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Prostate Cancer

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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Molecular Biology of Prostate Cancer
Screening for Prostate Cancer

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  • PubMed search for publications about Prostate Cancer - Limit search to: [Reviews]

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    MeSH term: Prostatic Neoplasms
    International US National Library of Medicine
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Latest Research Publications

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

Kanakavelu N, Jebaseelan Samuel J
Determination of patient set-up error and optimal treatment margin for intensity modulated radiotherapy using image guidance system.
J BUON. 2016 Mar-Apr; 21(2):505-11 [PubMed] Related Publications
PURPOSE: The geometrical uncertainties in the patient positioning during intensity modulated radiotherapy (IMRT) are crucial as there is potential to underdose the tumor and overdose the nearby critical structures. Image guided techniques provide a solution to assess the patient set-up uncertainties and help determine the optimal planning target volume (PTV) margin to the clinical tumor volume (CTV).
METHODS: A retrospective study was conducted to evaluate patient set-up errors along the three translational directions at different treatment sites such as the brain, the head and neck (H&N) and the prostate. A total of 60 patients' set-up error data was analysed to evaluate the systematic and random errors and the optimal CTV-PTV margin.
RESULTS: For brain and H&N sites, more than 90, 80 and about 100% of the total image acquisitions were less than 3 mm in lateral, longitudinal and vertical directions respectively. For the prostate cases, the frequency of patient set-up error to be less than 3 mm were 79.7, 75.6 and 80% in lateral, longitudinal and vertical directions respectively. About 0.6% had more than 7 mm error in the lateral and longitudinal directions for the prostate site. CTV-PTV margin of 3.4, 3.4 and 1.9 mm for brain cases, 3.5, 3 and 1.8 mm for H&N cases and 5, 4.6 and 4.5 mm for the prostate cases in the lateral, longitudinal and vertical directions respectively were determined.
CONCLUSION: Image guidance is an effective method to evaluate the accuracy of IMRT treatment delivery. The optimal CTV-PTV margin can be determined to ensure adequate dose to CTV, specific to the site.

Ding HY, Qian WQ, Xu J
MicroRNA-146b acts as a potential tumor suppressor in human prostate cancer.
J BUON. 2016 Mar-Apr; 21(2):434-43 [PubMed] Related Publications
PURPOSE: MicroRNAs (miRs) act as either tumor suppressors or oncogenes and are frequently deregulated in cancers. Although downregulation of miR-146b has been reported in various cancers, its role in prostate cancer is totally unknown.
METHODS: The miR-146b expression in 18 human prostate cancer lines with case-matched adjacent normal tissues was measured by quantitative RT-PCR. Furthermore, the expression levels of miR-146b in normal prostate and prostate cancer cell lines were assessed. Cell proliferation, apoptosis, migration and invasion assays were performed in overexpressing or knockdown miR-146b cells.
RESULTS: miR-146b expression was significantly reduced in all prostate tumor tissues. Furthermore, miR-146b was significantly decreased in prostate cancer cells as compared to normal prostate cells. Loss-of-function and gain-of-function showed that miR-146b induced apoptosis and suppressed cell proliferation, migration and invasion of the prostate cancer cell lines.
CONCLUSION: Our results demonstrated that miR-146b expression is downregulated in prostate tumor tissues and is a potential tumor suppressor miR, suggesting that miR-146b might be a potential clinical marker and therapeutic target for prevention and treatment of prostate cancer.

Li Z, Alyamani M, Li J, et al.
Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.
Nature. 2016; 533(7604):547-51 [PubMed] Related Publications
Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

Pouyanfar N, Monabbati A, Sharifi AA, Dianatpour M
Expression Levels of MMP9 and PIWIL2 in Prostate Cancer: a Case-Control Study.
Clin Lab. 2016; 62(4):651-7 [PubMed] Related Publications
BACKGROUND: Prostate cancer is the second most prevalent cancer in humans. Also, this is the most common malignancy and the sixth most important cause of death in men worldwide. The most routine diagnostic test for prostate cancer is PSA test which is associated with some limitations like too many false positive results. This study intends to investigate the role of MMP9 and PIWIL2 expression levels as different biomarkers in prostate cancer biopsy specimens. This study is one of the most brilliant studies in the field of prostate cancer research for the first time focusing on the investigation of the role of two different genes in prostate cancer in biopsy specimens and on formalin-fixed paraffin-embedded tissue types in order to detect the progression and prognosis of prostate cancer patients in early stages.
METHODS: Seventy formalin-fixed paraffin embedded samples (35 normal and 35 cancerous cases) were selected. Expression levels of PIWIL2 and MMP9 genes were evaluated, using real-time PCR.
RESULTS: MMP9 and PIWIL2 expression levels in cancerous tissues were significantly higher than the adjacent normal tissues (p < 0.05). The survival analysis showed a significant correlation between expression level of PIWIL2 and survival rate (p < 0.05), but such correlation was not observed in case of MMP9 (p > 0.05). Higher levels of MMP9 and PIWIL2 expression were strongly related to the Gleason score and age, using Pearson's correlation co- efficient test; however, this kind of association was not evident between prostate specific antigen (PSA) and expression levels of the genes of interest. The expression level of PIWIL2 had a significant correlation with metastasis rate, but this relationship was not seen in the case of MMP9.
CONCLUSIONS: The results confirmed the validity of PIWIL2 expression as a valuable prognostic biomarker for early diagnosis of prostate cancer.

