A comparison of magnetic resonance imaging techniques used to secure biopsies in prostate cancer patients

Introduction: Prostate cancer (PCa) is the most common diagnosed malignancy among the male population in the United States. The incidence is increasing with an estimated amount of 175.000 cases in 2019.

Areas covered: Primarily, PCa is generally detected by an elevated or rising serum prostate-specific antigen (PSA) and digital rectal examination (DRE) followed by pathological examination. Histopathology ultimately confirms the presence of PCa and determines a Gleason score. However, PSA and DRE have low specificity and sensitivity, respectively. Subsequently, accurate assessment of the aggressiveness of PCa is essential to prevent overdiagnosis and thus overtreatment of low-risk or indolent cancers. By visualizing PCa suspicious lesions and sampling them during the targeted biopsy, it is likely that the diagnostic accuracy of significant PCa improves. This article reviews the current imaging techniques used to secure biopsies in patients with a suspicion of PCa. The advantages and limitations of each technique are described.

Expert opinion: Multiparametric magnetic resonance imaging (mpMRI) and subsequent-targeted biopsy have improved the diagnostic accuracy of PCa detection in men with an elevated or rising serum PSA. Prostate lesions visible on mpMRI are easily targeted during either in-bore MRI-guided biopsy, cognitive fusion biopsy or MRI-TRUS fusion biopsy.     

Prostate-specific antigen screening,why have the guidelines changed?

Prostate cancer (PCa) constitutes a major health issue of the western world given its increasing rate of diagnosis and the fact that it is the second cause of cancer-related death among men. Although the incidence of PCa is rising, deaths from PCa are at the same time declining. This phenomenon has been largely attributed to the implementation of PCa screening. However PCa screening, which is mainly performed through serum prostate-specific antigen measurement, does not have the desired diagnostic accuracy. This results in a substantial proportion of men undergoing unnecessary biopsies and consequently given therapies for low-risk cancers that will have no effect in prolonging life and might as well only add morbidity. The current report will discuss the pros and cons of PCa screening in light of the recent modifications in the guidelines regarding the early diagnosis of PCa.     

The time-resolved fluorescence-based PCA3 test on urinary sediments after digital rectal examination; a Dutch multicenter validation of the diagnostic performance.

PURPOSE: To improve the specificity in prostate cancer diagnosis and to prevent unnecessary prostate biopsies, especially in the serum prostate-specific antigen (PSA) "gray zone" between 3 and 15 ng/mL, the implementation of prostate cancer-specific markers is urgently needed. The recently discovered prostate cancer antigen 3 (PCA3) is such a promising prostate cancer marker. In a previous single institution study, the PCA3 urine test clearly proved to be of diagnostic value. Therefore, the diagnostic performance of the PCA3 urine test was validated in a multicenter study. EXPERIMENTAL DESIGN: The first voided urine after digital rectal examination was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/mL who were to undergo prostate biopsies. We determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies. RESULTS: A total of 534 men (92%) had an informative sample. The area under the receiver-operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65%, the specificity was 66% (versus 47% for serum PSA), and the negative predictive value was 80%. CONCLUSIONS: In this multicenter study, we validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test. This study shows that the PCA3 urine test, when used as a reflex test, can improve the specificity in prostate cancer diagnosis and could prevent many unnecessary prostate biopsies.     

sE-cadherin serves as a diagnostic and predictive parameter in prostate cancer patients

Background

Measurement of prostate-specific antigen (PSA) advanced the diagnostic and prognostic potential for prostate cancer (PCa). However, due to PSA’s lack of specificity, novel biomarkers are needed to improve risk assessment and ensure optimal personalized therapy. A set of protein molecules as potential biomarkers was therefore evaluated in serum of PCa patients.

