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- The oncological outcome and validation of Japan Cancer of the Prostate Risk Assessment score among men treated with primary androgen-deprivation therapy. [JOURNAL ARTICLE]
- J Cancer Res Clin Oncol 2014 Sep 17.
Although androgen-deprivation therapy (ADT) for prostate cancer is initially effective, most tumors eventually recur even during ADT. To predict their prognosis, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score was developed. However, there is no validation of this model using data from a single institution. Therefore, in this study, we clarified the oncological outcome of primary ADT and its prognostic factors, as well as validated the J-CAPRA score model in our institution.This study included 248 Japanese patients with hormone-naïve prostate cancer who were treated with primary ADT from 1996 through 2012. The oncological outcome and prognostic significance of several clinicopathological factors were analyzed. Also, J-CAPRA risk stratification model was validated in this cohort.During a median follow-up period of 42.2 months, the median progression-free survival (PFS) and overall survival (OS) were 89.3 and 103.3 months, respectively. Multivariate analysis identified clinical T-stage and M-stage for PFS and cancer-specific survival (CSS) and clinical M-stage for OS as significant predictors. The accuracy of J-CAPRA score model for predicting PFS, CSS, and OS was validated by high c-indices.This study demonstrated the use of the J-CAPRA score system for predicting PFS, CSS, and OS among Japanese men treated with primary ADT in a single institution.
- Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP): study profor a randomized phase II trial. [JOURNAL ARTICLE]
- BMC Cancer 2014 Sep 15; 14(1):671.
Metastases-directed therapy (MDT) with surgery or stereotactic body radiotherapy (SBRT) is emerging as a new treatment option for prostate cancer (PCa) patients with a limited number of metastases (<=3) at recurrence - so called "oligometastases". One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life. However, the lack of a control group, selection bias and the use of adjuvant androgen deprivation therapy prevent strong conclusions from published studies.The aim of this multicenter randomized phase II trial is to assess the impact of MTD on the start of palliative ADT compared to patients undergoing active surveillance.Patients with an oligometastatic recurrence, diagnosed on choline PET/CT after local treatment with curative intent, will be randomised in a 1:1 ratio between arm A: active surveillance only and arm B: MTD followed by active surveillance. Patients will be stratified according to the location of metastasis (node vs. bone metastases) and PSA doubling time (<=3 vs. > 3 months). Both surgery and SBRT are allowed as MDT. Active surveillance means 3-monthly PSA testing and re-imaging at PSA progression. The primary endpoint is ADT-free survival. ADT will be started in both arms at time of polymetastatic disease (>3 metastatic lesions), local progression or symptoms. The secondary endpoints include progression-free survival, quality of life, toxicity and prostate-cancer specific survival.This is the first randomized phase 2 trial assessing the possibility of deferring palliative ADT with MDT in oligometastatic PCa recurrence.Trial registration: Clinicaltrials.gov identifier: NCT01558427.
- Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. [JOURNAL ARTICLE]
- Oncogene 2014 Sep 15.
Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).Oncogene advance online publication, 15 September 2014; doi:10.1038/onc.2014.302.
- Mechanistic Insights into the Catalysis of Electrochemical Proton Reduction by a Diiron Azadithiolate Complex. [JOURNAL ARTICLE]
- Inorg Chem 2014 Sep 15.
Cyclic voltammetry experiments and DFT calculations allowed us to establish a complete mechanism of the catalysis of electrochemical proton reduction by [Fe2(μ-SCH2N(H)CH2S)(CO)6] (Fe-adt) in acetonitrile. The proposed mechanism is fully consistent with the observed dependence of the voltammetric responses on the strength of the acid used as a proton source. Addition of moderately strong acids, such as CCl3CO2H (pKa = 10.7) or HOTs·H2O (pKa = 8.6), triggers the occurrence of new reduction events at potentials less negative than the reduction of Fe-adt, therefore ascribed to reduction of the protonated forms of the complex. Reduction of the N-protonated form seems to favor a tautomerization reaction leading to a Fe-H intermediate. On the other hand, addition of weak acids, such as ClCH2CO2H (pKa = 15.3), leads to direct protonation on the diiron site subsequently to reduction of the catalyst. A better understanding of the mechanism of proton reduction by the biologically relevant Fe-adt derivative could impact the design of improved catalysts inspired by FeFe-hydrogenase.
- Achievements and Perspectives in Prostate Cancer Phase 3 Trials from Genitourinary Research Groups in Europe: Introducing the Prostate Cancer Consortium in Europe. [JOURNAL ARTICLE]
- Eur Urol 2014 Sep 10.
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.To describe the collaborative groups in Europe and their academic phase 3 PCa trials.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.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.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.The Prostate Cancer Consortium in Europe was established to conduct comparative trials aiming at assessing new treatments for prostate cancer patients.
