Prostate Cancer
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Prostate cancer accounts for over a quarter of all cancers in men. The prostate is a small male sex gland located below the bladder, it produces fluid that becomes semen. Prostate cancer occurs mostly in older men, it is rare before the age of 50, and the risk increases with age. There has been an increase in the incidence of prostate cancer since the early 1980's, most likely due to an increased use of screening using the prostate-specific antigen (PSA) test. However, the role as screening for prostate cancer remains controversial. World-wide about 395,000 men are diagnosed with prostate cancer each year.

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Information for Patients and the Public
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Latest Research Publications
Screening for Prostate Cancer

Information Patients and the Public (31 links)

Information for Health Professionals / Researchers (10 links)

Latest Research Publications

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

Zhou J, Teng X
Primary extragastrointestinal stromal tumor of the prostate: a case report.
Anal Quant Cytol Histol. 2014; 36(1):55-60 [PubMed] Related Publications
BACKGROUND: The published literature on primary prostatic extragastrointestinal stromal tumor (EGIST) is limited to several isolated case reports. No long-term follow-up is currently available for these patients in order to determine if the biologic behavior of prostatic gastrointestinal stromal tumor is different from those occurring in other sites.
CASE: A 40-year-old man presented with symptoms of benign prostate hyperplasia. Magnetic resonance imaging revealed a huge prostatic mass restricted to the organ's capsule. After a complete resection and histopathologic study of the specimen, primary high-risk EGIST of the prostate was confirmed. The patient underwent adjuvant chemotherapy with imatinib. He has been observed for 32 months and is in good condition with no recurrence or metastasis.
CONCLUSION: Primary EGIST of the prostate is an extremely rare entity. It should be carefully distinguished from other spindle cell lesions. Complete surgical resection and chemotherapy with imatinib are important strategies of treatment.

Related: Gastrointestinal Stromal Tumors Imatinib (Glivec)

Montironi R, Lopez-Beltran A, Mazzucchelli R, et al.
Contemporary update on pathology-related issues on routine workup of prostate biopsy: sectioning, tumor extent measurement, specimen orientation, and immunohistochemistry.
Anal Quant Cytol Histol. 2014; 36(2):61-70 [PubMed] Related Publications
While the prime goal of the needle biopsy is to diagnose prostatic adenocarcinoma (PCa), once PCa is detected further descriptive information regarding the type of cancer, amount of tumor, and grade in prostate needle cores forms the cornerstone for contemporary management of the patient and to assess the potential for local cure and the risk for distant metastasis. This review gives an update on selected pathology-related issues on routine workup of prostate biopsy with special references to adequate histologic sectioning necessary to maximize cancer yield, tumor extent measurements and methodologies, specimen orientation, and the role of immunohistochemistry in the evaluation of the prostate. Multiple factors influence the diagnostic yield of prostate biopsies. Many of these factors are fixed and uncontrollable. Other factors are controlled by the urologist, including number of cores obtained, method and location of biopsy, and amount of tissue obtained. The yield of cancer is also controlled by the pathologist and histotechnologist. It is necessary to report the number of cores submitted and the number of positive cores, thereby giving the fraction of positive cores. The percentage involvement by carcinoma with or without the linear extent of carcinoma of the single core with the greatest amount of tumor should also be provided. Using the marking technique, we can add a new pathological parameter: pathological orientation. Cancer or atypical lesions can be accurately located within the biopsy specimen and integrated to biopsy approach. Probably the most common use of immunohistochemistry in the evaluation of the prostate is for the identification of basal cells, which are absent with rare exception in adenocarcinoma of the prostate and in general positive in mimickers of prostate cancer. If a case is still considered atypical by a uropathology expert after negative basal cell staining, positive staining for alpha-methylacyl-CoA-racemase can help establish in 50% of these cases a definitive diagnosis of cancer.

Kirby R
Optimising the management of early prostate cancer.
Practitioner. 2014; 258(1770):15-8, 2 [PubMed] Related Publications
One in eight men in the UK will be diagnosed with prostate cancer during their lifetime. The risk of prostate cancer is strongly age-related and is also linked with a Western lifestyle. Other risk factors include Afro-Caribbean ethnic origin and a positive family history. The more first-degree relatives affected the greater the risk of developing the disease. More than 70 familial prostate cancer susceptibility genes, including the important breast cancer gene BRCA2, have now been identified. A suspicion of a diagnosis of prostate cancer is usually based on either induration or nodularity of the prostate on digital rectal examination or, more commonly, a rise in serum prostate specific antigen (PSA) level. The usual cut-off point for PSA is taken as 4 ng/ml, but in men below 65 a value of more than 2.5 ng/ml should raise suspicion. A progressive rise in PSA over time may also indicate the possibility of the presence of a cancer within the prostate. When prostate cancer is suspected, increasingly urologists are requesting multiparametric magnetic resonance imaging of the gland before deciding whether or not a biopsy is indicated. The Gleason grading of any cancer identified is an important part of the decision-making process concerning the need for active treatment, as opposed to surveillance alone. Gleason pattern 6 cancers are regarded as low risk, Gleason 7 intermediate risk and 8-10 high risk. In patients diagnosed with intermediate- or high-risk prostate cancer further investigations are required to determine the local extent of the disease and to exclude the presence of metastases.

