Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors.

INTRODUCTION: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers. METHODS: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt reexpressing RCC4 and 786-O cells. RESULTS: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression - as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels. CONCLUSION: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.

Discrepancy between German S3 Guideline Recommendations and Daily Urologic Practice in the Management of Nonmuscle Invasive Bladder Cancer: Results of a Binational Survey.

INTRODUCTION: Guideline recommendations are meant to help minimize morbidity and to improve the care of nonmuscle invasive bladder cancer (NMIBC) patients but studies have suggested an underuse of guideline-recommended care. The aim of this study was to evaluate the level of adherence of German and Austrian urologists to German guideline recommendations. METHODS: A survey of 27 items evaluating diagnostic and therapeutic recommendations (15 cases of strong consensus and 6 cases of consensus) for NMIBC was administered among 14 urologic training courses. Survey construction and realization followed the checklist for reporting results of internet e-surveys and was approved by an internal review board. RESULTS: Between January 2018 and June 2019, a total of 307 urologists responded to the questionnaire, with a mean response rate of 71%. The data showed a weak role of urine cytology (54%) for initial diagnostics although it is strongly recommended by the guideline. The most frequently used supporting diagnostic tool during transurethral resection of the bladder was hexaminolevulinate (95%). Contrary to the guideline recommendation, 38% of the participants performed a second resection in the case of pTa low-grade NMIBC. Correct monitoring of Bacille Calmette-Guérin (BCG) response with cystoscopy and cytology was performed by only 34% of the urologists. CONCLUSIONS: We found a discrepancy between certain guideline recommendations and daily routine practice concerning the use of urine cytology for initial diagnostics, instillation therapy with a low monitoring rate of BCG response, and follow-up care with unnecessary second resection after pTa low-grade NMIBC in particular. Our survey showed a moderate overall adherence rate of 73%. These results demonstrate the need for sharpening awareness of German guideline recommendations by promoting more intense education of urologists to optimize NMIBC care thus decreasing morbidity and mortality rates.

Comparison of First-Line Anti-PD-1-Based Combination Therapies in Metastatic Renal-Cell Carcinoma: Real-World Experiences from a Retrospective, Multi-Institutional Cohort.

INTRODUCTION: The aim of this study was to test for differences in overall (OS) and progression-free survival (PFS) rates and toxicity in first-line immune checkpoint inhibition (IO) combination therapy in metastatic renal-cell carcinoma (mRCC) patients. METHODS: Between November 2017 and April 2021, 104 patients with histologically confirmed mRCC from 6 tertiary referral centers with either IO + IO (nivolumab + ipilimumab, n = 68) or IO + tyrosine kinase inhibitor (TKI) (pembrolizumab + axitinib, n = 36) were included. Kaplan-Meier and Cox regression analyses tested for OS and PFS differences. RESULTS: Of 104 mRCC patients, 68 received IO + IO (65.4%) and 36 IO + TKI (34.6%) therapy, respectively. Median age was 67 years (interquartile range: 57-70.3). Patients receiving IO + TKI were less likely to be poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium score (16.7 vs. 30.9%) and presented with lower T-stage, compared to IO + IO treated patients. Median PFS was 9.8 months (CI: 5.3-17.6) versus 12.3 months (CI: 7.7 - not reached) for IO + IO versus IO + TKI treatment, respectively (p = 0.22). Median OS was not reached, survival rates at 12 months being 73.9 versus 90.0% for IO + IO versus IO + TKI patients (p = 0.089). In subgroup analyses of elderly patients (≥70 years, n = 38), IO + TKI treatment resulted in better OS rates at 12 months compared to IO + IO (91.0 vs. 57.0%; p = 0.042). CONCLUSION: IO + IO and IO + TKI as first-line therapies in mRCC patients were both comparable as for the oncological outcome and toxicity.

Complex Soft Tissue Defects in Operative Urology: Pedicled Perforator Flaps of the Anterior Lateral Thigh for Tissue Reconstruction of the Lower Trunk.