Methods

Serum samples from patients undergoing radical prostatectomy (RPE) for biopsy-proven PCa without neoadjuvant treatment were compared to serum samples from healthy subjects. Preliminary screening of 119 proteins in 10 PCa patients and 10 controls was carried out by the Proteome Profiler Antibody Array. Those markers showing distinct differences between patients and controls were then further evaluated by ELISA in the serum of 165 PCa patients and 19 controls. Uni- and multivariate as well as correlation analysis were performed to test the capability of these molecules to detect disease and predict pathological outcome.

Results

Screening showed that soluble (s)E-cadherin, E-selectin, MMP2, MMP9, TIMP1, TIMP2, Galectin and Clusterin warranted further evaluation. sE-Cadherin, TIMP1, Galectin and Clusterin were significantly over- and MMP9 under-expressed in PCa compared to controls. The concentration of sE-cadherin, MMP2 and Clusterin correlated negatively and that of MMP9 and TIMP1 positively with the Gleason Sum at prostatectomy. Only sE-cadherin significantly correlated with the highest Gleason pattern. Compared to serum PSA, sE-cadherin provided an independent and better matching predictive ability for discriminating PCas with an upgrade at RPE and aggressive tumors with a Gleason Sum ≥7.

Conclusions

sE-cadherin performed most favorably from a large panel of serum proteins in terms of diagnostic and predictive potential in curatively treatable PCa. sE-cadherin merits further investigation as a biomarker for PCa.     

The clinical utility of measuring total PSA, PSA density, gamma-seminoprotein and gamma-seminoprotein/total PSA in prostate cancer prediction

BACKGROUND: To evaluate whether serum total prostate-specific antigen (PSA), PSA density (serum total PSA level divided by prostate volume), gamma-seminoprotein and gamma-seminoprotein/total PSA ratio could predict prostate cancer (PCa) prior to biopsy. METHODS: A total of 316 consecutive patients who had undergone transrectal prostate biopsy and/or transurethral resection were examined. The prostate volume was determined by transrectal ultrasonography (TRUS) and the ability of the above-mentioned four variables to distinguish PCa from benign prostatic hyperplasia (BPH) was evaluated. RESULTS: PCa was detected in 61 cases. Receiver-operating characteristic (ROC) analysis revealed that both the PSA density and serum total PSA were the most useful predictors of PCa among the four variables. For the patients with a serum total PSA level of 4.1-10.0 ng/ml, PSA density was significantly more accurate than total PSA (p < 0.005). An optimum PSA density value of 0.18 was chosen as a cutoff because it showed the highest sum of sensitivity and specificity, 92 and 54%, respectively. Using this PSA density cutoff, the number of biopsies could have been reduced to 57 from 63% when compared with a PSA density of 0.15. CONCLUSIONS: PSA density was significantly more accurate than other variables in predicting PCa. To avoid unnecessary biopsies, the PSA density cutoff value of 0.18 would be recommendable for determining a prostate biopsy for Japanese males with a serum total PSA level of 4.1-10.0 ng/ml.     

Should men with serum prostate-specific antigen < or =4 ng/ml and normal digital rectal examination undergo a prostate biopsy? A literature review

The clinical significance of a prostate cancer (PCa) cannot be determined solely by tumor volume (< or =0.5 cm(3)), as small tumors of higher Gleason grade and tumors occurring in younger men may become clinically significant even though the initial volume at diagnosis is small. A certain number of these minimal cancers are likely to remain clinically insignificant; however, it is unpredictable how many can progress beyond the curable stage by the time there is a rise in serum prostate-specific antigen (PSA) values. Compared to clinically detected PCa, PCa detected exclusively by PSA screening (clinical stage T1c) are less likely to be advanced but no more likely to be insignificant in terms of volume, pathologic stage, and Gleason pattern. Only 10-15% of PSA-detected cancers have the features of PCa found at autopsy or in cystoprostatectomy specimens. Actually, 25-30% of PCa are detected with PSA values between 2.5 and 4 ng/ml, and most of these cancers are clinically significant. Evidence from both retrospective and longitudinal studies has shown that the risk of a PCa is dependent on the patient's age and the initial serum PSA. This allows an individualized approach to PCa screening programs, and PSA cutoff values for biopsy indication may be lowered in selected patients.     

Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.

PURPOSE: Patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis. One effective strategy likely to improve the morbidity and mortality from pancreatic cancer would be the identification of accurate, noninvasive diagnostic markers that would enable earlier diagnosis of symptomatic patients and earlier detection of cancer in asymptomatic individuals at high risk for developing pancreatic cancer. In this study, we evaluated serum macrophage inhibitory cytokine-1 (MIC-1) as a marker of pancreatic cancer. EXPERIMENTAL DESIGN: MIC-1 expression in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines was determined using the National Center for Biotechnology Information serial analysis of gene expression database, oligonucleotide microarrays analysis, in situ hybridization, and immunohistochemistry. Serum MIC-1 levels were determined by ELISA in 80 patients with pancreatic adenocarcinomas, in 30 patients with ampullary and cholangiocellular carcinomas, in 42 patients with benign pancreatic tumors, in 76 patients with chronic pancreatitis, and in 97 healthy control subjects. The diagnostic performance of serum MIC-1 as a marker of pancreatic cancer was compared with that of serum CA19-9. RESULTS: Oligonucleotide microarray and serial analysis of gene expression data demonstrated that MIC-1 RNA levels were higher in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines than in nonneoplastic pancreatic ductal epithelium. MIC-1 expression was localized to the malignant epithelium in pancreatic adenocarcinomas by in situ hybridization. MIC-1 protein was expressed in 14 of 16 primary pancreatic adenocarcinomas (88%) by immunohistochemistry and was also expressed in some pancreata affected by pancreatitis but not in normal pancreas. Serum MIC-1 levels were significantly higher in patients with pancreatic ductal adenocarcinoma (mean +/- SD, 2428 +/- 2324 pg/ml) and in patients with ampullary and cholangiocellular carcinomas (2123 +/- 2387 pg/ml) than in those with benign pancreatic neoplasms (940 +/- 469 pg/ml), chronic pancreatitis (1364 +/- 1236 pg/ml), or in healthy controls (546 +/- 262 pg/ml). An elevated serum MIC-1 (defined as 2 SD above the mean for healthy controls) performed as well as CA19-9 (area under the receiver operating characteristic curve, 0.81 and 0.77, respectively), and the combination of MIC-1 and CA19-9 significantly improved diagnostic accuracy (P < 0.05; area under the receiver operating characteristic curve, 0.87; sensitivity, 70%; specificity, 85%). CONCLUSION: Serum MIC-1 measurement can aid in the diagnosis of pancreatic adenocarcinoma.     

Application of Urinary Volatile Organic Compounds (VOCs) for the Diagnosis of Prostate Cancer

BackgroundProstate cancer (PCa) screening using serum prostate-specific antigen (PSA) testing has caused unnecessary biopsies and overdiagnosis owing to its low accuracy and reliability. Therefore, there is an increased interest in identifying better PCa biomarkers. Studies showed that trained dogs can discriminate patients with PCa from unaffected men by sniffing urine. We hypothesized that urinary volatile organic compounds (VOCs) may be the source of that odor and could be used to develop urinary VOC PCa diagnosis models.Patients and MethodsUrine samples from 55 and 53 biopsy proven PCa-positive and -negative patients respectively were initially obtained for diagnostic model development. Urinary metabolites were analyzed by gas chromatography-mass spectrometry. A PCa diagnosis model was developed and validated using innovative statistical machine-learning techniques. A second set of samples (53 PCa-positive and 22 PCa-negative patients) were used to evaluate the previously developed PCa diagnosis model.ResultsThe analysis resulted in 254 and 282 VOCs for their significant association (P < .05) with either PCa-positive or -negative samples respectively. Regularized logistic regression analysis and the Firth method were then applied to predict PCa prevalence, resulting in a final model that contains 11 VOCs. Under cross-validation, the area under the receiver operating characteristic curve (AUC) for the final model was 0.92 (sensitivity, 0.96; specificity, 0.80). Further evaluation of the developed model using a testing cohort yielded an AUC of 0.86. As a comparison, the PSA-based diagnosis model only rendered an AUC of 0.54.ConclusionThe study describes the development of a urinary VOC-based model for PCa detection.     

