Comparison of PHI and PHI Density for Prostate Cancer Detection in a Large Retrospective Caucasian Cohort.

BACKGROUND: Beyond prostate-specific antigen (PSA), other biomarkers for prostate cancer (PCa) detection are available and need to be evaluated for clinical routine. OBJECTIVE: The aim of the study was to evaluate the Prostate Health Index (PHI) density (PHID) in comparison with PHI in a large Caucasian group >1,000 men. METHODS: PHID values were used from available patient data with PSA, free PSA, and [-2]pro-PSA and prostate volume from 3 former surveys from 2002 to 2014. Those 1,446 patients from a single-center cohort included 701 men with PCa and 745 with no PCa. All patients received initial or repeat biopsies. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curves comparing area under the ROC curves (AUCs), precision-recall approach, and decision curve analysis (DCA). RESULTS: PHID medians differed almost 2-fold between PCa (1.12) and no PCa (0.62) in comparison to PHI (48.6 vs. 33; p always <0.0001). However, PHID and PHI were equal regarding the AUC (0.737 vs. 0.749; p = 0.226), and the curves of the precision-recall analysis also overlapped in the sensitivity range between 70 and 100%. DCA had a maximum net benefit of only ∼5% for PHID versus PHI between 45 and 55% threshold probability. Contrary, in the 689 men with a prostate volume ≤40 cm3, PHI (AUC 0.732) showed a significant larger AUC than PHID (AUC 0.69, p = 0.014). CONCLUSIONS: Based on DCA, PHID had only a small advantage in comparison with PHI alone, while ROC analysis and precision-recall analysis showed similar results. In smaller prostates, PHI even outperformed PHID. The increment for PHID in this large Caucasian cohort is too small to justify a routine clinical use.

PHI density prospectively improves prostate cancer detection.

PURPOSE: To evaluate the Prostate Health Index (PHI) density (PHID) in direct comparison with PHI in a prospective large cohort. METHODS: PHID values were calculated from prostate-specific antigen (PSA), free PSA and [- 2]proPSA and prostate volume. The 1057 patients included 552 men with prostate cancer (PCa) and 505 with no evidence of malignancy (NEM). In detail, 562 patients were biopsied at the Charité Hospital Berlin and 495 patients at the Sana Hospital Offenbach. All patients received systematic or magnetic resonance imaging (MRI)/ultrasound fusion-guided biopsies. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curves comparing areas under the ROC-curves (AUC). The decision curve analysis (DCA) was performed with the MATLAB Neural Network Toolbox. RESULTS: PHID provided a significant larger AUC than PHI (0.835 vs. 0.801; p = 0.0013) in our prospective cohort of 1057 men from 2 centers. The DCA had a maximum net benefit of ~ 5% for PHID vs. PHI between 35 and 65% threshold probability. In those 698 men within the WHO-calibrated PSA grey-zone up to 8 ng/ml, PHID was also significantly better than PHI (AUC 0.819 vs. 0.789; p = 0.0219). But PHID was not different from PHI in the detection of significant PCa. CONCLUSIONS: Based on ROC analysis and DCA, PHID had an advantage in comparison with PHI alone to detect any PCa but PHI and PHID performed equal in detecting significant PCa.

Serum Vitamin D is Not Helpful for Predicting Prostate Cancer Aggressiveness Compared with the Prostate Health Index.

