Prognostic Factor In Prostate Cancer Research Articles

Abstract 254: Expression of the putative stem cell marker CD44 in prostate biopsies correlates with Gleason score in radical prostatectomies in patients with prostate cancer.

Abstract AIM: Prostate cancer is one of the leading causes of death among male oncology patients. There is growing evidence to support the hypothesis that cancer cells in the prostate are of stem cell origin. In this study we used CD44, as one of the most promising putative stem cell markers, to evaluate the prevalence of prostate cancer cells with stem cell like features in prostate biopsies and in radical prostatectomy specimens. We tested both types of specimen for the existence of a correlation between the expression of CD44 and commonly used prostate cancer prognostic factors such as Gleason grade, pathological stage (pT) according to TNM, patient age and preoperative plasma PSA levels. M&M: Formalin fixed paraffin embedded tissue samples from fifty two prostate biopsies and matched radical prostatectomy specimens were retrieved from the archives of the Pathology Department at the City Hospital, Poznan, Poland or from a collection of cases sent for consultation in the private laboratory of one of the authors (JB). Immunohistochemistry was performed on sections from all paraffin blocks using an anti-CD44 primary antibody (Abcam) according to the manufacturer's protocol. Using an OLYMPUS BX41 microscope, we counted at least 100 cancer cells from core biopsies and 500 cancer cells from radical prostatectomy specimens. Only cells with clearly visible membranous staining at 10x magnification were called positive for the expression of CD44. The percentage of cancer cells expressing CD44 was used for further analysis. The statistical analysis was based on Spearman and Person correlations performed in Microsoft Office Excel 2007. RESULTS: CD44 positive cancer cells were identified in forty three prostate biopsies (82%) and forty seven radical prostatectomy specimens (90%). There was a positive correlation between the expression of CD44 in cancer cells from prostate biopsies and in radical prostatectomy specimens. We also observed a negative correlation between CD44 expression in cancer cells and Gleason score, both in prostate biopsies and in radical prostatectomy material. When other clinical data were analysed, such as patient age, preoperative PSA serum levels or tumour stage (pT), only the first parameter was found to correlate positively with CD44 expression in prostate biopsies. CONCLUSION: To the best of our knowledge this study showed for the first time, that the level of CD44 expression in prostate biopsies correlates with that observed in matched radical prostatectomy specimens. Additionally, we confirmed the results of other authors which show that the percentage of CD44 expressing cancer cells in prostate biopsies negatively correlates with Gleason grade of tumours, both in prostate biopsies and in radical prostatectomy material. Citation Format: Konstanty Korski, Anna Malicka, Jan Breborowicz. Expression of the putative stem cell marker CD44 in prostate biopsies correlates with Gleason score in radical prostatectomies in patients with prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 254. doi:10.1158/1538-7445.AM2013-254

Correlation of Quantitative Diffusion-Weighted and Dynamic Contrast-Enhanced MRI Parameters With NCCN Risk Group, Gleason Score, and Maximum Tumor Diameter in Prostate Cancer

