High-grade Prostate Research Articles

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.

Association of 5-alpha-reductase inhibitor and prostate cancer incidence and mortality: a meta-analysis.

Background5-Alpha-reductase inhibitors (5-ARIs) have been suggested as potential chemopreventive agents for prostate cancer (PCa). This study was conducted to evaluate the effect of 5-ARIs on the incidence and mortality of PCa.MethodsThe PubMed, Embase and Cochrane Library databases were searched comprehensively from database inception to October 2019. The clinical outcomes included the incidence of overall PCa, high-grade (Gleason8-10) PCa, metastatic PCa, overall survival (OS), and cancer-specific survival (CSS).ResultsOverall, 23 studies were included in the present study, representing 11 cohort studies, 5 case-control studies, and 8 randomized controlled trials. The use of 5-ARIs was associated with a decreased risk of overall PCa [relative risk (RR) =0.77; 95% CI: 0.67–0.88; P<0.001] and increased risk of Gleason 8–10 PCa (RR=1.19; 95% CI: 1.01–1.40; P=0.036). In terms of metastatic PCa, there were no significant between-group differences (RR=1.23; 95% CI: 0.69–2.18; P=0.487). Furthermore, we found that prediagnostic 5-ARI usage was not associated with an increased risk of overall or prostate cancer mortality, with HRs of 1.00 (95% CI: 0.92–1.08; P=0.938) and 0.98 (95% CI: 0.80–1.21; P=0.881), respectively.ConclusionsIn conclusion, while male 5-ARI users were associated with a decreased risk of overall prostate cancer and increased risk of high-grade prostate cancer (Gleason 8–10), they were not associated with an increased risk of overall or prostate cancer mortality. 5-ARIs should be recommended carefully for use as chemopreventive agents.

Editorial Comment.

No AccessJournal of UrologyAdult Urology1 Feb 2021Editorial CommentThis article comments on the following:Clinical Utility of 4Kscore®, ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer Derya Tilki Derya TilkiDerya Tilki Department of Urology, Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001361.02AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 205(2), p. 460 Reference 1. : EAU - EANM - ESTRO - ESUR - SIOG Guidelines on Prostate Cancer. European Association of Urology 2020. Available at https://uroweb.org/guideline/prostate-cancer/. Google Scholar © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology8 Sep 2020Clinical Utility of 4Kscore®, ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer Volume 205Issue 2February 2021Page: 460-460 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Derya Tilki Department of Urology, Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany More articles by this author Expand All Advertisement PDF downloadLoading ...

Editorial Comment.

No AccessJournal of UrologyAdult Urology1 Feb 2021Editorial CommentThis article comments on the following:Clinical Utility of 4Kscore®, ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer Eric A. Klein Eric A. KleinEric A. Klein Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001361.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 205(2), p. 460 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology8 Sep 2020Clinical Utility of 4Kscore®, ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer Volume 205Issue 2February 2021Page: 460-460 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eric A. Klein Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio More articles by this author Expand All Advertisement PDF downloadLoading ...

PI-RADS 3 lesions: Does the association of the lesion volume with the prostate-specific antigen density matter in the diagnosis of clinically significant prostate cancer?