Milicević N, Mrcela M, Lukić I, et al.
Comparison between clinical significance of serum proinflammatory protein interleukin-6 and classic tumor markers total PSA, free PSA and free/total PSA prior to prostate biopsy.
Coll Antropol. 2014; 38(1):147-50 [PubMed] Related Publications
The aim of the study was to clarify whether serum levels of proinflammatory cytokine interleukin-6 (IL-6) could be a useful marker in prostate diseases. Serum IL-6 was determined prior to prostate biopsy procedure in 82 patients with prostate adenocarcinoma (PCa), 25 patients with benign prostatic hyperplasia (BPH), 24 patients with high-grade prostatic intraepithelial neoplasia (PIN) and 17 patients with chronic prostatitis. Serum IL-6 levels were compared with total PSA (tPSA), free PSA (fPSA) and the free/total ratio (f/tPSA) serum levels. Statistically significant difference was not found in serum IL-6 levels among the four groups (p = 0.088). However, the patients with poorly differentiated PCa with Gleason score (GS) 4 + 3 = 7 and > 7 had significantly higher serum IL-6 levels than the patients with moderately differentiated PCa with GS 3 + 4 = 7 and < 7 (p = 0.007). The findings suggest that serum IL-6 level might be a potentially useful marker for poorly differentiated PCa.

Related: KLK3

Mandić S, Horvat V, Marczi S, et al.
Association study of cytochrome P450 1A1*2A polymorphism with prostate cancer risk and aggressiveness in Croatians.
Coll Antropol. 2014; 38(1):141-6 [PubMed] Related Publications
Cytochrome P450 1A1 (CYP1A1) is an enzyme participating in the bioactivation of various endogenous and environmental reactive compounds that can bind to DNA and thus induce cancerogenesis. Gene encoding the enzyme is expressed in the prostate tissue and is polymorphic. CYP1A1*2A gene polymorphism is associated with elevated enzyme activity and/or inducibility which can lead to accumulation of genotoxic compounds and consequently to cancerogenesis. We examined the association of this polymorphism with prostate cancer (PCa) risk and aggressiveness. The case-control study consisted of 120 PCa patients and 120 benign prostatic hyperplasia (BPH) controls, in Croatian population. Regarding aggressiveness, PCa patients were grouped according to the Gleason score (GS), tumor stage (T) and existence of distant metastasis (M). The polymorphism was analyzed using real-time polymerase chain reaction (PCR). We did not observe association of mutated allele with PCa risk, neither with PCa aggressiveness. Furthermore, frequency of polymorphic genotype was slightly higher in BPH group (16.6% vs. 14.2%, respectively) and also in less aggressive form of PCa (20.4% vs. 9.6% for GS < 7; 15.6% vs. 9.1% for T < 3; 16.7% vs. 10.0% for no distant metastasis). Comparing our findings with other published results, we can assume that the ethnicity influence the genotype distribution and thus may affect the etiology of PCa, even possibly in the way to cause an opposite effect among different ethnic groups. Given the small number of participants, results should be validated on the larger sample size.

Wilton JH, Titus MA, Efstathiou E, et al.
Androgenic biomarker prof|ling in human matrices and cell culture samples using high throughput, electrospray tandem mass spectrometry.
Prostate. 2014; 74(7):722-31 [PubMed] Related Publications
UNLABELLED: BACKGROUND. A high throughput, high pressure liquid chromatographic (HPLC) method with triple quadrupole mass spectral detection (LC/MS/MS) was validated for the measurement of 5 endogenous androgens in human plasma and serum and applied to various in vivo and in vitro study samples to pursue a better understanding of the interrelationship of the androgen axis, intracrine metabolism, and castration-recurrent prostate cancer (CaP).
METHODS: A Shimadzu HPLC system interfaced with a Sciex QTRAP 5500 mass spectrometer with electrospray ionization was used with in line column-switching. Samples were liquid/liquid extracted and chromatographed on a Luna C18(2) column at 60°C with a biphasic gradient using a 15-min run time.
RESULTS: The method was validated for five androgens in human plasma and serum, and applied to four sets of samples. Plasma (n=188) and bone marrow aspirate (n=129) samples from patients with CaP, who received abiraterone acetate plus prednisone for up to 945 days(135 weeks), had undetectable androgens after 8 weeks of treatment. Plasma dehydroepiandrosterone(DHEA) concentrations were higher in African Americans than Caucasian Americans with newly diagnosed CaP. Analysis of prostate tumor tissue homogenates demonstrated reproducible testosterone (T) and dihydrotestosterone (DHT) concentrations with a minimal sample size of 1.0–2.0 mg of tissue. Finally, cell pellet and media samples from the LNCaP C4-2 cell line showed conversion of T to DHT.
CONCLUSION: The proposed LC/MS/MS method was validated for quantitation of five endogenous androgens in human plasma and serum, and effectively profiles androgens in clinical specimens and cell culture samples.

