A new modification of the chiron ACS assay for total prostate-specific antigen achieves equimolar response characteristics and improves the detection of prostate cancer

Nonequimolar-response assays for prostate-specific antigen (PSA) are criticized for overestimating total PSA in some men without prostate cancer (PCA), and underestimating total PSA in some men with PCA. We recently studied three nonequimolar-response PSA assays that had undergone modifications. While two of the studied assays achieved equimolar-response characteristics with improved areas under receiver operating characteristic (ROC) curves (AUC), the modification of the Chiron ACS PSA assay (ACS PSA2, Chiron) failed to achieve this. Recently, the ACS assay underwent another modification (ACS PSA, Bayer), which we investigated. Sera from 305 men (155 without and 150 with PCA, PSA greater than or equal to2 and less than or equal to30 mug/l, TandemE) were measured using both modifications of the ACS assay and equimolar-response reference methods (TandemR free and Tandem E, Hybritech). Molar response relative to the reference method and clinical performance (comparison of AUCs) between the previous and new ACS assay modifications were studied. The new modification of the ACS assay (ACS PSA, Bayer) achieved equimolar-response characteristics but reported lower values (average 10%) than the Tandem E assay. Compared to the previous modification (ACS PSA2, Chiron), a 3% improvement in AUC (p=0.01) was found. Using results of the redesigned equimolar-response assay (ACS PSA, Bayer), we calculated that 6 of 155 men without PCA in this sample set could be spared unnecessary biopsy compared with the previous nonequimolar-response assay (ACS PSA2, Chiron) without missing additional PCA (90% sensitivity). These data provide additional evidence for clinical advantages of equimolar-response over nonequimolar-response PSA assay formats

HIS-based electronic documentation can significantly reduce the time from biopsy to final report for prostate tumours and supports quality management as well as clinical research

<p>Abstract</p> <p>Background</p> <p>Timely and accurate information is important to guide the medical treatment process. We developed, implemented and assessed an order-entry system to support documentation of prostate histologies involving urologists, pathologists and physicians in private practice.</p> <p>Methods</p> <p>We designed electronic forms for histological prostate biopsy reports in our hospital information system (HIS). These forms are created by urologists and sent electronically to pathologists. Pathological findings are entered into the system and sent back to the urologists. We assessed time from biopsy to final report (TBF) and compared pre-implementation phase (paper-based forms) and post-implementation phase. In addition we analysed completeness of the electronic data.</p> <p>Results</p> <p>We compared 87 paper-based with 86 electronic cases. Using electronic forms within the HIS decreases time span from biopsy to final report by more than one day per patient (p < 0.0001). Beyond the optimized workflow we observed a good acceptance because physicians were already familiar with the HIS. The possibility to use these routine data for quality management and research purposes is an additional important advantage of the electronic system.</p> <p>Conclusion</p> <p>Electronic documentation can significantly reduce the time from biopsy to final report of prostate biopsy results and generates a reliable basis for quality management and research purposes.</p

CMDX©-based single source information system for simplified quality management and clinical research in prostate cancer

