Future Prostate Cancer Research Articles

Using prostate-specific antigen threshold to identify increased 4-year risk of prostate cancer.

4565 Background: Recent studies have shown a patient's prostate specific antigen (PSA) value can predict risk of future prostate cancer (PCa) development. In the European Randomized Study of Screening for Prostate Cancer (ERSPC), men with PSA ≥1.5 ng/mL had significantly greater risk of developing PCa within 4 years than men with PSA <1.5 ng/mL (9.2% vs 1.5%, respectively; OR=7.466; P<.001). A recent assessment in a Henry Ford population indicated that, across the lower spectrum of PSA values, PSA of 1.5 ng/mL optimally predicted future risk of PCa. The current analysis aimed to assess the PSA threshold value that optimally predicts future risk of PCa in a cohort of veterans. Methods: This is a retrospective analysis of men in the Veterans Health Administration database from 2000-2009. Men ≥40 years with a baseline PSA ≤4.0 ng/mL, not receiving 5-alpha reductase inhibitors, and without a PCa diagnosis prior to first PSA date were included and followed for 4 years. Patients diagnosed with PCa within 6 months of index were excluded. Optimal PSA threshold value for risk of future PCa development was determined by receiver operator characteristic (ROC) curves. Results: Of 150,293 patients identified for the analysis, 33,217 were classified as Caucasian, 20,680 as African American, 440 as Other Race (subsequently excluded due to a small sample size), and 95,956 patients had race missing. At baseline, mean age was 59.5 years and mean PSA was 1.11 ng/mL. Overall, 4-year rates of PCa were ∼1.3% for Caucasians and African Americans, and 0.97% for unknown race. Mean time to PCa diagnosis was 2.01 years across all patients. ROC curves indicated a 2.3 PSA threshold (area under the curve [AUC] = 73.5%) optimally predicted future PCa in Caucasians, and a 1.9 threshold (AUC = 84.3%) optimally predicted PCa in African Americans; across all patients, a 1.9 PSA threshold was optimal. Conclusions: A relatively low PSA threshold optimally predicted future cancer risk and may identify candidates for risk reduction strategies. Previous studies suggested a cutoff value for PSA >1.5 ng/mL as predictive of future PCa development; our results suggest a PSA threshold of ∼2.0 was most optimal in predicting PCa within 4 years. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline

Prostate-specific antigen screening: pro

Prostate cancer is the most common noncutaneous malignancy among men in the USA and is most frequently diagnosed through prostate-specific antigen (PSA)-based screening. Nevertheless, PSA testing has become increasingly controversial. In this review, we will present the evidence supporting the role of PSA in prostate cancer screening. Numerous studies have shown that the risk of current and future prostate cancer is directly related to the serum PSA level. Moreover, increasing PSA levels predict a greater risk of adverse pathologic features and worse disease-specific survival. Substantial epidemiologic evidence has suggested a reduction in advanced disease and improvements in prostate cancer survival rates since the introduction of PSA-based screening. Recently, evidence from a randomized trial further validated that PSA testing reduces both metastatic disease and prostate cancer-specific mortality. PSA is a valid marker for prostate cancer and its aggressiveness. Level 1 evidence is now available that PSA-based screening reduces both the rate of metastatic disease and prostate cancer-specific mortality.

2103 THE USEFULNESS OF BASELINE PSA FOR PREDICTION OF RISK OF DEVELOPING PROSTATE CANCER IN KOREAN MEN LOWER THAN 70 YEARS OLD

