Retrograde Pyelography in the Presence of Urothelial Bladder Cancer Does Not Affect the Risk of Upper Tract Urothelial Cancer: A Retrospective Analysis of a Single-Centre Cohort.

OBJECTIVE: Patients with bladder cancer (BC) are at risk of developing upper tract urothelial carcinoma (UTUC). Therefore, CT urography is recommended for follow-up. To avoid intravenous contrast agents, retrograde pyelography (RPG) is an alternative. However, it is still unclear whether RPG increases the incidence of UTUC. The aim of this study was to investigate the impact of RPG in the presence of BC on the risk of developing UTUC. PATIENTS AND METHODS: Retrospectively analysing a total of 3,680 RPGs between 2009 and 2016, all patients with simultaneous BC (group 1) and those without synchronous BC (group 2) during RPG were compared. All patients were risk stratified according to the EORTC bladder calculator. In patients without BC during RPG, risk stratification was based on the worst prior tumour characteristics. RESULTS: A total of 145 patients with a history of BC were analysed. Of these, 112 patients underwent RPG with simultaneous BC. UTUC developed in 6 of 112 patients (5.4%) and 58.9% (66/112) had high-risk BC according to the EORTC bladder calculator. In the control group, one out of 33 (3%) patients with metachronous high-risk BC developed UTUC. CONCLUSIONS: Using RPG in the presence of BC did not increase the risk of UTUC. Due to the predominant number of high-risk/high-grade tumours, individual tumour biology appears to be the primary driver for the development of UTUC.

First-line pazopanib in intermediate- and poor-risk patients with metastatic renal cell carcinoma: Final results of the FLIPPER trial.

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.

Circulating and tissue IMP3 levels are correlated with poor survival in renal cell carcinoma.

Tissue protein expression of IMP3 is emerging as a promising prognostic factor in renal cell carcinoma (RCC). The most commonly used immunohistochemical (IHC) antibody has been criticized for its low specificity. In addition, blood levels of IMP3 have not yet been analyzed in RCC. Therefore, we compared the prognostic performance of two different IMP3 IHC antibodies and assessed the prognostic relevance of IMP3 plasma levels in RCC. IMP3 levels were assessed in an overall number of 425 RCC (344× clear cell [ccRCC], 63× papillary [pRCC], 18× chromophobe [chRCC]) patients in three partly overlapping cohorts. Plasma IMP3 concentrations were determined by ELISA in 98 RCC (79× ccRCC, 15× pRCC, 4× chRCC) patients and 20 controls. IMP3 mRNA expression levels were analyzed in 73 frozen tissue samples (55× ccRCC, 12× pRCC, 6× chRCC), while protein expressions were assessed in 366 FFPE samples (294× ccRCC, 56× pRCC, 16× chRCC) using the M3626 and N-19 antibodies. IMP3 plasma and mRNA expression levels were significantly higher in patients compared to controls and in high-grade compared to low-grade tumors. In addition, IMP3 plasma and tissue protein levels (by M3626) were higher and IMP3 mRNA expression levels tended to be higher in patients with distant metastasis. Multivariate analyses in clear cell RCC revealed high IMP3 plasma concentration and mRNA expression as independent predictors of disease-specific survival. IMP3 immunostainings by M3626 but not by N-19 were independently associated with poor overall and disease-specific survival. High plasma and tissue levels of IMP3 are independently associated with poor RCC prognosis. The applied antibody significantly impacts the prognostic performance of analysis. IMP3 analysis may improve risk-stratification of RCC patients and therefore could help to optimize therapeutic and follow-up decisions.

Are there limits of robotic partial nephrectomy? TRIFECTA outcomes of open and robotic partial nephrectomy for completely endophytic renal tumors.

BACKGROUND: To compare the outcomes of robot-assisted (RAPN) and open partial nephrectomy (OPN) for completely endophytic renal tumors. METHODS: Consecutive patients undergoing OPN or RAPN for entirely endophytic tumors in four high-volume centers between 2008 and 2016 were identified. Endophytic masses were identified based on sectional imaging. Patient characteristics and surgical outcome were compared using Mann-Whitney-U-test and chi-squared-tests. Uni- and multivariate analyses were performed to identify predictors of TRIFECTA achievement and excisional volume loss. RESULTS: Out of 1128 patients, 10.9% (64) of RAPN and 13.9% (76) of OPN underwent surgery for entirely endophytic tumors. Operative time was longer for RAPN (169 vs 140 min, P = 0.03) while ischemia time was shorter (13 vs 18 min, P = 0.001). Complication rates were comparable (21% OPN vs 22% RAPN, P = 0.91) and TRIFECTA achievement was not different between the groups (68% OPN vs 75% RAPN, P = 0.39). In multivariate analyses type of surgery was not associated with TRIFECTA achievement or excisional volume loss. Here, only tumor complexity (OR 0.48, P = 0.001) and size (OR 1.01, P = 0.002) were independent predictors. CONCLUSION: For entirely endophytic tumors, both RAPN and OPN offer good TRIFECTA achievement. This encourages the use of NSS even for these highly complex tumors using the surgeon's preferred approach.