Detection of prostate cancer with a blood-based assay for early prostate cancer antigen

Prostate-specific antigen lacks specificity for prostate cancer, so the identification and characterization of a unique blood-based marker for the disease would provide for a more accurate diagnosis, reducing both unnecessary biopsies and patient uncertainty. We previously identified a novel biomarker for prostate cancer, early prostate cancer antigen (EPCA). EPCA antibodies positively stained the negative biopsies of men who, as much as 5 years later, were diagnosed with prostate cancer. The goal of this study was to determine whether EPCA antibodies could be used in a clinically applicable plasma-based immunoassay to specifically detect prostate cancer. Using an EPCA-based ELISA, the protein was measured in the plasma of 46 individuals, including prostate cancer patients, healthy individuals, other cancer patients, spinal cord injury victims, and patients with prostatitis. With a predetermined cutoff value of 1.7 absorbance at 450 nm, only the prostate cancer population, as a whole, expressed plasma-EPCA levels above the cutoff. Statistical analysis showed a significant difference in EPCA levels between the prostate cancer population and each of the other groups, specifically the healthy donors (P < 0.0001), bladder cancer patients (P = 0.03), and spinal cord injury patients (P = 0.001). Sensitivity of the EPCA assay for prostate cancer patients was 92% whereas the overall specificity was 94%. Specificity for the healthy donors was 100%. Although larger trials are required, this initial study shows the potential of EPCA to serve as a highly specific blood-based marker for prostate cancer. EPCA, when coupled with prostate-specific antigen, may help reduce the number of both unnecessary biopsies and undetected prostate tumors.     

Identification of specific DNA methylation sites on the Y-chromosome as biomarker in prostate cancer

As a diagnostic biomarker, prostate special antigen (PSA) tests always generate false positive results and lead to unnecessary and/or repeat biopsies. Therefore, there is an urgent need for developing more sensitive, specific diagnostic biomarkers. We epigenotyped methylated sites in cancer tissues and adjacent normal tissues from 66 patients. In comparation with normal adjacent tissues, we observed that there were 6 aberrant methylation sites in prostate cancer tissues on the Y-chromosome. We further performed pyrosequencing using urine of PCa patients and we identified one methylated site (cg05163709) as a potential biomarker. We evaluated the predictive capacity of the aberrant methylated sites using the area under receiver operating characteristic (ROC) curve (AUC). The ROC analysis showed a higher AUC for cg05163709 (0.915) than prostate-specific antigen (PSA, 0.769). These results indicated that aberrant DNA methylation of cg05163709 on the Y-chromosome could serve as a potential diagnostic biomarker with high sensitivity and specificity.     

Diagnostic Efficacy of PSMA and PSCA mRNAs Combined to PSA in Prostate Cancer Patients

Background: Serum Prostate-specific antigen (PSA) has been used for screening and diagnosis of prostate cancer (PCa) but it is burdened by its low accuracy, creating a need for reliable diagnostic markers. Despite prostate-specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) being widely expressed in the tissue of PCa, no definite conclusion regarding their use as clinical biomarkers due to their lacking organ specificity. Therefore, this study aimed to evaluate the peripheral blood levels of PSMA and PSCA mRNAs and examine their diagnostic significance as non-invasive integrated markers.Materials and Methods: 125 subjects were enrolled in this study. They were divided into 25 healthy controls, 25 BPH patients, and 75 PCa patients. The expression levels of PSMA and PSCA were determined using quantitative RT- PCR, in addition to measuring serum PSA.Results: Levels of PSMA and PSCA were over-expressed in PCa patients compared to controls and BPH patients and were found to be associated with increased susceptibility to PCa. Moreover, the diagnostic values of PSMA and PSCA to distinguish PCa patients from BPH patients and controls were inferior to that of PSA. However, the combination of PSMA and PSCA with PSA enhanced the efficacy of the latter.Conclusion: This study suggests that these genes were associated with malignant susceptibility. Concerning the duality of PSMA-PSA or PSCA-PSA, this implies the significance of their investigation together in peripheral blood of prostate patients.     

