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- Somatostatin analogs and disease control in castration-resistant prostate cancer: different biological behavior? Case series and review of the literature. [JOURNAL ARTICLE]
- Tumori 2014 May-Jun; 100(3):249-253.
Aims and background. Castration-resistant prostate cancer is a recent biological behavior where disease can elude androgen deprivation therapy (ADT). Several pathways have been described, including neuroendocrine dedifferentiation. Patients with neuroendocrine dedifferentiation show an increase in chromogranin A (CgA) along with a PSA increase. Our aim was to evaluate the response of patients with castration-resistant prostate cancer and high CgA serum levels after treatment with inhibitors of neuroendocrine cells (somatostatin analogs) in combination with ADT. Methods. From January 2009 to April 2011, 10 patients with castration-resistant prostate cancer and rising PSA levels along with a CgA increase were evaluated. The therapy was based on somatostatin analogs and LHRH anologs. Total PSA and CgA were measured every 2 months. Results. In 9 of the 10 patients, a reduction of the values of pre-treatment CgA was detected, while a reduction of PSA was found in 8 patients. No grade 2 or higher toxicity was recorded. Only 3 patients had grade 1 gastrointestinal toxicity. Time to progression was 13 months. Conclusion. Therapy with somatostatin analogs could increase the therapeutic window of ADT with a low toxicity profile in a subpopulation of patients with castration-resistant prostate cancer who experience a rise in CgA due to neuroendocrine regulation.
- Dose-escalated Radiation Therapy With and Without Short-course Androgen Deprivation for Intermediate-risk Prostate Cancer. [Journal Article]
- Anticancer Res 2014 Aug; 34(8):4189-93.
To investigate outcomes in intermediate-risk (IR) prostate cancer patients receiving dose-escalated external beam radiation therapy (RT) with or without short-course androgen deprivation (ADT).This study comprised of 203 patients with IR prostate cancer who were treated at a single institution to a dose of 7,560 cGy or more between 2003-2010. Of these, 62 (30.5%) patients received ADT. Biochemical recurrence, distant metastatic-free survival, prostate cancer-specific survival, and overall survival were analyzed using the Kaplan-Meier method.The median follow-up was 62 months and the median duration of ADT was 6 months. The 6-year biochemical control was 89.2% for those receiving RT plus ADT versus 76.7% in those receiving RT alone (p=0.02). There were no differences between the two groups regarding distant metastatic-free survival, prostate cancer-specific survival, and overall survival (respective p-values of 0.91, 0.50, 0.67).Dose-escalated RT and short-course ADT results in improved biochemical outcomes for IR prostate cancer.
- Salvage Radiotherapy after Radical Prostatectomy: Prediction of Biochemical Outcomes. [JOURNAL ARTICLE]
- PLoS One 2014; 9(7):e103574.
A significant proportion of patients undergoing salvage radiotherapy (RT) for biochemical recurrence (BCR) following radical prostatectomy (RP) may again experience BCR after salvage RT. Thus, we evaluated the clinical significances of different parameters on the biochemical outcome of RT in salvage setting.We reviewed the records of 212 patients who underwent salvage RT between November 2003 and December 2012 for BCR following primary RP. BCR-free survivals after salvage RT were estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to evaluate the impacts of clinicopathologic parameters on BCR following salvage RT.The overall median follow-up duration was 63.5 months. The BCR-free survival rate after salvage RT was 58.2% at 5 years. Multivariate analysis showed that a pre-RT prostate-specific antigen (PSA) level of ≤0.5 ng/mL, a pre-RT PSA doubling time (PSADT) of >4.5 months, concomitant androgen deprivation therapy (ADT) with salvage RT, and a positive surgical margin were independent predictors of favorable biochemical outcomes after salvage RT (hazard ratios [HR] = 3.012, 1.132, 2.000, and 1.805, respectively, p = less than 0.001, 0.013, 0.005, and 0.036, respectively). In the early (pre-RT PSA ≤0.5 ng/mL) salvage RT setting, concomitant ADT administration was also shown to be significantly associated with higher risk of BCR-free survival following salvage RT (HR = 2.611, p = 0.038).Lower pre-RT PSA value, longer PSADT before salvage RT, concomitant ADT administration, and a positive surgical margin were significant predictors of favorable biochemical outcomes following salvage RT performed for BCR after primary RP.
