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Screening for Prostate Cancer

Raised levels of prostate-specific antigen (PSA) are a common symptom of prostate cancer, however, it can be caused by other conditions too. Routinely screening of all men to check their levels of PSA is a controversial subject across the international medical community, healthcare providers and advocacy groups. This is because there are many risks (including invasive tests, 'false positives', unnecessary treatment and side effects) as well as potential benefits (earlier detection of disease when it is still curable), and the PSA test does not differentiate between slow growing tumours which may never need treatment and more aggressive prostate cancer. Research into better tests is needed.

Current policies vary between different countries. Some advocates recommend all men over 50 have an annual PSA test, many countries recommend against regular mass screening, but increasingly UK and recent US recommendations are for PSA testing to be a individual's decision to make an informed choice. It is complex and best discussed with your doctor.

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Information for Patients and the Public
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Prostate Cancer
Cancer Screening and Early Detection

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  • PubMed search for publications about Prostate Cancer Screening / PSA test - Limit search to: [Reviews]

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    MeSH term: Prostatic Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Graff JN, Beer TM
Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.
Oncology (Williston Park). 2015; 29(6):416-23 [PubMed] Related Publications
Skeletal-related events contribute substantially to morbidity, mortality and cost in men with metastatic castration-resistant prostate cancer (mCRPC). There are five agents available for treatment in mCRPC that reduce skeletal-related events. Here we discuss the efficacy and safety of zoledronic acid, denosumab, enzalutamide, abiraterone, and radium-223. We include data on and a discussion of duration of treatment with zoledronic acid and denosumab, the only two of these agents that do not have a clinically proven anticancer effect. Finally, we review the available data regarding the cost of denosumab compared with that of zoledronic acid.

Pacella E, Ricci F, Colecchia M, et al.
Prostatic and urothelial metastasis in the same lymph node: a case report.
Anal Quant Cytopathol Histpathol. 2015; 37(2):139-43 [PubMed] Related Publications
BACKGROUND: Collision metastasis is a rare phenomenon in which metastases of carcinoma from 2 separate primary tumors occur in the same lymph node. We summarize here the clinical course and highlight the histological challenges in the diagnosis of this rare phenomenon.
CASE: A biopsy performed due to gross hematuria by endoscopic resection revealed an infiltrative high-grade urothelial carcinoma in a 75-year-old man receiving androgen deprivation therapy due to biopsy-proven high-grade prostate cancer. A radical cystectomy, with regional lymphadenectomy and prostatectomy, was performed. Three nodes appeared to have metastatic foci from both primary tumors: prostatic and urothelial cancer. The presence of the 2 tumor types colliding in the same lymph nodes was confirmed by immunohistochemical stains.
CONCLUSION: In a patient with simultaneous tumors it is important to remember that a part of lymph node metastases with histological polymorphic appearance may result from a collision metastasis. In light of the important therapeutic consequences, a differential diagnosis is needed, suggesting appropriate immunohistochemical investigations.

Dugonjić AS, Usaj SK, Eri Z, Latinović LT
Significance of microvessel density in prostate cancer core biopsy.
Vojnosanit Pregl. 2015; 72(4):317-27 [PubMed] Related Publications
BACKGROUND/AIM: In prostate tumors, angiogenesis, measured as microvessel density, is associated with tumor stage and Gleason score. The aim of this study was determine neovascularization of prostatic adenocarcinomas in core biopsies and corresponding prostatectomies.
METHODS: The study population included 61 patients who underwent radical prostatectomy (RP) for localized prostate carcinoma patients and did not receive chemohormonal, or radiation therapy before surgery. Tumor blocks were immunostained using the endothelial-specific antibody CD31 and subsequently evaluated at x 400 magnification in both biopsies and corresponding prostatectomies.
RESULTS: When comparing microvessel density in core biopsies and corresponding prostatectomies, no statistically significant difference was found (p > 0.1). A statistically significant positive correlation was found when determining correlation between microvessel density (as linear and categorical variable, i.e., with the cut-off value of 48) that was associated with the Gleason score (p < 0.05) and tumor stage (p < 0.0001). There was no correlation between microvessel density and preoperative values of serum prostate-specific antigen (PSA) (p > 0.1).
CONCLUSION: Microvessel density can be reliably applied to needle prostate biopsy specimens. Quantification of the microvascular density in biopsies is an accurate pre-operative predictor of tumor stage, discriminating between organ-confined and organ-extending neoplasms.