Diler SB, Öden A
The T -786C, G894T, and Intron 4 VNTR (4a/b) Polymorphisms of the Endothelial Nitric Oxide Synthase Gene in Prostate Cancer Cases.
Genetika. 2016; 52(2):249-54 [PubMed] Related Publications
In previously conducted some studies it has been revealed that nitric oxide (NO) and nitric oxide synthase (NOS) system play a significant role in carcinogenesis. Nitric oxide (NO) is regulated by endothelial nitric oxide synthase (eNOS) enzyme which is one of the isoenzymes of NO synthase (NOS). In this study we have tried to come to a conclusion about whether eNOS gene T -786C, G894T and Intron 4 VNTR (4a/b) polymorphisms might be considered as a risk factor causing prostate cancer (PCa) or not. A total of 200 subjects were included in this research. 84 patients with PCa (mean age 70.0 ± 6.4) and 116 healthy controls (mean age 69.9 ± 7.5) were recruited in this case-control study. Genomic DNA was extracted using the QIAamp DNA Blood Mini Kit (QIAGEN GmbH, Maryland, USA), according to the manufacturer's guidelines. The T-786C, G894T and Intron 4 VNTR (4a/b) polymorphisms were amplified using polymerase chain reation (PCR), detected by restriction fragment length polymorphism (RFLP). For T -786C polymorphism CC genotype [odds ratio (OR): 0.34, 95% confidence interval (CI): 0.15-0.78, P = 0.009)] and allele frequency (OR: 0.631, CI: 0.421-0.946, P = 0.026) is significant for control. In patients with PCa eNOS G894T polymorphism, both GT (OR: 0.069, CI: 0.027-0.174; P = 0.0001) and TT (OR: 0.040, CI: 0.013-0.123; P = = 0.0001) genotype distribution, and also T allele frequency (OR: 0.237, CI: 0.155-0.362, P = 0.0001) were considered significant statistically. While genotype distribution for the other polymorphism eNOS, intron 4 VNTR (4a/b), is insignificant statistically, "a" allele frequency was found out to be significant (OR: 2.223, CI: 1.311-3.769, P = 0.003). In this study we indicated that genotype and allele frequencies of eNOS T -786C and G894T polymorphisms are statistically significant in patients with PCa. eNOS T -786C and G894T polymorphisms may be associated with PCa susceptibility in the Turkish population. In contrast, intron 4 VNTR (4a/b) polymorphism may not be related to PCa susceptibility in these patients.

Sack BS, Langenstroer P, Guralnick ML, et al.
Cystectomy and Urinary Diversion for the Management of a Devastated Lower Urinary Tract Following Prostatic Cryotherapy and/or Radiotherapy.
WMJ. 2016; 115(2):70-3 [PubMed] Related Publications
INTRODUCTION: We investigated the outcomes and quality of life measures in men who underwent cystectomy and urinary diversion for devastating lower urinary tract toxicity after prostatic radiotherapy and/or cryotherapy for the treatment of prostate cancer.
METHODS: Records of patients who underwent cystectomy and urinary diversion for the management of a devastated lower urinary tract following prostatic radiotherapy or cryotherapy were reviewed retrospectively. A postoperative, retrospective quality of life (QOL) survey was designed specific to this patient subset and obtained by telephone interview.
RESULTS: Extirpative surgery with urinary diversion for management of a devastated lower urinary tract was performed on 15 patients with a mean age of 72 years (range 63-82). Toxicities leading to bladder removal included bladder neck contractures, prostatic necrosis, incontinence, osteomyelitis, bladder calculi, fistulae, urethral strictures, abscesses, necrotizing fasciitis, and radiation/hemorrhagic cystitis. The mean number of failed conservative, minimally invasive interventions per patients prior to cystectomy was 3.7 (range 1-12). The average time period from major complication following radiotherapy/cryotherapy to cystectomy was 29.1 months (range 5-65). The QOL survey showed all of the patients who completed the survey (n = 13) would undergo the procedure again and 11 (85%) would have undergone the procedure an average of 13.2 months sooner (range 5-36).
CONCLUSION: Toxicities secondary to prostatic radiotherapy or cryotherapy may be debilitating. Our results demonstrate that cystectomy with urinary diversion can improve QOL in patients with a devastated lower urinary tract.

Palmbos PL, Hussain MH
Targeting PARP in Prostate Cancer: Novelty, Pitfalls, and Promise.
Oncology (Williston Park). 2016; 30(5):377-85 [PubMed] Related Publications
Metastatic prostate cancer remains a highly lethal disease with no curative therapeutic options. A significant subset of patients with prostate cancer harbor either germline or somatic mutations in DNA repair enzyme genes such as BRCA1, BRCA2, or ATM. Emerging data suggest that drugs that target poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes may represent a novel and effective means of treating tumors with these DNA repair defects, including prostate cancers. Here we will review the molecular mechanism of action of PARP inhibitors and discuss how they target tumor cells with faulty DNA repair functions and transcriptional controls. We will review emerging data for the utility of PARP inhibition in the management of metastatic prostate cancer. Finally, we will place PARP inhibitors within the framework of precision medicine-based care of patients with prostate cancer.