You have accessJournal of UrologyProstate Cancer: Detection and Screening IV1 Apr 20102103 THE USEFULNESS OF BASELINE PSA FOR PREDICTION OF RISK OF DEVELOPING PROSTATE CANCER IN KOREAN MEN LOWER THAN 70 YEARS OLD Kyung Kgi Park, Sang Un Park, Seung Hwan Lee, Dong Suk Kim, and Byung Ha Chung Kyung Kgi ParkKyung Kgi Park More articles by this author , Sang Un ParkSang Un Park More articles by this author , Seung Hwan LeeSeung Hwan Lee More articles by this author , Dong Suk KimDong Suk Kim More articles by this author , and Byung Ha ChungByung Ha Chung More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2177AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent studies have shown that prostate specific antigen (PSA) values can be used to predict risk of developing prostate cancer (PCa) in the future. Among western man in their 40s and 50s, a baseline PSA level above the median value for age is a stronger predictor of future risk of prostate cancer than family history or race. This current analysis aimed to validate the ability of baseline PSA to predict the future risk of PCa in a Korean population of men within a routine health checkup METHODS This is a retrospective analysis of men who had been invited to our institute for a routine health checkup between 2000 - 2004 with at least 4 years of follow-up data. Men 40 and <69 years of age, with a baseline PSA value between 0 - 4.0 ng/mL, not receiving 5-alpha reductase inhibitors were included. Men were followed for at least 4 years after their first PSA value. The risk of PCa diagnosis was evaluated based on a age specific median PSA value of korean men, and was assessed by logistic regression, controlling for age RESULTS A total of 6654 patients were included in the analysis. At baseline, patients had a mean age of 50 years and a mean PSA of 0.96 ng/mL. Mean follow up was 8.3 years. Age specific median PSA were 0.79 ng/ml in 40¡<>±s, 0.81 ng/ml in 50¡±s, 0.93 ng/ml in 60¡±s. Overall, 0.6% of patients with baseline PSA of more than age specific median were diagnosed with PCa after about 6.4 years, compared to 0.03% of patients with a baseline PSA of lower than age specific median. In a multivariate analysis (controlling for age), patients with a baseline PSA of more than median were 11.59 times more likely to be diagnosed with PCa over at least 4 years than patients with baseline PSA of lower than median (OR = 11.59; 95% CI: 1.5-90.2; p < 0.018) CONCLUSIONS This analysis validates that men with baseline PSA values between age specific median PSA and 4.0 ng/mL are at a significantly increased risk for developing future prostate cancer compared to those with a PSA value below the median. Despite of the low number of object and relatively short follow up time, baseline PSA may be used to estimate future risk of prostate cancer in Korean men. Seoul, Republic of Korea© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e817-e818 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyung Kgi Park More articles by this author Sang Un Park More articles by this author Seung Hwan Lee More articles by this author Dong Suk Kim More articles by this author Byung Ha Chung More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

336 SHIFTING INPATIENT TO OUTPATIENT CARE FOR PROSTATE CANCER

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Practice Patterns, Cost Effectiveness I1 Apr 2010336 SHIFTING INPATIENT TO OUTPATIENT CARE FOR PROSTATE CANCER Sean Zhang, Ted Skolarus, and Brent Hollenbeck Sean ZhangSean Zhang More articles by this author , Ted SkolarusTed Skolarus More articles by this author , and Brent HollenbeckBrent Hollenbeck More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.402AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer spending accounts for approximately $7 billion in national health expenditures annually and continually outpaces the growth of GDP. Changes in payment mechanisms, inpatient care patterns, and an abundance of new technologies in the outpatient setting may have shifted spending patterns harboring important implications for how best to address future prostate cancer spending growth. In this context, we investigated the trends in Medicare expenditures for prostate cancer care. METHODS We identified 111,711 patients diagnosed with prostate cancer and sorted them into 144 cohorts based on their month of diagnosis from January 1992 through December 2003 using SEER-Medicare data. All Medicare payments for prostate cancer-related care were tallied and adjusted for inpatient, outpatient institutional, physician services, home health and hospice care for the first 2 years following diagnosis. Using a differencing method, we estimated the contributions of price and quantity to variations in per capita Medicare expenditures for the first 2 years of prostate cancer care. RESULTS Over the study period, per capita Medicare expenditures for the first 2 years of care increased 20% from $8,933 to $10,734 (Figure). A 57% decrease in per capita inpatient (Part A) Medicare expenditures ($3,499 to $1,500), was largely offset by spending growth in physician services (83%, $3,317 to $6,062) and outpatient institutional care (62%, $1,847 to $2,996). Increases in outpatient spending (Part B) were primarily attributed to increases in the quantity of both physician and outpatient institutional services, rather than price. CONCLUSIONS Overall, Medicare is spending more during the first 2 years following diagnosis for beneficiaries with prostate cancer. Instead of inpatient care, physician services are now the primary cost driver of Medicare expenditures for prostate cancer. Although prospective payment systems for inpatient (DRGs) and outpatient institutional care (APCs) may have impacted their respective domains, no such mechanism exists for physician services to control spending growth. Ann Arbor, MI© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e133-e134 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sean Zhang More articles by this author Ted Skolarus More articles by this author Brent Hollenbeck More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract B79: Xanthohumol from hops (Humulus lupulus L.) is a novel antiandrogen