PURPOSE: We evaluated the usefulness of serum 25-hydroxyvitamin D as a marker of aggressive prostate cancer and for active surveillance compared to PHI (Prostate Health Index). MATERIALS AND METHODS: Of 480 prospectively biopsied men 222 had prostate cancer and 258 had no evidence of malignancy. In all men prostate specific antigen was less than 20 ng/ml. We measured 25-hydroxyvitamin D, prostate specific antigen, free prostate specific antigen and -2proPSA using a commercially available immunoassay system. PHI was calculated according to the equation, -2proPSA/free prostate specific antigen × âˆšPSA. We determined 25-hydroxyvitamin D using a 2-step competitive binding immunoenzymatic vitamin D assay. RESULTS: The 25-hydroxyvitamin D concentrations were not associated with Gleason grade according to the 2014 ISUP (International Society of Urological Pathology) consensus conference Gleason grading system. PHI values were higher with increasing Gleason grade. Median 25-hydroxyvitamin D did not differ between men with prostate cancer vs no evidence of malignancy (50.6 vs 48.2 nmol/l, p = 0.192) or in ISUP Gleason subgroups despite seasonal variations of 25-hydroxyvitamin D. However, PHI values significantly differed between the subgroup with no evidence of malignancy and all Gleason subgroups (p <0.0001). The ROCs of all men revealed an advantage of PHI over 25-hydroxyvitamin D (AUC 0.78 vs 0.535, p <0.0001). PHI could also significantly better separate patients with no evidence of malignancy from those with nonaggressive disease (ISUP Gleason grade 1) from those with aggressive prostate cancer (ISUP Gleason grades 2-5). CONCLUSIONS: It remains highly improbable that 25-hydroxyvitamin D could be used as decision or selection marker for aggressive prostate cancer or for active surveillance compared to accepted markers, as recently suggested.

Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis.

Bone metastases are characterized by increased osteoblastic and/or osteolytic processes depending on the tumor type. The altogether destructive effect of metastasis formation promoted by increased metabolic activity raises the release of components from the osseous metabolism into the blood stream. These components are either enzymes directly involved in the alteration processes, metabolites/proteins that develop during this or bone matrix proteins released during this. These biomarkers are categorized in relation to their involvement in the bone formation or resorption as bone formation and resorption markers. Based on a PubMed literature search, a critical appraisal of the various biomarkers for diagnostic, prognostic, and monitoring purposes is given for patients with skeletal metastases caused by breast, prostate, lung, or renal cell carcinomas.

Urinary thiosulfate as failed prostate cancer biomarker - an exemplary multicenter re-evaluation study.

BACKGROUND: In 2013, thiosulfate in urine has been proposed as promising prostate cancer (PCa) biomarker. However, a missing comparison with other proven PCa markers suggested a re-evaluation study. Therefore, together with the authors from the initial study, the diagnostic accuracy of thiosulfate was compared with that of urinary prostate cancer associated 3 (PCA3), serum prostate health index (Phi), and percent free prostate-specific antigen (%fPSA). Thiosulfate was further measured in a multicenter approach to exclude center-related biases. METHODS: Thiosulfate, calculated as ratio of thiosulfate to urinary creatinine (TS/Crea ratio), was measured in two cohorts in a total of 269 patients. In the retrospective study (n=160) PCA3, Phi, PSA, and %fPSA were compared with the TS/Crea ratio between patients with and without PCa according to the prostate needle biopsy results. The second prospective cohort included 109 patients from four centers. RESULTS: The median TS/Crea ratio was not statistically different between the patients with and without PCa. The receiver-operating characteristics showed that the TS/Crea ratio was unable to discriminate between patients with and without PCa in contrast to %fPSA, Phi, and PCA3. In all four centers, the low median TS/Crea ratios (<1 mmol/mol) in both patient cohorts were confirmed and thiosulfate was again not able to distinguish between them (p-values, 0.13-0.90). CONCLUSIONS: This study could not confirm the previously observed high median TS/Crea ratio in PCa patients in comparison to non-PCa patients. Thiosulfate subsequently failed as PCa biomarker while PCA3 and Phi showed the expected diagnostic improvement.

Comparison of surgical technique (open vs. laparoscopic) on pathological and long term functional outcomes following radical prostatectomy.