Chen LN, Rubin RS, Othepa E, et al.
Correlation of HOXD3 promoter hypermethylation with clinical and pathologic features in screening prostate biopsies.
Prostate. 2014; 74(7):714-21 [PubMed] Related Publications
BACKGROUND: Molecular markers that can discriminate indolent cancers from aggressive ones may improve the management of prostate cancer and minimize unnecessary treatment.Aberrant DNA methylation is a common epigenetic event in cancers and HOXD3 promoter hypermethylation (H3PH) has been found in prostate cancer. Our objective was to evaluate the relationship between H3PH and clinicopathologic features in screening prostate biopsies.
METHODS: Ninety-two patients who underwent a prostate biopsy at our institution between October 2011 and May 2012 were included in this study. The core with the greatest percentage of the highest grade disease was analyzed for H3PH by methylation-specific PCR. Correlational analysis was used to analyze the relationship between H3PH and various clinical parameters. Chi-square analysis was used to compare H3PH status between benign and malignant disease.
RESULTS: Of the 80 biopsies with HOXD3 methylation status assessable, 66 sets were confirmed to have cancer. In the 14 biopsies with benign disease there was minimal H3PH with the mean percentage of methylation reference (PMR) of 0.7%. In contrast, the HOXD3 promoter was hypermethylated in 16.7% of all cancers and in 50% of high risk tumors with an average PMR of 4.3% (P=0.008). H3PH was significantly correlated with age (P=0.013), Gleason score (P=0.031) and the maximum involvement of the biopsy core (P=0.035).
CONCLUSIONS: H3PH is associated with clinicopathologic features. The data indicate that H3PH is more common in older higher risk patients. More research is needed to determine the role of this marker in optimizing management strategies in men with newly diagnosed prostate cancer.

Dumache R, Puiu M, Motoc M, et al.
Prostate cancer molecular detection in plasma samples by glutathione S-transferase P1 (GSTP1) methylation analysis.
Clin Lab. 2014; 60(5):847-52 [PubMed] Related Publications
BACKGROUND: Prostate cancer (PCa) represents the most commonly diagnosed type of malignancy among men in Western European countries and the second cause of cancer-related deaths among men worldwide. Methylation of the CpG island has an important role in prostate carcinogenesis and progression. The purpose of the study was to analyse the diagnostic value of aberrant promoter hypermethylation of the gene for glutathione S-transferase P1 (GSTP1) in plasma DNA to discriminate between prostate cancer (PCa) and benign prostatic hyperplasia (BPH) patients by minimally invasive methods.
METHODS: Aberrant promoter hypermethylation was investigated in DNA isolated from plasma samples of 31 patients with diagnostic of PCa and 44 cancer-free males (control subjects). Extracted genomic DNA was bisulfite treated and analyzed using methylation-specific polymerase chain reaction (MS-PCR) technique.
RESULTS: Hypermethylation of the GSTP1 gene was detected in plasma samples from 27 of 31 (92.86%) patients with PCa. Genomic DNA from plasma samples from the 44 controls without genitourinary cancer revealed promoter hypermethylation of GSTP1 gene in 3 (10.6%) of the 44 patients. Receiver operating curve (ROC) included clinico-pathological parameters such as: serum PSA levels, pathological stage, Gleason score, hypermethylation status of GSTP1 gene, and it gave a predictive accuracy of 93% with a sensitivity and specificity of 95% and 87%, respectively.
CONCLUSIONS: In this study, we have evaluated the ability of GSTP1 gene to discriminate between PCa and BPH patients in genomic DNA from plasma samples by non-invasive methods.

Related: GSTP1

Boyer MJ, Salama JK, Lee WR
Palliative radiotherapy for prostate cancer.
Oncology (Williston Park). 2014; 28(4):306-12 [PubMed] Related Publications
Radiotherapy is an effective tool for the palliation of symptoms commonly caused by prostate cancer. The majority of painful bone metastases respond equally well to single or multiple fractions of external radiotherapy. Retreatment with a second course of radiation induces pain responses in approximately 50% of patients. For more diffuse metastases, either hemibody radiation or systemic radiopharmaceuticals can reduce pain, and radium-223 is associated with improved survival in men with castration-resistant prostate cancer. Hematuria, bladder outlet obstruction, and rectal compression are all improved with palliative radiotherapy. The ability of stereotactic body radiation therapy to reduce pain compared with standard external radiation is being investigated, as is its role in treating those with limited metastatic disease.

Bradley CJ, Dahman B, Anscher M
Prostate cancer treatment and survival: evidence for men with prevalent comorbid conditions.
Med Care. 2014; 52(6):482-9 [PubMed] Related Publications
BACKGROUND: The absence of evidence-based guidelines for prostate cancer treatment led the Institute of Medicine to include localized prostate cancer treatment among the 25 most important topics for comparative effectiveness research.
OBJECTIVE: This study compared prostate cancer treatment and survival in men with and without prevalent comorbid conditions.
RESEARCH DESIGN: The sample comprised elderly men, aged 66 years and older, extracted from SEER-Medicare data, between 2004 and 2009 (N=73,563). Treatment and survival for men with at least 1 of 4 prevalent comorbid conditions were compared with men who did not have any of the 12 Charlson comorbid conditions. The sample was stratified by comorbid condition and low-risk, intermediate-risk, and high-risk disease.
RESULTS: Over half of men received some form of cancer-directed treatment, irrespective of comorbid condition. Men who have congestive heart failure (CHF) or multiple comorbid conditions were less likely to be treated, whereas men with diabetes were more likely to be treated. With the exception of men with CHF, men with comorbid conditions and low-risk disease received no survival benefit from any type of treatment.
CONCLUSIONS: Most men received treatment, particularly radiation therapy, regardless of comorbid condition. The evidence suggests more caution should be used when treating men with low-risk disease and comorbid conditions as they are at risk for adverse events and additional medical costs, without a survival benefit.

