[Impact of the experience of urological senior physicians in Germany on professional and personal aspects]. / Welchen Einfluss hat die Dauer der Oberarzttätigkeit auf die Berufsausübung und Zufriedenheit urologischer OberärztInnen in Deutschland?

BACKGROUND: Urological senior physicians in Germany are a heterogeneous group with various clinical priorities and career objectives. To date, there are no reliable data concerning the impact of the time span for which senior physicians have been holding their position on professional, personal and position-linked aspects. MATERIAL AND METHODS: The objective of this study was a comparative analysis of perspectives, private and professional settings, specific job-related activities and individual professional goals of urological senior physicians in Germany based on their experience in this position assessed as number of years (dichotomised at 8 years as senior physician). As part of a cross-sectional study, a 55-item web-based questionnaire was designed, which was sent via a link to members of a mailing list of the German Society of Urology. The survey was available for urological senior physicians between February and April 2019. Group differences were evaluated using multivariate regression models. RESULTS: 107 of 192 evaluable questionnaires were completed by senior physicians holding this position for less than 8 years (< 8y senior physicians), 85 were completed by senior physicians holding this position for at least 8 years (≥ 8y senior physicians). < 8y senior physicians worked significantly more often at university hospitals (42.1 % vs. 18.8 %, p = 0.002). Overall, 82.4 % of ≥ 8y senior physicians assessed themselves autonomously safe in performing open surgery, compared to 39.3 % among < 8y senior physicians (p < 0.001). No significant differences concerning the self-assessment were found for endourological procedures (94.1 % vs. 87.9 %) and for the overall lower-rated self-assessment concerning laparoscopy (29.4 % vs. 20.6 %) and robotic surgery (14.1 % vs. 10.3 %). Despite the high management responsibility associated with their position, only about one third of participants (34.8 %) had received specific postgraduate education preparing them for managing and executive tasks. CONCLUSION: This study shows significant differences among senior physicians regarding surgical skills depending on the time span they hold their position. Moreover, there is considerable dissatisfaction regarding the development of leadership skills and the preparation for managing tasks. In order to ensure availability of senior staff members for the field of urology in the future, it is important to consider their professional needs and to overcome existing shortcomings by education programs within well-orchestrated human resources development strategies.

Partial nephrectomy preserves renal function without increasing the risk of complications compared with radical nephrectomy for renal cell carcinomas of stages pT2-3a.

OBJECTIVES: To compare the operative and functional result of partial and radical nephrectomy in renal cell carcinomas of stages pT2-3a. METHODS: Consecutive patients with renal cell carcinoma of stages pT2-3a, cN0 and cM0, who underwent partial or radical nephrectomy between January 2005 and October 2019 at a tertiary care center were included. Data were collected retrospectively. End-points included severe postoperative complications (Clavien-Dindo classification ≥3), acute and chronic renal function impairment, and overall survival. Uni- and multivariable outcome analyses were based on logistic regression. RESULTS: A total of 158 patients were included (110 radical nephrectomy and 48 partial nephrectomy). Over time, partial nephrectomy was increasingly used. A RENAL score ≥10 was the only independent predictor influencing the surgical approach (radical nephrectomy vs partial nephrectomy, odds ratio 8.62, 95% confidence interval 3.32-22.37, P < 0.001). No significant differences in complications for radical nephrectomy versus partial nephrectomy were found (12.7% vs 8.3%, P = 0.424). Renal function was better preserved in the partial nephrectomy group (the latest chronic kidney disease stage ≥3: radical nephrectomy 73% vs partial nephrectomy 41%, P = 0.005). The surgical approach was a significant factor for chronic kidney disease (odds ratio 51.07, 95% confidence interval 3.57-730.59, P = 0.004). Overall survival did not significantly differ between radical nephrectomy and partial nephrectomy (mean overall survival 85.86 months, 95% confidence interval 3.83-78.36 vs 81.28 months, 95% confidence interval 4.59-72.29, P = 0.702). CONCLUSIONS: In selected patients, partial nephrectomy can be used in large or locally advanced renal cell carcinoma. Compared with radical nephrectomy, it allows better preservation of renal function without harboring an increased risk of severe postoperative complications.