Huesch MD, Ong MK
Prostate Cancer Care Before and After Medicare Eligibility.
Inquiry. 2016; 53 [PubMed] Related Publications
Prior studies suggest Medicare eligibility confers significant and substantial reductions in mortality and beneficial increases in health service utilization. We compared 13,882 patients diagnosed with prostate cancer at ages 63 to 64 years with 14,774 patients diagnosed at ages 65 to 66 (controls) in 2004 to 2007. Compared with controls, patients diagnosed with prostate cancer before Medicare eligibility had no statistically significant or meaningful differences in cancer stage, time to treatment, or type of treatment.

Rosenkrantz AB, Pujara AC, Taneja SS
Use of a Quality Improvement Initiative to Achieve Consistent Reporting of Level of Suspicion for Tumor on Multiparametric Prostate MRI.
AJR Am J Roentgenol. 2016; 206(5):1040-4 [PubMed] Related Publications
OBJECTIVE: The purpose of this article is to evaluate the utility of a quality improvement (QI) initiative in achieving long-term adherence to an evolving structured format for reporting the level of suspicion for tumor on prostate MRI examinations.
MATERIALS AND METHODS: The original QI initiative occurred over a 4-month period in 2010, before which prostate MRI was reported using free text. The initiative consisted of development of a section-wide macro, an initial group training session, ordering physician input regarding the structured report's value, subsequent weekly sessions for ongoing review, and timely individualized feedback in instances of nonuse. The initial structured report included pick lists for describing the level of suspicion for tumor as negative, low, medium, or high. Pick lists were modified in 2011 to incorporate a 5-point Likert scale and again in 2015 to incorporate Prostate Imaging Data and Reporting System (PI-RADS) version 2. These refinements were implemented after accelerated training periods. The frequency of reports providing an MRI-based suspicion level during these periods was assessed.
RESULTS: Fifty-five percent of reports provided an MRI-based level of suspicion for tumor before the initiative. For various cohorts evaluated after the initiative (using structured reports based on the low, medium, or high scheme; a numeric Likert scale; or PI-RADS), this frequency improved to 95-100% (p < 0.001). Among reports without a suspicion level, potential confounding factors included marked artifact from hip prosthesis and overt diffuse tumor.
CONCLUSION: The QI initiative achieved excellent adherence in reporting a suspicion level for tumor on prostate MRI examinations. The described components of the initiative were useful for maintaining long-term adherence that persisted after serial modifications to the report lexicon.

Luo J, Beer TM, Graff JN
Treatment of Nonmetastatic Castration-Resistant Prostate Cancer.
Oncology (Williston Park). 2016; 30(4):336-44 [PubMed] Related Publications
Patients with nonmetastatic castration-resistant prostate cancer (CRPC) are a heterogeneous population with regard to risk of progression to metastatic disease. Treatment selection for nonmetastatic CRPC must balance the risk of disease progression with the side effects of available therapies. Several medication classes are available for use in treating these patients, and other newer agents are under active clinical trial investigation. Here we review current therapies for nonmetastatic CRPC and discuss the recently completed and ongoing trials for this emerging disease state.

Rozenberg R, Thornhill RE, Flood TA, et al.
Whole-Tumor Quantitative Apparent Diffusion Coefficient Histogram and Texture Analysis to Predict Gleason Score Upgrading in Intermediate-Risk 3 + 4 = 7 Prostate Cancer.
AJR Am J Roentgenol. 2016; 206(4):775-82 [PubMed] Related Publications
OBJECTIVE: The objective of our study was to evaluate whole-lesion quantitative apparent diffusion coefficient (ADC) for the prediction of Gleason score (GS) upgrading in 3 + 4 = 7 prostate cancer.
MATERIALS AND METHODS: Fifty-four patients with GS 3 + 4 = 7 prostate cancer diagnosed at systematic transrectal ultrasound (TRUS)-guided biopsy underwent 3-T MRI and radical prostatectomy (RP) between 2012 and 2014. A blinded radiologist contoured dominant tumors on ADC maps using histopathologic correlation. The whole-lesion mean ADC, ADC ratio (normalized to peripheral zone), ADC histogram, and texture analysis were compared between tumors with GS upgrading and those without GS upgrading using multivariate ROC analyses and logistic regression modeling.
RESULTS: Tumors were upgraded to GS 4 + 3 = 7 after RP in 26% (n = 14) of the 54 patients, and tumors were downgraded after RP in none of the patients. The mean ADC, ADC ratio, 10th-centile ADC, 25th-centile ADC, and 50th-centile ADC were similar between patients with GS 3 + 4 = 7 tumors (0.99 ± 0.22, 0.58 ± 0.15, 0.77 ± 0.31, 0.94 ± 0.28, and 1.15 ± 0.24, respectively) and patients with upgraded GS 4 + 3 = 7 tumors (1.02 ± 0.18, 0.55 ± 0.11, 0.71 ± 0.26, 0.89 ± 0.20, and 1.11 ± 0.16) (p > 0.05). Regression models combining texture features improved the prediction of GS upgrading. The combination of kurtosis, entropy, and skewness yielded an AUC of 0.76 (SE = 0.07) (p < 0.001), a sensitivity of 71%, and a specificity of 73%. The combination of kurtosis, heterogeneity, entropy, and skewness yielded an AUC of 0.77 (SE = 0.07) (p < 0.001), a sensitivity of 71%, and a specificity of 78%.
CONCLUSION: In this study, whole-lesion mean ADC, ADC ratio, and ADC histogram analysis were not predictive of pathologic upgrading of GS 3 + 4 = 7 prostate cancer after RP. ADC texture analysis improved accuracy.