BACKGROUND: Few studies to date have directly compared outcomes of retropubic (RRP) and laparoscopic (LRP) radical prostatectomy. We investigated a single institution experience with RRP and LRP with respect to functional and pathological outcomes. METHODS: 168 patients who underwent RRP were compared to 171 patients who underwent LRP at our institution. Pathological and functional outcomes including postoperative urinary incontinence and erectile dysfunction (ED) of the two cohorts were examined. RESULTS: Patients had bilateral, unilateral and no nerve sparing technique performed in 83.3%, 1.8% and 14.9% of cases for RRP and 23.4%, 22.8% and 53.8% of cases for LRP, respectively (p < 0.001). Overall positive surgical margin rates were 22.2% among patients who underwent RRP compared to 26.5% of patients who underwent LRP (p = 0.435). Based upon pads/day, urinary continence postoperatively was achieved in 83.2% and 82.8% for RRP and LRP, respectively (p = 0.872). Analysis on postoperative ED was limited due to lack of information on the preoperative erectile status. However, postoperatively there were no differences with respect to ED between the two cohorts (p = 0.151). Based on ICIQ-scores, surgeons with more experience had lower rates of postoperative incontinence irrespective of surgical technique (p = 0.001 and p < 0.001 for continuous and stratified data, respectively). CONCLUSIONS: RRP and LRP represent effective surgical approaches for the treatment of clinically localized prostate cancer. Pathological outcomes are excellent for both surgical techniques. Functional outcomes including postoperative urinary incontinence and ED are comparable between the cohorts. Surgeon experience is more relevant than surgical technique applied.

Tissue metabolite profiling identifies differentiating and prognostic biomarkers for prostate carcinoma.

Metabolomic research offers a deeper insight into biochemical changes in cancer metabolism and is a promising tool for identifying novel biomarkers. We aimed to evaluate the diagnostic and prognostic potential of metabolites in prostate cancer (PCa) tissue after radical prostatectomy. In matched malignant and nonmalignant prostatectomy samples from 95 PCa patients, aminoadipic acid, cerebronic acid, gluconic acid, glycerophosphoethanolamine, 2-hydroxybehenic acid, isopentenyl pyrophosphate, maltotriose, 7-methylguanine and tricosanoic acid were determined within a global metabolite profiling study using gas chromatography/liquid chromatography-mass spectrometry. The data were related to clinicopathological variables like prostate volume, tumor stage, Gleason score, preoperative prostate-specific antigen and disease recurrence in the follow-up. All nine metabolites showed higher concentrations in malignant than in nonmalignant samples except for gluconic acid and maltotriose, which had lower levels in tumors. Receiver -operating characteristics analysis demonstrated a significant discrimination for all metabolites between malignant and nonmalignant tissue with a maximal area under the curve of 0.86 for tricosanoic acid, whereas no correlation was observed between the metabolite levels and the Gleason score or tumor stage except for gluconic acid. Univariate Cox regression and Kaplan-Meier analyses showed that levels of aminoadipic acid, gluconic acid and maltotriose were associated with the biochemical tumor recurrence (prostate-specific antigen > 0.2 ng/mL). In multivariate Cox regression analyses, aminoadipic acid together with tumor stage and Gleason score remained in a model as independent marker for prediction of biochemical recurrence. This study proved that metabolites in PCa tissue can be used, in combination with traditional clinicopathological factors, as promising diagnostic and prognostic tools.

Impact of positive surgical margins on oncological outcome following laparoscopic radical prostatectomy (LRP): long-term results.