IntroductionCurrently, a new subclassification of the Pi-RADS 3 lesions and subgroups is being used: 3a (indolent or low-risk lesions with volume <0.5 ml) and 3b (significant or high-risk lesions with volume ≥0.5 ml). The prostate-specific antigen density (PSAd) has been identified as a diagnostic tool that helps to predict clinically significant prostate cancer (csCaP). The aim of this study is to evaluate the association of the volume of the Pi-RADS 3 lesions and the PSAd in the diagnosis of csCaP. Material and MethodsWe conducted a retrospective study that included prostate biopsies performed using a transperineal approach and guided by ultrasound between 2015 and 2020. csCaP was defined as Gleason score ≥3 + 4. The population was divided into groups according to the Pi-RADS 3 subclassification and the PSAd value. We calculated sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of 3b lesions for the detection of high-grade prostate cancer, alone and combined with PSAD groups. ResultsIn total, 99 patients with Pi-RADS 3 lesions were included. Forty-three patients were in group 3a and 56, in 3b. Mean PSA was 7.28 ± 2.6 ng/ml. Pi-RADS 3a lesion did not present csCaP but 17.8% of Pi-RADS 3b lesion did. In group 3b with PSAd > 0.15, 62.5% presented csCaP. In those Pi-RADS 3b with PSAd ≤ 0.15, all biopsies were insignificant prostate cancer (isCaP) and 40 biopsies could have been avoided. Considering 3b as positive for csCaP detection, sensitivity was 100%, specificity 48.3%, NPV 17.8%, and PPV 100%. When adding PSAd to group 3b, sensitivity was 100%, specificity was 86.9%, NPV was 62.5%, PPV was 100%. In total, only the subgroup 3b with PSAd > 0.15 presented csCaP and 83.8% biopsies could be avoided. ConclusionsIn this series, the association of the volume of PIRADS 3 lesion and the PSAd improves specificity and PPV contributing to improve the management of csCaP.

PSA density in the diagnosis of prostate cancer in the Chinese population: results from the Chinese Prostate Cancer Consortium.

We performed this study to investigate the diagnostic performance of prostate-specific antigen density (PSAD) in a multicenter cohort of the Chinese Prostate Cancer Consortium. Outpatients with prostate-specific antigen (PSA) levels ≥4.0 ng ml−1 regardless of digital rectal examination (DRE) results or PSA levels <4.0 ng ml−1 and abnormal DRE results were included from 18 large referral hospitals in China. The diagnostic performance of PSAD and the sensitivity and specificity for the diagnosis of prostate cancer (PCa) and high-grade prostate cancer (HGPCa) at different cutoff values were evaluated. A total of 5220 patients were included in the study, and 2014 (38.6%) of them were diagnosed with PCa. In patients with PSA levels ranging from 4.0 to 10.0 ng ml−1, PSAD was associated with PCa and HGPCa in both univariate (odds ratio [OR] = 45.15, P < 0.0001 and OR = 25.38, P < 0.0001, respectively) and multivariate analyses (OR = 52.55, P < 0.0001 and OR = 26.05, P < 0.0001, respectively). The areas under the receiver operating characteristic curves (AUCs) of PSAD in predicting PCa and HGPCa were 0.627 and 0.630, respectively. With the PSAD cutoff of 0.10 ng ml−2, we obtained a sensitivity of 88.7% for PCa, and nearly all (89.9%) HGPCa cases could be detected and biopsies could be avoided in 20.2% of the patients (359/1776 cases). Among these patients who avoided biopsies, only 30 cases had HGPCa. We recommend 0.10 ng ml−2 as the proper cutoff value of PSAD, which will obtain a sensitivity of nearly 90% for both PCa and HGPCa. The results of this study should be validated in prospective, population-based multicenter studies.

KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.

Value of MRI texture analysis for predicting high-grade prostate cancer

PurposeTo explore the potential value of MRI texture analysis (TA) combined with prostate-related biomarkers to predict high-grade prostate cancer (HGPCa). Materials and methodsEighty-five patients who underwent MRI scanning, including T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) prior to trans-rectal ultrasound (TRUS)-guided core prostate biopsy, were retrospectively enrolled. TA parameters derived from T2WI and DWI, prostate-specific antigen (PSA), and free PSA (fPSA) were compared between the HGPCa and non-high-grade prostate cancer (NHGPCa) groups using independent Student's t-test and the Mann-Whitney U test. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the predictive value for HGPCa. ResultsUnivariate analysis showed that PSA and entropy based on apparent diffusion coefficient (ADC) map differed significantly between the HGPCa and NHGPCa groups and showed higher diagnostic values for HGPCa (area under the curve (AUC) = 82.0% and 80.0%, respectively). Logistic regression and ROC curve analyses revealed that kurtosis, skewness and entropy derived from ADC maps had diagnostic power to predict HGPCa; when the three texture parameters were combined, the area under the ROC curve reached the maximum (AUC = 84.6%; 95% confidence interval (CI): 0.758, 0.935; P = 0.000). ConclusionTA parameters derived from ADC may be a valuable tool in predicting HGPCa. The combination of specific textural parameters extracted from ADC map may be additional tools to predict HGPCa.