Cao Y, Lindström S, Schumacher F, et al.
Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.
J Natl Cancer Inst. 2014; 106(6):dju085 [PubMed] Related Publications
BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.
METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.
RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.
CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

Related: Signal Transduction USA

Vieira I, Burke L, Marks-Maran D
Prostate cancer follow-up needs: do patients and professionals agree?
Br J Nurs. 2014 May 8-21; 23(9):S12, S14-9 [PubMed] Related Publications
BACKGROUND: With recent changes in the economy and the drive for cost-effective health care, current practices in the NHS need to be reviewed and revised. In light of this, the aim of this study is to investigate the perceived benefits of routine follow-up of patients with prostate cancer and to examine perceptions of prostate cancer patients and health professionals about who should follow-up patients and where and when this should take place.
METHODS: A service evaluation was carried out on a sample of patients receiving follow-up assessment following radical treatment for prostate cancer and health professionals in a specialist cancer urology unit in an acute NHS trust in south-east England. Data were collected through patient (n=47) and health professional (n=17) questionnaires and through a group discussion with a sample of patients (n=52).
RESULTS: There was agreement between patients and professionals that the main purpose of follow-up consultation was to review the prostate-specific antigen (PSA) blood test and assess urinary symptoms. The majority of patients and professionals wanted follow-up in the hospital with face-to-face consultation. There was general agreement that assessments should be carried out every six months. An overwhelming majority of patients (95%) felt that it was important to have easy access to the urology cancer nurses and doctors.
CONCLUSION: Patients want to maintain the traditional model of hospital based follow-up in specialist urology cancer clinics. However, this approach is not economically sustainable. If this is to change we need to work with our patients to develop a service that meets their needs. For a new approach to follow-up to meet the needs of patients, they need to be confident that they have access to expert advice and support, and are assured of referral back to the urology team if required. Nurses are ideally placed to play a key role in the development of such a service.

Related: KLK3

Cannon-Albright LA, Farnham JM, Bailey M, et al.
Identification of specific Y chromosomes associated with increased prostate cancer risk.
Prostate. 2014; 74(9):991-8 [PubMed] Related Publications
BACKGROUND: Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists.
METHODS: A novel analysis of a computerized population-based resource linking genealogy and cancer data was used to test the hypothesis of a role of the Y chromosome in prostate cancer predisposition. Using a statewide cancer registry from 1966 linked to a computerized genealogy representing over 1.2 million descendants of the Utah pioneers, 1,000 independent sets of males, each set hypothesized to share the same Y chromosome as represented in genealogy data, were tested for a significant excess of prostate cancer.
RESULTS: Multiple Y chromosomes representing thousands of potentially at-risk males were identified to have a significant excess risk for prostate cancer.
CONCLUSIONS: This powerful and efficient in silico test of an uncommon mode of inheritance has confirmed evidence for Y chromosome involvement in prostate cancer.

Related: Chromosome Y

Zuhlke KA, Johnson AM, Tomlins SA, et al.
Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer.
Prostate. 2014; 74(9):983-90 [PubMed] Related Publications
BACKGROUND: Family history of prostate cancer is a well-recognized risk factor. Previous linkage studies have reported a putative prostate cancer susceptibility locus at chromosome 17q21-22. SPOP (Speckle-type POZ protein) maps to the 17q21-22 candidate linkage region and is one of the most frequently mutated genes in sporadic prostate cancers.
METHODS: We performed targeted next generation sequencing to analyze 2009 exons from 202 genes in a candidate linkage region on chromosome 17q21-22 using 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n=54) and Johns Hopkins University (n=40) including the exons and UTRs of SPOP.
RESULTS: We identified a novel SPOP missense mutation (N296I) in a man with prostate cancer diagnosed at age 43. This mutation completely segregates with prostate cancer affection status among the men in this family. The N296I mutation resides within the evolutionarily conserved Bric-a-brac, Tramtrack, Broad-complex (BTB) domain, involved in recruiting targets to Cul3 for degradation. Analysis of the prostate tumor from this individual verified the presence of heterozygous N296I as well as an ERG fusion.
CONCLUSIONS: We have discovered a novel mutation in SPOP that tracks with prostate cancer within a family and is predicted to be deleterious. Taken together, our results implicate SPOP as a candidate gene for hereditary prostate cancer.

Related: Chromosome 17

Kim JY, Banerjee T, Vinckevicius A, et al.
A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer.
Mol Cell. 2014; 54(4):613-25 [PubMed] Article available free on PMC after 22/05/2015 Related Publications
Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.

Related: Signal Transduction MLL gene

Ye L, Yao XD, Wan FN, et al.
MS4A8B promotes cell proliferation in prostate cancer.
Prostate. 2014; 74(9):911-22 [PubMed] Related Publications
BACKGROUND: Prostate cancer cells must maintain or achieve the further ability of proliferation during the progression. The molecular mechanisms, however, remain poorly understood. We identified a novel oncogene, termed membrane-spanning 4-domains, subfamily A, member 8B (MS4A8B), over-expressed in prostate cancer.
METHODS: We firstly detected MS4A8B mRNA in 13 types of paired human normal and cancer tissues by real-time polymerase chain reaction (RT-PCR). In 140 clinically localized prostate cancer samples from radical prostatectomy, immunohistochemical staining was performed to study MS4A8B and PCNA protein level as an index of proliferative activity, TUNEL staining as an index of apoptosis. As MS4A8B RNAi and cDNA transfection technologies were used, the effect of MS4A8B on cellular vitality was determined in vitro and in vivo.
RESULTS: MS4A8B mRNA was over-expressed specifically in prostate cancer. Positive ratios of MS4A8B protein expression were 1.94%, 5.92%, and 62.8% in benign, HPIN and prostate cancer, respectively. Moreover, MS4A8B was positively associated with Gleason score, the proliferation index. In vitro, MS4A8B knockdown resulted in G1 -S cell cycle arrest and descended vitality, MS4A8B over-expression with accelerated S phase entry, elevated vitality in prostate cancer cells. Moreover, it was also found that expression of MS4A8B led to changes of Cyclin D1 , Cyclin E1 and PCNA. LNCaP cells transfected with sh-MS4A8B lentivirus particles grew more slowly when subcutaneously injected into the flanks of nude mice.
CONCLUSIONS: We conclude that the expression of MS4A8B expression promotes cell proliferation and plays an important role in carcinogenesis and progression of prostate cancer.

