Background Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. Methods An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort ( n = 413) as training set and validated in an independent multi-center prospective cohort ( n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. Results An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85–1.01) and 0.93 (95% CI: 0.87–0.99) in the retrospective and prospective urine cohorts respectively. Kaplan–Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. Conclusions The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.

Dear Editor, Currently no accurate prognostic test is available to predict prostate cancer (PCa) biochemical recurrence (BCR) after treatment or cancer metastasis.1-7 To address the unmet medical need, we developed a novel 23-Gene Classifier urine test as the first accurate and noninvasive tool for PCa prognosis with potential to improve cancer treatment. We used previously identified biomarkers with differential gene expression in PCa and benign prostate as candidates for BCR prediction and metastasis.8-10 Discriminant analysis was used to assess the ability of various combinations of mRNA expression quantities of the biomarker candidates in prostate tissue specimens collected before prostatectomy with BCR information during follow-up as classifiers to distinguish BCR and non-BCR patients. A 23-Gene Classifier consisting of PTEN, PIP5K1A, CDK1, TMPRSS2, ANXA3, HIF1A, FGFR1, BIRC5, AMACR, CRISP3, PMP22, GOLPH2, EZH2, GSTP1, PCA3, VEGFA, CST3, CCNA1, CCND1, FN1, MYO6, KLK3, and PSCA was found to predict BCR with the highest accuracy. We followed STARD guidelines for biomarker validation. Detailed patient cohorts and study methods are described in Supplementary Methods. The prostate epithelial cells are released into the urine so urine can be used as a noninvasive liquid biopsy source to detect prostate-specific biomarkers for PCa prognosis. The 23-Gene Classifier was developed as a urine test for BCR prognosis using urines collected without digital rectal examination (DRE). Using BCR Urine Prediction Algorithm, the mRNA levels of the 23 genes were used to generate a classification score to predict the patients as having BCR or Non-BCR (Supplementary Methods). A multicenter study was designed prospectively using retrospectively collected urine samples without DRE from 520 patients before prostatectomy or other treatments (IND-CHTN cohort). Forty-six patients developed BCR during the follow-up period averaging 8 years (Table 1). A total of 105 patients from the cohort were randomly selected as a training set to test the 23-Gene Classifier urine test for BCR prediction and the resulting area under the receiver operating characteristic curve (AUC) was 0.94 (95% CI 0.87-1.01). The prognostic performance of the 23-Gene Classifier urine test to predict BCR-free survival was validated in the remaining patients (n = 414). The patients were divided into two risk groups based on diagnosis by the 23-Gene Classifier and Kaplan-Meier survival analysis showed statistically significant association of the 23-Gene Classifier Negative group with shorter BCR-free survival (∼60% BCR-free survival at 48 months) as compared with the 23-Gene Classifier Positive group (100% BCR-free survival at 120 months) (Figure 1A) (log rank P = 0.000). In contrast, the two groups segregated by cancer stage or Gleason score had much smaller difference in BCR-free survival (Figures 1B and C). Univariate and multivariate Cox regression analysis was performed and the 23-Gene Classifier had a hazard ratio (HR) of 1730.90 (95% CI 4.52-6.63E+5) in the univariate analysis (Table 2), which indicated that the patients with a positive 23-Gene Classifier score was 1731 times more likely to have BCR than patients with a negative 23-Gene Classifier score and the BCR prediction was statistically significant (P = 0.014). Its predictive power remained large and significant in multivariate regression after adjusting for cancer stage and Gleason score with HR of 1795.01 (95% CI 4.30-7.49E+5) (P = 0.015). In contrast, cancer stage and Gleason score had much lower HR and were statistically insignificant (Table 2). In addition, univariate and multivariate logistic regression and discriminant analysis were performed to measure the predictive accuracy of the 23-Gene Classifier. The result showed high accuracy with sensitivity of 100% (95% CI 100-100%), specificity of 86.29% (95% CI 82.80-89.79%), and AUC of 0.93 (95% CI 0.90-0.96) (P < 0.0001) (Tables S1 and 3, Figure 1G). Cross-validation of the 23-Gene Classifier showed similarly high accuracy in BCR prediction (Table 3). In contrast, cancer stage and Gleason score had much lower specificity and AUC (Table 3, Figures 1H and I). 