The Biomarker Potential of Caveolin-1 in Penile Cancer.

Various types of human cancers were characterized by an altered expression of epithelial or stromal caveolin-1 (CAV1). However, the clinical significance of CAV1 expression in penile cancer remains largely unknown. Here the expression patterns of CAV1 were analyzed in a retrospective cohort (n=43) of penile squamous cell carcinomas (SCC). Upon penile cancer progression, significantly increased CAV1-levels were determined within the malignant epithelium, whereas within the tumor stroma, namely the fibroblastic tumor compartment harboring activated and/or cancer associated fibroblasts, CAV1 levels significantly decline. Concerning the clinicopathological significance of CAV1 expression in penile cancer as well as respective epithelial-stromal CAV1 distributions, high expression within the tumor cells as well as low expression of CAV1 within the stromal compartment were correlated with decreased overall survival of penile cancer patients. Herein, CAV1 expressions and distributions at advanced penile cancer stages were independent of the immunohistochemically proven tumor protein p53 status. In contrast, less differentiated p16-positive tumor epithelia (indicative for human papilloma virus infection) were characterized by significantly decreased CAV1 levels. Conclusively, we provide further and new evidence that the characteristic shift in stromal-epithelial CAV1 being functionally relevant to tumor progression even occurs in penile SCC.

Detection of Significant Prostate Cancer Using Target Saturation in Transperineal Magnetic Resonance Imaging/Transrectal Ultrasonography-fusion Biopsy.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) and targeted biopsies (TBs) facilitate accurate detection of significant prostate cancer (sPC). However, it remains unclear how many cores should be applied per target. OBJECTIVE: To assess sPC detection rates of two different target-dependent magnetic resonance imaging (MRI)/transrectal ultrasonography (TRUS)-fusion biopsy approaches (TB and target saturation [TS]) compared with extended systematic biopsies (SBs). DESIGN, SETTING, AND PARTICIPANTS: Retrospective single-centre outcome of transperineal MRI/TRUS-fusion biopsies of 213 men was evaluated. All men underwent TB with a median of four cores per MRI lesion, followed by a median of 24 SBs, performed by experienced urologists. Cancer and sPC (International Society of Urological Pathology grade group ≥2) detection rates were analysed. TB was compared with SB and TS, with nine cores per target, calculated by the Ginsburg scheme and using individual cores of the lesion and its "penumbra". OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer detection rates were calculated for TS, TB, and SB at both lesion and patient level. Combination of SB + TB served as a reference. Statistical differences in prostate cancer (PC) detection between groups were calculated using McNemar's tests with confidence intervals. RESULTS AND LIMITATIONS: TS detected 99% of 134 sPC lesions, which was significantly higher than the detection by TB (87%, p = 0.001) and SB (82%, p < 0.001). SB detected significantly more of the 72 low-risk PC lesions than TB (99% vs 68%, p < 0.001) and 10% (p = 0.15) more than that detected by TS. At a per-patient level, 99% of men harbouring sPC were detected by TS. This was significantly higher than that by TB and SB (89%, p = 0.03 and 81%, p = 0.001, respectively). Limitations include limited generalisability, as a transperineal biopsy route was used. CONCLUSIONS: TS detected significantly more cases of sPC than TB and extended SB. Given that both 99% of sPC lesions and men harbouring sPC were identified by TS, the results suggest that this approach allows to omit SB cores without compromising sPC detection. PATIENT SUMMARY: Target saturation of magnetic resonance imaging-suspicious prostate lesions provides excellent cancer detection and finds fewer low-risk tumours than the current gold standard combination of targeted and systematic biopsies.

Prognostic role of bland thrombus in patients treated with resection of renal cell carcinoma with inferior vena cava tumor thrombus.

