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.

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.

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.

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.

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.

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.

Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis.

The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9-148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients.

68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT.

PURPOSE: Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. PATIENTS AND METHODS: One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). RESULTS: The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. CONCLUSIONS: The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.

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.

The devastated bladder outlet: treatment options.

PURPOSE OF REVIEW: The purpose of this study is to review and discuss recently published studies of therapeutic options in cases with the combination of severe sphincteric damage and recurrent stricture of the bladder neck or anastomosis in patients with postradical prostatectomy. RECENT FINDINGS: Recent focus has been on successful management of recurrent bladder neck contracture with urethral dilatation or endoscopic techniques even in patients with prior history of additional radiation therapy. In addition, some authors include injectable agents in their armamentarium for the treatment of recurrent bladder neck stricture. Failure of all attempts to restore the bladder outlet and urethral patency results in a devastated bladder outlet with persistence of urinary incontinence, sometimes worsened when combined with recurrent obstruction. For this small subgroup of patients with severe damage of the lower urinary tract, treatment options are rare. In the current literature, several case series can be found, but no clinical trials exist to provide an evidence-based approach to this severe disorder. Open reconstructive techniques or urinary diversion with reservoirs made from bowel are necessary in these patients. In recent studies, laparoscopic and robot-assisted approaches have also been described. SUMMARY: In case of a 'nonreconstructible' devastated bladder outlet treatment, options are limited. These devastating conditions require a definitive surgical solution. Bladder neck closure, continent vesicostomy in most cases combined with augmentation or urinary diversion with or without cystectomy are last resort techniques for this problem.

Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. METHODS: Five patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. RESULTS: Injection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). CONCLUSION: (68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder.

BACKGROUND: To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. RESULTS: We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. CONCLUSIONS: This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.

Matched-pair analysis of renal function in the immediate postoperative period: a comparison of living kidney donors versus patients nephrectomized for renal cell cancer.

PURPOSE: Living kidney donation (LKD) involves little risk for the donor and provides excellent functional outcome for transplant recipients. However, contradictory data exist on the incidence and degree of impaired renal function (IRF) in the donor. Only few studies compared the incidence of IRF in donors with that of patients having undergone radical nephrectomy (RN). METHODS: From 1992 to 2012, 94 healthy subjects underwent an open nephrectomy for living kidney donation at the University Medical Center of Würzburg. These patients were compared with matched subjects who had the same surgical procedure for renal cell carcinoma at the Carl-Thiem Hospital Cottbus (1:1 matching using propensity scores). RESULTS: In the LKD-group, no complication ≥ Grade 3 according to the Clavien-Dindo classification occurred. Donors had a preoperative median estimated glomerular filtration rate (eGFR) of 85.1 ml/min which changed to 54.4, 57.0 and 61.0 ml/min (all p < 0.001 in comparison with baseline) on postoperative days 7-10, 365 and 730, respectively. While median eGFR between LKD- and RN-groups was nearly equal (85.1 vs. 85.3 ml/min; p = 0.786), median immediate postoperative eGFR was significantly lower in the LKD-group (54.3 vs. 60 ml/min; p = 0.002). Furthermore, in LKD, the percentage decrease compared with baseline was significantly higher (34.4 vs. 32 %; p = 0.017). CONCLUSIONS: In living kidney donors, median eGFR decreased by 34.4 % immediately after surgery. Compared with matched RN-patients, immediate postoperative IRF is significantly more pronounced. One explanation may be that in kidney tumor patients, compensatory adaptive filtration activity of the contralateral kidney sets in already preoperatively.

Impact of miR-21, miR-126 and miR-221 as prognostic factors of clear cell renal cell carcinoma with tumor thrombus of the inferior vena cava.

Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.

Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3.

A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high-risk prostate cancer, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness, and apoptosis in prostate cancer at least partially via STAT1/STAT3-mediated activation of the JAK/STAT signaling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signaling pathway. miR-221 expression sensitized prostate cancer cells for IFN-γ-mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk prostate cancer.

Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. METHODS: Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). RESULTS: RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. CONCLUSIONS: A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.