Related: Apoptosis KLK3

Araujo A, Cook LM, Lynch CC, Basanta D
An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer.
Cancer Res. 2014; 74(9):2391-401 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases.

Chiarugi P, Paoli P, Cirri P
Tumor microenvironment and metabolism in prostate cancer.
Semin Oncol. 2014; 41(2):267-80 [PubMed] Related Publications
Prostate cancer is no longer viewed mostly as a disease of abnormally proliferating epithelial cells, but rather as a disease affecting the complex interactions between the cells of the prostate epithelial compartment and the surrounding stromal compartment in which they live. Indeed, the microenvironment in which tumor cells evolve towards an aggressive phenotype is highly heterogeneous, as it is composed of different cell populations such as endothelial cells, fibroblasts, macrophages, and lymphocytes, either resident or trans-differentiated by bone marrow-derived mesenchymal stem cells recruited at the tumor site. Cancer-associated fibroblasts, the most abundant population within this microenvironment, exert a mandatory role in prostate cancer progression as they metabolically sustain cancer cell survival and growth, recruit inflammatory and immune cells, and promote cancer cells stemness and epithelial mesenchymal transition, thereby favoring metastatic dissemination of aggressive cancers. The interruption of this two-compartment crosstalk, together with the idea that stromal cells are mostly vulnerable, being drug-sensitive, could lead to the development of anticancer therapies that target tumor stromal elements.

Related: Signal Transduction

Chung CC, Hsing AW, Edward Yeboah, et al.
A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry.
Prostate. 2014; 74(6):579-89 [PubMed] Related Publications
BACKGROUND: Genome-wide association studies (GWAS) have identified that a ∼1 M region centromeric to the MYC oncogene on chromosome 8q24.21 harbors at least five independent loci associated with prostate cancer risk and additional loci associated with cancers of breast, colon, bladder, and chronic lymphocytic leukemia (CLL). Because GWAS identify genetic markers that may be indirectly associated with disease, fine-mapping based on sequence analysis provides important insights into patterns of linkage disequilibrium (LD) and is critical in defining the optimal variants to nominate for biological follow-up.
METHODS: To catalog variation in individuals of African ancestry, we resequenced a region (250 kb; chr8:128,050, 768–128, 300,801, hg19) containing several prostate cancer susceptibility loci as well as a locus associated with CLL. Our samples included 78 individuals from Ghana and 47 of African-Americans from Johns Hopkins University.
RESULTS: After quality control metrics were applied to next-generation sequence data, 1,838 SNPs were identified. Of these, 285 were novel and not yet reported in any public database. Using genotypes derived from sequencing, we refined the LD and recombination hotspots within the region and determined a set of tag SNPs to be used in future fine-mapping studies. Based on LD, we annotated putative risk loci and their surrogates using ENCODE data, which should help guide laboratory studies.
CONCLUSIONS: In comparison to the 1000 Genome Project data, we have identified additional variants that could be important in establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and CLL.

Related: Chromosome 8

Hui J, Xu Y, Yang K, et al.
Study of genetic variants of 8q21 and 8q24 associated with prostate cancer in Jing-Jin residents in northern China.
Clin Lab. 2014; 60(4):645-52 [PubMed] Related Publications
BACKGROUND: To identify the genetic risk of six genetic variants at 8q21 and 8q24 (including rs1512268, A; rs12543663, C; rs10086908, C; rs1016343, T; rs13252298, A, and rs6983561, C) associated with prostate cancer in Beijing and Tianjin (Jing-jin) area residents in northern China.
METHODS: 574 subjects were enrolled. Blood samples and clinical information were collected from histologically confirmed prostate cancer cases (n = 286) and clinically evaluated matched normal controls (n = 288) from Chinese men in northern China. Six SNPs at 8q21 and 8q24 were genotyped by high-resolution melt and sequencing in subjects. We compared statistical differences between the prevalence of risk genotypes with prostate cancer in cases and controls and analyzed the association between clinical covariates and risk loci in case groups to infer their relationship with aggressive prostate cancer.
RESULTS: Three genotypes of rs10086908, CC (OR = 2.48; 95% CI = 1.02 - 5.98, p = 0.037) rs1016343, TT (OR = 1.64, 95% CI = 1.07 - 2.53, p = 0.023); and rs6983561, CC (OR = 1.91; 95% CI = 1.09 - 3.63, p = 0.044) at 8q24 were identified to be associated with prostate cancer risk in Jing-jin Chinese. The D' values of both two-locus haplotypes (T-A: rs1016343 vs. rs13252298; T-C: rs1016343 vs. rs6983561) were 0.907 and 0.859, respectively, the three-locus haplotype, only TAC constituted by the loci (rs1016343, T; rs13252298, A; rs6983561, C) was also associated with prostate cancer (p = 0.033), revealing rs1016343 vs. rs6983561 with significant differences between cases and controls. According to clinical covariates and odds ratios of risk genotypes relative to non-risk genotypes, rs6983561, CC was associated with age (OR = 2.5; 95% CI = 1.02 - 6.13, p = 0.039), and tumor aggressiveness (OR = 1.15; 95% Cl = 1.06 - 1.23, p = 0.013).
CONCLUSIONS: The loci including rs10086908, rs1016343, and rs6983561 at 8q24 could be associated with prostate cancer in Jing-jin residents in northern China. Our results suggest that these loci could influence susceptibility to prostate cancer in the northern Chinese population.