OBJECTIVES: To assess the impact of the presence of bland thrombus (BT) on prognosis of patients treated with resection of renal cell carcinoma (RCC) with inferior vena cava tumor thrombus (IVCTT). MATERIALS AND METHODS: The medical records of a total of 145 consecutive postsurgical RCC patients with level I-IV IVCTT were reviewed from January 2008 to August 2018. Associations of BT with clinicopathological variables were estimated by chi-square test or Student's t-test. Kaplan-Meier method and multivariate Cox proportional hazard model were used. The eighth TNM staging system, "Spiess PE" model, University of California at Los Angeles Integrated Staging System and Stage, Size, Grade, and Necrosis (SSIGN) score were selected to assess whether BT could improve their predictive abilities. RESULTS: BT was observed in 34 (23.4%) patients and was significantly associated with increased levels of IVCTT (P = 0.004) and invasion of IVC wall (P = 0.030). Multivariable Cox analyses revealed that tumor grade, T stage, M stage, tumor thrombus consistency and BT were independent risk factors for both progression-free survival and overall survival. The concordance indexes ranged from a low of 0.652 in TNM to a high of 0.731 in SSIGN, and integrating BT into each base model led to an increased predictive accuracies of 6.2% for TNM (P = 0.025), 4.0% for "Spiess PE" model (P = 0.069), 2.1% for University of California at Los Angeles Integrated Staging System (P = 0.149) and 1.2% for SSIGN (P = 0.290), respectively. CONCLUSIONS: Presence of BT was independently associated with survival in postsurgical patients with RCC-IVCTT. Routine consideration of BT as an adjunct to TNM staging system may be suggested.

Serum and tissue syndecan-1 levels in renal cell carcinoma.

BACKGROUND: The proteoglycan syndecan-1 is involved in cell proliferation, adhesion and angiogenesis. It was shown to be involved in cancer progression in different tumor entities. So far, the role of syndecan-1 in renal cell carcinoma (RCC), one of the most common diseases in urologic oncology, was little described. Purpose of the present study was to obtain serum concentrations and tissue expression levels of syndecan-1 in a cohort of patients diagnosed with RCC. METHODS: Clinical and follow-up data were obtained from 413 RCC patients. SDC1 levels were determined in serum samples of 100 patients by enzyme-linked immunosorbent assay and tissue SDC1 expression was measured by immunohistochemistry (IHC) in 343 cases. Results were correlated with clinicopathological and follow-up data. RESULTS: Five and ten years overall and cancer specific survival were 67% and 56% [overall survival (OS)] and 79% and 76% [cancer-specific survival (CSS)]. In female patients and locally advanced disease (≥T3), tissue SDC1 expression was decreased (female 85.6% vs. male 71.1% low tissue SDC1 expression, P=0.0153 and ≤T2 70.0% vs. ≥T3 87.2% low tissue SDC1 expression, P=0.0055) compared to male patients and organ confined disease. Locally advanced tumor stage, presence of lymph node or distant metastases, high Fuhrman grading and clear cell carcinoma as histopathological subtype were independent prognostic factors for reduced CSS and OS. There was no impact of serum SDC1 (sSDC1) serum concentration or SDC1 tissue protein expression on OS, CSS or recurrence free survival (RFS) in uni- or multivariable analysis. CONCLUSIONS: sSDC1 concentration or SDC1 tissue protein expression levels had no influence on patients' prognosis in the present cohort of patients diagnosed with RCC.

Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1.

Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals.

Progression-related loss of stromal Caveolin 1 levels fosters the growth of human PC3 xenografts and mediates radiation resistance.

Despite good treatment results in localized prostate tumors, advanced disease stages usually have a pronounced resistance to chemotherapy and radiotherapy. The membrane protein caveolin-1 (Cav1) functions here as an important oncogene. Therefore we examined the impact of stromal Cav1 expression for tumor growth and sensitivity to ionizing radiation (IR). Silencing of Cav1 expression in PC3 cells resulted in increased tumor growth and a reduced growth delay after IR when compared to tumors generated by Cav1-expressing PC3 cells. The increased radiation resistance was associated with increasing amounts of reactive tumor stroma and a Cav1 re-expression in the malignant epithelial cells. Mimicking the human situation these results were confirmed using co-implantation of Cav1-silenced PC3 cells with Cav1-silenced or Cav1-expressing fibroblasts. Immunohistochemically analysis of irradiated tumors as well as human prostate tissue specimen confirmed that alterations in stromal-epithelial Cav1 expressions were accompanied by a more reactive Cav1-reduced tumor stroma after radiation and within advanced prostate cancer tissues which potentially mediates the resistance to radiation treatment. Conclusively, the radiation response of human prostate tumors is critically regulated by Cav1 expression in stromal fibroblasts. Loss of stromal Cav1 expression in advanced tumor stages may thus contribute to resistance of these tumors to radiotherapy.