To determine if there is a correlation between quantitative parameters from diffusion-weighted (DWI) and dynamic contrast-enhanced (DCE) MRI with NCCN risk group, Gleason score (GS), and maximum tumor diameter (MTD) in prostate cancer. In this IRB approved retrospective study we reviewed 3T multiparametric MRI reports on patients with biopsy-proven prostate cancer performed during evaluation for radiation treatment or as part of an active surveillance protocol. DCE pharmacokinetic modeling parameters evaluated included: Ktrans (forward volume transfer constant, minute-1), Kep (reverse reflux rate constant between extracellular space and plasma, minute-1), and iAUGC (initial area under the gadolinium concentration curve in the first 30 seconds after injection, mmol/L sec). The average values of regions of interest on the apparent diffusion coefficient (ADC) maps of diffusion weighted imaging (b values of 0, 100, 400, and 800 s2/mm) were also recorded. The relationship between MRI metrics and NCCN risk group, GS, and MTD were examined using one-way analysis of variance (ANOVA). Statistical significance was defined as p < 0.05. 52 patients were included in the study. 37%, 44%, and 19% had low (L), intermediate (I), or high (H) risk disease per NCCN risk groups. One-way ANOVA analysis revealed iAUGC scores were significantly different when stratified by L/I/H risk groups (mean ± SD 8.9 ± 5.0, 9.8 ± 5.1, 13.8 ± 4.1) (p = 0.05), GS (9.1 ± 4.8, 9.8 ± 5.2, 13.8 ± 4.1) (p = 0.05), and MTD ≤ 2 cm vs > 2 cm (9.6 ± 4.8, 14.5 ± 5.0) (p = 0.02). Ktrans and Kep were not significantly different when stratified by risk grouping or GS. Ktrans was significantly different when stratified by MTD ≤ 2 cm vs > 2 cm (0.5 ± 0.3, 0.9 ± 0.6) (p = 0.01) but Kep was not. ADC significantly correlated with L/I/H risk groups (1071 ± 220, 1040 ± 225, 851 ± 66) (p = 0.02) and GS (1063 ± 229, 1046 ± 217, 851 ± 66) (p = 0.02) but not MTD ≤ 2 cm vs > 2 cm. iAUGC values significantly correlate with NCCN risk group, GS, and MTD. Ktrans also significantly correlates with MTD but ADC values did not. Further investigation is warranted to determine whether these MRI metrics are complementary or independent prognostic factors in prostate cancer.

Cardiovascular Comorbidity and Mortality in Men With Prostate Cancer Treated With Brachytherapy-Based Radiation With or Without Hormonal Therapy

To assess the impact of coronary artery disease (CAD) risk factors and sequelae on the risk of all-cause mortality (ACM) in men treated for prostate cancer (PC). The study cohort comprised 5077 men with PC consecutively treated with curative intent between 1997 and 2006 at the Chicago Prostate Cancer Center. Cox and Fine and Gray's competing risks regression multivariable analyses were performed, assessing whether cardiovascular comorbidity impacted the risk of ACM and PC-specific mortality, respectively, adjusting for CAD risk factors (diabetes mellitus, hypercholesterolemia, or hypertension) and sequelae (congestive heart failure or myocardial infarction), age, year and type of treatment, and known PC prognostic factors. When compared with men with no comorbidity there was a significantly increased risk of ACM in men with congestive heart failure or myocardial infarction (adjusted hazard ratio [AHR] 1.96, P<.001) and in men with diabetes mellitus (AHR 1.60, P=.03) and hypertension (AHR 1.25, P=.04). In contrast, men with hypercholesterolemia had a similar risk of ACM (AHR 0.68, P=.17) when compared with men with no comorbidity. Other factors associated with a significantly increased risk of ACM included age (AHR 1.09, P<.001), prostate-specific antigen level (AHR 1.25, P=.008), and Gleason score 8-10 disease (AHR 1.71, P=.003). Cardiovascular comorbidity did not impact the risk of PC-specific mortality. In addition to age and unfavorable PC prognostic factors, select CAD risk factors and sequelae are associated with an increased risk of ACM in men treated for PC. These comorbidity prognostic factors predict time courses of mortality from competing causes, which may be factored into the decision-making process when considering management options for PC in a given individual.

High-Density Lipoprotein and Prostate Cancer: An Overview

Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field.

Influence of Race on Outcomes of Patients with Localized Prostate Cancer Considered Intermediate or High Risk of Biochemical Failure Treated with High Dose Rate Brachytherapy and External Beam Radiotherapy

