Pumpkin Center, NC, United States
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Thomas J.-A.,Duke Prostate Center | Thomas J.-A.,Durham Veterans Affairs Hospital | Antonelli J.A.,Duke Prostate Center | Antonelli J.A.,Durham Veterans Affairs Hospital | And 16 more authors.
Cancer Causes and Control | Year: 2013

Purpose Epidemiological data are conflicting regarding the association between androgenetic alopecia (AA) and prostate cancer (CaP). We examined the relationship between these two conditions. Materials and methods We performed a case-control study at a Veterans Affairs Hospital among 708 men: 312 healthy controls, 167 men with CaP, and 229 men without CaP on prostate biopsy. Participants were asked to selfdescribe hair patterns at ages 30 and 40 and at study enrollment. We tested the association between hair pattern (overall, vertex, or frontal) and CaP status using logistic regression analysis adjusting for multiple clinical features. Disease grade was similarly examined as a secondary outcome. Results Relative to healthy controls, younger age of AA onset was significantly associated with increased CaP risk (p = 0.008). Similar patterns were noted for frontal (p = 0.005) and not vertex balding (p = 0.22). When compared with biopsy-negative men, a similar pattern was seen with younger age of AA onset having higher risk of CaP, though this was not significant (p = 0.07). A suggestion for younger age of AA onset for frontal (p = 0.07) being associated with CaP versus biopsy-negative men was also observed. Overall balding (yes/no) was associated with greater than twofold increase in high-grade disease (p = 0.02). Conclusions Men reporting earlier AA onset were at increased CaP risk and suggestively had more aggressive disease. Contrary to other studies, frontal balding was the predominant pattern associated with elevated CaP risk. Further study is required to confirm these findings in a larger sample and to better understand the role of AA, androgens, and CaP biology. © Springer Science+Business Media Dordrecht 2013.


Sonpavde G.,University of Alabama at Birmingham | Pond G.R.,McMaster University | Armstrong A.J.,Duke Prostate Center | Galsky M.D.,Mt Sinai Tisch Cancer Institute | And 13 more authors.
BJU International | Year: 2014

Objective To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.Results An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.Conclusions Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints. © 2014 The Authors.


Lloyd J.C.,Durham Medical Center | Lloyd J.C.,Duke Prostate Center | Masko E.M.,Durham Medical Center | Masko E.M.,Duke Prostate Center | And 9 more authors.
Prostate Cancer and Prostatic Diseases | Year: 2013

BACKGROUND:Previous mouse studies suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. To our knowledge, no study has yet compared the effect of multiple different fats on PCa progression. We sought to systematically compare the effect of fish oil, olive oil, corn oil and animal fat on PCa progression.METHODS:A total of 96 male severe combined immunodeficient mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were randomized to a Western diet based on fish oil, olive oil, corn oil or animal fat (35% kilocalories from fat). Animals were euthanized when tumor volumes reached 1000 mm 3. Serum was collected at death and assayed for PSA, insulin, insulin-like growth factor-1 (IGF-1), IGF-1-binding protein-3 and prostaglandin E-2 (PGE-2) levels. Tumors were also assayed for PGE-2 and cyclooxygenase-2 levels, and global gene expression was analyzed using Affymetrix microarrays.RESULTS:Mice weights and tumor volumes were equivalent across groups at randomization. Overall, fish oil consumption was associated with improved survival relative to other dietary groups (P=0.014). On gene expression analyses, the fish oil group had decreased signal in pathways related to mitochondrial physiology and insulin synthesis/secretion. CONCLUSIONS:In this xenograft model, we found that consuming a diet in which fish oil was the only fat source slowed tumor growth and improved survival compared with that in mice consuming diets composed of olive oil, corn oil or animal fat. Although prior studies showed that the amount of fat is important for PCa growth, this study suggests that the type of dietary fat consumed may also be important. © 2013 Macmillan Publishers Limited All rights reserved.