Abstract Xanthohumol (XN), a prenylated chalcone from hops, possesses a broad spectrum of chemopreventive actions, including anti-inflammatory, antioxidant, and anti-estrogenic mechanisms, and inhibits tumor growth in vitro and in vivo. This study aimed to investigate the anti-androgenic potential of XN with regard to prostate carcinogenesis. In hormone-depleted, androgen-sensitive LNCaP human prostate cancer cells, XN at a concentration of 10 µM inhibited prostate specific antigen (PSA) secretion induced by 25 nM dihydrotestosterone (DHT) by more than 90% (p&amp;lt;0.001) after 24, 48 and 72 h of incubation. In a concentration range of 0.4 to 50 µM, XN dose-dependently inhibited PSA secretion (p&amp;lt;0.001) with a halfmaximal inhibitory concentration of 3.1 ± 0.32 µM after 48 h of incubation. Also, DHT-PSA-and insulin like growth factor (IGF-1) mRNA expression was dose-dependently inhibited by increasing XN concentrations (p&amp;lt;0.05), measured by quantitative RT-PCR. Western Blot analyses of cytosolic and nuclear protein lysates revealed that XN inhibited DHT-induced nuclear translocation of the androgen receptor (AR). Furthermore, in a yeast AR assay, XN inhibited AR-transcription at concentrations of 10 to 100 µM. Docking calculations of XN to the AR indicate steric interactions between the prenyl moiety of XN and Trp741, which could destabilize the AR C-terminal helix 12 and thus further explain the antagonist activity of XN. To investigate anti-androgenic action of XN in vivo, a Hershberger assay with male orchiectomizedWistar rats was performed. Prostate and seminal vesicle weight gain was stimulated by subcutaneous application of 0.2 mg/kg body weight (bw) testosterone propionate (TP). After 12 days, no significant inhibitory effects of oral XN (10 and 30 mg/kg bw) on prostate weights was observed, whereas the anti-androgen flutamide used as a positive control inhibited the 1.2-fold induction of prostate weights by 78% (p&amp;lt;0.001). However, seminal vesicle weight gain induced by TP was significantly reduced by 56 and 29% by XN treatment (10 and 30 mg/kg bw), respectively, and by 92% by flutamide application. Quantitative RT-PCR analyses of prostate RNA confirmed the anti-androgenic effects of XN in vivo. XN and flutamide significantly reduced the expression of androgen-dependent target genes PSA, AR, IGF-1, prostate binding protein C3, myostatin and tyrosine aminotransferase (p&amp;lt;0.05). Taken together, in the present study XN was identified as a potent novel anti-androgen, which might be of use for future prostate cancer prevention trials. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B79.

Promising tumor‐associated antigens for future prostate cancer therapy

Prostate cancer (CaP) is one of the most prevalent malignant diseases among men in Western countries. There is currently no cure for metastatic castrate-resistant CaP, and median survival for these patients is about 18 months; the high mortality rate seen is associated with widespread metastases. Progression of CaP from primary to metastatic disease is associated with several molecular and genetic changes that can affect the expression of specific tumor-associated antigens (TAAs) or receptors on the cell surface. Targeting TAAs is emerging as an area of promise for controlling late-stage and recurrent CaP. Several reviews have summarized the progress made in targeting signaling pathways for CaP but will not be discussed here. We describe some important CaP TAAs. These include prostate stem-cell antigen, prostate-specific membrane antigen, MUC1, epidermal growth factor receptor, platelet-derived growth factor and its receptor, urokinase plasminogen activator and its receptor, and extracellular matrix metalloproteinase inducer. We summarize recent advancements in our understanding of their role in CaP metastasis, as well as potential therapeutic options for targeting CaP TAAs. We also discuss the origin, identification, and characterization of prostate cancer stem cells (CSCs) and the potential benefits of targeting prostate CSCs to overcome chemoresistance and CaP recurrence.

