[Imaging in nephroureterolithasis]. / Bildgebung bei Nephroureterolithiasis.

In the acute diagnostics of a suspected nephroureterolithiasis, ultrasonography should be the examination modality of choice. In cases of suspected urolithiasis, unclear flank pain with fever or in cases of a solitary kidney, a noncontrast computed tomography (CT) scan should always subsequently be performed. If the sonography findings are inconclusive in pregnant women a magnetic resonance imaging (MRI) examination can be considered. If there are indications for urinary diversion, a retrograde imaging study should be performed as part of the urinary diversion. This or CT imaging is also suitable for preinterventional imaging before shock wave lithotripsy, percutaneous nephrolithotomy or ureteroscopy. Postinterventional imaging is not always necessary and sonography is often sufficient. In a conservative treatment approach an abdominal plain X­ray can be used for follow-up assessment.

CD15 is a risk predictor and a novel target in clear cell renal cell carcinoma.

INTRODUCTION: Tumor cells use adhesion molecules like CD15 or sialylCD15 (sCD15) for metastatic spreading. We analyzed the expression of CD15 and sCD15 in clear cell renal cell carcinoma (ccRCC) regarding prognosis. METHODS: A tissue microarray containing tissue specimens of 763 patients with ccRCC was immunohistochemically stained for CD15 and sCD15, their expression quantified using digital image analysis and the impact on patients' survival analyzed. The cell lines 769p and 786o were stimulated with CD15 or control antibody in vitro and the effects on pathways activating AP-1 and tumor cell migration examined. RESULTS: ccRCC showed a broad range of CD15 and sCD15 expression. A high CD15 expression was significantly associated with favorable outcome (p<0.01) and low-grade tumor differentiation (p<0.001), whereas sCD15 had no significant prognostic value. Tumors with synchronous distant metastasis had a significantly lower CD15 expression compared to tumors without any (p<0.001) or with metachronous metastasis (p<0.01). Tumor cell migration was significantly reduced after CD15 stimulation in vitro, but there were no major effects on activating pathways of AP-1. CONCLUSION: CD15, but not sCD15, qualifies as a biomarker for risk stratification and as an interesting novel target in ccRCC. Moreover, the data indicates a contribution of CD15 to metachronous metastasis. Further research is warranted to decipher the intracellular pathways of CD15 signaling in ccRCC in order to characterize the CD15 effects on ccRCC more precisely.

Cavoatrial hypernephroma resection on cardiopulmonary bypass: Mild/normo-versus moderate hypothermia.

INTRODUCION: Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors. It extends up into the systemic veins and right atrium. Surgical extraction of such extensions is usually carried out using cardiopulmonary bypass (CPB) with moderate hypothermic (MH) being frequently applied in order to obtain a clear surgical field. However, due to obvious disadvantages of hypothermia, approaches with mild/normothermia (NT) during CPB have also been established. The current study aims to compare the outcomes of patients undergoing RCC tumor and extensions resection using MH versus NT. MATERIAL AND METHODS: This is a retrospective, non-randomized study. All patients who underwent RCC tumor and extensions resection for stage III or IV (Staehler) RCC in a single center between 2006 and 2020 were included. During surgery, MH or NT were applied. CPB was realized using aortic and bicaval cannulation. We compared the procedural times, transfusion requirements and postoperative outcomes, respectively between the MH and NT groups. RESULTS: A total of 24 consecutive patients (n(NT) = 12, n(MH) = 12) were included in the study (median age NT 68.5 and MH 66.5). The study only showed a significant difference in heart-lung machine times (median CPB time NT 45.5 min and MH 110.0 min, p = 0.004). All other results, loss of drainage, administration of blood products, as well as the postoperative course and mortality were comparable in both groups. CONCLUSION: The results showed a high perioperative and long-term mortality. The perioperative course was similar after surgery with NT or MH. Therefore, NT which minimizes potential complications of MH should be preferred.

Hydronephrotic pelvic kidney mimicking urinary retention in an 18-year-old male.