Galectin-3: a possible complementary marker to the PSA blood test

The prostate-specific antigen (PSA) test has served as a blood marker of prostate cancer (PCa), and for monitoring recurrence/metastasis in patients after therapeutic intervention. However, the applicability/reliability of the PSA test was recently questioned as it is not without challenges, in particular in men who have PCa without an elevated PSA (false negative), or in men who are disease-free with elevated levels of PSA (false positive). Galectin-3 is a tumor-associated protein; present in the seminal fluid and is a substrate for the PSA enzyme e.g., a chymotrypsin-like serine protease. We hypothesized that the cleavage status and level of galectin-3 in the prostate tissue and sera are associated with PCa. Thus, we compared galectin-3 levels obtained from sera of non-cancer urology patients to those of metastatic PCa patients. The data were confirmed by analyzing PCa tissue arrays. Here, we report that galectin-3 levels in the sera of patients with metastatic PCa were uniformly higher as compared to the non-cancer patient controls. The data suggest that galectin-3 serum level may be a useful serum complementary marker to the PSA blood test to be used for initial and follow-up PSA complimentary diagnostic/prognostic tool for recurrence in PCa patients.     

Molecular forms of prostate‐specific antigen in serum with concentrations of total prostate‐specific antigen <4 μg/L: Are they useful tools for early detection and screening of prostate cancer?

Molecular forms of prostate-specific antigen (PSA) improve the differentiation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) in men with total PSA concentrations between 4 and 10 microg/l. To evaluate the diagnostic utility of free PSA (fPSA) and complexed PSA forms for identification of men with PCa in the low PSA range of <4 microg/l, total PSA (tPSA), alpha(1)-antichymotrypsin complexed PSA (PSA-ACT) and fPSA (Roche Elecsys [ES] system) as well as tPSA and complexed PSA (cPSA) (Bayer Immuno 1 system) were measured in archival serum samples from 31 untreated patients with PCa, 66 patients with BPH, and 90 men without prostatic disease. The median ratios of fPSA/tPSA, PSA-ACT/tPSA and cPSA/tPSA were significantly different between patients with BPH and PCa (27.2 vs. 19.4%, 64 vs. 88%, 77.2 vs. 88.2%, p < 0.05). No associations between PSA forms and tumor stage and grade were found. Analysis of the receiver operating characteristic curves showed that these ratios could discriminate better between BPH and PCa patients than determination of the analytes tPSA, fPSA, cPSA and PSA-ACT alone. The use of one of the ratios would have eliminated roughly half of the unnecessary biopsies in this study. The ratios should be considered as potential tools to increase the selectivity of PCa detection at low PSA concentration. The ratios fPSA/tPSA and cPSA/tPSA can be determined using commercially available assays so that one of these ratios could be preferred instead of PSA-ACT determination. The ratios could be useful in assessing the risk of PCa in the individual and therefore in deciding on prostate biopsy for final diagnosis.     

Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases.