Use of PSA threshold to identify an increased 4-year risk of a prostate cancer diagnosis in U.S. men

5051 Background: Recent studies have shown that prostate specific antigen (PSA) values can be used to predict risk of developing prostate cancer (PCa) in the future. In the European Randomized Study of Screening for PCa (ERSPC) subjects with PSA of ≥1.5 ng/mL had a significantly greater risk of developing PCa after 4 years than subjects with PSA of &lt;1.5 ng/mL (9.2% vs 1.5%, respectively; OR = 7.466; p &lt; 0.001). This current analysis aimed to validate the ability of PSA of ≥1.5 ng/mL to predict the future risk of PCa in a US population of men within the Henry Ford Healthcare System (HFHS). Methods: This is a retrospective analysis of men enrolled in the Health Alliance Plan of the HFHS between 1997–2004 with at least 4 years of follow-up data. Men ≥40 years of age, with a baseline PSA value between 0–4.0 ng/mL, not receiving 5-alpha reductase inhibitors were included. Men were followed for 4 years after their first PSA value. The risk of 4-year PCa diagnosis was evaluated based on a 1.5 ng/mL PSA threshold, and was assessed by logistic regression, controlling for age and race. Results: A total of 21,502 patients were included in the analysis. At baseline, patients had a mean age of 55 years and a mean PSA of 1.0 ng/mL. Overall, 7.9% of patients with baseline PSA of 1.5–4 ng/mL were diagnosed with PCa after 4 years, compared to 0.5% of patients with a baseline PSA of &lt;1.5 ng/mL. In a multivariate analysis (controlling for race and age), patients with a baseline PSA of 1.5–4 ng/mL were 12 times more likely to be diagnosed with PCa over 4 years than patients with baseline PSA of &lt;1.5 ng/mL (OR = 12.4; 95% CI: 9.7–15.9; p &lt; 0.0001). African Americans (n = 6,367) with baseline PSA 1.5–4 ng/mL vs baseline PSA&lt;1.5 ng/mL had an even higher risk of being diagnosed with PCa over 4 years (OR = 17.0; 95% CI: 11.0–26.1; p &lt; 0.0001). Conclusions: This analysis validates that men with PSA values 1.5 to 4 ng/mL are at a significantly increased risk for developing future prostate cancer compared to those with a PSA value below the 1.5 threshold. This threshold also confers increased 4-year risk in African American men. [Table: see text]

Role of maximum androgen blockade in advanced prostate cancer

Androgen ablation is the mainstay treatment for advanced prostate cancer (PC). Researchers proposed that maximum androgen blockade (MAB) therapy with antiandrogen agent in combination with castration might result in a better outcome among patients with advanced PC. In the last two decades, numerous trials and pooled data analyses were conducted to optimize the role of MAB in the treatment of metastatic PC. Non-steroidal antiandrogens administered as part of MAB proved to have a small (3%) survival benefit, however, the magnitude of this difference is of questionable clinical significance. Available evidence suggests that MAB should not be routinely offered to patients with metastatic PC, however, it should remain a reasonable option when discussing management. The standard first line treatment should be a monotherapy, consisting of orchiectomy or LHRH agonist. MAB still has a role as a short-term therapy (2-4 weeks). The ongoing large sample population based prospective studies may add new dimensions in the use of MAB in treatment of the prostate cancer in future.

Defining Increased Future Risk for Prostate Cancer: Evidence From a Population Based Screening Cohort

Previous studies have examined the relationship among prostate specific antigen, other predictive factors and current prostate cancer risk. We examined the population risk during 4 years, defined a prostate specific antigen associated with this risk and clarified the contribution of other predictive factors. The population consisted of men 55 to 70 years old screened at the first and second screening rounds 4 years apart in the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. The proportion of men with a positive prostate biopsy (initiated for a prostate specific antigen of 3.0 ng/ml or greater) and the mean population prostate specific antigen were calculated. Multivariate modeling was conducted using a proportional odds regression model to establish significant predictors of a positive biopsy from round 1 to round 2 of screening. Among men with no previous prostate biopsy the 4-year risk of prostate cancer was 5.1%, which was associated with a mean prostate specific antigen of 1.5 ng/ml at the first screening. An increased prostate specific antigen was a highly significant predictive factor for biopsy detectable prostate cancer 4 years later. Increasing log total prostate volume and a previous negative biopsy were associated with a significant reduction in risk of a positive prostate biopsy 4 years later. A prostate specific antigen of 1.5 ng/ml or greater in men older than 50 years represents an indicator for greater than average future risk of prostate cancer. Prostate specific antigen and other factors can be used to define future prostate cancer risk in addition to current use as a diagnostic marker for prostate cancer.