Tsvetkova A, Todorova A, Todorov T, et al.
Molecular and clinico-histological data in aggressive prostate cancer patients from Bulgaria.
J BUON. 2015 Mar-Apr; 20(2):498-504 [PubMed] Related Publications
PURPOSE: Metastatic prostate cancer (PCa) is one of the leading causes of death in men worldwide. We report Bulgarian patients with strongly aggressive, castration-resistant PCa.
METHODS: PCA3 overexpression, GSTP1 promoter hyper-methylation, TMPRSS2-ERG gene fusions, IVS1-27G>A in the KLF6 gene and mutations in androgen receptor (AR) gene, for diagnostic purposes were assessed. PCR, real-time PCR (RT-PCR), sequencing, and bisulfite conversion of DNA were applied. We correlated the molecular data to the histological and clinical findings.
RESULTS: The obtained molecular profile in 11 PCa Bulgarian patients coincided with the clinico-histological data of strongly aggressive PCa. Association was detected between the tumor stage (assessed by TNM as T3 and T4) and the detected molecular profile of aggressive cancer behavior with one exception, assessed as T2. None of our patients had positive family history of prostate cancer and no somatic mutations were detected in the AR gene. All patients showed normal genotype with respect to the KLF6 IVS1- 27G>A polymorphism. The rest of the markers were positive in fresh prostatic tissues and biopsies from all patients, whereas only one blood sample showed triple positive result.
CONCLUSIONS: The appearance of PCa-specific markers in blood was considered as a predictor for a PCa (micro) dissemination into the circulation. The GSTP1 promoter hypermethylation is the earliest epigenetic alteration, which indicates cancerous changes and the first and long-lasting marker that is detectable in blood circulation. The molecular profile needs to be strictly monitored during treatment, which is of great help in determining the patient's individual response to therapy.

Adaramoye O, Erguen B, Oyebode O, et al.
Antioxidant, antiangiogenic and antiproliferative activities of root methanol extract of Calliandra portoricensis in human prostate cancer cells.
J Integr Med. 2015; 13(3):185-93 [PubMed] Related Publications
OBJECTIVE: Prostate cancer (PCa) is a major health concern. Calliandra portoricensis (CP) is traditionally known for its analgesic, anti-ulcerogenic and anticonvulsant properties. However, its antiproliferative properties for PCa still need to be investigated.
METHODS: Antioxidant activities of CP were determined by 1,1-diphenyl-2-picryhydrazyl (DPPH) and hydroxyl (OH(-)) radicals-scavenging methods. PC-3 and LNCaP (androgen-refractory and androgen-dependent PCa-derived cell lines) were cultured and treated with CP (10, 50 and 100 μg/mL). Effects of CP on cells were determined by cytotoxicity assay (lactate dehydrogenase, LDH) and viability assay (sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate, XTT). DNA fragmentation was detected by cell death detection enzyme-linked immunosorbent assay plus kit. CP was tested as an inhibitor of angiogenesis using chicken chorioallantoic membrane (CAM) assay.
RESULTS: CP showed significant scavenging of DPPH and OH(-) radicals. CP significantly (P<0.05) inhibited lipid peroxidation in a dose-dependent manner. Precisely, CP (10, 50 and 100 μg/mL) inhibited PC-3 and LNCaP growth by 7%, 74% and 92%, and 27%, 73%, and 85% respectively at 48 h. CP had low toxicity in vitro at its half inhibitory concentration dose. Detection of cell death induced by CP at 50 μg/mL showed higher enrichment factors in LNCaP (7.38±0.95) than PC-3 (3.48±0.55). Also, treatment with CP (50 μg/mL) significantly reduced network of vessels in CAM, suggesting its antiangiogenic potential.
CONCLUSION: Calliandra portoricensis elicited antioxidant, antiangiogenic and antiproliferative effects in PCa cells.

Shukla P, Mathur V, Kumar A, et al.
Nanoemulsion based concomitant delivery of curcumin and etoposide: impact on cross talk between prostate cancer cells and osteoblast during metastasis.
J Biomed Nanotechnol. 2014; 10(11):3381-91 [PubMed] Related Publications
An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 μM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 μM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 μM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.

Robinson D, Van Allen EM, Wu YM, et al.
Integrative clinical genomics of advanced prostate cancer.
Cell. 2015; 161(5):1215-28 [PubMed] Article available free on PMC after 21/05/2016 Related Publications
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