Background: Histopathological evaluation of prostatectomy specimens is crucial to decision-making and prediction of patient outcomes in prostate cancer (PCa). Topographical information regarding PCa extension and positive surgical margins (PSM) is essential for clinical routines, quality assessment, and research. However, local hospital information systems (HIS) often do not support the documentation of such information. Therefore, we investigated the feasibility of integrating a cMDX-based pathology report including topographical information into the clinical routine with the aims of obtaining data, performing analysis and generating heat maps in a timely manner, while avoiding data redundancy. Methods: We analyzed the workflow of the histopathological evaluation documentation process. We then developed a concept for a pathology report based on a cMDX data model facilitating the topographical documentation of PCa and PSM; the cMDX SSIS is implemented within the HIS of University Hospital Muenster. We then generated a heat map of PCa extension and PSM using the data. Data quality was assessed by measuring the data completeness of reports for all cases, as well as the source-to-database error. We also conducted a prospective study to compare our proposed method with recent retrospective and paper-based studies according to the time required for data analysis. Results: We identified 30 input fields that were applied to the cMDX-based data model and the electronic report was integrated into the clinical workflow. Between 2010 and 2011, a total of 259 reports were generated with 100% data completeness and a source-to-database error of 10.3 per 10,000 fields. These reports were directly reused for data analysis, and a heat map based on the data was generated. PCa was mostly localized in the peripheral zone of the prostate. The mean relative tumor volume was 16.6%. The most PSM were localized in the apical region of the prostate. In the retrospective study, 1623 paper-based reports were transferred to cMDX reports; this process took 15 ± 2 minutes per report. In a paper-based study, the analysis data preparation required 45 ± 5 minutes per report. Conclusions: cMDX SSIS can be integrated into the local HIS and provides clinical routine data and timely heat maps for quality assessment and research purposes.

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

The CAPRA&PDE4D5/7/9 prognostic model is significantly associated to adverse post-surgical pathology outcomes

Objectives: To investigate the association of the prognostic risk score CAPRA&amp;PDE4D5/7/9 as measured on pre-surgical diagnostic needle biopsy tissue with pathological outcomes after radical prostatectomies in a clinically low–intermediate-risk patient cohort. Patients and Methods: RNA was extracted from biopsy punches of diagnostic needle biopsies. The patient cohort comprises n = 151 patients; of those n = 84 had low–intermediate clinical risk based on the CAPRA score and DRE clinical stage &lt;cT3. This cohort (n = 84) was investigated for pathology outcomes in this study. RT-qPCR was performed to determine PDE4D5, PDE4D7 and PDE4D9 transcript scores in the cohorts. The CAPRA score was inferred from the relevant clinical data (patient age, PSA, cT, biopsy Gleason, and percentage tumor positive biopsy cores). Logistic regression was used to combine the PDE4D5, PDE4D7 and PDE4D9 scores to build a PDE4D5/7/9_BCR regression model. The CAPRA&amp;PDE4D5/7/9_BCR risk score used was same as previously published. Results: We investigated three post-surgical outcomes in this study: (i) Adverse Pathology (any ISUP pathological Gleason grade &gt;2, or pathological pT stage &gt;pT3a, or tumor penetrated prostate capsular status, or pN1 disease); (ii) any ISUP pathological Gleason &gt;2; (iii) any ISUP pathological Gleason &gt;1. In the n = 84 patients with low to intermediate clinical risk profiles, the clinical-genomics CAPRA&amp;PDE4D5/7/9_BCR risk score was significantly lower in patients with favorable vs. unfavorable outcomes. In univariable logistic regression modeling the genomics PDE4D5/7/9_BCR as well as the clinical-genomics CAPRA&amp;PDE4D5/7/9_BCR combination model were significantly associated with all three post-surgical pathology outcomes (p = 0.02, p = 0.0004, p = 0.04; and p = 0.01, p = 0.0002, p = 0.01, respectively). The clinically used PRIAS criteria for the selection of low-risk candidate patients for active surveillance (AS) were not significantly associated with any of the three tested post-operative pathology outcomes (p = 0.3, p = 0.1, p = 0.1, respectively). In multivariable analysis adjusted for the CAPRA score, the genomics PDE4D5/7/9_BCR risk score remained significant for the outcomes of adverse pathology (p = 0.04) and ISUP pathological Gleason &gt;2 (p = 0.004). The negative predictive value of the CAPRA&amp;PDE4D5/7/9_BCR risk score using the low-risk cut-off (0.1) for the three pathological endpoints was 82.0%, 100%, and 59.1%, respectively for a selected low-risk cohort of n = 22 patients (26.2% of the entire cohort) compared to 72.1%, 94.4%, and 55.6% for n = 18 low-risk patients (21.4% of the total cohort) selected based on the PRIAS inclusion criteria. Conclusion: In this study, we have shown that the previously reported clinical-genomics prostate cancer risk model CAPRA&amp;PDE4D5/7/9_BCR which was developed to predict biological outcomes after surgery of primary prostate cancer is also significantly associated with post-surgical pathology outcomes. The risk score predicts adverse pathology independent of the clinical risk metrics. Compared to clinically used active surveillance inclusion criteria, the clinical-genomics CAPRA&amp;PDE4D5/7/9_BCR risk model selects 22% (n = 8) more low-risk patients with higher negative predictive value to experience unfavorable post-operative pathology outcomes