BACKGROUND: Complex soft tissue defects involving the lower abdomen, perineum, and groin (LAPG) represent reconstructive challenges following urologic surgery. Consequently, these often require an interdisciplinary approach involving plastic surgery. While pedicled flaps from the lower abdomen are a reliable option, previous placement of colostomies and urinary urostomies renders these flap types unavailable. Here, the pedicled anterolateral thigh perforator (ALT) flap represents a reliable pedicled alternative which can harvest from the thigh. MATERIALS AND METHODS: A retrospective data analysis of pedicled perforator flaps harvested from the thigh to reconstruct soft tissue defects was conducted. Seven patients treated in the urology department with soft tissue defects following tumor resection, infection, and dehiscence were included. RESULTS: In all patients, the ALT flap was utilized successfully to reconstruct soft tissue defects up to 450 cm2 in size. All flaps survived. In 1 case, prolonged wound healing was observed. All defects were adequately addressed with no recurrence of dehiscence or fistula formation. CONCLUSIONS: Pedicled perforator flaps represent a valid option for the soft tissue reconstruction of the lower abdomen and perineum when a pedicled rectus abdominis flap is no longer available. This flap is, therefore, a good option in an interdisciplinary approach to soft tissue reconstruction, especially following urologic surgery, which is predominantly performed in the LAPG region.

Troubleshooting of failed continence mechanisms in the ileocecal pouch: Operative technique and long-term results of the intussuscepted ileal nipple valve.

OBJECTIVES: To provide a detailed step-by-step operative technique, and to report on long-term functional and metabolic outcomes in secondary continence mechanisms in the form of secondary intussuscepted ileal nipple valves in revisional surgery of ileocecal pouches. METHODS: From May 1997 to May 2015, 18 female and 10 male patients suffering from dysfunctional primary continence mechanisms of their ileocecal pouch underwent revisonal surgery to create a secondary ileal nipple valve at our tertiary referral center. The average follow-up period was 65.4 months. RESULTS: After surgery, 24 patients were continent by day and night, and four patients showed minor incontinence with the use of a safety pad. The average frequency of clean intermittent catheterization decreased both during the day and at night. The diameter of the catheters used for clean intermittent catheterization increased significantly. No patient showed stomal stenosis, change of stool habits or metabolic situation in the follow-up period. Furthermore, the creation of the secondary ileal nipple valves did not affect the capacity of the reservoir. In the long-term follow up, two patients required the construction of a third continence mechanism, making for an overall success rate of 92% in the study group. CONCLUSION: To our knowledge, this is the first study of long-term results after the creation of secondary ileal nipple valves. We provide evidence that the creation of a secondary ileal nipple valve is a safe and reliable procedure for continence restoration in ileocecal pouches with excellent functional and metabolic long-term outcomes.

Endovascular therapy of arterioureteral fistulas.

Background: Arterioureteral fistulas (AUFs) are severe pathologies of different origin and with increasing incidence frequently appear in patients with underlying extensive malignancy and after pelvic surgery. AUF therapy is challenging since symptoms are frequently non-specific and patients are often unsuitable surgical candidates due to comorbidities. Since experiences with endovascular treatment strategies are limited, the feasibility, effectiveness, and safety were evaluated in a consecutive case series. Patients and methods: A retrospective analysis of five patients with endovascular AUF exclusion was performed. Probable predisposing factors for an AUF included history of pelvic malignancy with oncologic surgery in four patients, radiotherapy in four patients, and indwelling ureteral stents in four patients. Clinical presentation, diagnostic management, and site of fistula were assessed. Furthermore, technical and clinical success as well as complications were evaluated. Results: All patients presented with gross haematuria. In four patients, haematuria occurred during endoscopic ureteral stent manipulation. Affected vessels were the internal pudendal artery in one, intrarenal segmental artery and external iliac artery in two, and internal iliac artery in another two patients. Treatment included coil embolisation (n = 2), plug embolisation (n = 3), particulate embolisation (n = 1), and covered stent implantation (n = 2). Technical success was achieved in all procedures. In two cases, re-intervention was necessary due to AUF recurrence, resulting in a clinical success rate of 60.0%. One major complication class D was documented. Conclusions: AUFs can be treated effectively and safely using endovascular techniques. Diagnostic and therapeutic management of this rare entity requires a high level of awareness for potential risk factors as well as an optimal multidisciplinary coordination.

miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo.