Purpose: There is a growing need to identify prognostic factors in prostate cancer (pca) to avoid excessive or inappropriate treatment of patients. It may be helpful to identify patients with poor outcomes who would be candidates for more intensive treatments. Methods: we performed a retrospective analysis of data of the charts of all unfavorable PCA treated with the combination of High-Dose-Rate Brachytherapy (HDR-BT) and External Beam Radiotherapy (EBRT) at the department of radiation oncology (ac camargo cancer center), sao paulo, brazil, between 1997 and 2010. Ethnicity definition was based on 4 categorizations: black, mulatto, white and asiatic. We included 229 patients (age range 47-83 years). The median follow-up was 70.3 months (range, 36 –155 months). There were 7.4% (17) yellow, 79.0% (181) white, 7.9% (18) black and 5.7% (13) mulatto patients. Results: EBRT and HDR-BT doses ranged from 40 to 54 gy and 16 to 30 gy given in 4 fractions, respectively. Actuarial 5- and 10-year overall and disease free survical (DFS) rates were 87.6%, 61.3%, 90.9% and 54.2%, respectively. On univariate analysis prognostic factors related to improved DFS were white/asiatic race (p 20 gy (p<0.001) and gleason-score <7 (p<0.001). On multivariate analysis black/mulatto race (p=0.037), advanced clinical stage (p=0.038) and HDR-BT dose <20gy (p<0.001) were associated with biochemical failure. Conclusion: The race seems to be one of the markers of prognosis for PCA. Already known predictive factors of biochemical failure were confirmed in our analysis (clinical stage, gleason score). An improved DFS was related to HDR-BT dose escalation. Further studies are still necessary to provide more information about clinical and genetic predictive factors of aggressiveness that can be used to guide a personalized dose intensification treatment.

Histologic Criteria and Pitfalls in the Diagnosis of Lymphovascular Invasion in Radical Prostatectomy Specimens

Lymphovascular invasion is a known independent prognostic factor in prostate cancer. The objective of this study is to describe reliable morphologic features for identification of lymphovascular invasion in prostatectomy specimens and avoid misinterpretation of its mimickers. A total of 364 foci of lymphovascular invasion were analyzed in 264 slides from 170 prostatectomies. The average tumor volume was 25.5%. Tumor emboli were seen inside the tumor (8%), at the front edge of the tumor (30%), separated from the tumor (32%), and distant from the tumor (30%). Tumor emboli were more frequent per case and more often in an extraprostatic location in lymph node-positive cases (P<0.05). One hundred thirty-four emboli were in a single thin-walled vessel, 227 were in a thin-walled vessel next to an artery, and 3 were seen inside an artery. Twenty-eight tumor emboli were attached to a vessel wall, 18 had proteinaceous material in the vascular lumen, and 14 were surrounded by erythrocytes. The following mimickers were seen: retraction artifact and perineural invasion-all cases; cancer impinging upon vascular space-45 foci; tangential sections of endothelium-10 foci; displacement of benign and collapsed malignant glands-16 and 27 foci, respectively; retraction with erythrocytes-3 cases; intravascular degenerating tumor cells-3 foci; malignant glands in atrophic ducts-4 foci; and myofibroblastic proliferation in thrombosed vessels-2 foci. In 50 stained blocks, CD31 and D2-40 immunostaining studies confirmed all lymphovascular invasions diagnosed by hematoxylin and eosin staining and demonstrated emboli in 47 lymphatic and 16 blood vessels. In summary, the current study identifies features of true lymphovascular invasion and how to distinguish them from mimickers on routine hematoxylin and eosin sections.

Neoadjuvant Hormonal Therapy Use and the Risk of Death in Men with Prostate Cancer Treated with Brachytherapy Who Have No or at Least a Single Risk Factor for Coronary Artery Disease