Perioperative Blood Transfusion Is a Predictor of Acute and Chronic Renal Function Deterioration after Partial and Radical Nephrectomy for Renal Cell Carcinoma.

INTRODUCTION: The aim was to evaluate the impact of perioperative blood transfusions (PBTs) on renal function after surgery for renal cell carcinoma (RCC). METHODS: Consecutive patients with RCC who underwent partial nephrectomy or radical nephrectomy between 2005 and 2015 at a tertiary care center were included. Minimum follow-up period was 6 months. A PBT was defined as the transfusion of packed erythrocyte concentrate (EC) within 7 days before until 30 days after surgery. The multivariable analyses were carried out by Cox regression. RESULTS: The overall cohort included 851 patients, of whom 93 (10.9%) received a PBT. The median follow-up was 46 months (range 28-72). In case of a PBT, a median of 2 EC was transfused. PBT patients were older and had a poorer performance status and more comorbidities as well as locally more advanced or metastatic tumors. In the multivariable analyses, PBT was an independent prognostic factor for acute as well as chronic renal impairment (hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.45-5.10, p = 0.002 and HR 2.23, 95% CI 1.26-3.70, p = 0.007). CONCLUSION: PBT is associated with acute and chronic deterioration of kidney function after surgery for RCC. Thus, it may be used to identify patients requiring close nephrological monitoring.

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.

Nephrometry Scores: The Effect of Imaging on Routine Read-out and Prediction of Outcome of Nephron-sparing Surgery.

BACKGROUND/AIM: This study investigated the impact of available preoperative imaging on the reliability and predictive accuracy of RENAL and PADUA nephrometry-scoring systems for renal tumors. PATIENTS AND METHODS: Five urologists determined RENAL and PADUA scores using preoperative imaging data (computed tomography and magnetic resonance imaging) of 100 patients admitted for partial nephrectomy with the following combinations: T0: transverse planes without excretory phase (EP), TC0: transverse and coronal planes without EP, TC1: transverse and coronal planes with EP. Reference standard was obtained by a uro-radiologist. Ischemia time was used as surrogate for surgical complexity. RESULTS: Assignment of EP significantly reduced interobserver-variability among urologists (p<0.0001). Predictive accuracy for surgical complexity or correct assignment to nephrometry risk groups did not depend on image planes or EP. CONCLUSION: Interobserver variability, but not predictive accuracy of nephrometric systems, is affected by additional usage of EP.

Outcome of papillary versus clear cell renal cell carcinoma varies significantly in non-metastatic disease.

Renal cell carcinoma (RCC) comprises a heterogenous group of tumors. Traditionally, papillary RCC (pRCC) is associated with a favorable outcome compared to clear cell RCC (ccRCC), while other series report equivalent or worse prognosis. In this paper we comparatively evaluate outcome of pRCC versus ccRCC in two large multi-institutional databases (cohort study), including distribution of pRCC subtypes 1 and 2. Retrospective data of 1,943 surgically treated pRCC patients from 17 European/ North American centers between 1984-2015 were compared to 5,600 ccRCC patients from a database comprising 11 European/ North American centers (1984-2011). Median follow-up was 64.6 months. Differences between pRCC, subtypes, and ccRCC were compared with t-tests, Chi^2-tests, and exact Fisher tests. Cancer-specific mortality was analyzed with cumulative incidence curves and Cox cause-specific hazard models. The robustness of our results was examined with sensitivity analyses. We present that cancer-specific mortality rates and variables as stage, lymph node, and distant metastasis differ significantly between groups. Furthermore, we demonstrate that patients with non-metastatic pRCC had a significantly better cancer-specific mortality (HR 0.76, p = 0.007), when compared to ccRCC. Additionally, pRCC type 2 versus ccRCC exhibited no difference in cancer-specific mortality (HR 0.9, p = 0.722), whereas pRCC type 1 versus ccRCC displayed a risk of death reduced by 69% (p = 0.044). Taken together, outcome of pRCC versus ccRCC varies significantly in non-metastatic disease. Furthermore, pRCC type 2 exhibited no difference in cancer-specific mortality, whereas pRCC type 1 displayed a significantly reduced risk of death. Consequently, there is urgent need to respect histopathological entities and their subtypes, when assigning follow-up or targeted therapy to RCC patients.