- Phylobiochemical Characterization of Class-Ib Aspartate/Prephenate Aminotransferases Reveals Evolution of the Plant Arogenate Phenylalanine Pathway. [JOURNAL ARTICLE]
- Plant Cell 2014 Jul 28.
The aromatic amino acid Phe is required for protein synthesis and serves as the precursor of abundant phenylpropanoid plant natural products. While Phe is synthesized from prephenate exclusively via a phenylpyruvate intermediate in model microbes, the alternative pathway via arogenate is predominant in plant Phe biosynthesis. However, the molecular and biochemical evolution of the plant arogenate pathway is currently unknown. Here, we conducted phylogenetically informed biochemical characterization of prephenate aminotransferases (PPA-ATs) that belong to class-Ib aspartate aminotransferases (AspAT Ibs) and catalyze the first committed step of the arogenate pathway in plants. Plant PPA-ATs and succeeding arogenate dehydratases (ADTs) were found to be most closely related to homologs from Chlorobi/Bacteroidetes bacteria. The Chlorobium tepidum PPA-AT and ADT homologs indeed efficiently converted prephenate and arogenate into arogenate and Phe, respectively. A subset of AspAT Ib enzymes exhibiting PPA-AT activity was further identified from both Plantae and prokaryotes and, together with site-directed mutagenesis, showed that Thr-84 and Lys-169 play key roles in specific recognition of dicarboxylic keto (prephenate) and amino (aspartate) acid substrates. The results suggest that, along with ADT, a gene encoding prephenate-specific PPA-AT was transferred from a Chlorobi/Bacteroidetes ancestor to a eukaryotic ancestor of Plantae, allowing efficient Phe and phenylpropanoid production via arogenate in plants today.
- Prostate cancer: Say no to ADT for localized disease. [JOURNAL ARTICLE]
- Nat Rev Urol 2014 Jul 29.
- Sexual Bother in Men with Advanced Prostate Cancer Undergoing Androgen Deprivation Therapy. [JOURNAL ARTICLE]
- J Sex Med 2014 Jul 24.
Men with advanced prostate cancer (APC) undergoing androgen deprivation therapy (ADT) often experience distressing sexual side effects. Sexual bother is an important component of adjustment. Factors associated with increased bother are not well understood.This study sought to describe sexual dysfunction and bother in APC patients undergoing ADT, identify socio-demographic and health/disease-related characteristics related to sexual bother, and evaluate associations between sexual bother and psychosocial well-being and quality of life (QOL).Baseline data of a larger psychosocial intervention study was used. Pearson's correlation and independent samples t-test tested bivariate relations. Multivariate regression analysis evaluated relations between sexual bother and psychosocial and QOL outcomes.The Expanded Prostate Cancer Index Composite sexual function and bother subscales, Center for Epidemiologic Studies Depression Scale, Functional Assessment of Cancer Therapy-General, and Dyadic Adjustment Scale were the main outcome measures.Participants (N = 80) were 70 years old (standard deviation [SD] = 9.6) and reported 18.7 months (SD = 17.3) of ADT. Sexual dysfunction (mean = 10.1; SD = 18.0) was highly prevalent. Greater sexual bother (lower scores) was related to younger age (β = 0.25, P = 0.03) and fewer months of ADT (β = 0.22, P = 0.05). Controlling for age, months of ADT, current and precancer sexual function, sexual bother correlated with more depressive symptoms (β = -0.24, P = 0.06) and lower QOL (β = 0.25, P = 0.05). Contrary to hypotheses, greater sexual bother was related to greater dyadic satisfaction (β = -0.35, P = 0.03) and cohesion (β = -0.42, P = 0.01).The majority of APC patients undergoing ADT will experience sexual dysfunction, but there is variability in their degree of sexual bother. Psychosocial aspects of sexual functioning should be considered when evaluating men's adjustment to ADT effects. Assessment of sexual bother may help identify men at risk for more general distress and lowered QOL. Psychosocial interventions targeting sexual bother may complement medical treatments for sexual dysfunction and be clinically relevant, particularly for younger men and those first starting ADT. Benedict C, Traeger L, Dahn JR, Antoni M, Zhou ES, Bustillo N, and Penedo FJ. Sexual bother in men with advanced prostate cancer undergoing androgen deprivation therapy. J Sex Med **;**:**-**.
- 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.