BACKGROUND: Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. METHODS: miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4-2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. RESULTS: Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. CONCLUSIONS: Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.

Cognitive Status and Functional Dexterity as Outcome Predictors Following Urinary Diversion: A Combined Retrospective and Prospective Observational Study.

PURPOSE: The study aimed to evaluate the impact of the validated functional dexterity test and the Mini-Mental Status test on subjective functional outcomes, medical care situation, and health-related quality of life (HRQoL) after urinary diversion (UD). PATIENTS AND METHODS: A total of 106 patients (n = 26 ileal conduits, n = 29 neobladders, and n = 51 ileocecal pouches) were included in this combined retrospective (n = 77) and prospective (n = 29) observational study. All patients performed the 2 tests mentioned above and filled out self-designed questionnaires with diversion and HRQoL items. In the prospective cohort, the tests were performed preoperatively and the questionnaires were filled out preoperatively as well as 3 and 6 months after surgery. RESULTS: Reduced dexterity and cognitive skills were significantly associated with increased patient age and subjective constraints in stoma care of ileal conduits, self-catheterization in ileocecal pouches, and continence in neobladders. Overall HRQoL, however, was not affected by dexterity or cognitive measures. CONCLUSIONS: Assessing the cognitive status and functional dexterity of patients undergoing UD might provide a useful objective clinical tool to aid in decision-making regarding the type of UD and postoperative medical care situation. Further prospective data are needed to confirm these findings and further simplify the methods used here.

Impact of E-Cadherin and ß-Catenin as Prognostic Factor in Renal Cell Carcinoma with Tumor Thrombus of the Vena Cava.

PURPOSE: Renal cell carcinoma (RCC) forming tumor thrombus (TT) of vena cava (VC) is characterized by poor prognosis. Nevertheless, the outcome of patients after radical surgery varies. To date only limited data concerning prognostic biomarkers in this RCC subgroup are available. METHODS: Out of 159 patients with pT3b/c RCC, 95 patients without synchronous distant metastases at time of diagnosis were included in the study cohort. After immunohistochemical (IHC) evaluation of E-cadherin and ß-Catenin expression, association with clinical, histopathological and survival was assessed by univariate analysis, multivariate analysis, and Kaplan-Meier-analysis. Cancer-specific survival (CSS) rates and overall survival (OS) rates were estimated using Kaplan-Meier analysis and compared using Log rank test. RESULTS: We found a significant correlation between E-cadherin overexpression and initial lymph node metastasis (ρ = 0.300, p = 0.003), positive surgical margins (ρ = 0.210, p = 0.043), and the development of distant metastases (ρ = 0.258, p = 0.012). Furthermore, we observed a significant correlation of ß-Catenin overexpression with higher tumor stage pT3c (ρ = 0.230, p = 0.028) and initial lymph node metastases (ρ = 0.236, p = 0.025). Survival analysis revealed a statistically significant association of both E-cadherin and ß-Catenin overexpression with worse CSS (p < 0.001 and p = 0.007, respectively) and OS (p < 0.001 and p = 0.041, respectively). Multivariate analysis revealed initial lymph node metastasis as the only predictive factor for worse OS (HR 4.54, 95% CI 2.30-8.93; p < 0.001). E-Cadherin and ß-Catenin expression failed to be significant in multivariable analysis for OS and CSS. CONCLUSIONS: In a large series of RCC with TT of VC high IHC expression of E-cadherin and ß-Catenin was associated with initial lymph node metastasis and with both worse OS and worse CSS. This might help to identify patients at risk for recurrence who might benefit from adjuvant therapy or stricter follow-up.

Serous-lined, stapled pouch wall plication: initial results of a simple and quick novel continence mechanism in troubleshooting secondary to continent cutaneous urinary diversion.