McClure P, Elnakib A, Abou El-Ghar M, et al.
In-vitro and in-vivo diagnostic techniques for prostate cancer: a review.
J Biomed Nanotechnol. 2014; 10(10):2747-77 [PubMed] Related Publications
This paper overviews one of the most important, interesting, and challenging problems in oncology, early diagnosis of prostate cancer. Developing effective diagnostic techniques for prostate cancer is of great clinical importance and can improve the effectiveness of treatment and increase the patient's chance of survival. The main focus of this study is to overview the different in-vitro and in-vivo technologies for diagnosing prostate cancer. This review discusses the current clinically used in-vitro cancer diagnostic tools, such as biomarker tests and needle biopsies and including their applications, advantages, and limitations. Moreover, the current in-vitro research tools that focus on the role of nanotechnology in prostate cancer diagnosis have been detailed. In addition to the in-vitro techniques, the current study discusses in detail developed in-vivo non-invasive state-of-the-art Computer-Aided Diagnosis (CAD) systems for prostate cancer based on analyzing Transrectal Ultrasound (TRUS) and different types of magnetic resonance imaging (MRI), e.g., T2-MRI, Diffusion Weighted Imaging (DWI), Dynamic Contrast Enhanced (DCE)-MRI, and multi-parametric MRI, focusing on their implementation, experimental procedures, and reported outcomes. Furthermore, the paper addresses the limitations of the current prostate cancer diagnostic techniques, outlines the challenges that these techniques face, and introduces the recent trends to solve these challenges, which include biomarkers used in in-vitro lab-on-a-chip nanotechnology-based methods.

Galunska B, Gerova D, Kosev P, et al.
Serum 25-hydroxy vitamin D levels in Bulgarian patients with prostate cancer: a pilot study.
Clin Lab. 2015; 61(3-4):329-35 [PubMed] Related Publications
BACKGROUND: The antiproliferative effect of the active form of vitamin D on cancer cells and its ability to induce cell differentiation and suppression of tumor-induced angiogenesis in the last decade has provoked enormous research for the elucidation of its role in the prevention of different types of cancer and in slowing down the malignancy progression. The aim of the present pilot study was to determine the circulating 25-hydroxy vitamin D (25OHD) levels in Bulgarian prostate cancer (PCa) patients and to investigate their relationship with various determinants associated with the severity and progression of the disease.
METHODS: A total of 53 male patients (mean age 67.0 ± 7.1 years) with clinical suspicion for PCa were enrolled in the study. All patients were subjected to systemic transrectal ultrasound-guided tru-cut prostate biopsies (10 cores at least). Detected tumors were graded using the Gleason grading system. Prostate specific antigen (PSA) serum levels were measured immunochemically. The 25OHD assay was performed by a validated HPLC-UV method. Other covariates (BMI, age, family history of PCa) were collected by interview at the time of hospitalization. One-way ANOVA with Kruskal Wallis statistics was used for comparison of medians of different parameters. The level of significance was set at p < 0.05.
RESULTS: Significantly lower 25OHD levels were detected in PCa patients compared to those with benign prostate hyperplasia (BPH) (p < 0.05). Patients with high grade tumors (Gleason score ≥ 7) showed significantly lower 25OHD levels, while those with low grade tumors (Gleason score < 7) revealed better 25OHD status (50.49 vs. 63.17 nmol/L, p < 0.05). A moderate negative correlation between 25OHD levels and the Gleason score was established (Spearman r = -0.46, p < 0.05). Significant seasonal variations in 25OHD levels, both for PCa and BPH patients, were detected (p < 0.01).
CONCLUSIONS: This preliminary study shows an association between 25OHD status and classical markers characterizing the severity of PCa. The results might suggest a potential beneficial role of vitamin D for PCa patients. Further prospective studies are needed to strengthen the interrelationships between 25OHD levels and variables related with PCa and to test them for causality.

Lin CC, Gray PJ, Jemal A, Efstathiou JA
Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: Clinically lymph node-positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base.
METHODS: Patients with cN+ PCa and without distant metastases diagnosed between 2004 and 2011 were included. Five-year overall survival for patients diagnosed between 2004 and 2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics, and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality.
RESULTS: Of 3540 total patients, 32.2% were treated with ADT alone and 51.4% received ADT+RT. Compared with ADT alone, patients treated with ADT+RT were younger and more likely to have private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values. After PS matching, 318 patients remained in each group. Compared with ADT alone, ADT+RT was associated with a 50% decreased risk of five-year all-cause mortality (HR = 0.50, 95% CI = 0.37 to 0.67, two-sided P < .001; crude OS rate: 71.5% vs 53.2%).
CONCLUSIONS: Using a large national database, we have identified a statistically significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated by randomized trials, suggest that a substantial proportion of such patients at high risk for prostate cancer death may be undertreated, warranting a reevaluation of current practice guidelines.

Sedelaar JP, Schalken JA
The need for a personalized approach for prostate cancer management.
BMC Med. 2015; 13:109 [PubMed] Article available free on PMC after 21/05/2016 Related Publications
The stratification of patients for treatment of prostate cancer is based on very general parameters like prostate-specific antigen, Gleason score, and TNM classification. We use these rough parameters for selection of active surveillance, active treatment, and even for the treatment selection in metastasized or castration-resistant prostate cancers. Up to now, we have not used individualized genetic classifiers for detailed sub-stratification, thus treating all patients as equal, and being only moderately successful. With the expected increase in systemic treatments, there is an apparent need for such classifiers. We will address these needs in this short commentary.