We present a case of a hydronephrotic pelvic kidney in an 18-year-old male reporting about inability to void. Ultrasound showed a hypoechogenic mass mimicking a full urinary bladder. Anticipating urinary retention, a foley was inserted but no urin could be aspirated. Imaging showed a hydronephrotic pelvic kidney with no relevant function obstructing the urinary bladder and the contralateral ureter. Nephrectomy was performed and postoperative course was uneventful. A hydronephrotic pelvic kidney is a rare but important differential diagnosis in young men reporting lower abdominal pain and inability to void.

Salvage Radiotherapy for Recurrent Prostate Cancer after High-Intensity Focused Ultrasound Therapy: Quality of Life and Functional Outcome.

INTRODUCTION: The aim of this study was to evaluate toxicity, oncological and functional outcome, and quality of life after salvage radiotherapy for recurrent prostate cancer after high-intensity focused ultrasound (HIFU) therapy. METHODS: A total of 13 patients undergoing salvage radiotherapy for biopsy-proven prostate cancer recurrence after HIFU therapy were included and followed up every 3 months. Oncological outcome (by PSA measurements), toxicity (according to CTCAE criteria), and functional outcome were evaluated. Quality of life was assessed by standardized questionnaires (QLQ-C30 and QLQ-PR25) at baseline, 3 months, and 12 months after salvage treatment. RESULTS: Median age of patients was 80 years (interquartile range [IQR] 75-82). Patients underwent normofractionated salvage radiotherapy with median 73.6 Gy. PSA nadir was reached at 6 months and was 0.2 ng/mL. Median follow-up was 76 months (IQR 55-96). Biochemical recurrence occurred in 3 patients (23.1%) at a median of 36.4 months. No gastrointestinal (GI) or genitourinary (GU) toxicity ≥ grade 3 was noted during follow-up. Early and late grade II GI toxicity occurred in 1 patient (7.7%), respectively. GU toxicity grade II was noted in up to 53.8% at 3 months and 61.5% at 12 months. In terms of health-related quality of life, there was no statistically significant difference at 3 and 12 months compared to the baseline. Only differences were seen in sexual functioning (3 and 12 months) and in diarrhea (3 months), affecting patients' wellbeing. DISCUSSION/CONCLUSION: Salvage radiotherapy after HIFU treatment can be performed safely, thereby providing acceptable recurrence-free survival without severe impact on post-interventional quality of life.

Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer.

BACKGROUND: Mutations in DNA damage repair genes, in particular genes involved in homology-directed repair, define a subgroup of men with prostate cancer with a more unfavorable prognosis but a therapeutic vulnerability to PARP inhibition. In current practice, mutational testing of prostate cancer patients is commonly done late i.e., when the tumor is castration resistant. In addition, most sequencing panels do not include TP53, one of the most crucial tumor suppressor genes in human cancer. In this proof-of-concept study, we sought to extend the clinical use of these molecular markers by exploring the early prognostic impact of mutations in TP53 and DNA damage repair genes in men with primary, nonmetastatic prostate cancer undergoing radical prostatectomy (RPX). METHODS: Tumor specimens from a cohort of 68 RPX patients with intermediate (n = 11, 16.2%) or high-risk (n = 57, 83.8%) disease were analyzed by targeted next generation sequencing using a 37 DNA damage repair and checkpoint gene panel including TP53. Sequencing results were correlated to clinicopathologic variables as well as PSA persistence or time to PSA failure. In addition, the distribution of TP53 and DNA damage repair gene mutations was analyzed in three large publicly available datasets (TCGA, MSKCC and SU2C). RESULTS: Of 68 primary prostate cancers analyzed, 23 (33.8%) were found to harbor a mutation in either TP53 (n = 12, 17.6%) or a DNA damage repair gene (n = 11, 16.2%). The vast majority of these mutations (22 of 23, 95.7%) were detected in primary tumors from patients with high-risk features. These mutations were mutually exclusive in our cohort and additional data mining suggests an enrichment of DNA damage repair gene mutations in TP53 wild-type tumors. Mutations in either TP53 or a DNA damage repair gene were associated with a significantly worse prognosis after RPX. Importantly, the presence of TP53/DNA damage repair gene mutations was an independent risk factor for PSA failure or PSA persistence in multivariate Cox regression models. CONCLUSION: TP53 or DNA damage repair gene mutations are frequently detected in primary prostate cancer with high-risk features and define a subgroup of patients with an increased risk for PSA failure or persistence after RPX. The significant adverse impact of these alterations on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.