OBJECTIVES: To report a novel and straightforward technique of a secondary continent outlet for continent cutaneous urinary diversion (CCUD) reservoirs without the need for further bowel resection, reducing operating time and length of hospitalization. PATIENTS AND METHODS: From 2015 to 2017, six patients with unreconstructable, incontinent outlets (out of a total pool of 595 patients with CCUD) have undergone the technique described in the present paper at our department. The technique relies on the Mitrofanoff principle, using a stapled full-thickness pouch wall plication, which creates a flap-valve continence mechanism. RESULTS: All patients enjoyed full continence with ease of clean intermittent catheterization (CIC) in the postoperative period and on follow-up to a mean (range) of 12.4 (7-18) months. No major complications were encountered in any patient and the average capacity of the reservoirs was not compromised by the procedure (540 mL preoperatively vs 500 mL in further follow-up). CONCLUSION: In revisional surgery for secondary CCUD incontinence, especially if the patient has already lost a significant amount of bowel or has previously undergone radiation therapy, the technique described here represents a safe and effective alternative to restore continence.

Repair of an Autologous Saphenous Vein Graft Aneurysm Ten Years after Renal Artery Reconstruction during Live Donor Renal Transplantation.

Saphenous vein graft (SVG) aneurysms (SVGA) after renal transplantation represents a rare vascular complication with subsequent challenging multidisciplinary treatment. We present a case of a 30-year-old female who received a live donor kidney transplantation for end-stage renal disease that was caused due to the hemolytic uremic syndrome. Postoperatively, an insufficient graft perfusion due to an arterial kinking was noted and repaired using an autologous SVG interposition. Ten years later, a 3-cm aneurysm of the SVG at the anastomotic site with the common iliac artery was discovered. Multidisciplinary surgical exploration with excision of the aneurysm-carrying vein graft and interposition of a new autologous SVG was successfully carried out with preservation of renal allograft's function. Treatment of SVGA after rental transplantation with a new autologous SVG is challenging but feasible, requiring a multidisciplinary approach in order to guarantee successful rates and to prevent allograft loss.

Long-term results of ileal ureteric replacement: a 25-year single-centre experience.

OBJECTIVE: To report the long-term outcomes of ileal ureteric replacement (IUR) in complex reconstruction of the urinary tract. PATIENTS AND METHODS: From 1991 to 2016, IUR was performed in 157 patients with structural or functional ureteric loss. In 52 patients, bilateral IUR became necessary. Implantation sites where either the native urinary bladder (n = 79) or intestinal reservoirs (n = 78). In the latter group, the technique was used at the time of primary urinary diversion (n = 34), in a secondary approach (n = 29), and in undiversion or conversion procedures (n = 15). Anti-refluxive implantation was performed in 37 patients. In eight patients the ileal ureter was implanted into the cutis as an ileal conduit. All patients were followed prospectively according to a standardised protocol. RESULTS: The mean follow-up was 54.1 months. In 114 patients with dilatation of the upper urinary tract before surgery a significant improvement of the dilatation was confirmed in 98 patients. Serum creatinine levels decreased or remained stable in 147 of the 157 patients. Reflux was present in all cases without and in six cases with an anti-reflux mechanism. In six patients, operative revision became necessary because of severe metabolic acidosis, mucus obstruction or stenosis of the ileal ureter. CONCLUSIONS: To our knowledge, this is the world's largest single-centre series of IUR reported to date. Long-term follow-up confirms that this approach is a safe and reliable solution, even under complex conditions. Anti-refluxive implantation is recommended for intestinal reservoirs, whereas reflux prevention seems to be of minor importance when the native bladder is chosen as the site of implantation.

Preoperative C-Reactive Protein Values as a Potential Component in Outcome Prediction Models of Metastasized Renal Cell Carcinoma Patients Receiving Cytoreductive Nephrectomy.