Organ Preservation Is Less Frequently Performed in Women Surgically Treated for Papillary Renal Cell Carcinoma-Results of a Comprehensive Multicenter Study.

OBJECTIVE: To analyze the impact of gender on the clinicopathologic features and survival of patients with surgically treated papillary renal cell carcinoma (papRCC) using a comprehensive international multicenter database. MATERIALS AND METHODS: Data of 2325 patients undergoing surgery for unilateral papRCC between 1984 and 2015 in 17 European and North American centers were retrospectively collated. The impact of clinicopathologic features on the likelihood of nephron-sparing surgery (NSS) was evaluated using a multivariable logistic regression model. The influence on cancer-specific mortality (CSM) and other-cause mortality was analyzed by multivariable competing-risk regression models. Finally, subgroup analyses were conducted for organ-confined (n = 2075) and non-organ-confined tumors (n = 250). The median follow-up was 47 months. RESULTS: The study cohort included 1782 (77%) male patients (male-to-female ratio 3.3:1.0). Considering age, symptoms at presentation, performance status, pathologic tumor size, stage, and grade, we observed that there were no significant gender-specific differences. In contrast, female patients underwent NSS significantly less frequently (P <.001). On multivariable analysis, the likelihood of NSS was 72% higher in male patients after adjusting for all relevant cofactors (P <.001). No significant gender-specific differences in terms of CSM and other-cause mortality were demonstrated, but CSM was 59% lower in female patients in the subgroup of organ-confined tumors (P = .001). CONCLUSION: No impact of gender on survival was found analyzing this large cohort of patients undergoing surgery for papRCC. However, CSM appears to be lower in female patients with organ-confined disease. In this context, it is interesting that the likelihood of NSS seems to be significantly higher in male patients.

Prognostic and discriminative power of the 7th TNM classification for patients with surgically treated papillary renal cell carcinoma: results of a multi-institutional validation study (CORONA subtype project).

OBJECTIVE: Studies on the prognostic reliability of the Union for International Cancer Control tumor, node, metastasis (TNM) staging system for renal cell carcinoma (RCC) predominantly focus on clear-cell RCC. Therefore, the aim of this study was to investigate whether the oncological prognosis of surgically treated papillary RCC (papRCC) patients is reliably given by the current TNM system, by analyzing the largest database reported to date. MATERIALS AND METHODS: Data on 2325 papRCC patients who underwent surgical treatment in 1984- 2015 were collated from 17 international centers (median follow-up 47 months). Tumor stage was adapted to the 7th edition of the TNM system. Multivariable, bootstrap-corrected Cox regression models were applied to assess the independent impact of the TNM system on cancer-specific mortality (CSM) and all-cause mortality (ACM). RESULTS: The median age at diagnosis was 63 years (interquartile range 54-70 years) and 77% of patients were male. Nephron-sparing surgery was performed in 42%, and 82% were with symptom free at diagnosis. In 6.7% (n = 156), organ metastasis (stage M1) was present at the time of surgery. On multivariable analysis, the TNM system and Fuhrman grade had an independent impact on both CSM and ACM, while patient age affected ACM only. The discriminative ability of the pT classification was significant for both endpoints: 5 year CSM rates were 5%, 17%, 36% and 56% for stages pT1, pT2, pT3 and pT4, respectively (each p < 0.001). The pT classification contributed significantly to the predictive accuracy of the CSM and ACM models by 6.3% and 2.5%, respectively (each p < 0.001). CONCLUSIONS: The 2010 TNM staging system can be reliably applied to papRCC patients and allows certain prognostic discrimination.

Metabolic Syndrome Negatively Impacts the Outcome of Localized Renal Cell Carcinoma.