Single-Center Evaluation of Treatment Success Using Two Different Protocols for MRI-Guided Transurethral Ultrasound Ablation of Localized Prostate Cancer.

OBJECTIVES: To assess differences in 24-month oncologic and functional outcomes in men with low to intermediate-risk prostate cancer treated with MRI-guided transurethral ultrasound ablation (TULSA) using intentionally conservative versus intensified treatment parameters. PATIENTS AND METHODS: Patients from a single center involved in two multicenter trials were included in this analysis. This included 14 of 30 patients with Gleason 3 + 3 from a Phase I study using intentionally conservative treatment parameters, and 15 of 115 patients with Gleason ≤ 3 + 4 from a pivotal study using intensified parameters. Follow-up data compared across these cohorts included 12-month biopsy and MRI for all patients, and 24-month PSA, micturition and quality of life (IIEF, IPSS, IPSS-QOL). The prognostic value of baseline parameters and PSA kinetics on 12-month histological recurrence was evaluated by logistic regression. RESULTS: 12-month biopsy revealed clinically significant residual disease in 4 (29%) and 2 (14%) patients from the Phase I and pivotal studies, respectively. PSA nadir was 0.7 ng/ml for Phase I and 0.5 ng/ml for pivotal study patients. Patient age at diagnosis, use of MRI fusion/systematic prostate biopsy, number of obtained cores at initial biopsy, PSA course, and PSA nadir were identified as prognostic factors for treatment success. All but one patient from each cohort maintained erection firmness sufficient for penetration. No cases of pad use were reported at 24 months. There were no Grade 4 or higher adverse events, and no late toxicity related to the procedure. CONCLUSION: Two-year follow-up demonstrated the efficacy of TULSA for the treatment of localized prostate cancer, and the durability of PSA and functional outcomes. Intensifying treatment parameters in the pivotal trial had no impact on safety or functional outcomes through 24 months, while reducing the recurrence rate for clinically significant disease. Careful patient selection by MRI fusion/systematic prostate biopsy and adequate follow-up through routine 12-month biopsy are recommended.

Standardized Magnetic Resonance Imaging Reporting Using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation Criteria and Magnetic Resonance Imaging/Transrectal Ultrasound Fusion with Transperineal Saturation Biopsy to Select Men on Active Surveillance.

BACKGROUND: Contemporary selection criteria for men with prostate cancer (PC) suitable for active surveillance (AS) are unsatisfactory, leading to high disqualification rates based on tumor misclassification. Conventional biopsy protocols are based on standard 12-core transrectal ultrasound (TRUS) biopsy. OBJECTIVE: To assess the value of magnetic resonance imaging (MRI)/TRUS fusion biopsy over 4-yr follow-up in men on AS for low-risk PC. DESIGN, SETTING, AND PARTICIPANTS: Between 2010 and 2018, a total of 273 men were included. Of them, 157 men with initial 12-core TRUS biopsy and 116 with initial MRI/TRUS fusion biopsy were followed by systematic and targeted transperineal MRI/TRUS fusion biopsies based on Prostate Cancer Research International Active Surveillance criteria. MRI from follow-up MRI/TRUS fusion biopsy was assessed using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) scoring system. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: AS-disqualification rates for patients on AS initially diagnosed by either 12-core TRUS biopsy or by MRI/TRUS fusion biopsy were compared using Kaplan-Meier estimates, log-rank tests, and regression analyses. We also analyzed the influence of negative primary MRI and PRECISE scoring to predict AS disqualification using Kaplan-Meier estimates, log-rank tests, and receiver operating characteristic (ROC) curve analysis. RESULTS AND LIMITATIONS: Of men diagnosed by 12-core TRUS biopsy, 59% were disqualified from AS based on the results of subsequent MRI/TRUS fusion biopsy. In the initial MRI fusion biopsy cohort, upgrading occurred significantly less frequently (19%, p<0.001). ROC curve analyses demonstrated good discrimination for the PRECISE score with an area under the curve of 0.83. No men with a PRECISE score of 1 or 2 (demonstrating absence or downgrading of lesions in follow-up MRI) were disqualified from AS. In our cohort, a negative baseline MRI scan was not a predictor of nondisqualification from AS. Limitations include transperineal approach and extended systematic biopsies used with MRI/TRUS fusion biopsy, which may not be representative of other centers. CONCLUSIONS: MRI/TRUS fusion biopsies allow a reliable risk classification for patients who are candidates for AS. The application of the PRECISE scoring system demonstrated good discrimination. PATIENT SUMMARY: In this study, we investigated the value of multiparametric magnetic resonance imaging (MRI) and MRI/transrectal ultrasound (TRUS) fusion biopsies for the assessment of active surveillance (AS) reliability using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation criteria. Standard TRUS biopsies lead to significant underestimation of prostate cancer. In contrast, MRI/TRUS fusion biopsies allowed for a more reliable risk classification. For appropriate inclusion into AS, men should receive either an initial or a confirmatory MRI/TRUS fusion biopsy.