Shah M, Denlinger CS
Optimal post-treatment surveillance in cancer survivors: is more really better?
Oncology (Williston Park). 2015; 29(4):230-40 [PubMed] Related Publications
A substantial rise in the number of cancer survivors has led to management questions regarding effective post-treatment surveillance strategies. Although a number of professional societies have proposed surveillance guidelines, clinical practice varies; the general trend is toward more intensive strategies. The evidence supporting intensive surveillance is relatively lacking, with most studies showing that more intense surveillance regimens have minimal, if any, impact on outcomes in terms of survival, quality of life, or overall cost-effectiveness. This has been demonstrated in breast cancer, and data supporting a similar conclusion may be evolving in colorectal cancer, where large prospective studies call into question the utility of intensive surveillance; in prostate cancer, retrospective data suggest a similar trend. In this review, we discuss the established guidelines and current evidence regarding post-treatment surveillance, and we propose general management strategies in prostate, colorectal, and breast cancers.

Raslau D, Summerfield DT, Abu Dabrh AM, et al.
The risk of prostate cancer in pilots: a meta-analysis.
Aerosp Med Hum Perform. 2015; 86(2):112-7 [PubMed] Related Publications
BACKGROUND: Aviation exposes pilots to various occupationally related hazards, including ionizing radiation and chemical combustion. The possible increased risk of prostate cancer among pilots in comparison to the general population is a subject of debate. This systematic review and meta-analysis aimed to determine the quality of supporting evidence and magnitude of this association.
METHODS: All studies pertaining to prostate cancer in pilots were retrieved from multiple databases and from a manual search. Any study that assessed the incidence of prostate cancer relative to the incidence in the general population was included regardless of language or size. A random effect model was used to pool relative risks (RR) across studies. Heterogeneity was assessed using the Q statistic and I².
RESULTS: Eight studies with a low risk of bias were included in the meta-analysis. Pilots had an increased risk of developing prostate cancer compared to the general population [RR 2.0; 95% confidence interval (CI), 1.5-2.7]. The analysis was associated with substantial heterogeneity (I² = 79%). Several subgroups had significantly increased risk, such as African American pilots (RR 10.00; 95% CI, 5.04-19.86) and military pilots (RR 3.30; 95% CI, 2.03-5.39).
CONCLUSION: Pilots are at least twice as likely to develop prostate cancer compared to the general population. The implications of these findings are important considering the high prevalence of prostate cancer and the large number of pilots in the workforce.

Lu K, Liu C, Tao T, et al.
MicroRNA-19a regulates proliferation and apoptosis of castration-resistant prostate cancer cells by targeting BTG1.
FEBS Lett. 2015; 589(13):1485-90 [PubMed] Related Publications
MicroRNAs (miRNAs) play a significant role in tumor development. Recent studies indicate that miRNAs are implicated in prostate cancer (PCa). In this study, we found that miR-19a expression was significantly increased in castration-resistant prostate cancer (CRPC) tissues compared with androgen-dependent prostate cancer (ADPC) tissues. We found that inhibiting the overexpression of miR-19a in CRPC cells suppressed proliferation and increased apoptosis. Additionally, we found that miR-19a repressed BTG1 expression by binding to its 3'-untranslated region. The overexpression of BTG1 in CRPC cells significantly suppressed proliferation and increased apoptosis. We conclude that miR-19a regulates proliferation and apoptosis of CRPC cells by directly targeting the tumor suppressor gene BTG1.

Karaca B, Degirmenci M, Ozveren A, et al.
Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines.
Cancer Chemother Pharmacol. 2015; 75(6):1273-80 [PubMed] Related Publications
PURPOSE: Docetaxel (DTX) is widely used for the treatment of metastatic prostate and breast cancers. Despite the clinical success of DTX, drug-related cumulative toxicity restricts its clinical use in cancer therapy. Thus, there is an urgent need for new therapeutic options. Octreotide (OCT) is a synthetic somatostatin analog that induces apoptosis in different cancer cell lines in vitro. In this study, we investigated the possible synergistic apoptotic effects of DTX in combination with OCT in prostate and breast cancer cell lines.
METHODS: The XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by Cell Death Detection ELISA(Plus) Kit. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. Levels of SSTR2 and SSTR5 proteins were determined by western blot analysis.
RESULTS: DTX and OCT combination induced apoptosis in both breast and prostate cancer cells in a concentration- and time-dependent manner. Moreover, combination treatment resulted in inhibition of anti-apoptotic proteins such as Bcl-2 and Bcl-xL and induction of pro-apoptotic proteins Bax, Cytochrome c and IAPs in all of the tested cancer cell lines. SSTR2 and SSTR5 protein levels were induced as compared to any agent alone.
CONCLUSIONS: These results indicate that this combination treatment is a significant inducer of apoptosis in a synergistic manner in breast and prostate cancer cells. This strong synergism helps to lower the dose of DTX in both types of cancers, thus letting DTX to be used for longer periods by delaying resistance development and lesser side effects.