The aim of this study was to analyze the impact of metabolic syndrome (MetS) on outcome of patients with localized renal cell carcinoma (RCC). A retrospective database was compiled consisting of 646 patients who underwent surgery for localized RCC between 2005 and 2014. A total of 439 patients were eligible for final analysis. For diagnosis of MetS, the WHO criteria of 1998 were used. Median follow-up was 32 months (ranging from 2 to 119). Kaplan-Meier and log-rank analyses were performed to compare patients with and without MetS or its components. Univariate and multivariate logistic regression identified prognostic factors for progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). In our cohort, 9.8% (n = 43) of patients were diagnosed with MetS. There were no differences between patients with and without MetS regarding clinicopathological parameters with the exception of patients' age (p = 0.002). Kaplan-Meier and log-rank analyses revealed a shorter PFS for patients with MetS (p = 0.018), whereas no differences were found for each of the single components of MetS, namely, diabetes mellitus (DM) (p = 0.332), BMI >30 kg/m2 (p = 0.753), hypertension (p = 0.451), and hypertriglyceridemia (p = 0.891). Logistic regression identified age (HR = 1.92, p = 0.03), tumor stage (HR = 4.37, p < 0.001), grading (HR = 4.57, p < 0.001), nodal status (HR = 3.73, p = 0.04), surgical margin (HR = 1.96, p = 0.04), concomitant sarcomatoid differentiation (HR = 5.06, p < 0.001), and MetS (HR = 1.98, p = 0.04) as independent factors for PFS. For CSS, only age (HR = 2.62, p = 0.035), tumor stage (HR = 3.06, p < 0.02), and grading (HR = 6.83, p < 0.001) were significant. In conclusion, patients with localized RCC and MetS show significantly reduced PFS and might profit from specific consultation and follow-up.

Tumor size and invasiveness matters for partial nephrectomy: External validation and modification of the arterial based complexity score.

BACKGROUND: Outcome of partial nephrectomy (PN) depends on anatomic features of the renal tumor, which can be assessed by nephrometry scores. The aim was to externally validate and refine the Arterial Based Complexity (ABC) score and to compare it to established systems. METHODS: Tumors of 300 patients undergoing PN were categorized according to the ABC, RENAL, and PADUA score. Size and tumor invasiveness were combined to form the ABCD score. Correlation analysis and multivariate logistic regression was performed to validate and compare the respective scores as predictors of surgical outcome. RESULTS: The ABC score shows significant correlation with ischemia time (IT) (P < 0.01), opening of the collecting system (CS) (P < 0.01), and conversion to nephrectomy (P = 0.01). In the multivariate analysis, the ABC score was predictive for on-clamp excision (P < 0.01) and opening of the CS (P < 0.01) only. The RENAL and ABCD scores were independent predictors for complications (P = 0.02, P = 0.05), IT (P < 0.01, P = 0.03), on clamp excision (P < 0.01, P < 0.01), and opening of the CS (P < 0.01, P < 0.01). CONCLUSIONS: The ABC score correlates well with surgical parameters. Expanding the score by tumor diameter gives the ABCD system. It has similar predictive effectiveness to the well-established RENAL score, but features simplicity by only assessing invasiveness and tumor size.

Bladder Neck Contracture After Radical Prostatectomy: What Is the Reality of Care?

OBJECTIVES: To evaluate the therapeutic methods and algorithms currently used in the treatment of bladder neck contracture (BNC) after radical prostatectomy (RP). MATERIALS AND METHODS: Heads of 170 urologic departments in Germany, listed at the German Society of Urology (DGU), were invited to participate in an Internet-based customized survey. The questions consisted of an epidemiologic part (kind of hospital, state of practice) and questions inquiring used surgical techniques with their respective incidence and given algorithms for therapy. RESULTS: Of 170 contacted heads of urologic departments in Germany, 84 responded to the questionnaire (return rate 49.41%). The most common treatment modalities are transurethral resection, cold knife incision, hot knife incision, and dilation in descending order. For those institutions using several treatment modalities, 56 (66.67%) follow a therapeutic algorithm, while 28 (33.33%) follow no set order of treatment. However, among the 56 institutions with a set algorithm, 33 different approaches were identified. Of 84 institutions, 29 (34.52%) perform open reanastomosis in case of recurrent BNC, the remaining 55 (65.48%) do not. CONCLUSION: Despite several published guidelines on urethral strictures, numerous self-employed treatment algorithms are used to treat BNC. Although treatment results of these algorithms and the underlying treatment modalities cannot be determined with this work, it highlights the necessity for further studies comparing the different surgeries to allow for a more evidence-based approach.