100% (100-100%) 7.28% (4.63-9.92%) 10.88% (7.77-13.99%) 100% (100-100%) 100% (100-100%) 2.43% (0.86-3.99%) 10.40% (7.42-13.37%) 100% (100-100%) 100% (100-100%) 86.29% (82.80-89.79%) 45.16% (35.05-55.28%) 100% (100-100%) 23G classifier Cross-validation 100% (100-100%) 86.17% (82.14-90.20%) 45.07% (33.50-56.64%) 100% (100-100%) 100% (100-100%) 88.11% (84.81-91.41%) 48.84% (38.27-59.40%) 100% (100-100%) 16.67% (4.49-28.84%) 99.04% (97.16-100.91%) 85.71% (59.79-111.64%) 77.44% (70.34-84.55%) 48.57% (32.01-65.13%) 96.12% (92.39-99.85%) 80.95% (64.16-97.75%) 84.62% (78.08-91.15%) 86.11% (74.81-97.41%) 100% (100-100%) 100% (100-100%) 95.41% (91.49-99.34%) 23G classifier Cross-validation 87.50% (64.58-110.42%) 100% (100-100%) 100% (100-100%) 96.97% (91.12-102.82%) 85.71% (74.12-97.31%) 100% (100-100%) 100% (100-100%) 95.37% (91.41-99.33%) In silico validation study was conducted to test if the 23-Gene Classifier can also be used in prostate tissue specimens for BCR prognosis using a tissue cohort MSKCC (Table 1). Its similarly high prognostic performance (Tables 2 and 3, Figures 1D-F, K-N) validated the results from the urine study and confirmed the 23-Gene Classifier as a more accurate prognostic tool for BCR prediction than cancer stage and Gleason score. Accurate prediction of cancer metastasis at diagnosis is important for patients to be treated early with effective therapies to prevent development of castration-resistant metastatic cancer and reduce mortality. We tested if the 23-Gene Classifier urine test could be used for metastatic cancer prediction. We tested its performance in the multicenter, retrospective IND-CHTN Cohort (n = 520), a multicenter, prospective 7-HOSPITALS Cohort (n = 207), and a combination cohort combining the patients (n = 727) (Table 1). mRNA expression quantities of the 23 genes were used to classifier each sample as metastatic or nonmetastatic cancer using MET Urine Prediction Algorithm and such classification was compared with the metastatic cancer diagnosis by the imaging measurements to calculate the predictive performance (Supplementary Methods). The result showed that the 23-Gene Classifier urine test had similarly high accuracy in predicting metastatic cancer in the retrospective, prospective and combination cohorts (AUC of 0.92 [95% CI 0.79-1.05] for the retrospective cohort, 0.89 [95% CI 0.83-0.95] for the prospective cohort, and 0.98 [95% CI 0.96-1.01] for the combination cohort) (P < 0.0001). In contrast, Gleason score had much lower specificity and AUC (Table S2 and Figure 2). Development of accurate and actionable prognostic tests is important and urgently needed for PCa treatment. None of the clinicopathological parameters, nomograms, or biomarker panels used in clinic or reported in publications was capable of accurately predicting BCR or cancer metastasis with HR above 20 or AUC above 0.9.1-7 The 23-Gene Classifier had HR above 40 and AUC above 0.9 in all cohorts assessed, suggesting its higher accuracy and more robust performance for PCa prognosis. In addition, the 23-Gene Classifier can be used with prostate tissue specimens. In this study, we developed and validated a novel 23-Gene Classifier that can be used as a highly accurate and noninvasive urine test for prediction of BCR and cancer metastasis with great potential to improve PCa treatment and reduce mortality in clinical practice. The authors would like to thank C. Yun for excellent technical support and S. Liao for skillful assistance in urine collection. The retrospective urine study was approved by IRB at San Francisco General Hospital (IRB #: 15–15816) to use archived urine sediment samples acquired from Cooperative Human Tissue Network Southern Division and Indivumed GmbH. These organizations obtained ethical approval and patient consent prior to collection of patient urine samples. The prospective urine study was approved by IRB at Shenzhen People's Hospital (Study Number: P2014-006) to use urine samples collected from patients treated at the collaborating hospitals in the study with prior consent. All authors have agreed to publish the manuscript. The data supporting this study are available from the corresponding authors upon reasonable request or are publicly available in GEO. Heather Johnson is an employee of Olympia Diagnostics, Inc., and inventor of a pending patent application of prostate cancer diagnostic and prognostic biomarkers. No conflict of interest or financial interest was declared by the other authors. This study was supported by grants from Sanming Project of Medicine in Shenzhen (SZSM201412014), The Science and Technology Foundation of Shenzhen (JCYJ20170307095620828), The Science and Technology Foundation of Shenzhen (JCYJ20160422145718224), and The Shenzhen Urology Minimally Invasive Engineering Center (GCZX2015043016165448) (to Jinan Guo, and Kefeng Xiao); funds from Olympia Diagnostics, Inc. (to Heather Johnson); the Swedish Cancer Society (CAN2017/381), The Swedish Children Foundation (TJ2015-0097), H2020-MSCA-ITN-2018 GlycoImaging (721279), The Swedish National Research Council, the Malmö Cancer Foundation, the Government Health Innovation Grant, the Medical Faculty, Lund University, Kempestiftelserna, Umeå University, Medical Faculty Grants, the Norland Fund for Cancer Forskning, Insamlings Stiftelsen, Umeå University, Bioteknik medel, the Medical Faculty, Umeå University, Medical Faculty Grants, Umeå University, and grant from Umeå University Center for Microbiology Research (UCMR) and Biofilm Center at Malmö University (to Jenny Persson). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. HJ, CZ, LC, KX, and JLP contributed to study concept and design. HZ, JG, XF, CZ, KX, AHBW, and LC participated in study coordination and supervision. JG, TX, FL, and WT contributed to sample collection. XZ, JG, HJ, HZ, and XF contributed to sample processing and analysis. HZ, HJ, AJ, AS, ND, and JLP contributed to data collection and processing, and statistical analysis. HJ, PA, ND, LK, AS, and JLP contributed to data interpretation. XZ, HJ, and JLP contributed to literature search. JG, HJ, HZ, JLP, and CZ contributed to manuscript writing. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