Related: Chromosome 8

Arsov C, Jankowiak F, Hiester A, et al.
Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy--a pilot study.
Anticancer Res. 2014; 34(5):2459-66 [PubMed] Related Publications
BACKGROUND/AIM: Initial inaccurate staging is a common problem associated with active surveillance (AS) for patients detected by transrectal ultrasound-guided prostate biopsy (TRUS-GB). Subsequently, repeated biopsies are necessary to monitor such patients. Thus, in addition to the already established clinicopathological criteria, there is a considerable demand for new, objective decision criteria to more accurately select AS candidates. Recently, a novel RNA expression signature derived from 31 cell-cycle progression (CCP) genes has been shown to be a strong predictor of outcome in patients after radical prostatectomy or radiotherapy. This is a qualitative pilot study to evaluate the prognostic value of the CCP-score (CCP-S) for the first time in men managed with AS after MRI-guided prostate biopsy (MRI-GB).
PATIENTS AND METHODS: Nine patients previously diagnosed with prostate cancer during an ongoing, prospective trial assessing MRI-GB with additional TRUS-GB and were subsequently managed with AS. CCP-S were retrospectively derived from biopsy specimens. The CCP-S is defined as the expression level of 31 CCP genes, normalized to 15 housekeeping genes, and is clinically validated in a range between -1.3 and 4.7. To assess the estimated 10-year mortality risk (without curative treatment), the CCP-S from each patient was combined with the individual CAPRA (Cancer of the Prostate Risk Assessment) score (CAPRA-S).
RESULTS: Median patient age was 72 (range=58-77) years. Mean pre-biopsy PSA level was 6.33±1.94 (range 4.23-9.97) ng/ml. Eight cases had Gleason score 6 (3+3) and one cancer had Gleason score 7 (3+4). Median CCP-S was -0.9 (range=-1.5 to 0.0). Combining CCP-S with CAPRA-S [CAPRA-S: 1 (n=4), 2 (n=4), 3 (n=1)] the estimated 10-year mortality risk was not calculable for three patients because their CCP-S [CCP-S -1.4 (n=2) and -1.5 (n=1)] was outside the validated range. For the other 6 patients the estimated 10-year mortality ranged from 1.0-3.0%.
CONCLUSION: The CCP-S confirms accurate staging of AS patients detected by MRI-based biopsy strategies and may significantly reduce inaccurate staging of AS patients and subsequent unnecessary re-biopsies. The CCP score may help to more accurately select for active surveillance candidates.

Related: Watchful Waiting - Prostate Cancer

Manferrari F, Brunocilla E, Baccos A, et al.
Laparoscopic radical prostatectomy: 10 years of experience at a single institution.
Anticancer Res. 2014; 34(5):2443-8 [PubMed] Related Publications
BACKGROUND/AIM: The Urological Clinic of the S. Orsola-Malpighi University Hospital, Bologna has been carrying out laparoscopic radical prostatectomy since 2002. In this study, we report the results after 10 years of LRP, analyzing in particular the oncological and functional aspects.
PATIENTS AND METHODS: Between March 2002 and August 2011, 400 patients underwent laparoscopic radical prostatectomy. Cancer control, recovery of continence and potency were evaluated at 1, 3, 6 and 12 months. All data were retrospectively collected on the basis of thorough clinical and pathological examination.
RESULTS: Follow-up ranged from 10 to 122 months. Pathological examination revealed pT2 and pT3 cancers in 63.5% and 36.5% of patients, respectively. The incidence of positive surgical margins and biochemical relapse rate was 33.8% and 12.0%, respectively.
CONCLUSION: 10 Years after the first laparoscopic radical prostatectomy was performed at our Center, we can state that it is a reliable alternative to traditional surgery, with satisfactory oncological and functional results.

Zavaski ME, Korus A, Staff I, et al.
Prostate biopsy volume predicts final tumor volume.
Conn Med. 2014; 78(3):167-72 [PubMed] Related Publications
AIM: To assess the ability of prostate biopsy volume to effectively predict actual tumor volume, and whether increasing the number of prostate biopsy cores improves the ability to forecast actual tumor volume.
METHODS: 765 patients who underwent robotic radical prostatectomy (2009-2010) were identified. Of these, 663 had complete demographics, biopsy, and final pathology data available. The number ofbiopsy samples, biopsy tumor volume, and actual tumor volume were calculated from pathology reports.
RESULTS: Data from 663 radical prostatectomy specimens indicated a positive linearrelationship between biopsy tumor volume and actual tumor volume (R=0.524, P< 0.0001). The number ofbiopsy samples collected (i.e., < or =6, 7-8, 9-10, 11-12, 13-14, or > or =15) did not affect the ability of biopsy tumor volume to predict final tumor volume.
CONCLUSIONS: The routine collection of biopsy tumor volume may prove useful in predicting actual tumor volume and the construction of more effective preoperative nomograms.