Mohan P, Yuvaraj A, Abraham G, et al.
Occurrence of double primary malignancies in an African renal transplant recipient.
Saudi J Kidney Dis Transpl. 2016; 27(2):377-80 [PubMed] Related Publications
A 63-year-old African male with end stage renal disease who received a renal transplantation from his daughter after successful treatment of hepatitis C virus, type 1 genotype developed metastatic Kaposi's sarcoma and subsequently adenocarcinoma of the prostate. He was successfully treated with chemotherapy and reduction of immunosuppression and switch over to rapamycin.

Serrano NA, Anscher MS
Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment Recommendations.
Oncology (Williston Park). 2016; 30(3):229-36 [PubMed] Related Publications
The population of patients with intermediate-risk prostate cancer are a large and heterogeneous group with highly variable prognoses, which present a challenge to efforts to develop standardized treatment recommendations. New classification systems have been proposed that modify the existing National Comprehensive Cancer Network guidelines and that subdivide men with intermediate-risk prostate cancer into favorable and unfavorable subgroups. This review will examine the changing landscape of intermediate-risk prostate cancer and the effects on treatment decisions that may result from this new classification. The literature provides evidence that men with favorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with low-risk prostate cancer and thus may be candidates for active surveillance, dose-escalated radiation therapy without short-term androgen deprivation therapy (ADT), or, interestingly, standard-dose radiation therapy plus short-term ADT. Conversely, patients with unfavorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with high-risk prostate cancer. These patients would not be candidates for active surveillance and may in fact require long-term ADT in addition to standard-dose or dose-escalated radiation therapy instead of 4 to 6 months of ADT.

Kamdar SN, Ho LT, Kron KJ, et al.
Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis.
Clin Epigenetics. 2016; 8:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer.
RESULTS: Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus-specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer.
CONCLUSIONS: Our results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation. Subsequently, our characterization of key cellular pathways exhibiting dynamic enrichment patterns for methylation and hydroxymethylation marks may allow us to identify differentially epigenetically modified target genes implicated in prostate cancer tumorigenesis.

Kushnir T, Gofrit ON, Elkayam R, et al.
Impact of Androgen Deprivation Therapy on Sexual and Hormonal Function in Patients Receiving Radiation Therapy for Prostate Cancer.
Isr Med Assoc J. 2016; 18(1):49-53 [PubMed] Related Publications
BACKGROUND: Androgen deprivation therapy (ADT) added to radiation therapy (RT) in intermediate to high risk prostate cancer negatively impacts quality of life.
OBJECTIVES: To compare health-related quality of life (HR-QOL) in patients receiving combined RT with and without ADT METHODS: The study population comprised patients treated with definitive RT for prostate cancer who completed the Expanded Prostate Cancer Index Composite-26 form between 3 and 24 months after completing RT. Covariance and a stepwise backward logistic regression model was used.
RESULTS: Data were available for 143 patients who received RT+ADT and 70 who received RT alone. The sexual function and hormonal vitality scores of patients receiving RT+ADT were significantly lower than those receiving RT alone (P < 0.0001). Patients with only compulsory school education had significantly lower sexual function scores than patients with university level education (P ≤ 0.005). Patients with depression had significantly lower hormonal vitality scores than those without depression (P ≤ 0.0001).
CONCLUSIONS: The addition of ADT to RT is responsible for decrements in quality of life in the sexual and hormonal vitality domains, which is further compounded by depression and lack of education. This underlines the need to improve education, identify and treat depression, and develop strategies to improve the quality of life of patients receiving combination therapy.

Vignani F, Bertaglia V, Buttigliero C, et al.
Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer.
Cancer Treat Rev. 2016; 44:61-73 [PubMed] Related Publications
Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

McCann SM, Jiang Y, Fan X, et al.
Quantitative Multiparametric MRI Features and PTEN Expression of Peripheral Zone Prostate Cancer: A Pilot Study.
AJR Am J Roentgenol. 2016; 206(3):559-65 [PubMed] Related Publications
OBJECTIVE: The objective of our study was to investigate associations between quantitative image features of multiparametric MRI of the prostate and PTEN expression of peripheral zone prostate cancer.
MATERIALS AND METHODS: A total of 45 peripheral zone cancer foci from 30 patients who had undergone multiparametric prostate MRI before prostatectomy were identified by a genitourinary pathologist and a radiologist who reviewed histologic findings and MR images. Histologic sections of cancer foci underwent immunohistochemical analysis and were scored according to the percentage of tumor-positive cells expressing PTEN as negative (0-20%), mixed (20-80%), or positive (80-100%). Average and 10th percentile apparent diffusion coefficient (ADC) values, skewness of T2-weighted signal intensity histogram, and quantitative perfusion parameters (i.e., forward volume transfer constant [K(trans)], extravascular extracellular volume fraction [ve], and reverse reflux rate constant between the extracellular space and plasma [k(ep)]) from the Tofts model were calculated for each cancer focus. Associations between the quantitative image features and PTEN expression were analyzed with the Spearman rank correlation coefficient (r).
RESULTS: Analysis of the 45 cancer foci revealed that 21 (47%) were PTEN-positive, 12 (27%) were PTEN-negative, and 12 (27%) were mixed. There was a weak but significant negative correlation between Gleason score and PTEN expression (r = -0.30, p = 0.04) and between k(ep) and PTEN expression (r = -0.35, p = 0.02). There was no significant correlation between other multiparametric MRI features and PTEN expression.
CONCLUSION: This preliminary study of radiogenomics of peripheral zone prostate cancer revealed weak-but significant-associations between the quantitative dynamic contrast-enhanced MRI feature k(ep) and Gleason score with PTEN expression. These findings warrant further investigation and validation with the aim of using multiparametric MRI to improve risk assessment of patients with prostate cancer.