•CernitinTM inhibit enzyme COX-2 and reduce the production of prostaglands which are known to cause pain during inflammation.•Simultaneously, CernitinTMtreatment may lead to recycling the AA to the cell membrane resulting in reduced AA release.•CernitinTM treatment inhibits conversion of testosterone to DHT, through inhibition of 5α-reductase enzyme.•Thus, decreasing AR/DHT interaction which ultimately leads to decrease proliferation and reduces PSA level.

Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available. Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups. Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892–0.942) in the retrospective cohort ( n = 520), AUC of 0.959 (95% CI 0.935–0.983) in the prospective cohort ( n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort ( n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1–3 cancer subgroups. Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.

Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function. This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not. GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques. Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.

Background Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. Methods Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. Results The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963–0.929) in the retrospective cohort ( n = 614), AUC of 0.901 (0.929–0.873) in the prospective cohort ( n = 396), and AUC of 0.936 (0.956–0.916) in the large combination cohort ( n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors ( p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980–0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947–0.909) in the combination cohort ( n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. Conclusions The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.

The pollen extract Cernitin® is widely used for treatment of benign prostatic hyperplasia (BPH) and non-bacterial chronin prostatitis. However, little is known about the underlying molecular mechanisms to explain the clinical effects of Cernitin®. In this study, we sought to investigate the cellular mechanisms by which Cernitin® induces its effects on human prostatic cell lines BPH-1 and WPMY-1 and primary human peripheral blood mononuclear cells (hPBMCs) in vitro. We examined the effects of Cernitin® formulas T60 and GBX on the protein expression, proliferation, and cytokines production. Results revealed that Cernitin® upregulated antiinflammatory cytokine interleukin (IL)-10 and its receptors IL-10RA and IL-10B in addition to the upregulation of tumour necrosis factor-related apoptosis-inducing ligand in hPBMC. Interestingly, the levels of proinflammatory cytokines IL-6 and IL-8 were also increased. Furthermore, Cernitin® had significantly increased the level of IL-10 in BPH-1 and WPMY-1 cells. The level of IL-6 was also significantly increased in these cells although both T60 and GBX inhibited STAT-3 phosphorylation. Moreover, Cernitin® formulas had significantly reduced androgen receptor and prostate-specific antigen protein expression in stromal cells (p < .05). Treatment with GBX and T60 had significantly inhibited proliferation of BPH (p < .001) and stromal cells (p < .05), in a dose-dependent manner. Taken together, treatment with Cernitin® showed to regulate cytokines level in both prostatic cell lines and hPBMCs and it was associated with decreased androgen receptor and prostate-specific antigen levels WPMY-1 cells.

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55-69yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. PATIENT SUMMARY: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated.

Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients.