The Value of Prostate-specific Antigen Density for Prostate Imaging-Reporting and Data System 3 Lesions on Multiparametric Magnetic Resonance Imaging: A Strategy to Avoid Unnecessary Prostate Biopsies.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has excellent sensitivity in detecting significant prostate cancer (sPC). Nevertheless, uncertainty exists regarding the management of Prostate Imaging-Reporting and Data System (PI-RADS) 3 lesions. OBJECTIVE: To investigate whether PI-RADS 3 lesions in combination with clinical parameters, especially prostate-specific antigen density (PSAD), can be used to exclude sPC. DESIGN, SETTING, AND PARTICIPANTS: A total of 455 consecutive biopsy-naïve men underwent MRI-guided transperineal prostate fusion biopsy at our department between 2017 and 2018. We identified 101 patients who had exclusively one or more PI-RADS 3 lesions on mpMRI. sPC was defined as intermediate- and high-risk PC (according to the D'Amico risk classification). OUTCOME MEASURES AND STATISTICAL ANALYSIS: Univariate logistic regression analysis was performed to test different clinical factors as predictors of sPC in men with PI-RADS 3 lesions. The probability of sPC prediction was calculated for different PSAD thresholds. RESULTS AND LIMITATIONS: Among patients with PI-RADS 3 lesions, PSAD was a significant predictor of sPC (p = 0.005). For a PI-RADS score of 3 the probability of excluding sPC was 85% (86/101), which increased to 98% (42/43) when combined with PSAD <0.1 ng/ml/ml. CONCLUSIONS: Inclusion of PSAD < 0.1 ng/ml/ml in the strategy for biopsy-naïve patients with equivocal mpMRI findings would allow a reduction in prostate biopsies in 43% (43/101) of cases at the cost of missing a very small number (2%, 1/43) of intermediate-risk PCs. PATIENT SUMMARY: At high-volume tertiary care centers with significant experience in prostate multiparametric magnetic resonance imaging, immediate biopsies could be safely omitted for men with lesions with a Prostate Imaging-Reporting and Data System score of 3 and prostate-specific antigen density of PSAD < 0.1 ng/ml/ml. Any decision to omit an immediate biopsy should be associated with close monitoring.

Relief of Lower Urinary Tract Symptoms After MRI-Guided Transurethral Ultrasound Ablation for Localized Prostate Cancer: Subgroup Analyses in Patients with Concurrent Cancer and Benign Prostatic Hyperplasia.