Macrophage-inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor beta superfamily. It is up-regulated by nonsteroidal anti-inflammatory drugs and is highly expressed in human prostate cancer leading to high serum MIC-1 concentrations with advanced disease. A role for MIC-1 has been implicated in the process of early bone formation, suggesting that it may also mediate sclerosis at the site of prostate cancer bone metastases. Consequently, the aim of this study was to retrospectively determine the relationship of serum MIC-1 concentration and other markers related to current and future prostate cancer bone metastasis in a cohort of 159 patients with prostate cancer. Serum markers included cross-linked carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and amino-terminal propeptide of type I procollagen (PINP). The mean values of all the biomarkers studied were significantly higher in patients with baseline bone metastases (BM+, n = 35), when compared with those without bone metastases (BM-, n = 124). In a multivariate logistic model, both MIC-1 and PINP independently predicted the presence of baseline bone metastasis. Based on receiver operator curve analysis, the best predictor for the presence of baseline bone metastasis was MIC-1, which was significantly better than carboxy-terminal telopeptide of type I collagen, prostate-specific antigen, and PINP. Patients who experienced bone relapse had significantly higher levels of baseline MIC-1 compared with patients who did not (1476.7 versus 988.4; P = 0.03). Current use of acetylsalicylic acid did not influence serum MIC-1 levels in this cohort. Although requiring validation prospectively, these results suggest that serum MIC-1 determination may be a valuable tool for the diagnosis of current and future bone metastases in patients with prostate cancer.     

Urinary exosomal prostate-specific antigen is a noninvasive biomarker to detect prostate cancer: Not only old wine in new bottles

The study aimed at evaluating the performance of urinary exosomal prostate-specific antigen (UE-PSA) to predict the results of initial prostate biopsies and discriminate clinically significant prostate cancer (Gleason score ≥ 7, csPCa) from nonsignificant PCa (Gleason score < 7, nsPCa) plus benign patients. Two hundred seventy-two consecutive participants were admitted who underwent a prostate biopsy. The UE-PSA expression was detected by enzyme-linked immunosorbent assay (ELISA). The predictive power and clinical value of UE-PSA was assessed by receiver operating characteristic (ROC), decision curve analysis (DCA) and waterfall plots. UE-PSA was upregulated in PCa compared to benign patients (P < .001) and csPCa compared to nsPCa plus benign patients (P < .001). UE-PSA achieved an AUC of 0.953 (0.905-0.989) in distinguishing PCa from benign patients and an AUC of 0.879 (0.808-0.941) in predicting csPCa from nsPCa plus benign patients. These results were validated in an additional multicenter cohort. In addition, DCA showed that UE-PSA achieved the highest net benefit at almost any threshold probability compared to tPSA and %fPSA. As the waterfall plot showed, the UE-PSA assay could avoid 57.6% (155 cases) and 34.6% (93 cases) unnecessary biopsies while only missing 2.6% (7 cases) and 1.5% (4 cases) of the cases of csPCa at the cutoff value of 90% and 95% sensitivity, respectively. We validated that UE-PSA presented great diagnostic power and clinical utility to diagnose PCa and csPCa. UE-PSA could be a promising noninvasive biomarker to improve PCa detection.     

Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues

Macrophage inhibitory cytokine-1 (MIC-1) gene is a member of transforming growth factor-beta superfamily and was reported to be highly overexpressed in human prostate cancer using microarray technology. The aim of this study was to evaluate the quantitative expression of MIC-1 in malignant and benign prostate tissues and to associate expression levels with clinicopathological parameters of prostate cancer. Matched (paired) prostatic tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 66 patients who underwent radical prostatectomy. Quantitative RT-PCR was performed using SYBR Green I on the Roche LightCycler system. Macrophage inhibitory cytokine-1 gene overexpression in cancerous tissues was observed in 88% of cases, compared to noncancerous tissues (P<0.001). The expression level of MIC-1 in cancerous tissues was significantly higher than in noncancerous tissue (P<0.001). Higher expression of MIC-1 gene was significantly associated with higher Gleason score (P=0.004). The expression of the MIC-1 gene in prostate cancer is significantly higher than in noncancerous tissues, especially in more aggressive forms of the disease (Gleason score>5). This is in contrast to prostate-specific antigen that is downregulated in higher-grade tumours. The upregulation of MIC-1 in prostate cancer and in advanced and more aggressive prostatic tumours suggests that MIC-1 protein should be evaluated as a potential diagnostic and prognostic biomarker.     