Quero L, Rozet F, Beuzeboc P, Hennequin C
The androgen receptor for the radiation oncologist.
Cancer Radiother. 2015; 19(3):220-7 [PubMed] Related Publications
Androgen deprivation therapy is widely used in combination with radiotherapy for the treatment of prostate cancer. The knowledge of the biology of the androgen axis could help the radiation oncologist to combine both modalities in an efficient way. Moreover, new drugs have recently been approved and their role in combination with radiation needs pre-clinical and clinical studies. This review summarized the main data on the biology of androgen receptor and the potential implications for the physician. Mechanisms of interactions between androgen deprivation therapy and radiotherapy are also presented and discussed.

Sun X, Li Y, Yu J, et al.
miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1.
Jpn J Clin Oncol. 2015; 45(5):474-82 [PubMed] Related Publications
OBJECTIVE: Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion.
METHODS: The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively.
RESULTS: We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells.
CONCLUSIONS: miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic strategies for prostate cancer would be developed based on miR-128/zinc-finger E-box-binding homeobox 1 axis.

Nishikawa M, Miyake H, Fujisawa M
Enhanced Sensitivity to Sunitinib by Inhibition of Akt1 Expression in Human Castration-resistant Prostate Cancer PC3 Cells Both In Vitro and In Vivo.
Urology. 2015; 85(5):1215.e1-7 [PubMed] Related Publications
OBJECTIVE: To investigate whether antitumor activity of sunitinib is enhanced by silencing Akt1 in a human castration-resistant prostate cancer PC3 model.
MATERIALS AND METHODS: We initially established PC3 in which the expression vector containing a short hairpin ribonucleic acid targeting Akt1 was introduced (PC3/sh-Akt1). Changes in various phenotypes of PC3/sh-Akt1 after treatment with sunitinib were compared with those of PC3 transfected with control vector alone (PC3/C) both in vitro and in vivo.
RESULTS: When cultured in the standard medium, in vitro growth of PC3/sh-Akt1 was almost similar to that of PC3/C. However, compared with PC3/C, PC3/sh-Akt1 showed a significantly higher sensitivity to sunitinib, accompanying impaired phosphorylation of p44/42 mitogen-activated protein kinase, downregulation of Bcl-2, and upregulation of Bax. In addition, treatment with sunitinib significantly suppressed the migration ability of PC3/sh-Akt1 compared with that of PC3/C. In vivo, administration of sunitinib induced the significantly marked growth inhibition of PC3/sh-Akt1 compared with that of PC3/C, and apoptotic index in PC3/sh-Akt1 tumor in mice treated with sunitinib was significantly greater than that in PC3/C tumor.
CONCLUSION: Combined treatment with Akt1 inhibitor and sunitinib could be a promising therapeutic approach for men with castration-resistant prostate cancer.

Boniol M, Autier P, Perrin P, Boyle P
Variation of Prostate-specific Antigen Value in Men and Risk of High-grade Prostate Cancer: Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study.
Urology. 2015; 85(5):1117-22 [PubMed] Related Publications
OBJECTIVE: To investigate variations in prostate-specific antigen (PSA) levels among men with an initial normal PSA level in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study.
METHODS: Data were extracted from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial study data set on all men in the interventional arm, with 2 tests performed in a period of < 2 years and with an initial result of the first test <4 ng/mL. The range of variation between first and second tests was computed. Risks of cancer stratified on Gleason score were computed using logistic regression.
RESULTS: A total of 31,286 men had 2 PSA tests within 2 years and with an initial value < 4 ng/mL. From the first to the second test, the median variation of PSA levels was 3.4% (interquartile range, -15% to +26%). The variation in PSA value was not associated with the delay between the first and the second test (P = .36), age (P = .16), body mass index (P = .41), and race (P = .12). A total of 2,781 prostate cancers were diagnosed during follow-up. Adjusting for age and initial PSA level, the risk of prostate cancer increased linearly with increasing PSA level at the second test, with an odds ratio of 1.079 (95% confidence interval, 1.058-1.101) for each percent increase in PSA level. However, the variation in PSA was not associated with a higher Gleason score (P = .95 for level variations in cancer of Gleason score < 7 vs ≥ 7).
CONCLUSION: Although an increase in PSA level over time is associated with increased risk of prostate cancer, this association is not related to more aggressive tumors.