Green tea in chemoprevention of prostate cancer

Green tea as a main beverage is consumed worldwide. In the last few years, .green tea has been shown to induce apoptosis and to inhibit the infiltration and metastasis of prostate cancer by in vitro and in vivo experiments. Epidemiologic investigations and clinical trials also have demonstrated the chemopreventive role of green tea in prostate cancer, such as reducing the possibility of carcinogenesis of high-grade prostatic in-traepithelial neoplasia, and is hopeful to be applied as chemopreventive agent of prostate cancer in the future. Key words: Green tea; Prostatic neoplasms; Chemoprevention

The Arachidonic Acid Pathway and its Role in Prostate Cancer Development and Progression

The arachidonic acid pathway incorporates phospholipase, cyclooxygenase, lipoxygenase and epoxygenase enzymes. This pathway has been shown to have a major role in the development and progression of a number of cancers, including prostate cancer. We discuss the current status of research of this pathway in the area of prostate cancer, ranging from preclinical in vitro studies to human clinical trials. We performed an online search of the current and past peer reviewed literature on prostate cancer and arachidonic acid, phospholipase, cyclooxygenase, lipoxygenase, epoxygenase, platelet activating factor, prostaglandin and eicosanoid. We retrieved and evaluated all full-length articles published in English from the 1980s to January 2007. Epidemiological evidence suggested that nonsteroidal anti-inflammatory drugs may decrease the risk of prostate cancer. This effect, presumably through the inhibition of cyclooxygenase-2, has been validated in preclinical studies. Cyclooxygenase-2 inhibition has also decreased the rate of prostate specific antigen increase in men with biochemical recurrence after treatment for prostate cancer. Although lipoxygenase and secretory phospholipase A2 inhibition was also effective for decreasing prostate cancer growth in preclinical studies, to our knowledge these strategies have not yet been used in clinical trials. Cytosolic phospholipase A2, platelet activating factor and epoxygenase need further investigation to determine a role in prostate cancer. Evolving data suggest a significant role for some areas of the arachidonic acid pathway in prostate cancer. Inhibiting 1 or a number of these enzymes in combination may hold promise for future prostate cancer treatment.

Diagnostic Value of Free Prostate-Specific Antigen among Men with a Prostate-Specific Antigen Level of

ObjectivesThe percentage of free prostate-specific antigen (%fPSA) improves the diagnostic accuracy for prostate cancer when the serum level of total PSA (tPSA) is elevated. Approximately 14% of men with a tPSA below 3μg/l have prostate cancer on biopsy, but the diagnostic value of %fPSA in such men is rather unknown. The purpose was to estimate the impact of %fPSA on future prostate cancer risk among men with a normal tPSA in prostate cancer screening. Subjects and methodsThe first round of the Finnish arm of the European Randomized Trial for Screening of Prostate Cancer in 1996 to 1999 comprised 20,793 men aged 55–67 yr. Screen-negative men (tPSA level below 3.0μg/l, n=17,680) were followed up until the end of 2003. Cumulative risk of prostate cancer was calculated as a function of %fPSA. ResultsDuring the median follow-up of 5.8 yr (range, 0–7.7 yr), 327 men were diagnosed with prostate cancer and 25% of them had a Gleason score of 7 or higher. Five years after the first screening, cumulative risk of prostate cancer was 1.7% (95%CI, 1.5–1.9%). Men with a %fPSA in the lowest quartile (<14.2%) showed a 6.9-fold risk compared with those with a level in the highest quartile (>23.7%). ConclusionsIn men with a low serum tPSA, a low %fPSA is a strong predictor of later diagnosis of prostate cancer.

NMR-based metabolomics approach to target biomarkers for human prostate cancer

In the era of genomics and proteomics, metabolomics offers a unique way to probe the underlying biochemistry of malignant transformations. In the context of oncological metabolomics, the study of the global variation of metabolites involved in the development and progression of cancers, few existing techniques offer as much potential to discover biomarkers as nuclear magnetic resonance techniques. The most fundamental magnetic resonance methodologies with regard to human prostate cancer are magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging. Recent in vivo explorations have examined crucial metabolites that may indicate cancerous lesions and have the potential to direct treatment; while ex vivo studies of prostatic fluids and tissues have defined novel diagnostic parameters and indicated that magnetic resonance methodologies will be paramount in future prostate cancer management.