PURPOSE: To validate preoperative C-reactive protein (CRP) levels as a prognostic marker for survival in a metastasized renal cell carcinoma (mRCC) patient cohort receiving cytoreductive nephrectomy (CN). PATIENTS AND METHODS: By chart review, 146 mRCC patients receiving CN at our tertiary referral centre from 1997 to 2015 were identified retrospectively. All relevant clinicopathological features including laboratory parameters were collected and correlated to overall survival, progression-free survival and cancer-specific survival (CSS). The mean follow-up was 23 months (range 1-168 months). RESULTS: Besides the already established scoring systems like the MSKCC criteria, an elevated preoperative CRP level (≥0.5 mg/dL) was an independent predictor of CSS in our study group including the chosen postoperative adjuvant therapies (TKI vs. immunotherapy vs. others). With regard to morbidity, patients with a good performance status, small tumour size and adequate renal function/haematopoiesis experienced less complication rates, thereby profiting more from CN. CONCLUSIONS: Our data provide indication that preoperative CRP levels should be implemented in nomograms regarding the outcome prediction in mRCC to identify candidates likely to profit from CN.

Diagnosis and Clinical Management of Ruptured Ileocecal Pouches for Continent Cutaneous Urinary Diversion.

BACKGROUND AND OBJECTIVES: The study aimed to report on pouch ruptures in 5 patients with ileocecal reservoirs for continent cutaneous urinary diversion. PATIENTS AND METHODS: Five male patients aged 48-89 were referred to our department between 2000 and 2016 with a ruptured ileocecal pouch 16-175 months postoperatively. RESULTS: With an incidence of 0.95% in our series (5 ruptures in 529 pouch patients out of a pool of 1,182 radical cystectomies) a rupture of the ileocecal pouch is a rare but severe complication. In all the cases, the rupture was supported by the over-distension of the reservoir, while a traumatic self-catheterization was reported in 2 patients. The rupture occurred on the right lateral wall of the ileocecal pouch in 4 out of 5 cases and led to acute abdominal pain and inflammation. Pouchography was performed in all the patients and revealed a leakage in 4 of them. The rupture was verified intraoperatively in 1 patient. Open surgical exploration, drainage and repair were successfully performed in all 5 cases. CONCLUSIONS: Early diagnosis and immediate intervention are mandatory in the cases of pouch rupture to manage this severe complication, which is often related to reduction in patient compliance. Consequently, it is essential to raise awareness of this potentially life-threatening complication in patients with ileocecal pouches.

Long-Term Outcome of Nephron-Sparing Surgery Compared to Radical Nephrectomy for Renal Cell Carcinoma ≥4 cm - A Matched-Pair Single Institution Analysis.

PURPOSE: We investigated the long-term oncological and functional outcome of nephron-sparing surgery/partial nephrectomy (PN) versus radical nephrectomy (RN) for any renal cell carcinoma (RCC) ≥4 cm. PATIENTS AND METHODS: Between 1997 and 2013, we identified 128 patients undergoing PN for RCC ≥4 cm and matched this collective to 128 patients undergoing RN. We then compared overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS) and functional parameters in both groups. The median follow-up time was 58 months (3-210 months). RESULTS: Compared to RN, patients with a PN showed a significantly higher 10-year OS (77.0 vs. 63.0%, p = 0.04), CSS (90.6 vs. 71.7%, p = 0.002) and PFS (82.9 vs. 57.4%, p ≤ 0.001). Renal function preservation was better in the PN group (24 months estimated glomerular filtration rate: 68.2 ml/min for PN vs. 40.6 ml/min for RN, p ≤ 0.01) with significantly less new onset chronic kidney diseases. Total complication rate was comparable, whereas PN procedures showed more Clavien-Dindo grade I + II complications, portraying the technical challenge of PN in larger RCCs. CONCLUSIONS: Whenever feasible, PN should be considered for renal masses ≥4 cm, as this technique shows better long-term results regarding disease-specific survival and renal function preservation in our study group.

Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated PTEN Expression.