Intermittent androgen deprivation therapy (IADT) is now being increasingly opted by the treating physicians and patients with prostate cancer. The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects, and reduced treatment costs. IADT may also delay the progression to castration-resistant prostate cancer. However, the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials. Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer, e.g., population characteristics (both demographic and clinical), study design, treatment regimen, on- and off-treatment criteria, duration of active treatment, endpoints, and analysis. The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs. continuous androgen deprivation therapy for the treatment of prostate cancer. The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes, especially the disease (tumor) burden. Based on evidence, potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.

Age and prostate-specific antigen levels before and at the end of active treatment seem to predict off-treatment duration for degarelix as intermittent androgen deprivation treatment (ADT). This information could be valuable in proposing an algorithm to predict the off-treatment period, optimise visit schedules, and set the restart sate for ADT.

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

The antitumor properties of melatonin (MLT) are known for prostate cancer cells. This study investigated whether MLT affects prostate maturation and interferes with tissue injuries induced by diabetes. MLT was administered to Wistar rats from 5 weeks of age in the drinking water (10 μg/kg b.w.), and diabetes was induced at the 13th week by streptozotocin (4.5 mg/100g b.w., i.p.). The animals were euthanized in the 14th and 21st weeks. MLT reduced the immunostained cells for androgen receptor (AR) by 10% in younger rats. Diabetes decreased cell proliferation and increased apoptosis. MLT treatment impeded apoptosis (p = 0.02) and augmented proliferation (p = 0.0008) and PCNA content in prostate following long-term diabetes due to restoration of testosterone levels and expression of melatonin receptor type 1B. The effect of MLT (500 µM, 5 mM, and 10 mM) on androgen-dependent (22Rv1) and androgen-independent (PC3) cancer cells and human prostate epithelial cells (PNTA1) under normal and hyperglycemic conditions (HG, 450 mg/dL) was analyzed. Contrary to PNTA1 and 22Rv1 cells, MLT improved the proliferation of PC3 cells in hyperglycemic medium. The combined data indicated that MLT had proliferative and antiapoptotic effects in prostate cells subjected to HG levels and it seems to involve specific MLT pathways rather than AR.

Context: Phase 3 trials have made major contributions to advances in prostate cancer (PCa). However, funding limitations and excess bureaucracy are now making it difficult to conduct trials.Objective: To describe the collaborative groups in Europe and their academic phase 3 PCa trials.Evidence acquisition: Leaders of collaborative groups from Scandinavia, the European Organisation for Research and Treatment of Cancer (EORTC), France, Spain, the United Kingdom, Germany, Switzerland, The Netherlands, and Ireland were asked to provide information.Evidence synthesis: Approximately 40 academic European phase 3 trials focussing on PCa have been completed, and about 10 are accruing patients. Cross-border trials have been successfully conducted led by EORTC (11), Scandinavian Prostate Cancer Group (9), European Association of Urology (1), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficiency (STAMPEDE) (1), and the French Genito-Urinary Tumor Group (1). Among these studies were practise-changing trials showing the superiority of prostatectomy over watchful waiting in patients <65 yr of age, the benefits of combining androgen-deprivation therapy (ADT) with radiation therapy (RXT) in high-risk localised disease, the superiority of long-term versus short-term ADT, the benefit of RXT in men treated with ADT, and the role of adjuvant RXT. To bridge the numbers gap for phase 3 studies, the Prostate Cancer Consortium in Europe (PEACE) is a recently established initiative that aims to favour cross-border networks of investigators. PEACE 1 is testing the addition of abiraterone and that of RXT directed at the primary cancer in patients with de novo metastatic PCa treated with ADT. PEACE 2 is testing the addition of cabazitaxel and that of pelvic irradiation in patients with at least two criteria for high-risk localised PCa.Conclusions: European academic phase 3 trials have contributed to establishing the current standard treatment of PCa. The PEACE consortium was recently tasked with the goal of addressing unanswered questions and specific biology-related issues more efficiently.Patient summary: The Prostate Cancer Consortium in Europe was established to conduct comparative trials aiming at assessing new treatments for prostate cancer patients. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Abstract Introduction & Objectives. We have previously reported that response of prostate cancer (PC) to taxane therapy is based on the interplay between androgen receptor (AR) and c-jun However, the cellular mechanisms of taxane treatment in prostate cancer cells are not fully elucidated. The aim of this study was to investigate the effect of sustained down-regulation of c-jun on the outcome of taxane therapy using LNCaP cells transfected with c-jun shRNA, and to characterize the nature of the c-jun and AR interaction in regard to their corresponding promoter regions. Material & Methods. Chromatin immunoprecipitation (CHIP) assay was performed to examine gene recruitment. LNCaP cells were treated with Docetaxel (Doc) or Paclitaxel (Pac) and resulting chromatin preparations were analyzed by PCR. To analyse the impact of c-jun downregulation on AR and prostate cancer response to therapy we used LNCaP cells harboring stable knocked down c-jun (LNsiJun). Cells were exposed to Doc, Pac DHT for different time-points and the medium were subjected for PSA analysis using DELFIA 1234 fluorometer and cell response to drugs assessed by MTT assay. Results. Taxane treatment of LNsiJun cells led to a statistically significant decrease of cell viability compared to parental LNCaP cells (p<0,05) independent on the substance used. Interestingly, exposure of LNsiJun cells to DHT resulted in increased cell death. LNsiJun cells treated with docetaxel (Doc) showed an up-regulation of AR and PSA protein levels after 24 hours, whereas Paclitaxel (Pac) treatment resulted in a down-regulation of both proteins which matched our observations in parental LNCaP cells. To further investigate this taxane specific effect on AR, ChIP assay revealed that AR binds to the c-jun promoter region upon Doc exposure. However, Pac treatment failed to do so. Both taxanes resulted in an enhanced binding of c-jun to the corresponding promoter region. Conclusions. In conclusion, down-regulation of endogenous c-jun enhances sensitivity of LNCaP cells to taxane treatment. Binding of AR to the c-jun promoter is taxane specific and results in different expression levels of AR and PSA. Citation Format: Nishtman Dizeyi, Martina V. Tinzl, Marieke van der Molen, Julius Semenas, Per-Anders Abrahamsson. Androgen receptor recruitment to c-Jun promoter region regulates chemosensitivity of prostate cancer cells to taxane therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B15.