Mok Y, Kimm H, Shin SY, et al.
Screening Prostate-specific Antigen Concentration and Prostate Cancer Mortality: The Korean Heart Study.
Urology. 2015; 85(5):1111-6 [PubMed] Related Publications
OBJECTIVE: To evaluate the association between serum prostate-specific antigen (PSA) concentration from a screening test and prostate cancer mortality in an Asian population.
METHODS: We included 118,665 men in the Korean Heart Study, a large prospective cohort study of participants who voluntarily underwent private health examinations that included PSA-based prostate cancer screening. The baseline visit occurred between January 1994 and December 2004, and follow-up was through December 2011. Deaths from prostate cancer were ascertained from the underlying cause of death from a computerized search of death certificate data from the National Statistical Office in Korea. We used the Cox proportional hazards regression to estimate the association between serum PSA and risk of prostate cancer death adjusting the baseline age, cigarette smoking status, and body mass index.
RESULTS: During 1,381,901 person-years of follow-up, 6036 men died of any cause, and of these, 56 men died of prostate cancer. The multivariate-adjusted hazard ratio for prostate cancer death statistically significantly increased across PSA concentrations (P trend <.0001). The hazard ratio increased 7% per 1-ng/mL increase in PSA. The association between PSA concentration and death from prostate cancer was stronger in younger than in older men and in heavier than leaner men.
CONCLUSION: In conclusion, an increased screening PSA level is associated with an increased risk of prostate cancer death in Korean men. Our findings may have implications for the development of targeted PSA cutpoints for biopsy recommendation.

Ito Y, Ishiguro H, Kobayashi N, et al.
Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through the induction of MMP-2 activity.
Prostate. 2015; 75(10):1009-19 [PubMed] Related Publications
BACKGROUND: Obesity is known to be associated with prostate cancer development and progression, but the detailed mechanism is not clear. Monocyte chemotactic protein-1 (MCP-1) is secreted from cancer cells, stromal cells, and adipocytes, and it is involved in prostate cancer progression. Here we investigated the biological role of MCP-1 secreted from adipocytes for prostate cancer cells.
METHODS: Human pre-adipocytes (HPAds) were cultured and differentiated to mature adipocytes. Conditioned medium (CM) from HPAd cells was obtained using phenol red-free RPMI1640 medium. We performed a cytokine membrane array analysis to detect cytokines in the CM. To characterize the physiological function of MCP-1 in the CM, we performed an MTT-assay, a wound-healing and invasion assay with anti-MCP-1 antibody using three prostate cancer cell lines: DU145, LNCaP, and PC-3. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were evaluated by gelatin zymography. A qPCR and Western blotting were used to examine the mRNA and protein expression levels of MMP-2.
RESULTS: The cytokine membrane array of the CM showed a strong signal of MCP-1compared to the control medium, and we thus focused our attention on MCP-1 in the CM. The CM up-regulated the cancer cell proliferation, and the neutralization by anti-MCP-1 antibody inhibited the proliferative effect of the prostate cancer cell lines. The CM greatly increased the invasive activity in the prostate cancer cell lines, and anti-MCP-1 antibody decreased the invasiveness. Gelatin zymography revealed that the CM markedly enhanced the enzymatic activity of MMP-2, and anti-MCP-1 antibody down-regulated its effect. MMP-2 mRNA expression was undetected and the MMP-2 protein level was unchanged between the control medium and CM in DU145 cells.
CONCLUSIONS: MCP-1 from adipocytes enhances the growth and invasion activity of prostate cancer cells. The inhibition of MCP-1 derived from adipocytes might be an effective treatment for prostate cancer.

Hu X, Jia Y, Yu J, et al.
Loss of YAP protein in prostate cancer is associated with Gleason score increase.
Tumori. 2015 Mar-Apr; 101(2):189-93 [PubMed] Related Publications
AIMS AND BACKGROUND: To investigate the expression of YAP protein by immunohistochemistry in prostate cancer tissues and hyperplasia or normal prostate tissues adjacent to cancer, and establish the correlation of YAP expression with Gleason score.
METHODS AND STUDY DESIGN: The expression of YAP protein was evaluated in tissue microarray by immunohistochemistry. The samples included 66 radical prostatectomy specimens with clinically detected prostate cancer and 54 hyperplasia or normal prostate tissues adjacent to cancer.
RESULTS: YAP expression was present mainly in the nuclei of basal cells in both prostate cancer tissues and normal prostate or hyperplasia tissues adjacent to cancer. Cytoplasmic expression of YAP was weaker than nuclear expression in both malignant and nonmalignant luminal epithelial cells. YAP expression was decreased or lost in prostate cancer tissues; hyperplasia or normal prostate tissues adjacent to cancer exhibited stronger nuclear and cytoplasmic expression of YAP (p = 0.0001). Downregulation of YAP expression in prostate cancer samples correlated with Gleason score increase (p = 0.002).
CONCLUSIONS: This immunohistochemical study expands our knowledge of the expression and localization of YAP in prostate cancer tissue and nonmalignant prostate tissue adjacent to cancer. YAP might function as a tumor suppressor in prostate cancer. Such information may provide the foundation for the treatment of preneoplastic and neoplastic lesions of the prostate.