Defining Renal Masses: Comprehensive Comparison of RENAL, PADUA, NePhRO, and C-Index Score.

BACKGROUND: Nephrometry scores are designed for standardized reporting of renal tumors and predicting complications. Multiple scores are available, but there is a lack of systematic comparison. PATIENTS AND METHODS: A total of 305 consecutive patients admitted for open partial nephrectomy to 2 urological hospitals were prospectively assessed. Five cases with conversion to radical nephrectomy were excluded from further analysis. RENAL, PADUA, C-index, and NePhRO scores were obtained from preoperative sectional imaging. Additionally, interobserver variance between 2 urologists and a radiologist was analyzed for 50 patients. Linear and ordered logistic regression was used to evaluate the association between scores and surgical parameters. Receiver operating characteristic analysis was employed to assess the predictive value for requirement of ischemia and opening of the collecting system. RESULTS: High interobserver agreement was observed for RENAL (0.92 and 0.80), PADUA (0.81 and 0.85), NePhRO (0.94 and 0.82), and the C-index (0.98 and 0.95). All scores showed a significant association with opening of the collecting system (P < .016), requirement of on-clamp excision (P < .001), and ischemia time (P < .001). Logistic regression identified RENAL, PADUA, and NePhRO score to be an independent predictor for severe complications (P = .016, P = .011, and P = .005). No correlation was found for the C-index (ß = 0.98; P = .779). Predictive effectiveness for opening of the collecting system and for on-clamp excision showed comparable area under the curve values for the 4 scores. CONCLUSION: All scoring systems represent objective and reproducible measurement tools for renal tumor complexity, that correlate well with surgical outcome. RENAL, PADUA, and NePhRO score are comparable and seem to be superior to the more complex C-index system.

The soluble Decoy Receptor 3 is regulated by a PI3K-dependent mechanism and promotes migration and invasion in renal cell carcinoma.

BACKGROUND: Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown. METHODS: Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally, an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimens. RESULTS: Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K/AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells (NFAT). CONCLUSIONS: Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.

Prognostic value of melanoma-associated antigen A9 in renal cell carcinoma.

OBJECTIVE: The aim of this study was to evaluate the prognostic relevance of melanoma-associated antigen (MAGE) A9 in renal cell carcinoma (RCC). MATERIAL AND METHODS: Immunohistochemical staining for MAGE A9 was evaluated in a tissue microarray containing 587 RCC tumour tissue samples. Nuclear MAGE A9 expression was reviewed using a semiquantitative score. Follow-up has been surveyed since 1990 in a prospectively conducted tumour database. The effect of MAGE A9 expression on cancer-specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Subgroup analyses were performed for non-metastatic and metastatic disease. RESULTS: Median age in all patients was 63.2 years, 354 patients were male and 233 female, and 108 patients had metastatic disease. Median follow-up was 5.6 years for all patients and 9.0 years for patients still alive (range 0-19.9 years). High nuclear MAGE A9 expression was present in 326 tumour specimens (55.5%). In multivariate analyses high nuclear MAGE A9 expression was associated with poor CSS (p = 0.0027). Furthermore, tumour stage, lymph-node and distant metastasis, Fuhrman grade G3/4, Karnofsky index < 80% and male gender were associated with poor CSS. In subgroup analyses, results were concordant for patients with non-metastatic disease. In patients with metastatic disease, only Karnofsky index > 80% was a significant predictor for CSS; MAGE A9 expression could not be shown to be associated with CSS (p = 0.161). CONCLUSIONS: High nuclear MAGE A9 expression is independently associated with poor CSS in patients with non-metastatic RCC. The assessment of MAGE A9 expression can provide additional prognostic information and should be used in decision-making regarding adjuvant therapy in patients with non-metastatic disease.

