Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation and alterations in DNA repair: implications for therapeutic strategies.

BACKGROUND: Androgen signalling remains the seminal therapeutic approach for the management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells. METHODS: Using shRNA-mediated PDE4D7 knockdown in LNCaP cells and downstream analysis via RNA sequencing and phenotypic assays, we replicate clinical observations that diminished PDE4D7 expression promotes an aggressive prostate cancer phenotype. RESULTS: Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. In addition, we demonstrate that PDE4D7 loss affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors. CONCLUSION: Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.

Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer.

BACKGROUND: Revealing molecular mechanisms linked to androgen receptor activity can help to improve diagnosis and treatment of prostate cancer. Retinoic acid-induced 2 (RAI2) protein is thought to act as a transcriptional coregulator involved in hormonal responses and epithelial differentiation. We evaluated the clinical relevance and biological function of the RAI2 protein in prostate cancer. METHODS: We assessed RAI2 gene expression in the Cancer Genome Atlas prostate adenocarcinoma PanCancer cohort and protein expression in primary tumors (n = 199) by immunohistochemistry. We studied RAI2 gene expression as part of a multimarker panel in an enriched circulating tumor cell population isolated from blood samples (n = 38) of patients with metastatic prostate cancer. In prostate cancer cell lines, we analyzed the consequences of androgen receptor inhibition on RAI2 protein expression and the consequences of RAI2 depletion on the expression of the androgen receptor and selected target genes. RESULTS: Abundance of the RAI2 protein in adenocarcinomas correlated with the androgen receptor; keratins 8, 18, and 19; and E-cadherin as well as with an early biochemical recurrence. In circulating tumor cells, detection of RAI2 mRNA significantly correlated with gene expression of FOLH1, KLK3, RAI2, AR, and AR-V7. In VCaP and LNCaP cell lines, sustained inhibition of hormone receptor activity induced the RAI2 protein, whereas RAI2 depletion augmented the expression of MME, STEAP4, and WIPI1. CONCLUSIONS: The RAI2 protein functions as a transcriptional coregulator of the androgen response in prostate cancer cells. Detection of RAI2 gene expression in blood samples from patients with metastatic prostate cancer indicated the presence of circulating tumor cells.

The prognostic potential of alkaline phosphatase and lactic acid dehydrogenase in bmCRPC patients without significant PSA response under enzalutamide.

BACKGROUND: In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. METHODS: Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. RESULTS: In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). CONCLUSIONS: Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.

Specific spatial distribution patterns of tumor foci are associated with a low risk of biochemical recurrence in pT2pN0R0 prostate cancer.

BACKGROUND: The previous attempts for pT2 substaging of prostate cancer (PCa) were insufficient in providing prognostic subgroups and the search for new prognostic parameters to subcategorize pT2 PCa is, therefore, needed. Therefore, the current study investigated the association between tumor distribution patterns and the biochemical recurrence (BCR)-free survival rate in pT2pN0R0 PCa. METHODS: Following radical prostatectomy, the anatomical distribution of PCa in 743 men with pT1-pT3pN0 disease was analyzed to determine 20 types of PCa distribution patterns. Then, 245 men with pT2pN0R0 PCa was considered for prognostic evaluation with a mean follow-up period of 60 months. The spatial distribution patterns of PCa were evaluated using a cMDX©-based map model of the prostate. An analysis including 552,049 comparison operations was performed to assist in the evaluation of the similarity levels of the distribution patterns. A k-mean cluster analysis was applied to determine groups with similar distribution patterns. A decision-tree analysis was performed to divide these groups according to frequency of BCR. The BCR-free survival rate was analyzed using Kaplan-Meier curves. Predictors of progression were investigated using a Cox proportional hazards model. RESULTS: BCR occurred in 8.2% of the 245 men with pT2pN0R0 PCa. The median time of recurrence was 60 months (interquartile range [IQR]: 42-77). In univariate and multivariate analyses, the prostate volume and the distribution patterns were independent predictors for BCR, whereas the sub-staging of pT2 tumors, Gleason grading, prostate-specific antigen (PSA) level, and relative tumor volume were not. In the patients with pT2pN0R0 disease, PCa distribution patterns with the apical involvement were significantly associated with the risk of BCR (P = 0.001). CONCLUSION: The spread tumor patterns with the apical involvement are associated with a high-risk of BCR in the pT2 tumor stage. The vertical tumor spread could be considered in developing improved prognostic pT2 sub-categories.