Thomas II J.-A.,Durham Medical Center | Thomas II J.-A.,Duke Prostate Center | Gerber L.,Durham Medical Center | Gerber L.,Duke Prostate Center | And 9 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Coronary artery disease (CAD) and prostate cancer (PCa) are not only common diseases, but share many risk factors. To date, only a few studies have explored the relationship between CAD and PCa risk, with conflicting results. Methods: The four-year REDUCE study tested dutasteride 0.5 mg daily for PCa risk reduction in men with prostate specific antigen (PSA) of 2.5 to 10.0 ng/mL and a negative biopsy. Among men who underwent at least one on-study biopsy (n = 6,729; 82.8%), the association between CAD and overall PCa risk and disease grade was examined with logistic and multinomial logistic regression adjusting for clinicopathologic features, respectively. Results: Overall, 547 men (8.6%) had a history of CAD. Men with CAD were significantly older and had higher body mass index, PSA, and larger prostate volumes and were more likely to have diabetes, hypertension, and hypercholesterolemia and take aspirin and statins. On multivariate analysis, CAD was associated with a 35% increased risk of PCa diagnosis (OR = 1.35, 95% CI: 1.08-1.67, P = 0.007), while elevating risk of both low- (OR = 1.34, 95% CI: 1.05-1.73, P = 0.02) and high-grade disease (OR = 1.34, 95% CI: 0.95-1.88, P = 0.09). Conclusions: In a post hoc hypothesis developing secondary analysis of the REDUCE study, CAD was significantly associated with increased PCa diagnosis. Impact: If confirmed in other studies, this suggests CAD may be a novel PCa risk factor and suggests common shared etiologies. Whether lifestyle changes shown to reduce CAD risk (i.e., weight loss, exercise, cholesterol reduction, etc.) can reduce PCa risk, warrants further study. ©2012 AACR.


Younis I.R.,West Virginia University | George D.J.,Duke Prostate Center | George D.J.,Duke University | McManus T.J.,West Virginia University | And 10 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. Methods: Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m2) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. Results: Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). Conclusion: Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration. © 2014 Springer-Verlag.


Armstrong A.J.,Duke Prostate Center | Armstrong A.J.,Duke University | George D.J.,Duke Prostate Center | George D.J.,Duke University
Prostate Cancer and Prostatic Diseases | Year: 2010

In 2009, castration-resistant metastatic prostate cancer continues to account for more deaths in US men than any other cancer apart from lung cancer. Although novel targeted molecular, hormonal and immunologic agents are accelerating in their development in this disease, docetaxel and prednisone remain the standard palliative regimen for the majority of men who have progressed despite hormonal therapies. Thus, understanding the practical and often subtle issues of docetaxel initiation, duration of therapy, cessation of therapy and treatment holidays is critical for the informed use of this US Food and Drug Administration-approved regimen. In this review we address these topics in light of prognostic and predictive factors to help guide the rational use of docetaxel chemotherapy in men with this aggressive disease. © 2010 Nature Publishing Group. All rights reserved.


George D.,Duke University | Moul J.W.,Duke Prostate Center
Prostate | Year: 2012

Background: Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Recent preclinical and clinical studies have identified intracellular signaling pathways and changes in the tumor and bone microenvironment as potential key drivers of CRPC. This increased understanding of mechanisms associated with CRPC has driven the development of numerous new agents, many of which are poised to alter the current CRPC treatment landscape. Methods: A review of literature was conducted to identify ongoing and planned phase III studies of novel agents to treat CRPC. RESULTS Multiple studies were identified, including novel androgen biosynthesis inhibitors (abiraterone, TAK-700), androgen-receptor inhibitors (MDV3100), angiogenesis inhibitors (aflibercept, tasquinimod), endothelin antagonists (zibotentan, atrasentan), a Src tyrosine kinase inhibitor (dasatinib), a novel radiotherapy (radium-223), and new immunotherapies (ipilimumab and ProstVac). In addition, both sipuleucel-T (an immunotherapy) and cabazitaxel (third-generation taxane) and the RANK-L inhibitor, denosumab, have recently been approved by the US Food and Drug Administration. Conclusions: Various combinations of these agents could theoretically be used to treat future patients with CRPC by targeting multiple signaling pathways as well as aspects of the tumor and bone microenvironments. Additional research will be needed to understand how to best use these agents and individualize care to optimize CRPC patient outcomes. © 2011 Wiley Periodicals,Inc.


