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- Muscle and bone effects of androgen deprivation; current and emerging therapies. [JOURNAL ARTICLE]
- Endocr Relat Cancer 2014 Jul 23.
Prostate cancer and treatment with androgen deprivation therapy (ADT) affects large numbers of the male population. Endocrine effects of ADT are a critical consideration in balancing the benefits and risks of treatment on long-term survival and quality of life. This review highlights the latest advances in androgen manipulation in prostate cancer with an emphasis on muscle and bone effects of ADT which universally impact on the health and well-being of men undergoing ADT for prostate cancer. Muscle mass declines with ADT, however the evidence that this correlates with a decrease in muscle strength or a decrease in physical performance is discordant. Cortical bone decay also occurs associated with an increase in fracture risk, hence optimization of musculoskeletal health in men undergoing ADT is crucial. The role of exercise, current and emerging anabolic therapies on muscle as well as various new strategies to prevent bone loss in men undergoing ADT are discussed. Future well-designed, prospective controlled studies are required to elucidate effects of ADT on physical performance which are currently lacking, and larger randomised-controlled trials are required to test the efficacy of medical therapies and exercise interventions to target proven deficits and to ensure safety in men with prostate cancer.
- Differential Requirement for Src-family Tyrosine Kinases in the Initiation, Progression and Metastasis of Prostate Cancer. [JOURNAL ARTICLE]
- Mol Cancer Res 2014 Jul 22.
Prostate cancer (CaP) recurrence after androgen ablation therapy (ADT) remains a significant cause of mortality in aging men. Malignant progression and metastasis are typically driven by genetic and epigenetic changes controlled by the androgen receptor (AR). However, evidence suggests that activated non-receptor tyrosine kinases, including those of the Src family (SFK), directly phosphorylate AR, thereby activating its transcriptional activity in the absence of serum androgen levels. To ascertain whether CaP progression and metastasis require SFK members an autochthonous transgenic adenocarcinoma (AD) of the mouse prostate (TRAMP) model was crossed into Src-, Lyn- or Fyn-null backgrounds. Primary-site CaP formation was dependent on Src, to a lesser extent, Lyn, but not Fyn. Only Src-/-;TRAMP prostate tumors were marked by reactive stroma. SFK deficiency did not affect progression to neuroendocrine (NE) disease, although there were fewer new cancer cases initiating after 34 weeks in the SFK-/-;TRAMP mice compared to TRAMP controls. Fifteen to 21% of older (>33 weeks) Lyn- or Fyn-null TRAMP mice lacking primary-site tumors suffered from aggressive metastatic AD growths, compared with 3% of TRAMP mice. Taken with the data that TRAMP mice lacking Src or Lyn exhibited fewer macroscopic metastases compared to Fyn-/-;TRAMP and TRAMP controls, this suggests that SFK can either promote or suppress specific parameters of metastatic growth, possibly depending on cross-talk with primary tumors. These data identify critical, yet potentially opposing roles played by various SFKs in the initiation and metastatic potential of CaP using the TRAMP model. Implications: Genetically defined mouse models indicate a critical role for Src tyrosine kinase in prostate cancer initiation and metastatic progression.
- [Mechanisms of formation of post-vaccinal immune response in children immunized with APDT and ADT-M preparations]. [English Abstract, Journal Article]
- Zh Mikrobiol Epidemiol Immunobiol 2014 Mar-Apr; (2):72-8.