- Clinical (non-histological) diagnosis of advanced prostate cancer: Evaluation of treatment outcome after androgen deprivation therapy. [Journal Article]
- S Afr J Surg 2014 Aug; 52(3):82-5.
Introduction.Transrectal biopsy in suspected adenocarcinoma of the prostate (ACP) may cause significant morbidity and even mortality. A strong association between serum prostate-specific antigen (PSA) and tumour burden exists. If biopsy can be avoided in advanced disease, much morbidity and cost may be saved.
Objective.To evaluate the reliability of using PSA and clinical features to establish a non-histological diagnosis of ACP.Methods. Androgen deprivation therapy (ADT) was used in 825 (56.2%) of 1 467 men with ACP. The diagnosis of ACP was made histologically in 607 patients (73.6%) and clinically alone in 218 (26.4%), based on a serum PSA level of >60 ng/ml, and/or clinical evidence of a T3 - T4 tumour on digital rectal examination, and/or imaging evidence of metastases. We compared two randomly selected groups treated with bilateral orchidectomy (BO) based on a clinical-only (n=90) v. histological (n=96) diagnosis of ACP.
Results.There was no significant difference between the groups with regard to mean follow-up (26.1 v. 26.8 months), documented PSA relapse (70% v. 67.7%), and patients alive at last follow-up (91.1% v. 95.8%). ZAR1 068 200 (US$1 = ZAR8) was saved by treating men with advanced ACP on the basis of a clinical (non-histological) diagnosis only, and a total of ZAR24 321 000 was saved by using BO instead of luteinising hormone-releasing hormone agonists as ADT.
Conclusion.A reliable clinical (non-histological) diagnosis of advanced ACP can be made based on serum PSA and clinical features. This avoids the discomfort and potentially serious complications of biopsy and saves cost.
- New trends in androgen deprivation therapy: Summary of key research presented at AUA 2014. [Journal Article, Review]
- Can Urol Assoc J 2014 Jul; 8(7-8 Suppl 4):S134-6.
At the 2014 Annual Meeting of the American Urological Association (AUA), there were a number of educational sessions presenting new research regarding the use of androgen deprivation therapy (ADT). Two important themes related to ADT that emerged during the conference were the relationship between ADT and cardiovascular (CV) risk and the optimization of testosterone suppression. The following sections will provide highlights from the AUA sessions on these 2 topics.
- What we've learned so far about ADT. [Journal Article]
- Can Urol Assoc J 2014 Jul; 8(7-8 Suppl 4):S133.
- Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer. [Journal Article]
- Onco Targets Ther 2014.:1519-23.
Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT.Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package.Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis.There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for the treatment of prostate cancer.
- Computational Investigation of [FeFe]-Hydrogenase Models: Characterization of Singly and Doubly Protonated Intermediates and Mechanistic Insights. [JOURNAL ARTICLE]
- Inorg Chem 2014 Sep 10.
The [FeFe]-hydrogenase enzymes catalyze hydrogen oxidation and production efficiently with binuclear Fe metal centers. Recently the bioinspired H2-producing model system Fe2(adt)(CO)2(dppv)2 (adt=azadithiolate and dppv=diphosphine) was synthesized and studied experimentally. In this system, the azadithiolate bridge facilitates the formation of a doubly protonated ammonium-hydride species through a proton relay. Herein computational methods are utilized to examine this system in the various oxidation states and protonation states along proposed mechanistic pathways for H2 production. The calculated results agree well with the experimental data for the geometries, CO vibrational stretching frequencies, and reduction potentials. The calculations illustrate that the NH···HFe dihydrogen bonding distance in the doubly protonated species is highly sensitive to the effects of ion-pairing between the ammonium and BF4(-) counterions, which are present in the crystal structure, in that the inclusion of BF4(-) counterions leads to a significantly longer dihydrogen bond. The non-hydride Fe center was found to be the site of reduction for terminal hydride species and unsymmetric bridging hydride species, whereas the reduced symmetric bridging hydride species exhibited spin delocalization between the Fe centers. According to both experimental measurements and theoretical calculations of the relative pKa values, the Fed center of the neutral species is more basic than the amine, and the bridging hydride species is more thermodynamically stable than the terminal hydride species. The calculations implicate a possible pathway for H2 evolution that involves an intermediate with H2 weakly bonded to one Fe, a short H2 distance similar to the molecular bond length, the spin density delocalized over the two Fe centers, and a nearly symmetrically bridged CO ligand. Overall, this study illustrates the mechanistic roles of the ammonium-hydride interaction, flexibility of the bridging CO ligand, and intramolecular electron transfer between the Fe centers in the catalytic cycle. Such insights will assist in the design of more effective bioinspired catalysts for H2 production.