Critical assessment of tools to predict clinically insignificant prostate cancer at radical prostatectomy in contemporary men

BACKGROUND: Overtreatment of prostate cancer (PCa) is a concern, especially in patients who might qualify for the diagnosis of insignificant prostate cancer (IPCa). The ability to identify IPCa prior to definitive therapy was tested. METHODS: In a cohort of 1132 men a nomogram was developed to predict the probability of IPCa. Predictors consisted of prostate-specific antigen (PSA), clinical stage, biopsy Gleason sum, core cancer length and percentage of positive biopsy cores (percent positive cores). IPCa was defined as organ-confined PCa (OC) with tumor volume (TV) <0.5 cc and without Gleason 4 or 5 patterns. Finally, an external validation of the most accurate IPCa nomogram was performed in the same group. RESULTS: IPCa was pathologically confirmed in 65 (5.7%) men. The 200 bootstrap-corrected predictive accuracy of the new nomogram was 90% versus 81% for the older nomogram. However, in cutoff-based analyses of patients who were qualified by our and the older nomograms as high probability for IPCa, respectively 63% and 45% harbored aggressive PCa variants at radical prostatectomy (Gleason score 7-10, ECE, SVI, and/or LNI). CONCLUSIONS: Despite a high accuracy, currently available models for prediction of IPCa are incorrect in 10% to 20% of predictions. The rate of misclassification is even further inflated when specific cutoffs are used. As a consequence, extreme caution is advised when statistical tools are used to assign the diagnosis of IPCa.     

Diagnostic Role of Serum Free-to-Total Prostate Specific Antigen (PSA) Ratio in Prostate Cancer with Serum Total Concentration of PSA below 4 ng/mL

Purpose: To examine the effectiveness of serum free-to-total prostate specific antigen ratio (%fPSA) forthe detection of prostate cancer (PCa) in men with different serum total PSA (tPSA) categories. Materials andMethods: From January 2010 to December 2013, a total of 225 patients with lower urinary tract symptoms(LUTS) underwent tPSA and %fPSA measurements. Histological examination with calculation of Gleasonscore and whole body bone scans were performed in identified cases of PCa. Results: PCa was diagnosed in 44(19.6%) patients and the remaining 181 patients had benign prostate disease. PCa was detected in 5 (23.8%),13 (8.7%) and 26 (47.3%) cases with tPSA level ranges ≤4 ng/ml, 4 to 10 ng/ml and >10 ng/ml, respectively. Theaverage Gleason score was 7.2±0.2. Some 6 (13.6%) out of 44 PCa patients had bone metastases. The sensitivitywas 80% and specificity was 81.3% at the cut-off %fPSA of 15% in PCa patients with a tPSA level below 4 ng/mL. A lower %fPSA was associated with PCa patients with Gleason score ≥7 than those with Gleason score≤6 (11.7±0.98 vs. 16.5±2.25%, P=0.029). No obvious relation of %fPSA to the incidence of bone metastasis wasapparent in this study. Conclusions: The clinical application of %fPSA could help to discriminate PCa frombenign prostate disease in men with a tPSA concentration below 4 ng/mL.     

Different phenotypes in human prostate cancer: alpha6 or alpha3 integrin in cell-extracellular adhesion sites

The distribution of alpha6/alpha3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized alpha6/alpha3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The alpha6/alpha3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate-specific antigen (PSA). The associations were assessed by statistical methods. Eighty percent of the tumors expressed the alpha6 or alpha3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both alpha6 and alpha3 subunits, type II exclusively expressed alpha6 integrin, and type III expressed alpha3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The alpha6/alpha3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, alpha6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the alpha6 subunit did not colocalize with the alpha subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the alpha6beta1 and/or alpha3beta1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.