Serum Macrophage Inhibitory Cytokine-1 Concentrations Correlate with the Presence of Prostate Cancer Bone Metastases

Macrophage-inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor beta superfamily. It is up-regulated by nonsteroidal anti-inflammatory drugs and is highly expressed in human prostate cancer leading to high serum MIC-1 concentrations with advanced disease. A role for MIC-1 has been implicated in the process of early bone formation, suggesting that it may also mediate sclerosis at the site of prostate cancer bone metastases. Consequently, the aim of this study was to retrospectively determine the relationship of serum MIC-1 concentration and other markers related to current and future prostate cancer bone metastasis in a cohort of 159 patients with prostate cancer. Serum markers included cross-linked carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and amino-terminal propeptide of type I procollagen (PINP). The mean values of all the biomarkers studied were significantly higher in patients with baseline bone metastases (BM+, n = 35), when compared with those without bone metastases (BM-, n = 124). In a multivariate logistic model, both MIC-1 and PINP independently predicted the presence of baseline bone metastasis. Based on receiver operator curve analysis, the best predictor for the presence of baseline bone metastasis was MIC-1, which was significantly better than carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and PINP. Patients who experienced bone relapse had significantly higher levels of baseline MIC-1 compared with patients who did not (1476.7 versus 988.4; P = 0.03). Current use of acetylsalicylic acid did not influence serum MIC-1 levels in this cohort. Although requiring validation prospectively, these results suggest that serum MIC-1 determination may be a valuable tool for the diagnosis of current and future bone metastases in patients with prostate cancer.

Finasteride as a chemopreventive agent in prostate cancer: impact of the PCPT on urologic practice

Prostate cancer chemoprevention involves the use of natural and/or synthetic agents that inhibit or reverse the development of precancerous lesions or delay progression of these lesions to invasive disease. The recent completion of the first Phase III trial for prostate cancer prevention, the Prostate Cancer Prevention Trial (PCPT) using the drug finasteride, has provided the urologic community with the first evidence that a chemopreventive agent can reduce the risk of developing prostate cancer. The enthusiasm for the clear relative risk reduction in the finasteride arm of the trial has been tempered by the observation that the incidence of high-grade tumors was higher in men receiving finasteride compared to those on placebo. A question remains about whether the observed higher incidence in high-grade tumors is real or whether it is related to a pathologic or sampling artifact. The PCPT has instigated a great deal of debate, resulting in the larger urologic community being reluctant to recommend the widespread use of finasteride as a chemopreventive agent. This review summarizes the PCPT, analyzes its controversial results, and describes future prostate cancer chemoprevention studies.

Mechanisms Underlying the Development of Androgen-Independent Prostate Cancer

Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. The American Cancer Society estimates that during 2005, ∼232,090 new cases of prostate cancer will be diagnosed in the United States and 30,350 men

Numerical and functional assessment of blood dendritic cells in prostate cancer patients

Prostate cancer is one of the leading causes of cancer deaths in males and there are currently no effective treatments available for metastatic disease. Although recent clinical trials using dendritic cell (DC) based immunotherapy treatments have demonstrated safety, immunological responses, and some clinical efficacy, better vaccine delivery strategies need to be developed. We have undertaken the first detailed analysis of blood DC (BDC) subsets and their function in prostate cancer patients, with a view to utilizing immunoselected BDC for immunotherapy. We enumerated the CD11c+CD1c+, CD11c+CD16+, and CD11c-CD123+ BDC subsets in whole blood of prostate cancer patients using a single platform TruCOUNT assay. These subsets were identified and purified using flow cytometry and immunomagnetic selection, and their functional capacity analyzed by costimulatory molecule expression, cytokine secretion, and antigen presenting ability. There were no significant differences in the number or composition of these subsets compared to healthy donors and these cells could be purified with equal efficiency from both groups. The prostate cancer patients BDC had similar levels of key costimulatory molecules and cytokine expression profiles, compared to healthy donors, and these were upregulated to the same extent, in response to exogenous stimuli. BDC from both groups were capable of eliciting allogeneic proliferative responses and inducing autologous CD4+ responses to naïve and recall antigens, and antigen-specific CD8+ responses to influenza matrix protein and prostate specific antigen. These results indicate that an immunoselected CD1c+ BDC preparation could provide a suitable vaccine delivery vehicle for future prostate cancer immunotherapy trials.