PSA density lower cutoff value as a tool to exclude pathologic upstaging in initially diagnosed unilateral prostate cancer: impact on hemiablative focal therapy.

PURPOSE: To investigate prostate-specific antigen density as a predictor for pathologic upstaging in patients initially thought to have unilateral prostate cancer. METHODS: We analyzed 438 patients with unilateral prostate cancer in prostate biopsy samples that were treated with radical prostatectomy. Bilateral or extracapsular growth in the final surgical specimens was defined as upstaging. Using Kaplan-Meier curves and a multivariate Cox proportional hazard model, we evaluated the oncologic effect of pathologic upstaging on biochemical recurrence-free survival. Prostate-specific antigen density was evaluated as a diagnostic tool to predict upstaging using ROC-curve analysis. RESULTS: Of the patients, 30.8% had bilateral prostate cancer or extracapsular extension in the surgical specimen. Prostate-specific antigen density was a diagnostic predictor for pathologic upstaging in patients initially thought to have unilateral prostate cancer (AUC 0.62, P < 0.001). Using a lower cutoff value of PSA density <0.056 ng/ml/cm3, upstaging could be excluded in patients with a sensitivity of >98%. CONCLUSIONS: A considerable amount of patients that are initially diagnosed with unilateral prostate cancer on biopsy are underdiagnosed and are upstaged in the radical prostatectomy specimen. In general, AUC of PSA density is too low to use PSA density as diagnostic tool to predict pathologic upstaging in all patients. Nonetheless, PSA density could be used for hemiablative focal therapy decision making using a lower cutoff value of <0.056 ng/ml/cm3.

Molecular heterogeneity of TFE3 activation in renal cell carcinomas.

Renal cell carcinomas associated with Xp11.2 translocations have recently been identified as a distinct biological entity. The translocation results in the fusion of the transcription factor TFE3 to one of several different fusion partners including PRCC, PSF, NONO, ASPL or CTLC with consecutive overexpression of the chimeric protein. As the true frequency of these neoplasms as well as the biological properties of TFE3 activation in renal cell carcinomas are largely unknown, we have examined TFE3 expression as well as the underlying genetic alterations in a large, hospital-based series of renal cell carcinomas with long-term follow-up information. Out of a total of 876 tumours, TFE3 translocations were detected in five cases (0.6%). Three additional cases were identified in a second series of cases comprising of renal cell carcinomas developing in patients before the age of 50. However, using immunohistochemistry, 9% of all renal cell carcinomas showed some degree of TFE3 reactivity. Interestingly, these cases were associated with high nuclear grade, greater tumour extent and metastatic disease as well as an unfavourable patient outcome on uni- and multivariate analysis. Fluorescence in situ hybridisation (FISH) revealed TFE3 amplifications as an additional, novel mechanism leading to increased TFE3 expression levels. In conclusion, our data show that Xp11 translocation renal cell carcinomas are uncommon tumours accounting for <1% of adult renal cell carcinomas and that the diagnosis of Xp11 translocation renal cell carcinomas needs to be verified using molecular techniques. In turn, TFE3 overexpressing tumours show an aggressive behaviour and Xp11 translocation is only one of several possible underlying genomic alterations.

EZH2 depletion blocks the proliferation of colon cancer cells.