Background: MRI-guided transurethral ultrasound ablation (TULSA) offers minimally invasive thermal ablation of benign and malignant prostate tissue, using directional high-intensity ultrasound and real-time, magnetic resonance thermometry feedback control. Feasibility of TULSA for alleviating lower urinary tract symptoms (LUTSs) associated with benign prostatic hyperplasia (BPH) is retrospectively assessed in a subgroup of men from a localized prostate cancer study who also had LUTSs. Patients and Methods: TULSA was used to ablate 90% of the prostate gland in 30 men with localized prostate cancer, without plans to spare ejaculatory ducts. Mean ± standard deviation treatment time was 37 ± 10 minutes. Retrospective analysis was conducted on a subpopulation of nine patients who also suffered from LUTSs (International Prostate Symptom Score [IPSS] ≥ 12 at baseline) as well as a smaller subgroup of five patients with IPSS >12 and peak urinary flow (Qmax) <15 mL/second. Urinary symptom relief, continence, and erectile function were assessed using IPSS, International Index of Erectile Function (IIEF), and uroflowmetry. Results: At 12 months post-TULSA, IPSS improved significantly by 58% to 6.3 ± 5.0 (p = 0.003), with at least a moderate (≥6 points) reduction in eight of nine patients. IPSS quality of life improved in eight of nine patients. Erectile function (IIEF-EF) remained stable from 14.6 ± 9.3 at baseline to 15.7 ± 9.0 at 12 months. The proportion of patients with erections sufficient for penetration (IIEF Q2 ≥2) was unchanged. Full urinary continence (pad free and leak free) was achieved at 12 months in all patients. In five men who suffered from more severe symptoms, Qmax increased from 11.6 ± 2.6 mL/second to 22.5 ± 14.2 mL/second at 12 months (p = 0.126). Perfused prostate volume, measured on MRI, decreased 70% to 13.6 ± 4.6 mL (p = 0.003) at 12 months. All adverse events were mild to moderate (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1-2) with no serious events reported. Conclusions: This retrospective analysis demonstrates promising safety and feasibility of TULSA to relieve LUTSs, with improvement in IPSS comparable with modern, minimally invasive surgical therapies. Larger controlled studies with BPH-specific ablation plans in men seeking treatment for LUTSs are warranted.

Evolution of Salvage Radical Prostatectomy from Open to Robotic and Further to Retzius Sparing Surgery.

Salvage radical prostatectomy (sRP) has evolved from open to minimally invasive approaches. sRP can be offered to patients with local recurrence to improve biochemical recurrence (BCR)-free and overall survival. We evaluate oncological outcome and continence after retropubic (RRP), conventional (cRARP), and Retzius-sparing robotic (rsRARP) surgery. MATERIALS/METHODS: A total of 53 patients undergoing sRP between 2010 and 2020 were included. Follow-up included oncological outcome and continence. RESULTS: sRP was done as RRP (n = 25), cRARP (n = 7), or rsRARP (n = 21). Median blood loss was 900 mL, 500 mL, and 300 mL for RRP, cRARP, and rsRARP, respectively. At 12 months, 5 (20%), 0, and 4 (19%) patients were continent, 9 (36%), 3 (43%), and 7 (33%) had grade 1 incontinence, 5 (20%), 2 (29%), and 3 (14%) had grade 2 incontinence, and 3 (12%), 2 (29%), and 4 (19%) had grade 3 incontinence for RRP, cRARP, or rsRARP, respectively. During a mean follow-up of 52.6 months, 16 (64%), 4 (57%), and 3 (14%) developed BCR in the RRP-, cRARP-, and rsRARP-group, respectively. CONCLUSIONS: Over the years, sRP has shifted from open to laparoscopic/robotic surgery. RARP shows good oncological and functional outcome. rsRARP ensures direct vision on the rectum during preparation and can therefore increase safety and surgeon's confidence, especially in the salvage setting.

Magnetic resonance imaging-guided transurethral ultrasound ablation in patients with localised prostate cancer: 3-year outcomes of a prospective Phase I study.

OBJECTIVES: To report the 3-year follow-up of a Phase I study of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12-month safety and ablation precision were previously described. PATIENTS AND METHODS: As a mandated safety criterion, TULSA was delivered as near whole-gland ablation, applying 3-mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12-month biopsy and MRI, biannual follow-up included prostate-specific antigen (PSA), adverse events (AEs), and functional quality-of-life assessment, with repeat systematic biopsy at 3 years. RESULTS: A 3-year follow-up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1-0.4) ng/mL, stable to 0.8 (0.4-1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. CONCLUSION: With 3-year Phase I follow-up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy.

Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation of Prostate Cancer.

PURPOSE: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). MATERIALS AND METHODS: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. RESULTS: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCN® intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95-99) thermal coverage of target volume and spatial ablation precision of ±1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction ≥75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADS™ 3 or greater lesion at 12-month magnetic resonance imaging (p <0.05). CONCLUSIONS: The TACT study of magnetic resonance imaging-guided transurethral ultrasound whole gland ablation in men with localized prostate cancer demonstrated effective tissue ablation and prostate specific antigen reduction with low rates of toxicity and residual disease.