EGFR as a stable marker of prostate cancer dissemination to bones.

BACKGROUND: Prostate cancer (PCa) is among the most commonly diagnosed malignancies in men. Although 5-year survival in patients with localised disease reaches nearly 100%, metastatic disease still remains incurable. Therefore, there is a need for markers indicating metastatic dissemination. METHODS: EGFR overexpression (EGFRover) was tracked in 1039 primary tumours, circulating tumour cells from 39 d'Amico high-risk patients and metastatic samples from 21 castration-resistant PCa cases. EGFR status was compared to clinical parameters and multiple molecular factors were assessed using immunohistochemistry and gene ontology analysis. The functional aspect of EGFR was evaluated by plating PC-3 cells on soft and rigid matrices. RESULTS: EGFRover was found in 14% of primary tumours, where it was associated with shorter metastasis-free survival and was an independent indicator of worse overall survival. EGFRover correlated with a pro-migratory and pro-metastatic phenotype of tumour cells as well as rich collagen fibre content. All circulating tumour cells (detected in 13% of cases) were positive for EGFR, independent of their EMT-related phenotype. EGFRover was more prevalent in castration-resistant bone metastases (29% of patients) and supported growth of human PCa cells on rigid matrices mimicking bone stiffness. CONCLUSIONS: EGFRover is a stable, EMT-independent marker of PCa disseminating to rigid organs, preferentially bones.

Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer.

BRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumors. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors. BRCA1 gene dosage was assessed in 2398 tumor samples from 1,199 PCa patients using fluorescent in situ hybridization. It was compared to clinico-pathological parameters, patients' outcome as well as selected proteins (Ki-67, apoptosis marker, cytokeratins, vimentin, E- and N-cadherin, ALDH1 and EGFR) examined immunohistochemically. BRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T stage (p = 0.027), Gleason score (p = 0.039), shorter time to biochemical recurrence in patients with Gleason score > 7 independently of other factors (multivariate analysis, p = 0.005) as well as expression of proteins regulating stemness and epithelial-mesenchymal transition, that is, ALDH1 (p = 0.021) and EGFR (p = 0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p = 0.012) and expression of ALDH1 (p = 0.014). These results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell-like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain conceivably representing loss-of-function might mark more invasive tumors.

Blind Biobanking of the Prostatectomy Specimen: Critical Evaluation of the Existing Techniques and Development of the New 4-Level Tissue Extraction Model With High Sampling Efficacy.

BACKGROUND: Fresh tissue is mandatory to perform high-quality translation studies. Several models for tissue extraction from prostatectomy specimens without guidance by frozen sections are already introduced. However, little is known about the sampling efficacy of these models, which should provide representative tissue in adequate volumes, account for multifocality and heterogeneity of tumor, not violate the routine final pathological examination, and perform quickly without frozen section-based histological control. The aim of the study was to evaluate the sampling efficacy of the existing tissue extraction models without guidance by frozen sections ("blind") and to develop an optimized model for tissue extraction. METHODS: Five hundred thirty-three electronic maps of the tumor distribution in prostates from a single-center cohort of the patients subjected to radical prostatectomy were used for analysis. Six available models were evaluated in silico for their sampling efficacy. Additionally, a novel model achieving the best sampling efficacy was developed. RESULTS: The available models showed high efficacies for sampling "any part" from the tumor (up to 100%), but were uniformly low in efficacy to sample all tumor foci from the specimens (with the best technique sampling only 51.6% of the all tumor foci). The novel 4-level extraction model achieved a sampling efficacy of 93.1% for all tumor foci. CONCLUSIONS: The existing "blind" tissue extraction models from prostatectomy specimens without frozen sections control are suitable to target tumor tissues but these tissues do not represent the whole tumor. The novel 4-level model provides the highest sampling efficacy and a promising potential for integration into routine. Prostate 77: 396-405, 2017. © 2016 Wiley Periodicals, Inc.

The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone.

The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR <5 and 17 with NLR >5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9-2.8); p = 0.11). After multivariate adjustment (MVA), ECOG > 0-1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3-4.0); p < 0.01). In MVA, ECOG > 0-1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months) (HR: 4.1 (95%CI:1.1-15.8); p = 0.04). MVA showed a trend towards worse PFS for NLR-change to <5 (p = 0.11). NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months) (HR: 2.3 (95%CI:0.7-7.1); p = 0.15). MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.