Loriot Y, Miller K, Sternberg CN, et al.
Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.
Lancet Oncol. 2015; 16(5):509-21 [PubMed] Related Publications
BACKGROUND: Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial.
METHODS: In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991.
FINDINGS: Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001).
INTERPRETATION: In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer.
FUNDING: Astellas Pharma and Medivation.

Koukourakis MI, Kalamida D, Mitrakas A, et al.
Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer.
Biochem Biophys Res Commun. 2015; 461(2):268-74 [PubMed] Related Publications
INTRODUCTION: Radiotherapy is an equivalent alternative or complement to radical prostatectomy, with high therapeutic efficacy. High risk patients, however, experience high relapse rates, so that research on radio-sensitization is the most evident route to improve curability of this common disease.
MATERIALS AND METHODS: In the current study we investigated the autophagic activity in a series of patients with localized prostate tumors treated with radical radiotherapy, using the LC3A and the LAMP2a proteins as markers of autophagosome and lysosome cellular content, respectively. The role of autophagy on prostate cancer cell line resistance to radiation was also examined.
RESULTS: Using confocal microscopy on tissue biopsies, we showed that prostate cancer cells have, overall, high levels of LC3A and low levels of LAMP2a compared to normal prostate glands. Tumors with a 'highLC3A/lowLAMP2a' phenotype, suggestive of intensified lysosomal consumption, had a significantly poorer biochemical relapse free survival. The PC3 radioresistant cell line sustained remarkably its autophagic flux ability after radiation, while the DU145 radiosensitive one experiences a prolonged blockage of the autophagic process. This was assessed with aggresome accumulation detection and LC3A/LAMP2a double immunofluorescence, as well as with sequestrosome/p62 protein detection. By silencing the LC3A or LAMP2a expression, both cell lines became more sensitive to escalated doses of radiation.
CONCLUSIONS: High base line autophagy activity and cell ability to sustain functional autophagy define resistance of prostate cancer cells to radiotherapy. This can be reversed by blocking up-regulated components of the autophagy pathway, which may prove of importance in the field of clinical radiotherapy.

Karzai FH, Madan RA, Figg WD
Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer.
South Med J. 2015; 108(4):224-8 [PubMed] Related Publications
Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

Simper NB, Jones CL, MacLennan GT, et al.
Basal cell carcinoma of the prostate is an aggressive tumor with frequent loss of PTEN expression and overexpression of EGFR.
Hum Pathol. 2015; 46(6):805-12 [PubMed] Related Publications
Basal cell carcinoma (also referred to as adenoid cystic carcinoma) is a rare tumor of the prostate. Although largely characterized as indolent, poor outcomes have been reported in a considerable fraction of cases. As yet, optimum treatment strategies for this cancer have not been developed. This study investigates protein expression of common or potential molecular therapeutic targets and reports on the clinicopathological features of 9 new cases. We evaluated the expression of ERBB2, KIT, androgen receptor, PTEN, EGFR, ERG, and p53 via immunohistochemistry. We also examined EGFR amplification and TMPRSS2-ERG gene rearrangement by fluorescence in situ hybridization. The mean clinical follow-up was 44 months. We found that basal cell carcinoma behaved aggressively with almost one-half of the cases displaying high-risk pathologic features or local recurrence (44%). One patient died as a result of metastatic disease. The most consistent abnormalities included a loss of PTEN expression (56% of cases) and EGFR overexpression (67% of cases). EGFR overexpression occurred in the absence of gene amplification. The TMPRSS2-ERG rearrangement was not detected in any of the tumors studied, nor was ERG protein positivity identified by immunostaining. In addition, ERBB2, KIT, p53, and androgen receptor expressions were either absent or showed only weak, limited reactivity. Our results suggest that there is a high morbidity associated with this tumor, and more intense follow-up and additional treatment may be indicated. Furthermore, targeted therapies directed against the EGFR and PTEN proteins or their constitutive pathways may be promising for future clinical management.