PURPOSE: The impact of positive surgical margins (PSM) on biochemical recurrence (BCR) has been heavily debated in laparoscopic radical prostatectomy (LRP). The aim of this study was to investigate the impact of PSM on BCR following LRP in patients with extended follow-up. METHODS: Retrospective chart review of 1,845 patients who underwent LRP from 1999 to 2007. Predictors of PSM and BCR were identified utilizing univariate and multivariable logistic and Cox regression analyses, respectively. RESULTS: Five hundred and thirty-seven patients (29.1%) had a PSM. Median postoperative follow-up was 56 months. 10-year BCR-free survival was 59.2 and 82.9% for patients with and without PSM, respectively (p < 0.0001). Clinical stage T2 (OR 1.66; CI 1.23-2.25; p = 0.001), a biopsy Gleason sum > 7 (OR 1.84; CI 1.06-3.18; p = 0.031) and preoperative prostate-specific antigen (PSA) levels of 10-20 ng/mL (OR 1.58; CI 1.12-2.23; p = 0.010) and >20 ng/mL (OR 6.82; CI 3.51-13.27; p < 0.0001) were independent predictors of PSM. Prostate size was inversely associated with PSM (OR 0.99; CI 0.98-1.00; p = 0.002). On multivariable analysis, LRP Gleason score of 7 (HR 2.45; CI 1.67-3.40; p < 0.0001) and >7 (HR 4.76; CI 3.15-7.19; p < 0.0001), PSM (HR 1.49; CI 1.14-2.00; p = 0.003), advanced pathological stages (p < 0.001), and PSA 10-20 ng/mL (HR 1.46; CI 1.13-1.89; p = 0.004) were independent predictors of BCR. CONCLUSIONS: We demonstrated the independent predictive value of PSM for BCR in our LRP cohort with extended follow-up. Our results could potentially be transferred to robotic RP, in which long-term follow-up is lacking.

Value of prostate specific antigen density and percent free prostate specific antigen for prostate cancer prognosis.

PURPOSE: Limited data exist on the relationship of percent free prostate specific antigen and prostate specific antigen density with prostate cancer prognosis. Therefore, we compared percent free prostate specific antigen and prostate specific antigen density with prostate specific antigen, Gleason sum and stage to predict prostate cancer prognosis in a large cohort using a single prostate specific antigen and free prostate specific antigen assay. MATERIALS AND METHODS: Between 1999 and 2007 a total of 1,656 patients with prostate cancer underwent laparoscopic radical prostatectomy at the Charité Berlin. There were 322 patients excluded from analysis for a variety of reasons. The final 1,334 patients had prostate specific antigen, free prostate specific antigen, prostate volume and complete pathological analysis available. RESULTS: Median followup was 60.3 months (range 0.2 to 135). Median age (63 years, range 43 to 75) did not differ between the 1,092 patients without and the 242 with biochemical recurrence (p = 0.956), but prostate volume, prostate specific antigen and percent free prostate specific antigen differed significantly (p <0.0001). While prostate specific antigen and prostate specific antigen density increased significantly in patients with Gleason less than 7, 7 and greater than 7 tumors, percent free prostate specific antigen decreased significantly (p <0.0001). Prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density differed significantly between pT2 and pT3 tumors, and between patients with vs without positive surgical margins. On univariate analysis Gleason sum, pathological stage, positive surgical margin, total prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density were predictors of biochemical recurrence-free survival. Multivariate Cox regression analysis identified Gleason sum, pathological stage, positive surgical margin and prostate specific antigen density as independent predictors of biochemical recurrence-free survival, while percent free prostate specific antigen and total prostate specific antigen failed to be significant. CONCLUSIONS: Few models for prostate cancer prognosis include prostate specific antigen density. There is substantial value in prostate specific antigen density but not in percent free prostate specific antigen for improving prostate cancer prognosis and biochemical recurrence prediction.

Effect of quinolinyl acrylate derivatives on prostate cancer in vitro and in vivo.

Quinolines and acrylates are chemical compounds which were previously described as potential antitumor agents. In this study, a series of seven new quinolinyl acrylate derivatives were synthesized and evaluated against human prostate cancer cells PC-3 and LNCaP in vitro and in vivo. The most effective compound (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4 hydroxyphenyl) acrylate reduced the viability in both cell lines in a time- and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on the neoangiogenesis, clonogenic and MMP-9 activity. The effect in vivo was studied in PC-3 xenografts in nude mice. The results were concordant with the in vitro effects and showed decreased tumor growth in treated animals compared to controls. The study suggests the multi-target efficacy of the quinolinyl derivate against human prostate cancer cells and supports its potential therapeutic usefulness.