Study the mechanisms of formation of cell and humoral immunity against pertussis, diphtheria and tetanus in children immunized with immunobiological preparations (APDT vaccine and ADT anatoxin).30 practically healthy children (6 - 9 years of age) immunized with APDT and ADT-M preparations had TLR2, TLR4 expression determined in mononuclear cells (MNC). Vaccine preparations (APDT, ADT-M, AD-M, AT) and Corynebacterium diphtheriae gravis tox+, C. diphtheriae mitis tox- and Bordetella pertussis 345 were used as ligands. Cytokine production was determined in EIA. Content of anti-diphtheria, anti-tetanus and anti-pertussis antibodies--by PHA reaction and EIA.During stimulation with vaccines and B. pertussis 345 strain MNC were characterized by an increase (p < 0.05) of expression level of TLR2 and TLR4 and did not respond to stimulation with C. diphtheriae gravis tox+ and C. diphtheriae mitis tox- strains. Similar results were obtained during study of cytokine production (TNFalpha, IL-1, IL-6). A direct correlation between levels of antitoxic antibodies against diphtheria and tetanus (R = 0.486), antibacterial antibodies against pertussis and diphtheria was detected (R = 0.529).Analysis of cytokine production profile and determination of surface TLR expression can be used during evaluation of functional status of innate immunity cells and intensity of post-vaccinal immunity.
- USANZ: The 'Timing of androgen deprivation therapy in incurable prostate cancer' protocol (TOAD) - where are we now? Synopsis of the Victorian Cooperative Oncology Group PR 01-03 and TransTasman Radiation Oncology Group 03.06 clinical trial. [JOURNAL ARTICLE]
- BJU Int 2014 Jul 22.
To outline the development of the TOAD (Timing of Androgen Deprivation) protocol, a collaborative randomised clinical trial under the auspices of the Cancer Council Victoria, the Trans Tasman Radiation Oncology Group, and the Urological Society of Australia and New Zealand, which opened to recruitment in 2004 PATIENTS AND METHODS: The principal hypothesis for the trial was that the early introduction of ADT (experimental arm) at the time when curative therapies are no longer considered an option, would improve overall survival for these patients, whilst maintaining an acceptable quality of life; compared to waiting for disease progression or the development of symptoms (control arm). An increase in overall survival at five years of 10% was judged to be clinically worthwhile.Recruitment was slow, with fewer than half of the protocol requirement of 750 patients eventually accrued, but nonetheless it is considered that the trial will still contribute a major source of evidence in this area. The study closed to follow-up at the end of 2013, with data analysis commencing mid-2014, and with the primary publication anticipated to be submitted by the end of 2014.The question of timing of androgen deprivation still remains relevant in the current era of newer and more varied treatment modalities. Even with the advent of novel chemotherapy and the biological agents which are undergoing investigation for progressively earlier disease stages, the dilemma of when to commence palliative treatment in an asymptomatic patient will remain, unless or until these agents are shown to increase overall survival. The TOAD trial will contribute to answering at least in part, some of these questions.
- Sensitivity and specificity of PET/CT regarding the detection of lymph node metastases in prostate cancer recurrence. [Journal Article]
- Springerplus 2014.:340.
The aim of the study is to assess the efficacy of choline PET/CT regarding the detection of lymph node (LN) metastases in recurrent prostate cancer (PCa).49 patients with a biochemical recurrence of PCa (PSA >0.2 ng/ml) were included in the study. All patients were selected for further diagnostics with a choline-PET/CT. All patients underwent salvage extended lymphadenectomy. The PET/CT result and the histological findings were analyzed regarding the specificity and sensitivity and with respect to the localization of the metastases. The detection rate of LN metastases was analyzed with respect to interdependencies between the pre-PET/CT PSA-value as well as the role of prior ADT.41 out of 49 (83.6%) patients showed positive PET/CT results. Positive LNs were found in 27 out of 49 patients (55.1%). 48.9% of the PET-CT-findings proved true positive, 36.7% were found to be false positive. 8.1% proved true negative and 8.1% false negative. This results in a specificity of 22.7% and a sensitivity of 85.1%. Out of the true positive PET/CT scans, 61.9% were not congruent regarding the localization of positive LNs. In patients with PSA [greater than or equal to] 5 ng/ml, the sensitivity of the PET/CT result was 93.7%, while specificity was 0%. In 24 patients who underwent ADT prior to the PET/CT diagnostics, the sensitivity was 84.6% and specificity 9.0%.The reliability of PET/CT imaging for detection of LN metastases is limited by a high false-positive rate. The influence of ADT further diminishes the PET/CT reliability. Sensitivity of the PET/CT is highest in patients with a PSA of [greater than or equal to] 5 ng/ml. Based on our results, we propose the following conclusions: 1. There is no well-established diagnostic alternative to Choline-PET/CT Scan. Therefore this method may continue to be performed in patients with BCR. 2. It is not sufficient to remove only those LNs that show up in the PET/CT. 3. Salvage extended lymphadenectomy should follow a predefined template (e.g. the "Kiel template") and not just the PET/CT scan results.