Mahon KL, Lin HM, Castillo L, et al.
Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.
Br J Cancer. 2015; 112(8):1340-8 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.
METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.
RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).
CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Wieczorek K, Braczkowski RS, Skrzypek M, et al.
The comparison between vitamin d concentration in upper silesia patients with prostate cancer and with benign prostatic hyperplasia.
J Biol Regul Homeost Agents. 2015 Jan-Mar; 29(1):207-11 [PubMed] Related Publications
A number of studies have shown that vitamin D has a protective effect against the development of cancer, which may also be related to prostate cancer. Low serum vitamin D concentration has also been demonstrated in benign prostate hyperplasia. We compared serum vitamin D concentration in two groups of Polish men with prostate cancer and benign prostate hyperplasia. Each group comprised 30 patients. The concentration was determined by ELISA. To assess the difference between the study population, non-parametric Mann Whitney U test was used. The results revealed that patients with prostate cancer are deficient in vitamin D (median =25.3, quartiles q1 - q3: 13.4 -33.4). The concentration of vitamin D in the group of patients with prostate cancer was lower than in the group of benign prostatic hyperplasia with vitamin D deficiency (median =34.8, quartiles q1 - q3: 17.9 – 44.3). Vitamin D concentration in Polish men with prostate cancer is lower compared to patients with benign prostatic hyperplasia.

Chang JH, Lim Joon D, Davis ID, et al.
Comparison of [(11)C]choline Positron Emission Tomography With T2- and Diffusion-Weighted Magnetic Resonance Imaging for Delineating Malignant Intraprostatic Lesions.
Int J Radiat Oncol Biol Phys. 2015; 92(2):438-45 [PubMed] Related Publications
PURPOSE: The purpose of this study was to compare the accuracy of [(11)C]choline positron emission tomography (CHOL-PET) with that of the combination of T2-weighted and diffusion-weighted (T2W/DW) magnetic resonance imaging (MRI) for delineating malignant intraprostatic lesions (IPLs) for guiding focal therapies and to investigate factors predicting the accuracy of CHOL-PET.
METHODS AND MATERIALS: This study included 21 patients who underwent CHOL-PET and T2W/DW MRI prior to radical prostatectomy. Two observers manually delineated IPL contours for each scan, and automatic IPL contours were generated on CHOL-PET based on varying proportions of the maximum standardized uptake value (SUV). IPLs identified on prostatectomy specimens defined reference standard contours. The imaging-based contours were compared with the reference standard contours using Dice similarity coefficient (DSC), and sensitivity and specificity values. Factors that could potentially predict the DSC of the best contouring method were analyzed using linear models.
RESULTS: The best automatic contouring method, 60% of the maximum SUV (SUV60) , had similar correlations (DSC: 0.59) with the manual PET contours (DSC: 0.52, P=.127) and significantly better correlations than the manual MRI contours (DSC: 0.37, P<.001). The sensitivity and specificity values were 72% and 71% for SUV60; 53% and 86% for PET manual contouring; and 28% and 92% for MRI manual contouring. The tumor volume and transition zone pattern could independently predict the accuracy of CHOL-PET.
CONCLUSIONS: CHOL-PET is superior to the combination of T2W/DW MRI for delineating IPLs. The accuracy of CHOL-PET is insufficient for gland-sparing focal therapies but may be accurate enough for focal boost therapies. The transition zone pattern is a new classification that may predict how well CHOL-PET delineates IPLs.

Bryant RJ, Sjoberg DD, Vickers AJ, et al.
Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: Many men with elevated prostate-specific antigen (PSA) levels in serum do not have aggressive prostate cancer and undergo unnecessary biopsy. Retrospective studies using cryopreserved serum suggest that four kallikrein markers can predict biopsy outcome.
METHODS: Free, intact and total PSA, and kallikrein-related peptidase 2 were measured in cryopreserved blood from 6129 men with elevated PSA (≥3.0ng/mL) participating in the prospective, randomized trial Prostate Testing for Cancer and Treatment. Marker levels from 4765 men providing anticoagulated plasma were incorporated into statistical models to predict any-grade and high-grade (Gleason score ≥7) prostate cancer at 10-core biopsy. The models were corrected for optimism by 10-fold cross validation and independently validated using markers measured in serum from 1364 men. All statistical tests were two-sided.
RESULTS: The four kallikreins enhanced prostate cancer detection compared with PSA and age alone. Area under the curve (AUC) for the four kallikreins was 0.719 (95% confidence interval [CI] = 0.704 to 0.734) vs 0.634 (95% CI = 0.617 to 0.651, P < .001) for PSA and age alone for any-grade cancer, and 0.820 (95% CI = 0.802 to 0.838) vs 0.738 (95% CI = 0.716 to 0.761) for high-grade cancer. Using a 6% risk of high-grade cancer as an illustrative cutoff, for 1000 biopsied men with PSA levels of 3.0ng/mL or higher, the model would reduce the need for biopsy in 428 men, detect 119 high-grade cancers, and delay diagnosis of 14 of 133 high-grade cancers. Models exhibited excellent discrimination on independent validation among men with only serum samples available for analysis.
CONCLUSIONS: A statistical model based on kallikrein markers was validated in a large prospective study and reduces unnecessary biopsies while delaying diagnosis of high-grade cancers in few men.

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