BackgroundNeoadjuvant hormone therapy (NHT) use is associated with an increased risk of all-cause mortality (ACM) in men with a history of coronary artery disease (CAD)–induced congestive heart failure (CHF) or myocardial infarction (MI). However, its effect in men with no or at least a single risk factor for CAD stratified by prostate cancer (PCa) aggressiveness is unknown. ObjectiveTo assess whether NHT use affects the risk of ACM in men with low-, intermediate-, and high-risk PCa treated with brachytherapy who have no or at least a single risk factor for CAD. Design, setting, and participantsThis retrospective study cohort consisted of 5411 men with low-risk PCa (prostate-specific antigen [PSA] <10 ng/ml, Gleason score 6, and clinical stage T1–T2a); 4365 men with intermediate-risk PCa (PSA 10–20 ng/ml or Gleason score <8 or clinical stage <T3); and 1360 men with localized or locally advanced, high-risk PCa consecutively treated in a community-based, multi-institutional setting between 1991 and 2006. CAD risk factors included at least a history of diabetes mellitus, hypercholesterolemia, or hypertension. The median follow-up for men with low-, intermediate-, and high-risk PCa were 4.1, 4.4, and 4.6 yr, respectively. InterventionsMen were treated with or without a median duration of 4 mo of NHT followed by brachytherapy with or without supplemental external-beam radiation therapy (EBRT). Outcome measurements and statistical analysisCox regression multivariable analyses were performed to assess whether NHT use affected the risk of ACM in men with low-, intermediate-, and high-risk PCa, adjusting for age; year of brachytherapy; supplemental EBRT use; the presence of CAD risk factors; treatment propensity score; and known PCa prognostic factors, including pretreatment PSA level, biopsy Gleason score, and clinical stage. Results and limitationsNHT use was associated with a significantly increased risk of ACM in men with low-risk PCa (adjusted hazard ratio [HR]: 1.27; 95% confidence interval [CI], 1.07–1.51; p<0.01) but not in men with intermediate-risk (adjusted HR: 1.13; 95% CI, 0.96–1.35; p=0.15) or high-risk PCa (adjusted HR: 0.86; 95% CI, 0.66–1.13; p=0.28). Using an interaction model for the low-risk group, NHT use was associated with a significantly increased risk of ACM in the subgroup of men with at least a single CAD risk factor (adjusted HR: 1.36; 95% CI, 1.07–1.74; p=0.01) but not for men with no CAD risk factors (adjusted HR: 1.19; 95% CI, 0.95–1.51; p=0.13). ConclusionsFor men with no or at least a single risk factor for CAD, NHT use is associated with an increased risk of ACM in the setting of low-risk but not intermediate- or high-risk PCa. This effect is driven by the subgroup of men with at least a single risk factor for CAD. These results warrant prospective validation given the widespread use of NHT for prostate downsizing prior to brachytherapy.

Association hormonothérapie et radiothérapie dans le cancer de prostate localement avancé

Combination of radiotherapy and androgen deprivation is now considered as the standard of care for patients with a localized prostate cancer but poor prognostic factors. Two groups of randomized trials have led to this recommendation. Some have compared radiotherapy alone versus hormonal treatment and radiotherapy: these trials demonstrated, now with a long follow-up, an improvement in 10-year survival for the combined treatment. Three recent trials compared androgen deprivation alone or combined with radiotherapy; a benefit in survival was also demonstrated in favour of the combination. Some questions remained concerning the optimal duration of hormonal treatment, in view of its potential side effects. Patients in the intermediate prognostic groups could receive a short-term androgen deprivation, but those with a high Gleason score must be treated with a long-term hormonal treatment. Modalities of radiotherapy, regarding volumes and dose must also be precised in the next years.

Radical prostatectomy vs radiation therapy and androgen‐suppression therapy in high‐risk prostate cancer

What's known on the subject? and What does the study add? Prostate cancer is generally considered to be high risk when the prostate-specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is ≥8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is ≥2c. There is no consensus on the best treatment for men with prostate cancer that includes these high-risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined-modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of a prospective RCT where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. RCTs that compare RP to radiation-based regimens have been attempted but failed to accrue. To assess the risk of prostate cancer-specific mortality after therapy with radical prostatectomy (RP) or combined-modality therapy (CMT) with brachytherapy, external beam radiation therapy (EBRT) and androgen-suppression therapy (AST) in men with Gleason score 8-10 prostate cancer. Men with localised high-risk prostate cancer based on a Gleason score of 8-10 were selected for study from Duke University (285 men), treated between January 1988 and October 2008 with RP or from the Chicago Prostate Cancer Center or within the 21st Century Oncology establishment (372) treated between August 1991 and November 2005 with CMT. Fine and Gray multivariable regression was used to assess whether the risk of prostate cancer-specific mortality differed after RP as compared with CMT adjusting for age, cardiac comorbidity and year of treatment, and known prostate cancer prognostic factors. As of January 2009, with a median (interquartile range) follow-up of 4.62 (2.4-8.2) years, there were 21 prostate cancer-specific deaths. Treatment with RP was not associated with an increased risk of prostate cancer-specific mortality compared with CMT (adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6-5.6, P = 0.3). Factors associated with an increased risk of prostate cancer-specific mortality were a PSA concentration of <4 ng/mL (adjusted HR 6.1, 95% CI 2.3-16, P < 0.001) as compared with ≥4 ng/mL, and clinical category T2b, c (adjusted HR 2.9; 95% CI 1.1-7.2; P = 0.03) as compared with T1c, 2a. Initial treatment with RP as compared with CMT was not associated with an increased risk of prostate cancer-specific mortality in men with Gleason score 8-10 prostate cancer.