Federman DG, Pitkin P, Carbone V, et al.
Screening for prostate cancer: are digital rectal examinations being performed?
Hosp Pract (1995). 2014; 42(2):103-7 [PubMed] Related Publications
OBJECTIVE: Prostate cancer is common and prostate cancer screening is controversial; this retrospective observational study was conducted to determine the prevalence of digital rectal examination (DRE) in those in whom a prostate-specific antigen (PSA) test was performed.
METHODS: A manual review was performed of the electronic medical record for male veterans in the VA Connecticut Healthcare System without a history of known prostate cancer aged between 50 and 74 years who underwent PSA testing. Main Outcomes: Documentation of DRE (or refusal) within 12 months before or after the performance of a PSA test.
RESULTS: Less than half (47.6%) of patients underwent DRE. An additional 6.9% were offered DRE and refused. Although the provider gender was not associated with DRE, resident physicians were less likely to perform DRE than nonresidents; P = 0.01. Patients whose PSA was > 4.0 ng/mL were more likely to undergo DRE than those whose PSA was ≤ 4.0 ng/mL; P = 0.002. Those with body mass index (BMI) > 40 kg/m 2 were less likely to undergo DRE than those with BMI < 30 kg/m 2 ; P = 0.04.
CONCLUSIONS: Screening for prostate cancer remains controversial. We found a low rate of DRE among veterans in whom prostate cancer screening was entertained. Although the provider gender does not seem to influence DRE, resident physicians were less likely to perform DRE than other providers. Our finding that BMI > 40 kg/m 2 is associated with a lower rate of DRE than those with BMI < 30 kg/m 2 is consistent with screening for other cancers and should be explored further.

Related: Cancer Screening and Early Detection USA

Tsang DS, Alibhai SM
Bone health care for patients with prostate cancer receiving androgen deprivation therapy.
Hosp Pract (1995). 2014; 42(2):89-102 [PubMed] Related Publications
Patients with prostate cancer often receive androgen deprivation therapy (ADT) as part of their treatment regimen. However, treatment with ADT causes multiple side effects, including reduced bone mineral density (BMD), lower lean body mass, and a higher risk for fractures. Several organizations provide clinical practice guidelines for osteoporosis screening, prevention, and treatment in this population, but adherence to these guidelines remains low. Areas for improvement in provider adherence include baseline and follow-up BMD testing, as well as counseling regarding healthy bone behaviors such as calcium/vitamin D intake, lifestyle changes, and physical exercise. Comparison of osteoporosis care in breast cancer and non-oncology populations shows that suboptimal bone health care is not isolated to prostate cancer. A summary of the literature examining improvements in patient adherence and provider delivery of bone health care is included in this review, but high-quality studies are lacking. Patients may be the most receptive to written educational information delivered at or near the time of ADT initiation. Involvement of a primary care practitioner and oncologist in care delivery is associated with higher BMD test use. Institution-level programs that automatically initiate osteoporosis screening and management may be effective at reducing the incidence of hip fracture. Lastly, suggestions are provided for future approaches to knowledge translation and quality of care studies to improve bone health.

Xie F, Hopkins RB, Burke N, et al.
Time and labor costs associated with administration of intravenous bisphosphonates for breast or prostate cancer patients with metastatic bone disease: a time and motion study.
Hosp Pract (1995). 2014; 42(2):38-45 [PubMed] Related Publications
OBJECTIVES: To estimate, using a time and motion method, the time and labor costs associated with the administration of zoledronic acid and pamidronate in cancer patients with metastatic bone diseases.
METHODS: During clinic visits for participating patients receiving intravenous zoledronic acid or pamidronate, all times and activities associated with the administration of bisphosphonates were recorded by a trained observer using a stopwatch and data recording forms. The total time associated with the administration of bisphosphonates was estimated and converted to labor costs by applying corresponding health care professional hourly wage rates plus the fringe-benefit rate. The costs were presented in 2011 Canadian dollars.
RESULTS: A convenience sample of 37 patients from 2 hospital outpatient oncology clinics in Ontario and Quebec participated in the study. Nineteen patients were diagnosed with breast cancer and 18 with prostate cancer. The average patient age was 66 years, and patients had been diagnosed with cancer and metastatic bone disease for 8 years and 3 years, respectively. The times and costs associated with the administration of bisphosphonates for the 28 patients who did not receive concurrent chemotherapy during the scheduled clinic visits are also reported. The mean infusion time for patients receiving zoledronic acid was 20.6 minutes. With the use of ambulatory infusion devices, the mean infusion time of pamidronate was 23 minutes (limited to observations of patients who were seated during administration). In contrast, the mean infusion time using regular infusion devices was 162 minutes. The mean labor cost for administering zoledronic acid was $20. The mean labor cost for administering pamidronate was $10 using ambulatory infusion devices and $68 using regular infusion devices.
CONCLUSION: The time burden to cancer patients with metastatic bone disease who receive intravenous bisphosphonates and the costs to the health care system are substantial, especially when regular infusion devices are used.