Hötker AM, Mazaheri Y, Aras Ö, et al.
Assessment of Prostate Cancer Aggressiveness by Use of the Combination of Quantitative DWI and Dynamic Contrast-Enhanced MRI.
AJR Am J Roentgenol. 2016; 206(4):756-63 [PubMed] Related Publications
OBJECTIVE: The objective of this study was to investigate whether the apparent diffusion coefficient (ADC) value from DWI and the forward volume transfer constant (K(trans)) value from dynamic contrast-enhanced MRI independently predict prostate cancer aggressiveness, and to determine whether the combination of both parameters performs better than either parameter alone in assessing tumor aggressiveness before treatment.
MATERIALS AND METHODS: This retrospective study included 158 men with histopathologically confirmed prostate cancer who underwent 3-T MRI before undergoing prostatectomy in 2011. Whole-mount step-section pathologic maps identified 195 prostate cancer foci that were 0.5 mL or larger; these foci were then volumetrically assessed to calculate the per-tumor ADC and K(trans) values. Associations between MRI and histopathologic parameters were assessed using Spearman correlation coefficients, univariate and multivariable logistic regression, and AUCs.
RESULTS: The median ADC and K(trans) values showed moderate correlation only for tumors for which the Gleason score (GS) was 4 + 4 or higher (ρ = 0.547; p = 0.042). The tumor ADC value was statistically significantly associated with all dichotomized GSs (p < 0.005), including a GS of 3 + 3 versus a GS of 3 + 4 or higher (AUC, 0.693; p = 0.001). The tumor K(trans) value differed statistically significantly only between tumors with a GS of 3 + 3 and those with a primary Gleason grade of 4 (p ≤ 0.015), and it made a statistically significant contribution only in differentiating tumors with a GS of 4 + 3 or higher (AUC, 0.711; p < 0.001) and those with a GS of 4 + 4 or higher (AUC, 0.788; p < 0.001) from lower-grade tumors. Combining ADC and K(trans) values improved diagnostic performance in characterizing tumors with a GS of 4 + 3 or higher and those with a GS of 4 + 4 or higher (AUC, 0.739 and 0.856, respectively; p < 0.01).
CONCLUSION: Although the ADC value helped to differentiate between all GSs, the K(trans) value was only a benefit in characterizing more aggressive tumors. Combining these parameters improves their performance in identifying patients with aggressive tumors who may require radical treatment.

Tomasković I, Ulamec M, Tomić M, et al.
Validation of Epstein Biopsy Criteria for Insignificant Prostate Cancer in Contemporary Cohort of Croatian Patients.
Coll Antropol. 2015; 39(3):709-11 [PubMed] Related Publications
Only few reports validated contemporary Epstein criteria for insignificant prostate cancer, and only one being from Europe. Patients with insignificant prostate cancer should be offered active surveillance and spared radical treatment. In our study we tested Epstein biopsy criteria for predicting unfavorable final pathology and biochemical relapse in low risk prostate cancer patients, who were eligible for active surveillance but where treated with radical prostatectomy. Between January 2003 and January 2008, 586 patients were subjected to radical prostatectomy in our institution. Among them, 106 where eligible for active surveillance according to Epstein biopsy criteria for insignificant prostate cancer. We analyzed the presence of adverse pathological findings in the final pathohistological specimen after radical prostatectomy which excludes low risk disease. Adverse pathohistological findings were noted in 41 (38.6%) patients, who could have been offered active surveillance. During the follow up of 48 (12-72) months, biochemical relapse was noted in 6 (5.6%) patients. Although active surveillance is becoming more popular because of the long natural course of prostate cancer and fear of overtreatment of patients with indolent course of disease, both doctors and patients must be aware of potentially significant disease in this group and limitations of current preoperative criteria defining low risk patients.

