCA3 scores were correlated to patient's age. The collective was divided into four subcollectives by quartiles of age distribution. For every subcollective the cutoff value at specificity of ≥ 60 was determined. Results were classified by age-class specific cutoff values and test qualities were compared at different cutoffs. RESULTS: In the collective, 59.1% of patients had a positive biopsy. PCA3 correlated to patient's age in univariate and multivariate analysis (p < 0.001 each). The division into age subcollectives revealed groups < 60, 60 - 65, 66 - 69 and > 69 years. Median PCA3 values of patients without/with PC were 17/32, 27/42, 34/55 and 52/68 in the four age classes. Cutoff values for which specificity was determined with ≥ 60 were 23, 39, 42, and 65. Constant cutoff values showed lower sensitivities in younger and lower specificities in older patients. Only the age adjusted values revealed an improved performance with PPV 68.7, accuracy 59.5 and sensitivity 57.7 at specificity of 62.1% in the whole cohort. CONCLUSIONS: The study confirms that the PCA3 score increases with age. The recommended cutoff score of 35 is suitable especially for patients aged in their sixties. Lower reference values between 20 and 30 have to be taken into account in patients aged < 60 years and higher values around 40 to 50 may point to suspicion for PC in patients > 69 years. These results may further improve the diagnostic performance of the PCA3 test and keep the PCA3 test as a significant test in PC diagnostics along with new upcoming urine markers.

Impact of Histopathological Prostate Inflammation on Urine-Based Prostate Cancer Prediction Using the Prostate Cancer Gene 3 Score.

INTRODUCTION: The Prostate Cancer gene 3 (PCA3) urine test has gained importance in the diagnostic workup of prostate cancer (PC). Limited evidence suggests that PCA3 is not altered in the presence of inflammation. OBJECTIVE: To assess the impact of histological inflammation on PCA3. METHODS: PCA3 was evaluated in patients prior to prostate biopsy (n = 193) and to radical prostatectomy (n = 197). In patients without PC, inflammation was assessed and quantified by individual scores integrating grade and extent. Uni- and multivariate analyses were performed to assess the impact of inflammation grade on PCA3. RESULTS: The PCA3 scores prior to prostatectomy were lower (median 45) than those before positive biopsy (57; p = 0.008). Of 101 negative biopsies, 78% showed inflammation. The median PCA3 scores in the groups with no inflammation and with maximum grade 1 (n = 22), 2 (n = 38), and 3 (n = 19) inflammation were 45, 38, 27, and 25 (p = 0.016). The multivariate models revealed a decrease in PCA3 proportional to the grade and extent of inflammation (p < 0.04 each). CONCLUSIONS: The present data imply that the PCA3 score decreases in the presence of inflammation, which is relevant, for instance, to testing after a recently performed biopsy. In general, inflammation should be regarded as a factor putatively influencing PCA3 and other available and upcoming PC tests.

Determination of Free-PSA (fPSA) and fPSA/PSA-Ratio Using A Point-of-Care Device.

BACKGROUND: Prostate specific antigen (PSA) and free PSA (fPSA) are important tools for diagnosing prostate cancer (PC). Efforts are continuously undertaken to provide more patient-centered healthcare. The application of point-of-care (POC) systems for laboratory analyses represents a step in this direction. Previous investigations on total PSA measurements using a POC system (concile® Ω100 POC reader) showed good concordance with standard laboratory measurements. For the same POC reader a novel system for fPSA was developed. In the current study, we prospectively evaluated the quality of the POC system for fPSA. METHODS: Sixty-four patients undergoing PSA measurements in our outpatient clinic between 06/2015 and 09/2015 were enrolled in the study. We measured total PSA (tPSA) and fPSA with a POC reader system (concile® Ω100) and a standard laboratory system (Siemens Immulite 2000®) and compared the respective results using linear regression analyses for PSA, fPSA, and fPSA/tPSA ratio (%fPSA). RESULTS: The coefficients of determination (r²) for fPSA and %fPSA were 0.85 (p < 0.001) and 0.82 (p < 0.001) in the subgroup with total PSA between 4 and 10 ng/mL. In the subgroup with tPSA ≤ 4 ng/mL, r² for fPSA concile® was 0.55 (p < 0.001) and 0.10 (p = 0.088) for %fPSA. In the subgroup of tPSA > 10 ng/mL the r² for fPSA and %fPSA was 0.50 (p = 0.022) and 0.50 (p = 0.022), respectively. CONCLUSIONS: The POC fPSA values correlated well with the laboratory analyses, specifically in the clinically relevant diagnostic range of tPSA 4 - 10 ng/mL. These results complement the tPSA data obtained previously and indicate the reliability of the fPSA method and the resulting %fPSA score.

Simultaneous Extraction of RNA and Metabolites from Single Kidney Tissue Specimens for Combined Transcriptomic and Metabolomic Profiling.

Tissue analysis represents a powerful tool for the investigation of disease pathophysiology. However, the heterogeneous nature of tissue samples, in particular of neoplastic, may affect the outcome of such analysis and hence obscure interpretation of results. Thus, comprehensive isolation and extraction of transcripts and metabolites from an identical tissue specimen would minimize variations and enable the economic use of biopsy material which is usually available in limited amounts. Here we demonstrate a fast and simple protocol for combined transcriptomics and metabolomics analysis in homogenates prepared from one single tissue sample. Metabolites were recovered by protein precipitation from lysates originally prepared for RNA isolation and were analyzed by LC-QTOF-MS after HILIC and RPLC separation, respectively. Strikingly, although ion suppression was observed, over 80% of the 2885 detected metabolic features could be extracted and analyzed with high reproducibility (CV ≤ 20%). Moreover fold changes of different tumor and nontumor kidney tissues were correlated to an established metabolomics protocol and revealed a strong correlation ( rp ≥ 0.75). In order to demonstrate the feasibility of the combined analysis of RNA and metabolites, the protocol was applied to kidney tissue of metformin treated mice to investigate drug induced alterations.

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma.

The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.