High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer -Results from a prospective pilot study using a 37 gene panel.

BACKGROUND: Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naïve patients with a high risk for lethal disease outcome, however, has not been sufficiently explored. PATIENTS AND METHODS: Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel. RESULTS: The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naïve metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naïve metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%). CONCLUSIONS: This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naïve metastatic prostate cancer.

Recovery of pad-free continence in elderly men does not differ from younger men undergoing robot-assisted radical prostatectomy for aggressive prostate cancer.

PURPOSE: To analyze urinary continence outcome following robot-assisted radical prostatectomy (RARP) for aggressive prostate cancer in men aged ≥ 70 and < 70 years. METHODS: Retrospective analyses of prospectively collected long-term data from a monocentric cohort of 350 men with D'Amico high-risk prostate cancer undergone robot-assisted radical prostatectomy at a single institution between 2005 and 2016. The association between time since operation and zero-pad urinary continence recovery was comparatively analyzed by separate pre-operative and post-operative Cox proportional-hazard regression models. RESULTS: Median age in the age group ≥ 70 years was 73 years compared with 62 years in the < 70 year age group. Distribution of men receiving adjuvant and salvage radiotherapy/hormonal therapy was similar in both age groups. Urinary continence recovery rate at 12, 24, and 36 months after surgery of men aged ≥ 70 years was 66, 79 and 83%, respectively, and statistically similar to that of men < 70 years: 71, 81, and 85% (log-rank test p = 0.24). Multivariable analyses demonstrated no significant difference in return to continence between the two age groups (p = 0.28 and p = 0.17). In addition, clinical stage and type of nerve sparing (unilateral, bilateral or non-nerve sparing) were found to be independently predictive of pad-free continence recovery. CONCLUSIONS: Regardless of age, return to continence in men with aggressive prostate cancer undergoing RARP continues to improve way beyond the first 12 months after surgery. Considering the dire effects of post-operative radiotherapy on continence in this aggressive cancer cohort, advanced age alone should not discourage recommending multimodal therapy involving RARP.

Prognostic and Predictive Value of Tumor-infiltrating Leukocytes and of Immune Checkpoint Molecules PD1 and PDL1 in Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for patients with clear cell renal cell carcinoma (ccRCC), but not all patients benefit from ICI. One reason is the tumor microenvironment (TME) that has substantial influence on patient's prognosis and therapy response. Thus, we comprehensively analyzed the TME of ccRCC regarding prognostic and predictive properties. METHODS: Tumor-infiltrating CD3-positive T-cells, CD8-positive cytotoxic T-lymphocytes (CTLs), regulatory T-cells, B-cells, plasma cells, macrophages, granulocytes, programmed cell death receptor 1 (PD-1), and its ligand PD-L1 were examined in a large hospital-based series of ccRCC with long-term follow-up information (n = 756) and in another patient collective with information on response to nivolumab therapy (n = 8). Tissue microarray technique and digital image analysis were used. Relationship between immune cell infiltration and tumor characteristics, cancer-specific survival (CSS), or response to ICI was examined. RESULTS: Univariate survival analysis revealed that increased tumor-infiltrating B-cells, T-cells, and PD-1-positive cells were significantly associated with favorable CSS and high levels of intratumoral granulocytes, macrophages, cytotoxic T-cells, and PD-L1 significantly with poor CSS. High CTL or B-cell infiltration and high PD-L1 expression of ccRCC tumor cells qualified as independent prognostic biomarkers for patients' CSS. Significantly higher densities of intratumoral T-cells, CTLs, and PD-1-positive immune cells were observed in ccRCC with response to ICI compared with patients with mixed or no response (CD3: p = 0.003; CD8: p = 0.006; PD-1: p = 0.01). DISCUSSION: This study shows that subsets of tumor-infiltrating leukocytes in the TME and also PD-1/PD-L1 provide prognostic and predictive information for patients with ccRCC.