Tomasković I, Milicić V, Tomić M, et al.
Impact of Positive Surgical Margins after Radical Prostatectomy on Disease Progression and Adjuvant Treatment in Pathologically Localized Prostate Cancer.
Coll Antropol. 2015; 39(3):697-700 [PubMed] Related Publications
The aim of our study was to evaluate the impact of margin positivity in clinically and pathologically localized prostate cancer (pT2) after radical prostatectomy on biochemical recurrence and time to adjuvant treatment. We analyzed data from 371 patients who underwent radical prostatectomy. At the mean follow up of 36 (25-54) months, impact of margin positivity in pT2 patients on prostate specific antigen (PSA) recurrence and time to introduction of adjuvant treatment was noted. Out of 371 radical prostatectomies there were 277 (74.6%) pT2 and 94 (25.4%) pT3 (locally advanced) prostate cancers. Mean age was 67.6 years, mean Gleason score 6.78, mean preoperative PSA 11.45 ng/mL. Out of 277 pT2 pts., 233 (84%) had negative (SM-) and 44 (16%) positive surgical margins (SM+). Only 3% of SM- pts. had biochemical relapse (BCR). Among pT2 patients with SM+, 18 (41%) had BCR while 26 were free of recurrence at 3 years follow up. Positive surgical margins had an adverse impact on biochemical progression free survival (3% SM- vs. 41% SM+; p<0.001). No difference was found in age, preoperative PSA, Gleason score or follow up between BCR-SM+ and BCR+SM+ patients. Mean time to PSA recurrence in surgical margin positive pT2 patients was 15.7 months. Surgical margin status pT2 disease has an impact on biochemical progression but only 41% of margine positive patients show biochemical recurrence at 3 yr follow up. Not all SM+ patients need to receive treatment after radical prostatectomy. Longer follow up should be awaited to see the impact on overall survival in this group of patients.

Tomasković I, Milicić V, Tomić M, et al.
Biopsy Quantitative Patohistology and Seral Values of Prostate Specific Antigen-Alpha (1) Antichymotrypsine Complex in Prediction of Adverse Pathology Findings after Radical Prostatectomy.
Coll Antropol. 2015; 39(3):691-5 [PubMed] Related Publications
In this prospective study we examined the utility of parameters obtained on prostate needle biopsy and prostate specific antigen-alpha(1)-antichymotripsine complex (PSA-ACT) to predict adverse pathologic findings after radical prostatectomy. 45 consecutive patients assigned for radical prostatectomy due to clinically localized prostate cancer were included in the study. Prostate biopsy parameters such as number of positive cores, the greatest percentage of tumor in the positive cores, Gleason score, perineural invasion, unilaterality or bilaterality of the tumor were recorded. PSA-ACT was determined using sandwich immunoassay chemiluminiscent method (Bayer, Tarrytown, New York). We analyzed relationship of preoperative PSA, PSA-ACTand quantitative biopsy parameters with final pathology after prostatectomy. Adverse findings were considered when extracapsular extension of cancer (pT3) was noted. Postoperatively, 29 (64.4%) patients were diagnosed with pT2 disease and 16 (35.6%) with pT3 disease. There was a significant difference in localized vs. locally advanced disease in number of positive biopsy cores (p<0.001), greatest percentage of tumor in the core (p=0.008), localization of the tumor (p=0.003) and perineural invasion (p=0.004). Logistic regression was used to develop a model on the multivariate level. It included number of positive cores and PSA-ACT and was significant on our cohort with the reliability of 82.22%. The combination of PSA-ACT and a large scale of biopsy parameters could be used in prediction of adverse pathologic findings after radical prostatectomy. Clinical decisions and patients counselling could be influenced by these predictors but further confirmation on a larger population is necessary.

Dawn S, Légaré F
Engaging patients using an interprofessional approach to shared decision making.
Can Oncol Nurs J. 2015; 25(4):455-69 [PubMed] Related Publications
Many cancer treatment and screening decisions are difficult given that they rely upon patients' informed preferences. Interprofessional shared decision making is when two or more health care professionals collaborate with a patient to reach an agreed-upon decision. To support patients' engagement in shared decision making, effective interventions include patient decision aids and/or decision coaching. Patient decision aids are typically written or video-based resources, while decision coaching is provided by trained health care professionals who are supportive but non-directive. Both interventions make explicit the decision, provide balanced information on options based on the best available evidence, and help patients consider what matters most. The overall aim is to discuss how oncology nurses can engage in an interprofessional approach to shared decision making.

Geethakumari PR, Cookson MS, Kelly WK,
The Evolving Biology of Castration-Resistant Prostate Cancer: Review of Recommendations From the Prostate Cancer Clinical Trials Working Group 3.
Oncology (Williston Park). 2016; 30(2):187-95, 199 [PubMed] Related Publications
In 2008, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) developed consensus guidelines for clinical trial design and conduct that redefined trial endpoints, with a dual-objective paradigm: to (1) controlling, relieving, or eliminating disease manifestations at the start of treatment; and (2) preventing or delaying further disease manifestations. Clinical and translational research in prostate cancer has expanded our current-day understanding of the mechanisms of its pathogenesis, as well as the different clinicopathologic and molecular subtypes of the disease, and has improved the therapeutic armamentarium for the management of metastatic castration-resistant prostate cancer (CRPC). These new advances led to the development of the updated PCWG3 guidelines in 2015. In this review, we analyze our evolving understanding of the biology of CRPC, acquired resistance mechanisms, and emerging therapeutic targets in light of the updated PCWG3 guidelines. We present a joint perspective from the medical oncology and urologic disciplines on the ongoing efforts to advance clinical trial performance in order to discover new therapies for this fatal disease.