Prognostic significance of lymphovascular invasion in radical prostatectomy specimens

To synthesize the results of studies including lymphovascular invasion (LVI) in the multivariate analyses of potential prostate cancer prognostic factors. To determine the role of LVI as an independent prognostic factor for biochemical recurrence in prostate cancer. We performed a comprehensive systematic literature review of studies examining the association between LVI in prostatectomy specimens and prostate cancer recurrence. Ovid MEDLINE, Embase, Web of Knowledge, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects (DARE) and Google Scholar were searched from January 2000 to February 2009. The primary outcome of interest was biochemical recurrence measured by serum prostate specific antigen (PSA). One thousand two hundred and forty-eight papers met our search criteria. Of these, 19 articles meeting our selection criteria reported results of a multivariate analysis to evaluate LVI as an independent prognostic factor of biochemical recurrence. Eleven (58%) of these studies concluded that LVI was an independent prognostic factor. Significant heterogeneity in the study population, disease characteristics and quality of the studies prevented meta-analysis of the results. In the nine studies in which the magnitude of independent association of LVI with recurrence was reported, it ranged from an odds ratio or relative risk of 1.37 to 4.39. The existing literature is conflicting and of insufficient homogeneity to definitively establish LVI as an important independent prognostic factor of biochemical recurrence in prostate cancer prostatectomy specimens. Additional adequately powered studies are required to determine the clinical value of reports of LVI involvement. In the meantime, the use of LVI status as an independent prognostic factor for clinical prognostication and medical decision making is not recommended.

788 ABERRANT ACTIVATION OF PARACRINE LOOP BETWEEN PROSTATE CANCER CELLS AND CARCINOMA-ASSOCIATED FIBROBLASTS BY OVEREXPRESSION OF STROMAL INTERLEUKIN-6