A Multivariable Approach Using Magnetic Resonance Imaging to Avoid a Protocol-based Prostate Biopsy in Men on Active Surveillance for Prostate Cancer-Data from the International Multicenter Prospective PRIAS Study

Publisher Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.BACKGROUND: There is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS). OBJECTIVE: To determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI. DESIGN, SETTING, AND PARTICIPANTS: The Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed. RESULTS AND LIMITATIONS: A total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71-0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56-3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28-5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25-7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12-1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10-1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of <0.15 ng/ml cm3 (n = 315), 3% were reclassified to GG ≥2 and 0.6% to GG ≥3. At the confirmatory biopsy, reclassification to GG ≥2 and ≥3 was observed in 23% and 7% of the patients diagnosed without upfront MRI and in 19% and 6% of the patients diagnosed with upfront MRI, respectively. The multivariable analysis showed no significant difference in upgrading at the confirmatory biopsy between patients diagnosed with or without upfront MRI. CONCLUSIONS: Age, MRI outcome, PSA density, and percentage positive cores are significant predictors of reclassification at an MRI-informed biopsy. Patients with negative MRI and a PSA density of <0.15 ng/ml cm3 can safely omit a protocol-based prostate biopsy, whereas in other patients, a multivariable approach is advised. Being diagnosed with upfront MRI appears not to significantly affect reclassification risk; hence, a confirmatory MRI-Bx cannot totally be omitted yet. PATIENT SUMMARY: A protocol-based prostate biopsy while on active surveillance can be omitted in patients with negative magnetic resonance imaging (MRI) and prostate-specific antigen density <0.15 ng/ml cm3. A confirmatory biopsy cannot simply be omitted in all patients diagnosed with upfront MRI.Peer reviewe

Decision aid and cost compensation influence uptake of PSA-based early detection without affecting decisional conflict:a cluster randomised trial

International guidelines recommend to inform men about the benefits and harms of prostate specific antigen (PSA) based early detection of prostate cancer. This study investigates the influence of a transactional decision aid (DA) or cost compensation (CC) for a PSA test on the decisional behaviour of men. Prospective, cluster-randomised trial to compare two interventions in a 2 × 2 factorial design: DA versus counselling as usual, and CC versus noCC for PSA-testing. 90 cluster-randomised physicians in the administrative district of Muenster, Germany recruited 962 participants aged 55–69 yrs. in 2018. Primary endpoint: the influence of the DA and CC on the decisional conflict. Secondary endpoints: factors which altered the involvement of the men regarding their decision to take a PSA-test. The primary endpoint was analysed by a multivariate regression model. The choice to take the PSA test was increased by CC and reduced by the DA, the latter also reduced PSA uptake in men who were offered CC. The DA led to an increase of the median knowledge about early detection, changed willingness to perform a PSA test without increasing the level of shared decision, giving participants a stronger feeling of having made the decision by themselves. The DA did not alter the decisional conflict, as it was very low in all study groups. DA reduced and CC increased the PSA uptake. The DA seemed to have a greater impact on the participants than CC, as it led to fewer PSA tests even if CC was granted. Trial registration: German Clinical Trial Register (Deutsches Register Klinischer Studien DRKS00007687). Registered: 06/05/2015. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&amp;TRIAL_ID=DRKS00007687.</p