Long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Over the past decade, minimally invasive laparoscopic radical prostatectomy and more recently robot-assisted laparoscopic prostatectomy have been introduced and have proven equally effective compared with open surgery in terms of mid-term cancer control and complication rates. Because long-term data is lacking, open prostatectomy is still considered the 'gold standard' by some authors, who argue that minimally invasive approaches have to measure up to the excellent long-term results of open surgery. This study represents one of the largest series (1845 patients) of minimally invasive radical prostatectomy with extended follow-up (11.3 years) and detailed data on oncological outcome and postoperative incontinence. It therefore supplies previously lacking information on these details for minimally invasive prostate surgery and provides important information for patient counselling. OBJECTIVE: • To investigate biochemical recurrence (BCR) rates and data on postoperative incontinence in a large laparoscopic radical prostatectomy (LRP) cohort with extended follow-up. MATERIALS AND METHODS: • BCR and independent predictors of BCR were identified using Kaplan-Meier and Cox regression analysis of 1845 patients who underwent LRP from 1999 to 2007. • Urinary incontinence was evaluated by pads per day and stratified as follows: 0-1 pad: no incontinence; 2-3 pads: mild incontinence; and ≥ 3 pads: severe incontinence. RESULTS: • Organ-confined disease, extraprostatic extension, seminal vesicle invasion and lymph node metastasis were present in 71.3%, 20.5%, 6.7% and 3.2% of patients, respectively. The positive surgical margin rate was 29.2%. • Postoperatively, 74.9% of the patients were continent, while 9.2% had mild and 15.9% severe incontinence. • The mean follow-up was 5 years with a maximum follow-up of 11.3 years. • There were 51 overall deaths and six deaths from prostate cancer. The 5-year, 8-year and 10-year BCR-free survival rates were 83.9%, 78.6% and 75.6%, respectively. • On univariate analyses preoperative D'Amico risk classification, pathological tumour stage, postoperative Gleason sum and surgical margin status were predictors of BCR (P < 0.001). • On multivariable analysis, D'Amico classification, Gleason sum (P < 0.001), postoperative tumour stage (P < 0.001), nodal status (P < 0.001) and surgical margin status (P = 0.002) were independent predictors of BCR. CONCLUSIONS: • LRP offers excellent long-term functional and oncological results with a low incidence of BCR for patients with localized disease. • These results could be used for patient counselling before robot-assisted laparascopic prostatectomy (RALP) until long-term follow-up data for RALP is available.

Vitamin D Metabolites in Nonmetastatic High-Risk Prostate Cancer Patients with and without Zoledronic Acid Treatment after Prostatectomy.

There are limited and discrepant data on prostate cancer (PCa) and vitamin D. We investigated changes in three vitamin D3 metabolites in PCa patients after prostatectomy with zoledronic acid (ZA) treatment regarding their metastasis statuses over four years. In 32 patients from the ZEUS trial, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were measured with liquid chromatography coupled with tandem mass spectrometry at four time points. All the patients received daily calcium and vitamin D3. Bone metastases were detected in 7 of the 17 ZA-treated patients and in 5 of the 15 controls (without ZA), without differences between the groups (p = 0.725). While 25(OH)D3 and 24,25(OH)2D3 increased significantly after the study's start, with following constant values, the 1,25(OH)2D3 concentrations remained unchanged. ZA treatment did not change the levels of the three metabolites. 25(OH)D3 and 24,25(OH)2D3 were not associated with the development of bone metastases. In contrast, 1,25(OH)2D3 was also higher in patients with bone metastasis before the study's start. Thus, in high-risk PCa patients after prostatectomy, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were not affected by supportive ZA treatment or by the development of metastasis over four years, with the exception of 1,25(OH)2D3, which was constantly higher in metastatic patients. There might be potential prognostic value if the results can be confirmed.

Prevalence of Propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells.