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2012788 ABERRANT ACTIVATION OF PARACRINE LOOP BETWEEN PROSTATE CANCER CELLS AND CARCINOMA-ASSOCIATED FIBROBLASTS BY OVEREXPRESSION OF STROMAL INTERLEUKIN-6 Kenichiro Ishii, Yoichi Iwamoto, Manabu Kato, Kazuhiro Iguchi, Atsushi Mizokami, Kiminobu Arima, Taizo Shiraishi, and Yoshiki Sugimura Kenichiro IshiiKenichiro Ishii Tsu, Japan More articles by this author , Yoichi IwamotoYoichi Iwamoto Tsu, Japan More articles by this author , Manabu KatoManabu Kato Tsu, Japan More articles by this author , Kazuhiro IguchiKazuhiro Iguchi Gifu, Japan More articles by this author , Atsushi MizokamiAtsushi Mizokami Ishikawa, Japan More articles by this author , Kiminobu ArimaKiminobu Arima Tsu, Japan More articles by this author , Taizo ShiraishiTaizo Shiraishi Tsu, Japan More articles by this author , and Yoshiki SugimuraYoshiki Sugimura Tsu, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.876AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In the tumor microenvironment, activation of tumor-stromal interactions is considered to play a critical role in the promotion of tumorigenesis. During primary cancer progression, cancer cells generate the carcinoma-associated fibroblasts (CAFs) in adjacent normal fibroblasts, and then CAFs support the proliferation and invasion of adjacent cancer cells in a paracrine fashion. The serum level of interleukin-6 (IL-6) is a significant prognostic factor for prostate cancer (PCa) patients with disseminated diseases, suggesting positive roles of IL-6 in the aberrant activation of paracrine loop between PCa cells and CAFs. In this study, we investigated the relationship between responsiveness of PCa cells to stromal IL-6 and cellular AR signaling. METHODS The androgen-low-sensitive E9 cells were obtained from androgen-sensitive LNCaP cell population by limiting dilution method in regular culture condition. In contrast, the androgen-insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone-depleted condition. PCaSC-8 and PCaSC-9 cells were primary cultured from different human PCa specimens. RESULTS IL-6 and VEGF protein levels in both PCaSC-8 and PCaSC-9 cells were generally higher than normal human prostate stromal cells PrSC. In contrast to stromal cells, no IL-6 secretion from LNCaP, E9, and AIDL was detected. IL-6 treatment (10 ng/mL) suppressed cell proliferation of LNCaP and E9 accompanied with changes of cell morphology, i.e. induction of neuroendocrine-like differentiation. Induction of PSA secretion was observed only in IL-6-treated LNCaP. VEGF secretion was significantly increased in both IL-6-treated LNCaP and AIDL. A selective alpha1-adrenoceptor antagonist naftopidil (10 μM) but not tamsulosin suppressed IL-6-induced VEGF secretion in AIDL. CONCLUSIONS In this study, we have shown the evidence that secretions of IL-6 and VEGF from primary cultured CAFs derived PCa patients are generally higher than normal fibroblasts. Our results suggest that overexpression of stromal IL-6 might increase VEGF secretion from adjacent PCa cells in a paracrine fashion. Using LNCaP sublines, E9 and AIDL, differing in androgen-sensitivity, we demonstrated here that IL-6-induced VEGF secretion from PCa cells might be through cellular AR signaling-independent pathway. Identifying mechanisms underlying the aberrant activation of paracrine loop between PCa cells and CAFs is an initial step toward designing CAF-targeted therapy for treatment of PCa. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e322-e323 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenichiro Ishii Tsu, Japan More articles by this author Yoichi Iwamoto Tsu, Japan More articles by this author Manabu Kato Tsu, Japan More articles by this author Kazuhiro Iguchi Gifu, Japan More articles by this author Atsushi Mizokami Ishikawa, Japan More articles by this author Kiminobu Arima Tsu, Japan More articles by this author Taizo Shiraishi Tsu, Japan More articles by this author Yoshiki Sugimura Tsu, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Biologic activity of LSD1 inhibition by novel tranylcypromine structural analogues in prostate cancer cells.

82 Background: Hormonal strategies to inhibit androgen receptor (AR) signalling remain inadequate and so novel approaches are urgently required. Lysine (K)-specific demethylase 1A (LSD1), is an epigenetic AR co-activator which modifies chromatin structure through de-methylation of histone H3 lysine 9 at androgen response elements to activate transcriptional expression of AR target genes. LSD1 is over-expressed and a poor prognostic factor in prostate cancer. We have synthesised novel analogues of the monoamine oxidase (MAO) inhibitor tranylcypromine as LSD1 inhibitors to exploit MAO and LSD1 sequence homology. Methods: We utilised prostate cancer cell line models to investigate the biological effect of LSD1 inhibition using tranylcypromine analogues. Results: Chemical inhibition of LSD1 was effective in inhibiting cell proliferation in prostate cancer models with around 1000 fold greater potency for synthesised analogues over tranylcypromine in LNCaP prostate cancer cells. Chemical inhibition of LSD1 induced the predicted histone methylation changes consequent on LSD1 inhibition of mono- and di-methylation of histone H3 lysine 9. In addition LSD1 depletion, AR depletion and reduced expression of the AR target gene prostate-specific antigen was demonstrated. Fractional effect assays demonstrated synergistic interactions in cell proliferation assays for tranylcypromine analogues with the androgen receptor antagonists bicalutamide and MDV3100. Conclusions: Our data demonstrate biological activity of LSD1 inhibition in prostate cancer cells with depletion of AR signalling using optimised structural analogues of established drugs for non-cancer indications. Therapeutic targeting of LSD1 for prostate cancer would represent a novel therapeutic paradigm for this disease.