Soy Protein Isolates of Varying Isoflavone Content Exert Minor Effects on Serum Reproductive Hormones in Healthy Young Men ,

Inverse associations between soy and prostate cancer and the contribution of hormones to prostate cancer prompted the current study to determine whether soy protein could alter serum hormones in men. Thirty-five men consumed milk protein isolate (MPI), low-isoflavone soy protein isolate (SPI) (low-iso SPI; 1.64 +/- 0.19 mg isoflavones/d), and high-iso SPI (61.7 +/- 7.35 mg isoflavones/d) for 57 d each in a randomized crossover design. Twenty-four-hour urine samples indicated that urinary isoflavones were significantly increased by the high-iso SPI relative to the low-iso SPI and MPI. Serum collected on d 1, 29, and 57 of each treatment revealed that dihydrotestosterone (DHT) and DHT/testosterone were significantly decreased by the low-iso SPI [9.4% (P = 0.036) and 9.0% (P = 0.004), respectively] and the high-iso SPI [15% (P = 0.047) and 14% (P = 0.013), respectively], compared with the MPI at d 57. Other significant effects included a decrease in testosterone by the low-iso SPI relative to the MPI (P = 0.023) and high-iso SPI (P = 0.020) at d 29; an increase in dehydroepiandrosterone sulfate by the low-iso SPI relative to the MPI at d 29 (P = 0.001) and relative to the MPI (P = 0.0003) and high-iso SPI (P = 0.005) at d 57; and increases in estradiol and estrone by the low-iso SPI relative to the MPI at d 57 (P = 0.010 and P = 0.005, respectively). In conclusion, soy protein, regardless of isoflavone content, decreased DHT and DHT/testosterone with minor effects on other hormones, providing evidence for some effects of soy protein on hormones. The relevance of the magnitude of these effects to future prostate cancer risk requires further investigation.

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval.

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels. To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area. At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer. Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores. Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.

PTEN and p27Kip1 have a cooperative role on inhibition proliferation, modulation of cell cycle and inducing apoptosis in prostate cancer PC-3 cell

To investigate whether the human PC-3 cell infected with recombinant Ad-PTEN and Ad-p27Kip1 can steadily produce PTEN and p27Kip1 protein and change the biologic behaviors such as cell proliferation, cell cycle and apoptosis. The synergistic effect of PTEN and p27Kip1 on the therapy for prostate cancer has also been investigated. We constructed recombinant adenovirus vector of human tumor suppressor gene PTEN and p27Kip1. The viral titer was examined by plaque assay and the mRNA and protein expressions of PTEN and p27Kip1 in human prostate cancer cell line PC-3 infected with Ad-PTEN and Ad-p27Kip1 were determined by RT-PCR and Western blot respectively. MTT assay was used to determine the effect of PTEN and p27Kip1 on growth and proliferation of PC-3 cell; the change of cell cycle and apoptosis was examined by flow cytometry, and to compare between the combined therapy group and single gene therapy group. The viral titers of Ad-PTEN and Ad-p27Kip1 were 1.8 x 10(7) pfu/ml and 1.2 x 10(9) pfu/ml respectively. After infected by adenovirus, it had been verified that the mRNA and protein expression of PTEN and p27Kip1 were steady in human PC-3 cell. Ad-PTEN and Ad-p27 Kip1 inhibited the growth and proliferation of PC-3 cells. The progression of cell cycle of PC-3 cell was arrested in G(0)-G(1) phase, meanwhile the apoptosis rate of PC-3 was also affected after Ad-PTEN or/and Ad-p27 Kip1 infected. There was significant difference between combined therapy group and single gene therapy group. The recombinant Ad-PTEN and Ad-p27Kip1 vector were constructed successfully and the expression of specific PTEN and p27Kip1 was high, steadily in PC-3 cell line. These results suggested that combination of PTEN with p27Kip1 has an application value in treatment of prostate cancer in future.