Prostate cancer (PCa) is the second leading cause of male cancer deaths in the Western world. Mounting evidence has revealed that chronic inflammation can be an important initiating factor of PCa. Recent work has detected the anaerobic Gram-positive bacterium Propionibacterium acnes in cancerous prostates, but with wide-ranging detection rates. Here, using in situ immunofluorescence (ISIF), P. acnes was found in 58 out of 71 (81.7%) tested cancerous prostate tissue samples, but was absent from healthy prostate tissues (20 samples) and other cancerous tissue biopsies (59 mamma carcinoma samples). Live P. acnes bacteria were isolated from cancerous prostates and cocultured with the prostate epithelial cell line RWPE1. Microarray analysis showed that the host cell responded to P. acnes with a strong multifaceted inflammatory response. Active secretion of cytokines and chemokines, such as IL-6 and IL-8, from infected cells was confirmed. The host cell response was likely mediated by the transcriptional factors NF-κB and STAT3, which were both activated upon P. acnes infection. The P. acnes-induced host cell response also included the activation of the COX2-prostaglandin, and the plasminogen-matrix metalloproteinase pathways. Long-term exposure to P. acnes altered cell proliferation, and enabled anchorage-independent growth of infected epithelial cells, thus initiating cellular transformation. Our results suggest that P. acnes infection could be a contributing factor to the initiation or progression of PCa.

Between-method differences in prostate-specific antigen assays affect prostate cancer risk prediction by nomograms.

BACKGROUND: To date, no published nomogram for prostate cancer (PCa) risk prediction has considered the between-method differences associated with estimating concentrations of prostate-specific antigen (PSA). METHODS: Total PSA (tPSA) and free PSA were measured in 780 biopsy-referred men with 5 different assays. These data, together with other clinical parameters, were applied to 5 published nomograms that are used for PCa detection. Discrimination and calibration criteria were used to characterize the accuracy of the nomogram models under these conditions. RESULTS: PCa was found in 455 men (58.3%), and 325 men had no evidence of malignancy. Median tPSA concentrations ranged from 5.5 µg/L to 7.04 µg/L, whereas the median percentage of free PSA ranged from 10.6% to 16.4%. Both the calibration and discrimination of the nomograms varied significantly across different types of PSA assays. Median PCa probabilities, which indicate PCa risk, ranged from 0.59 to 0.76 when different PSA assays were used within the same nomogram. On the other hand, various nomograms produced different PCa probabilities when the same PSA assay was used. Although the ROC curves had comparable areas under the ROC curve, considerable differences were observed among the 5 assays when the sensitivities and specificities at various PCa probability cutoffs were analyzed. CONCLUSIONS: The accuracy of the PCa probabilities predicted according to different nomograms is limited by the lack of agreement between the different PSA assays. This difference between methods may lead to unacceptable variation in PCa risk prediction. A more cautious application of nomograms is recommended.

Sarcosine in prostate cancer tissue is not a differential metabolite for prostate cancer aggressiveness and biochemical progression.

PURPOSE: Sarcosine in prostate cancer tissue samples was recently reported to be increased during prostate cancer progression to metastasis and suggested to be a key metabolite of cancer cell invasion and aggressiveness. We reevaluated sarcosine in prostate cancer tissue samples as a potential indicator of tumor aggressiveness, and as a predictor of recurrence-free survival. MATERIALS AND METHODS: Sarcosine in matched samples of malignant and nonmalignant tissue from 92 patients with prostate cancer after radical prostatectomy was measured in the framework of a global metabolite profiling study of prostate cancer by gas chromatography/mass spectrometry. We related results to age, prostate volume, tumor stage, Gleason score, preoperative prostate specific antigen and biochemical recurrence, defined as a persistent prostate specific antigen increase of greater than 0.2 ng/ml. Nonparametric statistical tests, ROC curves and Kaplan-Meier analyses were done. RESULTS: Median sarcosine content in tissue was about 7% higher in matched malignant vs nonmalignant samples, which was significantly. Sarcosine values were not associated with tumor stage (pT2 vs pT3), tumor grade (Gleason score less than 7 vs 7 or greater) or biochemical recurrence. The lack of metastatic tissue samples was a study limitation. CONCLUSIONS: Sarcosine in prostate cancer tissue samples cannot be considered a suitable predictor of tumor aggressiveness or biochemical recurrence.

