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To the Editor: In their article on the PREVAIL trial, Beer et al. (July 31 issue) 1 report that enzalutamide was associated with decreased mortality in men with asymptomatic or minimally symptomatic castration-resistant prostate cancer, even though patients with poor-risk visceral disease were included and patients in the placebo group had received post-progression therapy more frequently and earlier than those receiving enzalutamide. The authors report that 40% of patients in the enzalutamide group and 70% of those in the placebo group underwent subsequent antineoplastic treatments. The two most common subsequent therapies were docetaxel and abiraterone. In patients with castration-resistant prostate cancer, . . .

ObjectiveOur aim was to assess and compare trends of urinary diversion (UD) for patients receiving radical cystectomy for the treatment of bladder cancer in the US and Germany, and to investigate decisive predictors for the choice of UD.MethodsWe analyzed the nationwide German hospital billing database and the Nationwide Inpatient Sample (NIS) from 2006 to 2014. Cases with a bladder cancer diagnosis combined with RC were included, and trends in the choice of UD, transfusion rates, length of stay, and mortality were assessed.ResultsFrom 2006 to 2014, the total number of RCs recorded within the NIS were 17,711, with a varying annual caseload of 1666–2009, while RC numbers increased from 5627 to 7390 in Germany (p < 0.001 for trends), with a total of 60,447 cases. The share of incontinent UD in the US remained stable at 93%, while increasing from 63.2 to 70.8% in Germany. Multivariate models indicated age and sex were the most important factors associated with the choice of UD in both countries, while hospital caseload and teaching status were less relevant factors in the US. In-hospital mortality was lower in the US compared with Germany (1.9% vs. 4.6%; p < 0.001), with significantly shorter hospital stays (10.7 days in the US vs. 25.1 days in Germany; p < 0.001).ConclusionsThe increasing age of patients with presumably higher comorbidity in recent years led to increased use of incontinent UD in Germany, while continent UD appears to be underused in the US. Mortality and transfusion rates were significantly lower in the US within a shorter hospital stay.

In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223. We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16. Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5–11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13–not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months–NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11–15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14–NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8–14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months–NA) than for patients with an ECOG PS of 1 (median 13 months, 11–NA) or an ECOG PS of 2 or more (median 7 months, 5–11); and for patients with no reported baseline pain (median NA, 16 months–NA) than for those with mild pain (median 14 months, 13–NA) or moderate–severe pain (median 11 months, 9–13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months–NA) than in those who did not receive these agents (median 13 months, 12–16), and in patients who received radium-223 plus denosumab (median NA, 15 months–NA) than in patients who received radium-223 without denosumab (median 13 months, 12–NA). Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials. Pharmaceutical Division of Bayer.

Purpose Outcomes of radical prostatectomy are prone to publication bias, because most of the data originated from highly specialized centers. We assessed in-hospital outcomes of all radical prostatectomies in Germany from 2006 to 2013 focusing on caseload volume, surgical approach, and certification status. Methods We analyzed the nationwide German hospital billing data covering 221,331 radical prostatectomies from 2006 to 2013. Outcomes were in-hospital mortality, surgical revision, and transfusion rates and the length of stay. Multivariate models described the impact of these factors. Results The yearly number of radical prostatectomies declined from 28,374 to 21,850. While shares of all other approaches decreased, shares for robot-assisted prostatectomy increased from 0.6 to 25.2%. Hospitals with ≥100 cases a year reported lower in-hospital mortality with 0.08 versus 0.17% for hospitals with <50 cases a year. On multivariate analysis, the odds for an individual death were doubled in hospitals with <50 cases a year. All other factors showed no significant impact on mortality. Concerning blood transfusion, the surgical approach was the strongest predictor with minimally invasive surgery (26% of the odds of conventional surgery) followed by caseload volume. Surgical revision was frequent in hospitals with lower rates of minimally invasive approaches (OR 1.6) and smaller caseloads (OR 1.4). Length of stay was reduced by 3 days for caseloads ≥200 a year, 2 days with minimally invasive approaches, and 1 day in certified prostate cancer centers. Lacking clinical information is a major limitation. Conclusions Annual caseload volume of hospitals is the most important factor for improved in-hospital outcomes.

Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation of the von Hippel-Lindau gene (VHL) which in turn leads to the induction of HIF1α target genes such as CA9 and VEGF. Furthermore, the angiogenic phenotype of ccRCC is also reflected by endothelial markers (CD31, CD34) or other tumor-promoting factors like Ki67 or survivin. Tissue microarrays from primary tumor specimens of 42 patients with metastatic ccRCC under sunitinib therapy were immunohistochemically stained for selected markers related to angiogenesis. The prognostic and predictive potential of theses markers was assessed on the basis of the objective response rate which was evaluated according to the RECIST criteria after 3, 6, 9 months and after last report (12-54 months) of sunitinib treatment. Additionally, VHL copy number and mutation analyses were performed on DNA from cryo-preserved tumor tissues of 20 ccRCC patients. Immunostaining of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β was significantly associated with the sunitinib response after 6 and 9 months as well as last report under therapy. Furthermore, HIF-1α, CA9, CD34, VEGFR1 and -3 and PDGRFα showed significant associations with progression-free survival (PFS) and overall survival (OS). In multivariate Cox proportional hazards regression analyses high CA9 membrane staining and a response after 9 months were independent prognostic factors for longer OS. Frequently observed copy number loss and mutation of VHL gene lead to altered expression of VHL, HIF-1α, CA9, and VEGF. Immunoexpression of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β in the primary tumors of metastatic ccRCC patients might support the prediction of a good response to sunitinib treatment.