β-catenin as a prognostic factor for prostate cancer (PCa)

IntroductionThe prostate cancer is difficult to predict, and treatment failure is associated with local infiltration, as well as distant metastases. Adhesion and migration abilities to of cancer cells play a major role in formation of metastasis. The participation of β-catenin in pathogene-sis of many types of cancer and benign processes has been an important discovery of recent years.Material and methodsThe studied material was obtained by transrectal, sextant core biopsy from 102 patients hospitalized in Department of Urology, Regional Hospital in Kalisz (2001-2004).The aim of our study was to determine the predictive value of β-catenin immunoexpression in prostate cancer, to analyze the prognostic aspect of some histopathological features and finally to assess the relationship between β-catenin immunoreactivity and the microscopic image of the tumor.Relationships between the investigated variables were analyzed using the Chi2 test of compatibility. We used the Kaplan-Meier curves to assess survival differences between groups of patients. Finally we established which of the studied factors significantly affect the patient outcome, using the method of Cox proportional hazard regression.ResultsIn prostate cancer in comparison with the normal epithelium, both the location and the strength of β-catenin immunoexpression are impaired.ConclusionsOur results indicate that the presence of disorders in β-catenin immunoexpression in prostate cancer cells indicates a high risk of death due to tumor progression and makes it imperative for immediate treatment procedures.

TP53INP1 as new therapeutic target in castration‐resistant prostate cancer

Prostate cancer (PC) is one of the most common malignancies in industrialized countries, and the second leading cause of cancer-related death in the United States. We recently showed that over-expression of tumor protein 53-induced nuclear protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. Moreover, treatment of castration-sensitive (CS) LNCaP tumor cells with a TP53INP1 antisense oligonucleotide (TP53INP1 ASO) inhibits proliferation and induces apoptosis. The aim of this study was to investigate variations of TP53INP1 expression in PC during androgen withdrawal therapy and in castration-resistant prostate cancer (CRPC). Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images were correlated with hormone therapy (HT) status in human PC. Northern blot analysis of TP53INP1 after castration was performed in LNCaP xenograft. Treatment of CR C4-2 tumor cells in vitro with TP53INP1 ASO was analyzed. We also analyzed the effect of TP53INP1 ASO treatment in vivo on tumor xenograft growth. TP53INP1 protein expression decreases during HT and increases after HT in human CRPC. TP53INP1 mRNA increases significantly in CR tumors of LNCaP xenograft. Moreover, treatment of CR C4-2 cells with TP53INP1 ASO downregulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. Finally, in vivo, TP53INP1 ASO treatment significantly inhibits the tumoral progression of CR C4-2 xenograft and enhances docetaxel cytotoxicity. These results suggest that TP53INP1 could be considered as a relevant-specific target for molecular therapy of CRPC.

Staging of prostate cancer

Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes.

Prognostic value of promoter hypermethylation of Retinoic Acid Receptor Beta (RARB) and CDKN2 (p16/MTS1) in prostate cancer

The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR). Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P<0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.

Hormonal Therapy or External-Beam Radiation With Brachytherapy and the Risk of Death From Prostate Cancer in Men With Intermediate Risk Prostate Cancer

PurposeTo determine whether external-beam radiotherapy (EBRT) improves disease control compared with supplemental androgen suppression therapy (AST) in men with intermediate-risk prostate cancer who are being treated with brachytherapy. Patients and MethodsA total of 807 men with intermediate-risk prostate cancer (T2bNXM0, Gleason ≤7, prostate-specific antigen [PSA] <20 ng/mL; or cT1c-T2bNXM0, Gleason 7) were consecutively treated with either AST and brachytherapy or EBRT and brachytherapy, between 1997 and 2007, and were followed up until September 21, 2007. A Fine and Gray competing risks multivariable regression model was used to assess whether AST or radiotherapy dose escalation reduced the risk of prostate-cancer–specific mortality (PCSM) when adjusting for age, PSA, Gleason score, and tumor category. ResultsTreatment with brachytherapy and with EBRT was associated with a significant increase in the risk of PCSM compared with brachytherapy and AST (adjusted hazard ratio [HR] 4.027 [95% CI, 1.168-13.89]; P = .027) after adjusting for age and prostate cancer prognostic factors. A Gleason score of 4+3 and increasing PSA were associated with worse PCSM (adjusted HR 8.882 [95% CI, 1.095-72.04]; P = .041; and adjusted HR 8.029 [95% CI, 2.38-28.8]; P = .0014, respectively). ConclusionSupplemental AST use compared with EBRT is associated with a lower risk of PCSM in men with intermediate-risk PC undergoing brachytherapy. Prospective validation in a randomized controlled trial is needed.