New 4-maleamic acid and 4-maleamide peptidyl chalcones as potential multitarget drugs for human prostate cancer.

PURPOSE: The objective of this study was to investigate the effect of new 4-maleamic acid and 4-maleamide peptidyl chalcone derivatives against human prostate cancer in vitro and in vivo. METHODS: From a series of 21 chalcones, the effects of the three best inhibitors of PC-3 and LNCaP cell viability on growth, including cell cycle changes, adhesion, migration, and cell invasion, as well as their ability to inhibit angiogenesis, clonogenic activity, and matrix metalloproteinases MMP-2 and MMP-9, were tested. The effects in vivo were studied in PC-3 and LNCaP xenografts. RESULTS: Three of the examined chalcones reduced cell viability in both cell lines in a strong dose- and time-dependent manner. An inhibition of the cell cycle progress was observed. These changes were accompanied with the inhibition of cell adhesion, migration, and invasion as well as with reduced neovascularization in chick embryos, tumor colony formation, and MMP-9 activity. The in vivo results demonstrated the strong activity of these structures as inhibitors of tumor development in nude mice compared to non-treated animals. CONCLUSION: The results suggest the multitarget efficacy of 4-maleamic acid and 4-maleamide peptidyl chalcones against human prostate cancer cells and emphasize the potential therapeutic relevance of these compounds.

The discriminative ability of Prostate Health Index to detect prostate cancer is enhanced in combination with miR-222-3p.

BACKGROUND: There is an urgent need for better prostate cancer (PCa) biomarkers due to the low specificity of prostate specific antigen (PSA). OBJECTIVE: Prostate Health Index (PHI) is an advanced PSA-based test for early detection of PCa. The present study aim was to investigate the potential improvement of diagnostic accuracy of PHI by its combination with suitable discriminative microRNAs (miRNAs). METHODS: A two-phase study was performed. In a discovery phase, a panel of 177 miRNAs was measured in ten men with biopsy proven PCa and ten men with histologically no evidence of malignancy (NEM). These results were validated in a second phase including 25 patients in each group. The patients of all groups were matched regarding their PSA values and PHI were measured. RESULTS: Based on data in the discovery phase, four elevated miRNAs were selected as potential miRNA candidates for further validation. A combination of miR-222-3p as the best discriminative miRNA with PHI extended the diagnostic accuracy of PHI from an AUC value of 0.690 to 0.787 and resulted in a sensitivity of 72.0% and a specificity of 84.0%. CONCLUSION: Circulating microRNAs show useful diagnostic potential in combination with common used biomarkers to enhance their diagnostic power.

Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma.

This study aimed to investigate the microRNA (miRNA) profile in prostate carcinoma tissue by microarray analysis and RT-qPCR, to clarify associations of miRNA expression with clinicopathologic data and to evaluate the potential of miRNAs as diagnostic and prognostic markers. Matched tumor and adjacent normal tissues were obtained from 76 radical prostatectomy specimens. Twenty-four tissue pairs were analyzed using human miRNA microarrays for 470 human miRNAs. Differentially expressed miRNAs were validated by TaqMan RT-qPCR using all 76 tissue pairs. The diagnostic potential of miRNAs was calculated by receiver operating characteristics analyses. The prognostic value was assessed in terms of biochemical recurrence using Kaplan-Meier and Cox regression analyses. Fifteen differentially expressed miRNAs were identified with concordant fold-changes by microarray and RT-qPCR analyses. Ten microRNAs (hsa-miR-16, hsa-miR-31, hsa-miR-125b, hsa-miR-145, hsa-miR-149, hsa-miR-181b, hsa-miR-184, hsa-miR-205, hsa-miR-221, hsa-miR-222) were downregulated and 5 miRNAs (hsa-miR-96, hsa-miR-182, hsa-miR-182, hsa-miR-183, hsa-375) were upregulated. Expression of 5 miRNAs correlated with Gleason score or pathological tumor stage. Already 2 microRNAs classified up to 84% of malignant and nonmalignant samples correctly. Expression of hsa-miR-96 was associated with cancer recurrence after radical prostatectomy and that prognostic information was confirmed by an independent tumor sample set from 79 patients. That was shown with hsa-miR-96 and the Gleason score as final variables in the Cox models build in the 2 patient sets investigated. Thus, differential miRNAs in prostate cancer are useful diagnostic and prognostic indicators. This study provides a solid basis for further functional analyses of miRNAs in prostate cancer.

Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort.

The majority of prostate cancers harbor recurrent gene fusions between the hormone-regulated TMPRSS2 and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERG rearrangements represent a distinct sub-class of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and gene expression signatures. This study describes the frequency of ERG rearrangement prostate cancer and three 5 prime (5') gene fusion partners (ie, TMPRSS2, SLC45A3, and NDRG1) in a large prostatectomy cohort. ERG gene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3, and NDRG1, were assessed using fluorescence in situ hybridization (FISH) on prostate cancer samples from 614 patients treated using radical prostatectomy. ERG rearrangement occurred in 53% of the 540 assessable cases. TMPRSS2 and SLC45A3 were the only 5' partner in 78% and 6% of these ERG rearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases showed concurrent TMPRSS2 and SLC45A3 rearrangements. TMPRSS2 or SLC45A3 rearrangements could not be identified for 5% of the ERG rearranged cases. From these remaining cases we identified one case with NDRG1 rearrangement. We did not observe any associations with pathologic parameters or clinical outcome. This is the first study to describe the frequency of SLC45A3-ERG fusions in a large clinical cohort. Most studies have assumed that all ERG rearranged prostate cancers harbor TMPRSS2-ERG fusions. This is also the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus, suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearranged prostate cancer. Incorporation of these less common ERG rearranged prostate cancer fusion assays could further increase the sensitivity of the current PCR-based approaches.

Prostate specific antigen density to predict prostate cancer upgrading in a contemporary radical prostatectomy series: a single center experience.

PURPOSE: We investigated the value of pretreatment prostate specific antigen density to predict Gleason score upgrading in light of significant changes in grading routine in the last 2 decades. MATERIALS AND METHODS: Of 1,061 consecutive men who underwent radical prostatectomy between 1999 and 2004, 843 were eligible for study. Prostate specific antigen density was calculated and a cutoff for highest accuracy to predict Gleason upgrading was determined using ROC curve analysis. The predictive accuracy of prostate specific antigen and prostate specific antigen density to predict Gleason upgrading was evaluated using ROC curve analysis based on predicted probabilities from logistic regression models. RESULTS: Prostate specific antigen and prostate specific antigen density predicted Gleason upgrading on univariate analysis (as continuous variables OR 1.07 and 7.21, each p <0.001) and on multivariate analysis (as continuous variables with prostate specific antigen density adjusted for prostate specific antigen OR 1.07, p <0.001 and OR 4.89, p = 0.037, respectively). When prostate specific antigen density was added to the model including prostate specific antigen and other Gleason upgrading predictors, prostate specific antigen lost its predictive value (OR 1.02, p = 0.423), while prostate specific antigen density remained an independent predictor (OR 4.89, p = 0.037). Prostate specific antigen density was more accurate than prostate specific antigen to predict Gleason upgrading (AUC 0.61 vs 0.57, p = 0.030). CONCLUSIONS: Prostate specific antigen density is a significant independent predictor of Gleason upgrading even when accounting for prostate specific antigen. This could be especially important in patients with low risk prostate cancer who seek less invasive therapy such as active surveillance since potentially life threatening disease may be underestimated. Further studies are warranted to help evaluate the role of prostate specific antigen density in Gleason upgrading and its significance for biochemical outcome.