- Androgen deprivation therapy for prostate cancer: long-term safety and patient outcomes. [Journal Article, Review]
- Patient Relat Outcome Meas 2014.:63-70.
Androgen deprivation therapy (ADT) constitutes the first-line treatment for patients with locally advanced tumors, recurrent or metastatic disease. Given its widespread use, clinicians should be familiar with common side effects of this treatment. This review focuses on common side effects of ADT and available treatment options to control the side effects. Also, it briefly compares continuous ADT with other therapeutic approaches for androgen deprivation in prostate cancer patients. Similar to hormonal medications, newer non-hormonal therapeutic options including gabapentin and acupuncture have at best moderate effect in controlling hot flashes in patients on ADT. Supervised and/or home exercise programs significantly improve ADT-related fatigue, metabolic/cardiovascular side effects, and cognitive dysfunction. Denosumab, a human monoclonal antibody against RANK-L, is more effective than bisphosphonates in preventing skeletal-related events in patients with metastatic or castrate-resistant prostate cancer and unlike bisphosphonates, it can also reduce the risk of vertebral fractures in men receiving ADT for non-metastatic prostate cancer. Toremifene, a selective estrogen receptor inhibitor, has dual beneficial effects on ADT-related osteoporosis and metabolic dysfunction. Metformin coupled with lifestyle modification is also a well-tolerated treatment for metabolic changes during ADT. While producing similar oncological outcomes, intermittent ADT is associated with higher quality of life in patients under ADT by improving bone health, less metabolic and hematologic complications, and fewer hot flashes and sexual dysfunction events.
- Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study. [JOURNAL ARTICLE]
- BMC Res Notes 2014 Jul 18; 7(1):459.
This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD).Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1-4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impression-Severity (CGI-S).Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received >=1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced >=1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both groups most MGH-SFI items exhibited improvement at week 52. Mean CGI-S improvement at week 52 (last observation carried forward) was -1.4 with bupropion and -1.5 with an SSRI/SNRI (efficacy sample).There were no unexpected AEs with long-term adjunctive aripiprazole therapy when added to either bupropion or SSRIs/SNRIs, and symptom improvement was similar between ADT groups. Sexual functioning in patients with MDD on antidepressants was also modestly improved after adding aripiprazole.Trial registration: ClinicalTrials.gov: NCT00095745 (November 9, 2004).
- Androgen deprivation therapy induces androgen receptor-dependent upregulation of Egr1 in prostate cancers. [Journal Article]
- Int J Clin Exp Pathol 2014; 7(6):2883-93.
Early growth response gene-1 (Egr1) has a crucial function in the development and progression of prostate cancer. However, whether Egr1 contributes to the transition of advanced androgen-independent prostate cancer (AIPC) from androgen-dependent prostate cancer (ADPC) remains largely unknown. To the best of our knowledge, through immunohistochemical staining methods, we were the first to identify that Egr1 is more highly expressed in AIPC clinical specimens than in androgen-dependent prostate cancer (ADPC). An in vitro study with quantitative RT-PCR and Western blot demonstrated that Egr1 also has a higher expression in androgen-independent PC3 cells than in the androgen-dependent LNCaP cells. Egr1 expression in LNCaP cells was significantly upregulated during the androgen deprivation treatment (ADT) and was re-downregulated through the addition of dihydrotestosterone. Although no variation in PC3 cells was identified, Egr1 responded to dihydrotestosterone and flutamide in the androgen receptor (AR)-transfected PC3 cells. Further investigation with Egr1 agonist and specific siRNA-targeting Egr1 revealed that Egr1 upregulation or downregulation was accompanied by a change in inhibitors of differentiation and DNA binding-1 (Id1) in the same direction in both LNCaP and PC3 cells. The variation is shown to be negatively regulated by androgen through AR during ADT. Our data suggested that upregulated Egr1 might partially contribute to the emergence of AIPC after prolonged ADT. This study also elucidated the potential mechanism underlying Id1 participation in the progression of prostate cancer. Understanding the key molecular events in the transition from ADPC to AIPC may provide new therapeutic intervention strategies for patients with AIPC.