Laparoscopic sentinel lymph node (SLN) versus extensive pelvic dissection for clinically localized prostate carcinoma

Lymph node metastasis is an important prognostic factor in prostate cancer (PC). The aim of this prospective study was to evaluate the accuracy of sentinel lymph node (SLN) biopsy by laparoscopy in staging locoregional patients with clinically localized PC. A transrectal ultrasound-guided injection of 0.3 ml/100 MBq (99m)Tc-sulphur rhenium colloid in each prostatic lobe was performed the day before surgery. Detection was performed intraoperatively with a laparoscopic probe (Gamma Sup CLERAD) followed by extensive resection. SLN counts were performed in vivo and confirmed ex vivo. Histological analysis was performed by haematoxylin-phloxine-saffron staining, followed by immunohistochemistry (IHC) if the SLN was free of metastasis. The study included 93 patients with PC at intermediate or high risk of lymph node metastases. The intraoperative detection rate was 93.5% (87/93). Nineteen patients had lymph node metastases, nine only in SLN. The false-negative rate was 10.5% (2/19). The internal iliac region was the primary metastatic site (43.3%). Metastatic sentinel nodes in the common iliac region beyond the ureteral junction were present in 13.3%. Limited or standard lymph node resection would have ignored 73.2 and 56.6% of lymph node metastases, respectively. Laparoscopy is suitable for broad identification of SLN metastasis, and targeted resection of these lymph nodes significantly limits the risk of extended surgical resection whilst maintaining the accuracy of the information.

Low serum testosterone levels are predictive of prostate cancer

Although hormones play fundamental roles in prostate growth, their clinical significance is not completely clear. Aims of present study were to assess whether testosterone and serum sex hormone levels are predictors of benign prostatic hyperplasia (BPH) or prostate cancer (PC) and to verify whether prostate cancer is associated with low testosterone levels, and to test association between testosterone levels and known prognostic factors in prostate cancer. In 206 consecutive patients with benign prostatic hyperplasia or prostate cancer testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin levels were tested and correlated with disease. In patients with prostate cancer, hormone levels were also correlated with known prognostic factors. Predictive value was assessed for age, prostate-specific antigen (PSA), PSA ratio, PSA density, prostate volume and serum sex hormone levels using multiple logistic regression analysis and receiver operating characteristic curves. Considering sex hormones, only testosterone levels were significantly lower in patients with prostate cancer than those with BPH; testosterone levels appear to be independent predictor of prostate cancer, enhancing predictive accuracy for BPH and PC. Testosterone levels do not seem to be associated with known clinical prognostic factors. This study supports experimental findings that testosterone levels are predictor of prostate cancer and that prostate cancer is frequently associated with low testosterone levels. In the diagnostic work-up for prostate cancer, adding testosterone determination to PSA test may improve predictive accuracy.

Duration of Short-Course Androgen Suppression Therapy and the Risk of Death As a Result of Prostate Cancer

We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories. Between February 2, 1996, and December 27, 2001, 761 men with unfavorable-risk PC were treated in Australia, New Zealand, Ireland, or the United States in a randomized trial with radiotherapy and 3, 4, or 6 months of AST (the study cohort). Competing risks regression was used to evaluate whether the duration of AST interacted with GS and was significantly associated with the risk of PCSM, adjusting for age, trial site, and PC prognostic factors. After a median follow-up of 10.9 years, 263 men died, 111 (42%) from PC. For all men, 6 versus 3 or 4 months of AST was associated with a reduced risk of PCSM (adjusted hazard ratio [AHR], 0.55; 95% CI, 0.36 to 0.82; P = .004). AHRs evaluating the impact of the duration of AST on the risk of PCSM were 0.67 (95% CI, 0.29 to 1.56; P = .35), 0.47 (95% CI, 0.25 to 0.85; P = .01), and 0.59 (95% CI, 0.30 to 1.19; P = .14) for men with GS ≤ 6, 7, and 8 to 10 PC, respectively. Therefore, the strongest evidence for this benefit was in men with GS 7 PC. AST durations of no less than 6 months should be considered when treating GS 7 PC with conventional dose RT.