Background: Previous studies of prostate cancer (PCa) risk and anthropometrics (ie, body measurements) were based on single measurements or obtained over limited time spans.Objective: To study the association between anthropometrics measured at multiple time points in life and their relation to later diagnosis, metastasis, or death from PCa.Design, setting, and participants: This case-control study includes 27 167 Swedish men enrolled in two population-based projects from 1974 to 1996. PCa diagnosis up to December 31, 2006, disease information, gestation time, and anthropometrics at birth, military conscript testing, and adulthood were collected. A total of 1355 PCa cases were matched with 5271 controls.Outcome measurements and statistical analysis: Univariate conditional logistic regression was used to determine whether clinical diagnosis, metastasis, or PCa death was associated with low birth weight (weight < 2500 g); with small size for gestational age; or with weight, length, or body mass index (BMI) at birth, adolescence (aged 16-22 yr), or early middle age (aged 44-50 yr).Results and limitations: Apart from weight at adolescence, which was associated with an increased risk of PCa diagnosis (odds ratio [OR] per 5 kg: 1.05; 95% confidence interval [CI], 1.01-1.09; p = 0.026), preadulthood measurements were not associated with any PCa end point. Adulthood parameters were not associated with diagnosis. In contrast, weight and BMI at early middle age were significantly associated with metastasis (OR per 5 kg: 1.13; 95% CI, 1.06-1.20; p < 0.0001, and OR: 1.09; 95% CI, 1.05-1.14; p < 0.0001) and death (OR per 5 kg: 1.11 (95% CI, 1.03-1.19; p = 0.005, and OR: 1.08; 95% CI, 1.03-1.13; p = 0.003), respectively. It remains unclear whether these results apply to men of nonwhite origin, to populations with active PCa screening programs, or to countries without socialized health care.Conclusions: The analyses of these large data sets demonstrate that significant effects of body characteristics (with links to metabolic syndrome) measured at early middle age are associated with PCa disease severity, metastatic progression, and outcome. Conversely, measurements at birth and adolescence are not associated with PCa prevalence or outcome.Patient summary: Increased weight and body mass index in adults is associated with a higher risk of prostate cancer metastasis and death. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Bone metastases are common among patients with stage IV genitourinary cancers Most patients with bone metastases develop at least one debilitating and potentially life-limiting skeletal-related event These events are associated with increased medical expenses and decreased quality of life Current guidelines recommend screening for bone metastases in men with high-risk prostate cancer but guidance for screening and treatment of bone metastases from genitourinary cancers varies by country and setting Several bisphosphonates have been evaluated in the advanced genitourinary cancer setting Zoledronic acid has demonstrated efficacy in significantly reducing the risk of skeletal-related events in patients with bone metastases from a broad range of solid tumors including prostate renal and bladder cancers and is recommended for preserving bone health