Dynamic changes of alkaline phosphatase are strongly associated with PSA-decline and predict best clinical benefit earlier than PSA-changes under therapy with abiraterone acetate in bone metastatic castration resistant prostate cancer.

BACKGROUND: Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone. METHODS: Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. RESULTS: Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2-4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥ 50% and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥ 50% and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥ 50% remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone. CONCLUSIONS: Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned.

The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged ≤65 years.

OBJECTIVES: To prospectively test the diagnostic accuracy of the percentage of prostate specific antigen (PSA) isoform [-2]proPSA (%p2PSA) and the Prostate Health Index (PHI), and to determine their role for discrimination between significant and insignificant prostate cancer at initial and repeat prostate biopsy in men aged ≤65 years. PATIENTS AND METHODS: The diagnostic performance of %p2PSA and PHI were evaluated in a multicentre study. In all, 769 men aged ≤65 years scheduled for initial or repeat prostate biopsy were recruited in four sites based on a total PSA (t-PSA) level of 1.6-8.0 ng/mL World Health Organization (WHO) calibrated (2-10 ng/mL Hybritech-calibrated). Serum samples were measured for the concentration of t-PSA, free PSA (f-PSA) and p2PSA with Beckman Coulter immunoassays on Access-2 or DxI800 instruments. PHI was calculated as (p2PSA/f-PSA × âˆšt-PSA). Uni- and multivariable logistic regression models and an artificial neural network (ANN) were complemented by decision curve analysis (DCA). RESULTS: In univariate analysis %p2PSA and PHI were the best predictors of prostate cancer detection in all patients (area under the curve [AUC] 0.72 and 0.73, respectively), at initial (AUC 0.67 and 0.69) and repeat biopsy (AUC 0.74 and 0.74). t-PSA and %f-PSA performed less accurately for all patients (AUC 0.54 and 0.62). For detection of significant prostate cancer (based on Prostate Cancer Research International Active Surveillance [PRIAS] criteria) the %p2PSA and PHI equally demonstrated best performance (AUC 0.70 and 0.73) compared with t-PSA and %f-PSA (AUC 0.54 and 0.59). In multivariate analysis PHI we added to a base model of age, prostate volume, digital rectal examination, t-PSA and %f-PSA. PHI was strongest in predicting prostate cancer in all patients, at initial and repeat biopsy and for significant prostate cancer (AUC 0.73, 0.68, 0.78 and 0.72, respectively). In DCA for all patients the ANN showed the broadest threshold probability and best net benefit. PHI as single parameter and the base model + PHI were equivalent with threshold probability and net benefit nearing those of the ANN. For significant cancers the ANN was the strongest parameter in DCA. CONCLUSION: The present multicentre study showed that %p2PSA and PHI have a superior diagnostic performance for detecting prostate cancer in the PSA range of 1.6-8.0 ng/mL compared with t-PSA and %f-PSA at initial and repeat biopsy and for predicting significant prostate cancer in men aged ≤65 years. They are equally superior for counselling patients before biopsy.

Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study.

OBJECTIVE: To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies. PATIENTS AND METHODS: In the global Prostate cancer Research International: Active Surveillance (PRIAS) study, men are prospectively followed on AS and repeat prostate biopsies are scheduled at 1, 4, and 7 years after the diagnostic biopsy, or once yearly if prostate-specific antigen-doubling time is <10 years. Data on complications after biopsy, including infection, haematuria, haematospermia, and pain, were retrospectively collected for all biopsies taken during follow-up in men from several large participating centres. Generalised estimating equations were used to test predictors of infection after biopsy. Competing risk analysis was used to compare the rates of men receiving further biopsies between men with and without previous complications. RESULTS: In all, 2 184 biopsies were taken in 1 164 men. Infection was reported after 55 biopsies (2.5%), and one in five men reported any form of complication. At multivariable analysis, the number of previous biopsies was not a significant predictor of infection (odds ratio 1.04, 95% confidence interval 0.76-1.43). The only significant predictor for infection was the type of prophylaxis used. Of all men with a complication at the diagnostic or first repeat biopsy, 21% did not have a repeat biopsy at the time a repeat biopsy was scheduled according to protocol, vs 12% for men without a previous biopsy complication. CONCLUSION: In our present cohort of men on AS, we found no evidence that repeat prostate biopsy in itself posed a risk of infection. However, complications after biopsy were not uncommon and after a complication men were less likely to have further biopsies. We should aim to safely reduce the amount of repeat biopsies in men on AS.