- Quality-of-life benefits of catheter ablation of persistent atrial fibrillation: a reanalysis of data from the SARA study. [JOURNAL ARTICLE]
- Europace 2014 Jul 15.
The recently published SARA study was a prospective, multi-centre randomized controlled trial that compared CA to antiarrhythmic drug therapy (ADT) in 146 patients with persistent atrial fibrillation (AF). The study found that recurrence of AF or atrial flutter occurred significantly less often in the CA arm compared to the ADT arm (29.6% vs. 56.3%, p = 0.002). Despite this clear superiority in terms of efficacy, the authors were not able to demonstrate a corresponding Quality of Life (QoL) improvement. We sought to investigate this apparent disparity using alternative analytical methods.We were able to show that a high coefficient of variation existed for all QoL measures at each time point which may explain the lack of statistical difference originally reported. We reanalyzed the raw QoL data from the SARA study using paired sample t-tests for the change in QOL for individual patients between baseline and 12 month (final) follow up. For patients randomized to ADT the difference in QoL after 12 months was not significant for any of the four QoL domains (global, physical, psychological and sexual) whereas for patients randomized to CA all comparisons were significant (global, p < 0.001; physical, p = 0.001; psychological, p < 0.001; sexual, p = 0.003).In the SARA study, after 12 months' follow up, CA significantly improved QoL for patients with persistent AF whereas medical therapy had no appreciable effect.
- Population-based analysis of treatment modalities and survival for clinically localized small-cell carcinoma of the prostate. [JOURNAL ARTICLE]
- Prostate Cancer Prostatic Dis 2014 Jul 15.
Background:Small-cell carcinoma of the prostate is an aggressive cancer whose rarity has prevented the development of a consensus management approach. The objective of the current study was to determine the treatment patterns and evaluate factors affecting overall survival for patients with localized small-cell carcinoma of the prostate.Methods:After querying the National Cancer Database, we identified all patients diagnosed with localized small-cell carcinoma of the prostate between 1998 and 2011 (n=287). Using Kaplan-Meier curves and Cox regression analyses, we assessed the effect of treatment and clinical stage on overall survival.Results:Treatments included radiation therapy in 46% (n=131), chemotherapy in 38% (n=107), androgen deprivation therapy (ADT) in 22% (n=63) and radical prostatectomy in 13% (n=38). Median overall survival was 14.8 months. Upon multivariate analysis, local therapy (radical prostatectomy or radiation therapy) was associated with improved survival (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.14-0.38, P<0.001). Advanced clinical stage predicted worse survival among all men (cT3: HR 2.83, 95% CI 1.27-6.32, P=0.011; cT4: HR 3.26, 95% CI 1.50-7.07, P=0.003) and men who received local therapy (cT3: HR 4.67, 95% CI 1.41-15.44, P=0.012; cT4: HR 4.01, 95% CI 1.14-14.08, P=0.03) but not among men who received no local therapy (cT3: HR 1.64, 95% CI 0.51-5.27, P=0.4; cT4: HR 2.35, 95% CI 0.74-7.48, P=0.15). Age, receipt of chemotherapy and ADT, and clinical stage T2 disease (compared with T1) did not predict survival.Conclusion:Men with localized small-cell carcinoma of the prostate have a poor overall survival. Local therapy may represent a suitable and underused modality for select patients.Prostate Cancer and Prostatic Disease advance online publication, 15 July 2014; doi:10.1038/pcan.2014.26.