The Enhancer of Zeste 2 (EZH2) protein has been reported to stimulate cell growth in some cancers and is therefore considered to represent an interesting new target for therapeutic intervention. Here, we investigated a possible role of EZH2 for the growth control of colon cancer cells. RNA interference (RNAi)-mediated intracellular EZH2 depletion led to cell cycle arrest of colon carcinoma cells at the G1/S transition. This was associated with a reduction of cell numbers upon transient transfection of synthetic EZH2-targeting siRNAs and with inhibition of their colony formation capacity upon stable expression of vector-borne siRNAs. We furthermore tested whether EZH2 may repress the growth-inhibitory p27 gene, as reported for pancreatic cancer. However, expression analyses of colon cancer cell lines and colon cancer biopsies did not reveal a consistent correlation between EZH2 and p27 levels. Moreover, EZH2 depletion did not re-induce p27 expression in colon cancer cells, indicating that p27 repression by EZH2 may be cell- or tissue-specific. Whole genome transcriptome analyses identified cellular genes affected by EZH2 depletion in colon cancer cell lines. They included several cancer-associated genes linked to cellular proliferation or invasion, such as Dag1, MageD1, SDC1, Timp2, and Tob1. In conclusion, our results demonstrate that EZH2 depletion blocks the growth of colon cancer cells. These findings might provide benefits for the treatment of colon cancer.

Selective transarterial embolization for posttraumatic renal hemorrhage: a second try is worthwhile.

PURPOSE: Selective percutaneous transarterial embolization has proved to be effective, safe treatment for posttraumatic renal hemorrhage but inefficacious procedures often lead to nephrectomy. Thus, the success rate of transarterial embolization should be maximized. MATERIAL AND METHODS: We retrospectively investigated the clinical success rate of transarterial embolization for posttraumatic bleeding. Study inclusion criteria were imaging evidence and clinical signs of hemorrhage or a hemoglobin decrease of more than 2 gm/dl in urological cases. We excluded spontaneous bleeding from analysis. RESULTS: A total of 21 patients with a median age of 66 years (range 12 to 78) met study inclusion criteria. Etiology was blunt trauma in 3 cases (14%), stab wound in 1 (5%) and an iatrogenic cause in 17 (81%). In 2 patients an active bleeding site could not be detected during selective angiography. Transarterial embolization was done in 19 patients and led to primary clinical success in 12 (63%), including 2 with grade V parenchymal injury. In 6 of 7 cases (86%) in which primary treatment failed transarterial embolization was repeated. It resulted in clinical success in 4 of 6 patients (67%) with equal efficiency (p =1). Three patients (16%) who could not be sufficiently treated with transarterial embolization underwent nephrectomy. CONCLUSIONS: When conservative measures fail and clinical symptoms or a relevant hemoglobin decrease occur, transarterial embolization should be considered. Since the success rate is equally high for initial and repeat interventions, re-intervention is justified when the clinical course allows.

Expression and prognostic relevance of the death receptor CD95 (Fas/APO1) in renal cell carcinomas.

CD95 (Fas/APO1) is one of the best known members of the death receptor family which can either mediate apoptosis or activate tumor-promoting pathways. Using a tissue microarray we investigated the association between the expression of CD95 and prognosis in 617 patients with renal cell carcinomas (RCCs). CD95 was expressed in the vast majority of RCCs. High CD95 expression was associated with lymph node metastasis and correlated negatively with disease-specific survival. Multivariate Cox regression analysis confirmed CD95 expression as an independent prognostic factor. In conclusion, high CD95 expression is a negative independent prognostic factor in RCCs which could be used to identify high-risk patients with a poor clinical prognosis.

Initial experience with temsirolimus in 2nd-, 3rd- and 4th-line therapy for metastatic renal cell cancer: good clinical response.

PURPOSE: To report our experience with temsirolimus in 2nd-, 3rd- and 4th-line therapy for patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In our prospectively maintained tumor registry, we identified 6 mRCC patients with temsirolimus in >1st-line systemic therapy. Patients were followed by weekly clinical and laboratory examination during admission of temsirolimus. Re-staging with chest CT and abdominal MRI was performed every 3 months. RESULTS: We observed excellent response rates. Progression-free survival (PFS) ranged from 6 to 40 months with a median of 15 months. Treatment was generally well tolerated. However, pneumonitis was observed in 4 of 6 patients. Drug-related pneumonitis led to severe dyspnea, with the result that treatment with temsirolimus had to be interrupted for a short period of time in 2 patients and discontinued in 1 patient. CONCLUSIONS: Temsirolimus proved to be a very good treatment option in 2nd- to 4th-line therapy with excellent response rates and manageable side effects. The incidence of pneumonitis must not be underestimated.