Purpose The tumor-suppressive microRNAs miR-26a and miR-138 are significantly down-regulated in prostate cancer (PCa) and have been identified as direct regulators of enhancer of zeste homolog 2 (EZH2), which is a known oncogene in PCa. In the present study, the influence of miR-26a and miR-138 on EZH2 and cellular function including the impact on the cell cycle regulating network was evaluated in PCa cells. Methods PC-3 and DU-145 PCa cells were transfected with 100 nM of miRNA mimics, siRNA against EZH2 (siR-EZH2) or control constructs for 4 h. Analyses of gene expression and cellular function were conducted 48 h after transfection. Results Both miRNAs influenced the EZH2 expression and activity only marginally, whereas siR-EZH2 led to a notable decrease of the EZH2 expression and activity. Both miRNAs inhibited short- and/or long-term proliferation of PCa cells but showed no effect on viability and apoptosis. In PC-3 cells, miR-26a and miR-138 caused a significant surplus of cells in the G0/G1 phase of 6 and 12 %, respectively, thus blocking the G1/S-phase transition. Treatment with siR-EZH2 was without substantial influence on cellular function and cell cycle. Therefore, alternative target genes involved in cell cycle regulation were identified in silico . MiR-26a significantly diminished the expression of its targets CCNE1, CCNE2 and CDK6, whereas CCND1, CCND3 and CDK6 were suppressed by their regulator miR-138. Conclusions The present findings suggest an anti-proliferative role for miR-26a and miR-138 in PCa by blocking the G1/S-phase transition independent of EZH2 but via a concerted inhibition of crucial cell cycle regulators.

Currently, voided urine cytology (VUC) serves as the gold standard for the detection of bladder cancer (BCa) in urine. Despite its high specificity, VUC has shortcomings in terms of sensitivity. Therefore, alternative biomarkers are being searched, which might overcome these disadvantages as a useful adjunct to VUC. The aim of this study was to evaluate the diagnostic potential of the urinary levels of selected microRNAs (miRs), which might represent such alternative biomarkers due to their BCa-specific expression. Expression levels of nine BCa-associated microRNAs (miR-21, -96, -125b, -126, -145, -183, -205, -210, -221) were assessed by quantitative PCR in urine sediments from 104 patients with primary BCa and 46 control subjects. Receiver operating characteristic (ROC) curve analyses revealed a diagnostic potential for miR-96, -125b, -126, -145, -183, and -221 with area under the curve (AUC) values between 0.605 and 0.772. The combination of the four best candidates resulted in sensitivity, specificity, positive and negative predictive values (NPV), and accuracy of 73.1%, 95.7%, 97.4%, 61.1%, and 80.0%, respectively. Combined with VUC, sensitivity and NPV could be increased by nearly 8%, each surpassing the performance of VUC alone. The present findings suggested a diagnostic potential of miR-125b, -145, -183, and -221 in combination with VUC for non-invasive detection of BCa in urine.

PurposeTo investigate acceptance and efficacy of recommended adjuvant radiotherapy in patients with positive lymph nodes at radical prostatectomy.MethodsAmong 495 patients with positive lymph nodes who consecutively underwent radical prostatectomy between 2007 and 2017, we investigated 347 patients who were recommended to undergo adjuvant radiotherapy by a multidisciplinary post-therapeutic tumor board and in whom information whether such treatment was eventually given was available. The median follow-up for censored patients was 5.4 years. Univariate analyses were performed using Kaplan–Meier curves, Mantel–Haenszel hazard ratios and log rank tests. Proportional hazard models for competing risks were used for multivariable analyses.ResultsAdjuvant radiotherapy was independently associated with lower overall mortality and in high-risk patients (Gleason score 8–10 or three or more involved lymph nodes) also with lower prostate cancer-specific mortality. In patients with a Gleason score of 8–10 or three or more involved lymph nodes, the hazard ratio for adjuvant radiotherapy was 0.455 (95% confidence interval 0.257–0.806, p = 0.0069) for overall and 0.426 (95% confidence interval 0.201–0.902, p = 0.0259) for prostate cancer-specific mortality. Among patients receiving adjuvant radiotherapy, there was a trend to lower mortality when such treatment was combined with adjuvant androgen deprivation.ConclusionAdjuvant radiotherapy decreased mortality in patients with positive lymph nodes at radical prostatectomy with further disease factors but not in patients with low-risk disease. Simultaneous androgen deprivation might increase efficacy. Multidisciplinary recommendations may possibly increase the use of adjuvant radiotherapy in this setting.