PURPOSE: Metformin (MF) acts as a tumour-suppressor in renal cell carcinoma (RCC) by inhibiting the AKT/mTOR pathway via AMPK activation. Here, we explore the influence of miR-21 and its target gene PTEN on MF effects in CAKI-1 and CAKI-2 cells. METHODS: Proliferation assays (MTS) and qRT-PCR after transient transfection with pre- and anti-miR-21 and MF treatment were conducted. AMPK-dependency was assessed via transfection of siAMPK. The expression of PTEN, AKT and miR-21 after transient pre-miR-21 transfection and MF treatment was analysed. RESULTS: We demonstrate that CAKI-1 cells, which were found to be less sensitive towards MF, showed a significant higher miR-21 and lower PTEN expression than CAKI-2. This was confirmed in a primary RCC collective (n = 28): miR-21 and PTEN expression correlated negatively. MF treatment lowered miR-21 AMPK-dependently and increased PTEN expression in the cell lines. Ectopic miR-21 regulation modulated MF sensitivity. Western blot analysis showed that pre-miR-21 transfection and MF treatment regulated PTEN expression with impact on pAKT levels in the cells. CONCLUSIONS: We show that differing MF sensitivity in RCC cells is associated with and mediated through the regulation of miR-21/PTEN expression with an impact on subsequent AKT signalling. This provides imaginable clinical implications regarding MF therapy of RCC patients for the future.

First-Line Immune Combination Therapies for Nonclear Cell Versus Clear Cell Metastatic Renal Cell Carcinoma: Real-World Multicenter Data From Germany.

INTRODUCTION: The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. MATERIALS AND METHODS: Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. RESULTS: Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P = .6). Median PFS was 13 versus 15 months (P = .9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P = .6) or a higher progression rate (HR: 1.0; P = 1.0). CONCLUSION: In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed.

MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer.

The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.

[New forms of immunotherapy in uro-oncology : HLA-independent therapeutic approaches with bispecific antibodies and CAR T cells]. / Neue Formen der Immuntherapie für die Uroonkologie : HLA-unabhängige Therapieansätze mit bispezifischen Antikörpern und CAR-T-Zellen.

Immunotherapies using bispecific antibodies and chimeric antigen receptor (CAR) T cells do not depend on previous activation of T cells by the human leukocyte antigen (HLA) system. These HLA-independent approaches displayed groundbreaking clinical results in hematological malignancies-leading to drug approvals for diseases like acute lymphocytic leukemia (ALL), B-cell Non-Hodgkin's lymphoma and multiple myeloma. Currently, several phase I/II trials are investigating the transferability of these results to solid tumors-especially prostate cancer. Compared to established immune checkpoint blockade, bispecific antibodies and CAR T cells have novel and heterogenous side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Treating these side effects and identifying suitable trial participants requires an interdisciplinary treatment approach.

Tin-filtered 100 kV Ultra-low-dose Abdominal CT for Calculi Detection in the Urinary Tract: A Comparative Study of 510 Cases.

OBJECTIVES: For detection of urinary calculi, unenhanced low-dose computed tomography is the method of choice, outperforming radiography and ultrasound. This retrospective monocentric study aims to compare a clinically established, dedicated low-dose imaging protocol for detection of urinary calculi with an ultra-low-dose protocol employing tin prefiltration at a standardized tube voltage of 100 kVp. METHODS: Two study arms included a total of 510 cases. The "low-dose group" was comprised of 290 individuals (96 women; age 49 ± 16 years; BMI 27.23 ± 5.60 kg/m2). The "ultra-low-dose group" with Sn100 kVp consisted of 220 patients (84 women; age 47 ± 17 years; BMI 26.82 ± 5.62 kg/m2). No significant difference was ascertained for comparison of age (p = 0.132) and BMI (p = 0.207) between cohorts. For quantitative assessment of image quality, image noise was assessed. RESULTS: No significant difference regarding frequency of calculi detection was found between groups (p = 0.596). Compared to the low-dose protocol (3.08 mSv; IQR 2.22-4.02 mSv), effective dose was reduced by 62.35% with the ultra-low-dose protocol employing spectral shaping (1.16 mSv; IQR 0.89-1.54 mSv). Image noise was calculated at 18.90 (IQR 17.39-21.20) for the low-dose protocol and at 18.69 (IQR 17.30-21.62) for the ultra-low-dose spectral shaping protocol. No significant difference was ascertained for comparison between groups (p = 0.793). CONCLUSION: For urinary calculi detection, ultra-low-dose scans utilizing spectral shaping by means of tin prefiltration at 100 kVp allow for considerable dose reduction of up to 62% over conventional low-dose CT without compromising image quality.