Caire A.A.,Duke Prostate Center | Sun L.,Duke Prostate Center | Robertson C.N.,Duke Prostate Center | Polascik T.J.,Duke Prostate Center | And 7 more authors.
Urology | Year: 2010

Objectives: To evaluate the US Preventative Services Task Force (USPSTF) recommendation to discontinue prostate-specific antigen (PSA) screening at age 75. Methods: Public survey: A cohort of 340 patients was surveyed at our PSA screening clinic and stratified by awareness of the recommendation and education level. Age (< 75, ≥ 75), race, health insurance status, knowledge of prostate cancer, and opinion on screening discontinuation at age 75 was evaluated between groups. Disease risk and survival analysis: A cohort of 4196 men who underwent radical prostatectomy between 1988 and 2008 was stratified into age groups: < 65, 65-74, and ≥ 75. Associations between clinicopathologic variables, disease risk, and survival were compared between age groups using univariate and multivariate analysis. Results: Approximately 78% of men surveyed disagreed with the USPSTF recommendation. The number of men who disagreed was not significantly different between awareness groups (P = .962). Awareness of new screening guidelines showed a significant difference (P = .006) between education groups. Age ≥ 75 years was predictive of high-risk disease based on D'Amico's criteria (odds ratio = 2.72, P = .003). Kaplan-Meier and Cox regression analyses showed an association of men aged ≥ 75 years with higher rate of PSA recurrence, distant metastasis, and disease specific death compared with the age groups of < 65 and 65-74 (P <.05). Conclusions: Men presenting to our PSA screening clinic disagreed with discontinuation of screening at age 75. Men aged ≥ 75 years had higher risk disease and poorer survival. The USPSTF recommendation was supported neither by public opinion nor disease risk and survival results. © 2010.


Tang P.,Duke Prostate Center | Sun L.,Duke Prostate Center | Uhlman M.A.,Duke Prostate Center | Robertson C.N.,Duke Prostate Center | And 4 more authors.
Journal of Urology | Year: 2010

Purpose: Studies show that initial prostate specific antigen higher than the median in young men predicts a subsequent higher risk of prostate cancer. To our knowledge this relationship has not been studied in patients stratified by race. Materials and Methods: A cohort of 3,530 black and 6,118 white men 50 years or younger with prostate specific antigen 4 ng/ml or less at the first prostate specific antigen screening was retrieved from the prostate center database at our institution. Patients were divided into groups based on initial prostate specific antigen 0.1 to 0.6, 0.7 to 1.4, 1.5 to 2.4 and 2.5 to 4.0 ng/ml. Univariate and age adjusted multivariate logistic regression was done to estimate the cancer RR in these prostate specific antigen groups. We calculated the prostate cancer rate at subsequent followups. Results: Median prostate specific antigen in black and white men was 0.7 ng/ml at age 50 years or less. The prostate cancer rate was not significantly different in the groups with prostate specific antigen less than 0.6 and 0.7 to 1.4 ng/ml in black or white men. Black and white men with initial prostate specific antigen in the 1.5 to 2.4 ng/ml range had a 9.3 and 6.7-fold increase in the age adjusted prostate cancer RR, respectively. At up to 9 years of followup initial prostate specific antigen 1.5 ng/ml or greater was associated with gradually increased detection at followup in black and white men. Conclusions: An initial prostate specific antigen cutoff of 1.5 ng/ml may be better than median prostate specific antigen 0.7 ng/ml to determine the risk of prostate cancer in black and white men 50 years old or younger. © 2010 American Urological Association Education and Research, Inc.

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