Related: Breast Cancer Canada Bisphosphonates Zoledronic acid (Zometa) Pamidronate (Aredia)

Deng X, He G, Liu J, et al.
Recent advances in bone-targeted therapies of metastatic prostate cancer.
Cancer Treat Rev. 2014; 40(6):730-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Prostate cancer is one of the most common malignancies affecting men worldwide, with bone being the most common site of metastasis in patients that progress beyond organ confinement. Bone metastases are virtually incurable and result in significant disease morbidity and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Several attractive molecules or pathways have been identified as new potential therapeutic targets for bone metastases caused by metastatic castration-resistant prostate cancer. In this review, we present the recent advances in molecular targeted therapies for prostate cancer bone metastasis focusing on therapies that target the bone cells and the bone microenvironment. The therapies covered in this review include agents that inhibit bone resorption, agents that stimulate bone formation, and agents that target the bone matrix. Suggestions to devise more effective molecular targeted therapies are proposed. Hopefully, with better understanding of the biology of the disease and the development of more robust targeted therapies, the survival and quality of life of the affected individuals could be significantly improved.

Related: Bisphosphonates Signal Transduction

Park JJ, Kim CK, Park SY, et al.
Prostate cancer: role of pretreatment multiparametric 3-T MRI in predicting biochemical recurrence after radical prostatectomy.
AJR Am J Roentgenol. 2014; 202(5):W459-65 [PubMed] Related Publications
OBJECTIVE: The purpose of this study is to retrospectively investigate whether pretreatment multiparametric MRI findings can predict biochemical recurrence in patients who underwent radical prostatectomy (RP) for localized prostate cancer.
MATERIALS AND METHODS: In this study, 282 patients with biopsy-proven prostate cancer who received RP underwent pretreatment MRI using a phased-array coil at 3 T, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced MRI (DCE-MRI). MRI variables included apparent tumor presence on combined imaging sequences, extracapsular extension, and tumor size on DWI or DCE-MRI. Clinical variables included baseline prostate-specific antigen (PSA) level, clinical stage, and Gleason score at biopsy. The relationship between clinical and imaging variables and biochemical recurrence was evaluated using Cox regression analysis.
RESULTS: After a median follow-up of 26 months, biochemical recurrence developed in 61 patients (22%). Univariate analysis revealed that all the imaging and clinical variables were significantly associated with biochemical recurrence (p < 0.01). On multivariate analysis, however, baseline PSA level (p = 0.002), Gleason score at biopsy (p = 0.024), and apparent tumor presence on combined T2WI, DWI, and DCE-MRI (p = 0.047) were the only significant independent predictors of biochemical recurrence. Of the independent predictors, apparent tumor presence on combined T2WI, DWI, and DCE-MRI showed the highest hazard ratio (2.38) compared with baseline PSA level (hazard ratio, 1.05) and Gleason score at biopsy (hazard ratio, 1.34).
CONCLUSION: The apparent tumor presence on combined T2WI, DWI, and DCE-MRI of pretreatment MRI is an independent predictor of biochemical recurrence after RP. This finding may be used to construct a predictive model for biochemical recurrence after surgery.

Itatani R, Namimoto T, Kajihara H, et al.
Triage of low-risk prostate cancer patients with PSA levels 10 ng/ml or less: comparison of apparent diffusion coefficient value and transrectal ultrasound-guided target biopsy.
AJR Am J Roentgenol. 2014; 202(5):1051-7 [PubMed] Related Publications
OBJECTIVE: The purpose of our study was to identify low-risk prostate cancer on the basis of the D'Amico clinical risk score in patients with prostate-specific antigen (PSA) levels 10 ng/mL or less who had undergone radical prostatectomy by comparing apparent diffusion coefficient (ADC) with transrectal ultrasound (TRUS)-guided target biopsy.
MATERIALS AND METHODS: In the preliminary study, we used receiver operating characteristic (ROC) analysis and determined the cutoff ADC to identify prostate cancer with a Gleason score of 6 or less for 117 patients. In the primary study, we assessed the combination of routine MRI (T2-weighted and diffusion-weighted imaging) plus the cutoff ADC value ("method A") to identify low-risk prostate cancer for another 89 patients. Their diagnostic value was compared with that of routine MRI combined with the Gleason score obtained from TRUS-guided target biopsies ("method B").
RESULTS: The preliminary study showed that a mean ADC of 1.04 × 10(-3) mm(2)/s was the best cutoff. In the primary study, accuracy was statistically higher with method A for each reader (p = 0.041).
CONCLUSION: In patients with PSA levels 10 ng/mL or less, the combination of MRI findings plus the cutoff ADC is significantly more accurate for the identification of low-risk prostate cancer than is the combination of MRI followed by TRUS-guided target biopsy.

Hoffman RM, Li J, Henderson JA, et al.
Prostate cancer deaths and incident cases among American Indian/Alaska Native men, 1999-2009.
Am J Public Health. 2014; 104 Suppl 3:S439-45 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
OBJECTIVES: We linked databases to improve identification of American Indians/Alaska Natives (AI/ANs) in determining prostate cancer death and incidence rates.
METHODS: We linked prostate cancer mortality and incidence data with Indian Health Service (IHS) patient records; analyses focused on residents of IHS Contract Health Service Delivery Area (CHSDA) counties. We calculated age-adjusted incidence and death rates for AI/AN and White men for 1999 to 2009; men of Hispanic origin were excluded.
RESULTS: Prostate cancer death rates were higher for AI/AN men than for White men. Death rates declined for White men (-3.0% per year) but not for AI/AN men. AI/AN men had lower prostate cancer incidence rates than White men. Incidence rates declined among Whites (-2.2% per year) and AI/ANs (-1.9% per year).
CONCLUSIONS: AI/AN men had higher prostate cancer death rates and lower prostate cancer incidence rates than White men. Disparities in accessing health care could contribute to mortality differences, and incidence differences could be related to lower prostate-specific antigen testing rates among AI/AN men.

Related: USA

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