Lamin-B1 is a senescence-associated biomarker in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is a von-Hippel-Lindau gene (VHL) associated tumor disease. In addition to activating the hypoxia inducible factor (HIF) dependent oxygen-sensing pathway, VHL loss also has an impact on a HIF-independent senescence program which functions as a tumorigenesis barrier. Lamin-B1 is a nuclear intermediate filament protein that exhibits effects on chromatin structure and gene expression and acts as a senescence effector. In the present study, the expression and prognostic relevance of Lamin-B1 in a large cohort of ccRCC patients was examined and the report presents initial functional data on possible therapeutic implications. The expression of Lamin-B1 was measured by immunohistochemistry using a tissue microarray containing tumor tissue samples from 763 ccRCC patients. Chi-squared tests, Kaplan-Meier curves and Cox regression models were used to investigate the possible association between Lamin-B1 expression, clinical and pathological characteristics and patient survival. High Lamin-B1 expression was associated with poor clinical outcomes and multivariate Cox regression analyses revealed that Lamin-B1 was an independent prognostic factor for cancer-specific survival. Furthermore in vitro data suggested that Lamin-B1 acted as a functional downstream senescence effector in RCC cell lines. In conclusion, patients affected by ccRCC with high Lamin-B1 expression exhibit poor prognosis. Lamin-B1 may serve as a tissue-based biomarker for new therapeutic agents targeting therapy-induced senescence.

Correlation between genomic index lesions and mpMRI and 68Ga-PSMA-PET/CT imaging features in primary prostate cancer.

Magnetic resonance imaging (MRI) and prostate specific membrane antigen (PSMA)- positron emission tomography (PET)/computed tomography (CT)-imaging of prostate cancer (PCa) are emerging techniques to assess the presence of significant disease and tumor progression. It is not known, however, whether and to what extent lesions detected by these imaging techniques correlate with genomic features of PCa. The aim of this study was therefore to define a genomic index lesion based on chromosomal copy number alterations (CNAs) as marker for tumor aggressiveness in prostate biopsies in direct correlation to multiparametric (mp) MRI and 68Ga-PSMA-PET/CT imaging features. CNA profiles of 46 biopsies from five consecutive patients with clinically high-risk PCa were obtained from radiologically suspicious and unsuspicious areas. All patients underwent mpMRI, MRI/TRUS-fusion biopsy, 68Ga-PSMA-PET/CT and a radical prostatectomy. CNAs were directly correlated to imaging features and radiogenomic analyses were performed. Highly significant CNAs (≥10 Mbp) were found in 22 of 46 biopsies. Chromosome 8p, 13q and 5q losses were the most common findings. There was an strong correspondence between the radiologic and the genomic index lesions. The radiogenomic analyses suggest the feasibility of developing radiologic signatures that can distinguish between genomically more or less aggressive lesions. In conclusion, imaging features of mpMRI and 68Ga-PSMA-PET/CT can guide to the genomically most aggressive lesion of a PCa. Radiogenomics may help to better differentiate between indolent and aggressive PCa in the future.

Genomic features of renal cell carcinoma with venous tumor thrombus.

A venous tumor thrombus (VTT) is a potentially lethal complication of renal cell carcinoma (RCC) but virtually nothing is known about the underlying natural history. Based on our observation that venous thrombi contain significant numbers of viable tumor cells, we applied multiregion whole exome sequencing to a total of 37 primary tumor and VTT samples including normal tissue specimens from five consecutive patients. Our findings demonstrate mutational heterogeneity between primary tumor and VTT with 106 of 483 genes (22%) harboring functional SNVs and/or indels altered in either primary tumor or thrombus. Reconstruction of the clonal phylogeny showed clustering of tumor samples and VTT samples, respectively, in the majority of tumors. However, no new subclones were detected suggesting that pre-existing subclones of the primary tumor drive VTT formation. Importantly, we found several lines of evidence for "BRCAness" in a subset of tumors. These included mutations in genes that confer "BRCAness", a mutational signature and an increase of small indels. Re-analysis of SNV calls from the TCGA KIRC-US cohort confirmed a high frequency of the "BRCAness" mutational signature AC3 in clear cell RCC. Our findings warrant further pre-clinical experiments and may lead to novel personalized therapies for RCC patients.