Analysis of topographical distribution of prostate cancer and related pathological findings in prostatectomy specimens using cMDX document architecture.

INTRODUCTION: Understanding the topographical distribution of prostate cancer (PCa) foci is necessary to optimize the biopsy strategy. This study was done to develop a technical approach that facilitates the analysis of the topographical distribution of PCa foci and related pathological findings (i.e., Gleason score and foci dimensions) in prostatectomy specimens. MATERIAL & METHODS: The topographical distribution of PCa foci and related pathologic evaluations were documented using the cMDX documentation system. The project was performed in three steps. First, we analyzed the document architecture of cMDX, including textual and graphical information. Second, we developed a data model supporting the topographic analysis of PCa foci and related pathologic parameters. Finally, we retrospectively evaluated the analysis model in 168 consecutive prostatectomy specimens of men diagnosed with PCa who underwent total prostate removal. The distribution of PCa foci were analyzed and visualized in a heat map. The color depth of the heat map was reduced to 6 colors representing the PCa foci frequencies, using an image posterization effect. We randomly defined 9 regions in which the frequency of PCa foci and related pathologic findings were estimated. RESULTS: Evaluation of the spatial distribution of tumor foci according to Gleason score was enabled by using a filter function for the score, as defined by the user. PCa foci with Gleason score (Gls) 6 were identified in 67.3% of the patients, of which 55 (48.2%) also had PCa foci with Gls between 7 and 10. Of 1173 PCa foci, 557 had Gls 6, whereas 616 PCa foci had Gls>6. PCa foci with Gls 6 were mostly concentrated in the posterior part of the peripheral zone of the prostate, whereas PCa foci with Gls>6 extended toward the basal and anterior parts of the prostate. The mean size of PCa foci with Gls 6 was significantly lower than that of PCa with Gls>6 (P<0.0001). CONCLUSION: The cMDX-based technical approach facilitates analysis of the topographical distribution of PCa foci and related pathologic findings in prostatectomy specimens.

Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

Prostate cancers detected on repeat prostate biopsies show spatial distributions that differ from those detected on the initial biopsies.

OBJECTIVE: To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx). PATIENTS AND METHODS: We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated. RESULTS: Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion. CONCLUSIONS: The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.

Exploring prostate cancer genome reveals simultaneous losses of PTEN, FAS and PAPSS2 in patients with PSA recurrence after radical prostatectomy.

The multifocal nature of prostate cancer (PCa) creates a challenge to patients' outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients' clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0-9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients' PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2-10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2-10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy.

The need for harmonized structured documentation and chances of secondary use - results of a systematic analysis with automated form comparison for prostate and breast cancer.

INTRODUCTION: Medical documentation is a time-consuming task and there is a growing number of documentation requirements. In order to improve documentation, harmonization and standardization based on existing forms and medical concepts are needed. Systematic analysis of forms can contribute to standardization building upon new methods for automated comparison of forms. Objectives of this research are quantification and comparison of data elements for breast and prostate cancer to discover similarities, differences and reuse potential between documentation sets. In addition, common data elements for each entity should be identified by automated comparison of forms. MATERIALS AND METHODS: A collection of 57 forms regarding prostate and breast cancer from quality management, registries, clinical documentation of two university hospitals (Erlangen, Münster), research datasets, certification requirements and trial documentation were transformed into the Operational Data Model (ODM). These ODM-files were semantically enriched with concept codes and analyzed with the compareODM algorithm. Comparison results were aggregated and lists of common concepts were generated. Grid images, dendrograms and spider charts were used for illustration. RESULTS: Overall, 1008 data elements for prostate cancer and 1232 data elements for breast cancer were analyzed. Average routine documentation consists of 390 data elements per disease entity and site. Comparisons of forms identified up to 20 comparable data elements in cancer conference forms from both hospitals. Urology forms contain up to 53 comparable data elements with quality management and up to 21 with registry forms. Urology documentation of both hospitals contains up to 34 comparable items with international common data elements. Clinical documentation sets share up to 24 comparable data elements with trial documentation. Within clinical documentation administrative items are most common comparable items. Selected common medical concepts are contained in up to 16 forms. DISCUSSION: The amount of documentation for cancer patients is enormous. There is an urgent need for standardized structured single source documentation. Semantic annotation is time-consuming, but enables automated comparison between different form types, hospital sites and even languages. This approach can help to identify common data elements in medical documentation. Standardization of forms and building up forms on the basis of coding systems is desirable. Several comparable data elements within the analyzed forms demonstrate the harmonization potential, which would enable better data reuse. CONCLUSION: Identifying common data elements in medical forms from different settings with systematic and automated form comparison is feasible.

Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer.

Prostasomes are microvesicles (mean diameter, 150 nm) that are produced and secreted by normal and malignant prostate acinar cells. It has been hypothesized that invasive growth of malignant prostate cells may cause these microvesicles, normally released into seminal fluid, to appear in interstitial space and therewith into peripheral circulation. The suitability of prostasomes as blood biomarkers in patients with prostate cancer was tested by using an expanded variant of the proximity ligation assay (PLA). We developed an extremely sensitive and specific assay (4PLA) for detection of complex target structures such as microvesicles in which the target is first captured via an immobilized antibody and subsequently detected by using four other antibodies with attached DNA strands. The requirement for coincident binding by five antibodies to generate an amplifiable reporter results in both increased specificity and sensitivity. The assay successfully detected significantly elevated levels of prostasomes in blood samples from patients with prostate cancer before radical prostatectomy, compared with controls and men with benign biopsy results. The medians for prostasome levels in blood plasma of patients with prostate cancer were 2.5 to sevenfold higher compared with control samples in two independent studies, and the assay also distinguished patients with high and medium prostatectomy Gleason scores (8/9 and 7, respectively) from those with low score (≤ 6), thus reflecting disease aggressiveness. This approach that enables detection of prostasomes in peripheral blood may be useful for early diagnosis and assessment of prognosis in organ-confined prostate cancer.

Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology.

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

High-grade prostatic intraepithelial neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: existence of HGPIN near prostate cancer.

PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). MATERIALS AND METHODS: We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. RESULTS: Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. CONCLUSIONS: HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa.

Multicenter evaluation of [-2]proprostate-specific antigen and the prostate health index for detecting prostate cancer.

BACKGROUND: Total prostate-specific antigen (tPSA) is flawed for prostate cancer (PCa) detection. [-2]proprostate-specific antigen (p2PSA), a molecular isoform of free PSA (fPSA), shows higher specificity compared with tPSA or percentage of free PSA (%fPSA). The prostate health index (Phi), a measure based on p2PSA and calculated as p2PSA/fPSA × âˆštPSA, was evaluated in a multicenter study for detecting PCa. METHODS: A total of 1362 patients from 4 different study sites who had tPSA values of 1.6-8.0 µg/L (668 patients with PCa, 694 without PCa) underwent ≥10 core biopsies. Serum concentrations of tPSA, fPSA (both calibrated against a WHO reference material), and p2PSA were measured on Access2 or DxI800 analyzers (Beckman Coulter). RESULTS: The percentage ratio of p2PSA to fPSA (%p2PSA) and Phi were significantly higher in all PCa subcohorts (positive initial or repeat biopsy result or negative digital rectal examination) (P < 0.0001) compared with patients without PCa. Phi had the largest area under the ROC curve (AUC) (AUC = 0.74) and provided significantly better clinical performance for predicting PCa compared with %p2PSA (AUC = 0.72, P = 0.018), p2PSA (AUC = 0.63, P < 0.0001), %fPSA (AUC = 0.61) or tPSA (AUC = 0.56). Significantly higher median values of Phi were observed for patients with a Gleason score ≥7 (Phi = 60) compared with a Gleason score <7 (Phi = 53; P = 0.0018). The proportion of aggressive PCa (Gleason score ≥7) increased with the Phi score. CONCLUSIONS: The results of this multicenter study show that Phi, compared with tPSA or %fPSA, demonstrated superior clinical performance in detecting PCa at tPSA 1.6-8.0 µg/L (i.e., approximately 2-10 µg/L in traditional calibration) and is better able to detect aggressive PCa.