Cormio L, Lucarelli G, Selvaggio O, et al.
Absence of Bladder Outlet Obstruction Is an Independent Risk Factor for Prostate Cancer in Men Undergoing Prostate Biopsy.
Medicine (Baltimore). 2016; 95(7):e2551 [PubMed] Related Publications
The purpose of this study was to investigate the relationship between bladder outlet obstruction (BOO) and the risk of being diagnosed with prostate cancer (PCa).Study population consisted of 2673 patients scheduled for the first prostate biopsy (PBx). All patients underwent uroflowmetry before PBx; those with a peak flow rate (PFR) <10 mL/s were considered to have BOO.The incidence of PCa was 41.3% (1104/2673) in the overall population and 34.1% (659/1905) in patients with serum prostate-specific antigen (PSA) ≤ 10 ng/mL. Univariate and multivariate logistic regression analyses showed that patients with BOO had a significantly (P < 0.0001) lower risk than those without BOO of being diagnosed with PCa (33.1% vs 66.9% in the overall population; 30% vs 70% in patients with PSA ≤ 10 ng/mL). As the presence of BOO was significantly correlated to a large prostate volume, another independent predictor of PBx outcome, we tested whether these parameters could be used to identify, in the subset of patients with PSA≤10 ng/mL, those who could potentially be spared from a PBx. If we would have not biopsied patients with BOO and prostate volume ≥60 mL, 14.5% of biopsies could have been avoided while missing only 6% of tumors. Only 10% of the tumors that would have been missed were high-risk cancers.In conclusion, in men undergoing PBx, the absence of BOO, as determined by a PFR ≥10 mL/s, is an independent risk factor for PCa. Our study provides ground for this simple, noninvasive, objective parameter being used, alone or in combination with prostate volume, in the decision-making process of men potentially facing a PBx.

Vue B, Zhang S, Chen QH
Synergistic Effects of Dietary Natural Products as Anti-Prostate Cancer Agents.
Nat Prod Commun. 2015; 10(12):2179-88 [PubMed] Related Publications
This review is to describe synergistic effects of various combinations of dietary natural products including curcumin, quercetin, soybean isoflavones, silibinin, and EGCG that have potential for the treatment of prostate cancer. These data can provide valuable insights into the future rational design and development of synergistic and/or hybrid agents for potential treatment of prostate cancer.

NiMhurchu E, O'Kelly F, Murphy IG, et al.
Predictive value of PI-RADS classification in MRI-directed transrectal ultrasound guided prostate biopsy.
Clin Radiol. 2016; 71(4):375-80 [PubMed] Related Publications
AIM: To correlate the results of transrectal ultrasound (TRUS)-guided targeted prostate biopsies (performed in the setting of at least one previous negative biopsy) with the Prostate Imaging Reporting and Data System (PI-RADS).
MATERIAL AND METHODS: Fifty-two patients (mean age 64 years, range 52-76 years), with previous negative prostate biopsy underwent magnetic resonance imaging (MRI)-directed TRUS-guided targeted and sectoral biopsy. A retrospective review of MRI examinations was carried out, blinded to biopsy results. PI-RADS scores (T2, diffusion-weighted imaging [DWI] and overall) were assigned on a per lesion basis, and localised to sextants. The scores were correlated with biopsy results, and the positive predictive values (PPV) of PIRADS scores for positive biopsies were calculated.
RESULTS: Overall, biopsies were positive in 23/52 (44.2%) patients. Eighty-one areas were targeted in 52 patients. On a per lesion basis, there was significant correlation between positive targeted biopsy and both T2 and overall PI-RADS score (p<0.001). The correlation between biopsy and DWI score was significant for peripheral zone tumours only, not for transitional zone tumours. The PPV of overall PI-RADS scores of 3, 4, and 5 were 10.6%, 44%, and 100%, respectively. The PPV of T2 PI-RADS scores of 3, 4, and 5 were 19.6%, 60%, and 100%, respectively. The PPV of DWI PI-RADS scores of 3, 4, and 5 were 50%, 27.3%, and 33%, respectively. When transitional tumours were excluded, the PPV of DWI PI-RADS 3, 4, and 5 were 40%, 43%, and 78%.
CONCLUSION: The PIRADS score provides an effective framework for determining the likelihood of prostate cancer on MRI. The DWI PI-RADS score correlates well with the presence of peripheral zone tumour on targeted biopsy, but not with transitional zone tumours.

Clermont PL, Crea F, Chiang YT, et al.
Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.
Clin Epigenetics. 2016; 8:16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities.
RESULTS: In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis.
CONCLUSIONS: Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

Wu JX, Lin LM, He JY, et al.
Radiotherapy Combined With Androgen Deprivation for Bone Oligometastases After Primary Curative Radiotherapy for Prostate Cancer: A Retrospective Study.
Medicine (Baltimore). 2016; 95(6):e2789 [PubMed] Free Access to Full Article Related Publications
To evaluate the effects and toxicity of radiotherapy (RT) combined with androgen deprivation (AD) for bone oligometastases after primary curative RT for prostate cancer (PCa).We retrospectively analyzed 30 consecutively treated PCa patients with bone oligometastases from April 2005 to July 2014. All patients underwent RT combined with AD for oligometastatic bones after curative RT for PCa. Measured outcomes included overall survival (OS) rate, local control (LC), progression-free survival (PFS), pain relief, and toxicities. Statistical analysis was performed with SPSS17.0.The median follow-up was 32.5 months (range, 0.6-50.3). The 3-year PFS and OS rates were 22.8% (95% CI, 13.4-37.5%) and 69% (95% CI, 51.7-81.1%), respectively. The number of bone oligometastases and RT schedule were found to be significantly associated with OS on univariate analysis (P < 0.05, respectively). The 3-year OS for patients with 1 and >1 metastases was 78.8% versus 42.2%, respectively (P = 0.037). The long-course RT was associated with better 3-year OS compared with short-course (76.4% vs 44.1%, P = 0.03). A total of 15 (83.3%, 15/18) patients achieved pain relief. No grade 3 toxicity was observed.Long-course RT combined with ADT was effective and well-tolerated in PCa patients with bone oligometastases after curative RT for PCa. Further randomized controlled trials are needed to corroborate the findings.

Ju-Kun S, Yuan DB, Rao HF, et al.
Association Between Cd Exposure and Risk of Prostate Cancer: A PRISMA-Compliant Systematic Review and Meta-Analysis.
Medicine (Baltimore). 2016; 95(6):e2708 [PubMed] Free Access to Full Article Related Publications
Several observational studies on the association between Cd exposure and risk of prostate cancer have yielded inconsistent results. To address this issue, we conducted a meta-analysis to evaluate the correlation between Cd exposure and risk of prostate cancer.Relevant studies in PubMed and Embase databases were retrieved until October 2015. We compared the highest and lowest meta-analyses to quantitatively evaluate the relationship between Cd exposure and risk of prostate cancer. Summary estimates were obtained using a random-effects model.In the general population, high Cd exposure was not associated with increased prostate cancer (OR 1.21; 95% CI 0.91-1.64), whereas the combined standardized mortality ratio of the association between Cd exposure and risk of prostate cancer was 1.66 (95% CI 1.10-2.50) in populations exposed to occupational Cd. In addition, high D-Cd intake (OR 1.07; 95% CI 0.96-1.20) and U-Cd concentration (OR 0.86; 95% CI 0.48-1.55) among the general population was not related to the increased risk of prostate cancer. In the dose analysis, the summary relative risk was 1.07 (95% CI 0.73-1.57) for each 0.5 μg/g creatinine increase in U-Cd and 1.02 (95% CI 0.99-1.06) for each 10 μg/day increase of dietary Cd intake. However, compared with nonoccupational exposure, high occupational Cd exposure may be associated with the increased risk of prostate cancer.This meta-analysis suggests high Cd exposure as a risk factor for prostate cancer in occupational rather than nonoccupational populations. However, these results should be carefully interpreted because of the significant heterogeneity among studies. Additional large-scale and high-quality prospective studies are needed to confirm the association between Cd exposure and risk of prostate cancer.

Lewis SL, Patel P, Song H, et al.
Image Guided Hypofractionated Postprostatectomy Intensity Modulated Radiation Therapy for Prostate Cancer.
Int J Radiat Oncol Biol Phys. 2016; 94(3):605-11 [PubMed] Related Publications
PURPOSE: Hypofractionated radiation therapy (RT) has promising long-term biochemical relapse-free survival (bRFS) with comparable toxicity for definitive treatment of prostate cancer. However, data reporting outcomes after adjuvant and salvage postprostatectomy hypofractionated RT are sparse. Therefore, we report the toxicity and clinical outcomes after postprostatectomy hypofractionated RT.
METHODS AND MATERIALS: From a prospectively maintained database, men receiving image guided hypofractionated intensity modulated RT (HIMRT) with 2.5-Gy fractions constituted our study population. Androgen deprivation therapy was used at the discretion of the radiation oncologist. Acute toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Biochemical recurrence was defined as an increase of 0.1 in prostate-specific antigen (PSA) from posttreatment nadir or an increase in PSA despite treatment. The Kaplan-Meier method was used for the time-to-event outcomes.
RESULTS: Between April 2008 and April 2012, 56 men received postoperative HIMRT. The median follow-up time was 48 months (range, 21-67 months). Thirty percent had pre-RT PSA <0.1; the median pre-RT detectable PSA was 0.32 ng/mL. The median RT dose was 65 Gy (range, 57.5-65 Gy). Ten patients received neoadjuvant and concurrent hormone therapy. Posttreatment acute urinary toxicity was limited. There was no acute grade 3 toxicity. Late genitourinary (GU) toxicity of any grade was noted in 52% of patients, 40% of whom had pre-RT urinary incontinence. The 4-year actuarial rate of late grade 3 GU toxicity (exclusively gross hematuria) was 28% (95% confidence interval [CI], 16%-41%). Most grade 3 GU toxicity resolved; only 7% had persistent grade ≥3 toxicity at the last follow-up visit. Fourteen patients experienced biochemical recurrence at a median of 20 months after radiation. The 4-year bPFS rate was 75% (95% CI, 63%-87%).
CONCLUSIONS: The biochemical control in this series appears promising, although relatively short follow-up may lead to overestimation. Late grade 3 GU toxicity was higher than anticipated with hypofractionated radiation of 65 Gy to the prostate bed, although most resolved.

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