Multiparametric MRI Results After Dose Escalated Radiotherapy Of Localized Prostate Cancer: 2 Year Follow-Up Of A Prospective Phase II Trial

Dose escalation has been known to improve biochemical recurrence-free survival in patients with localized prostate cancer with intermediate-to-high risk features. Recently, the use of Prostate Imaging-Reporting and Data System (PI-RADS) with multiparametric MRI (mpMRI) has become an advanced tool in the detection of high-grade bulky prostate cancer (PCa), providing a reporting schema to classify each lesion based on the likelihood of clinically significant cancer. A phase II trial involving dose escalation to intra-prostatic PI-RADS III-V lesions via image-guided radiotherapy (IGRT) and SBRT/SIB boost was conducted. The aim of this study is to examine the PI-RADS lesions two years after completing protocol treatment. It is hypothesized that dose escalation would eliminate these intra-prostatic lesions to improve tumor control. Patients with localized prostate cancer and mpMRI PIRADS III-V lesions were recruited to receive a course of IGRT to the prostate and seminal vesicle +/- pelvic lymph nodes (PLN) to a dose of 45 Gy in 25 fractions followed by SBRT boost, 18 Gy in 3 fraction to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) to the PI-RADS lesions. PI-RADS assessment using PI-RADS system 2.0 was evaluated by genitourinary radiologists. Patients were assessed every 3 months for the first 2 years and then every 6 months thereafter. Of a total of 50 patients recruited in the protocol, 14 patients repeated mpMRI approximately 2 years after initial pre-treatment mpMRI, which was subject for this analysis. Median age was 70 years (range: 59-83). All patients had PI-RADS lesions grade 3-5; 7 (50.0%), 6 (42.9%), and 1 (7.1%) patients having 1-3 lesions respectively. 4 (28.6%) patients, 8 (57.1%) patients, and 2 (14.3%) of patients had PI-RADS grade 3, 4, and 5 lesions respectively. Three (21.4%) patients had Gleason Score (GS) 8-10 and 11 (78.6%) had GS 7 disease. Median PSA was 6.06 ng/mL (range: 0.05-19.13). 10 (71.4%), 3 (21.4%), and 1 (7.1%) patients had stage T1, T2, and T3 tumor, respectively. 5 patients received treatment to the PLN and 9 received androgen deprivation therapy. Median follow up time was 28 months (range: 19-33). 14 (100%) patients had complete resolution of their PI-RADS lesions after dose escalated treatment. Two-year results of this prospective phase II trial suggested that high-dose radiotherapy (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) via IGRT with SBRT boost might be sufficient to eliminate high grade intra-prostatic lesions. A large long-term study is needed to correlate the resolution of the high-grade PI-RADS lesions with clinical outcomes and to determine if follow-up mpMRI 2 years after radiation is a surrogate for radiotherapy outcomes.

Recommended Definitions of Aggressive Prostate Cancer for Etiologic Epidemiologic Research.

In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute's Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

Local failure in high grade prostate cancer: the importance of local and systemic therapy.

Local failure in high grade prostate cancer: the importance of local and systemic therapy.

SC48 - Clinical utility of 4Kscore, ExosomeDx and SelectMDx and magnetic resonance imaging for the early detection of high-grade prostate cancer

SC48 - Clinical utility of 4Kscore, ExosomeDx and SelectMDx and magnetic resonance imaging for the early detection of high-grade prostate cancer

Precision Medicine Approach in Prostate Cancer

Prostate cancer is the most prevalent type of cancer and the second cause of death in men worldwide. Various diagnostic and treatment procedures are available for this type of malignancy, but High-grade or locally advanced prostate cancers showed the potential to develop to lethal phase that can be causing dead. Therefore, new approaches are needed to prolong patients' survival and to improve their quality of life. Precision medicine is a novel emerging field that plays an essential role in identifying new sub-classifications of diseases and in providing guidance in treatment that is based on individual multi-omics data. Multi-omics approaches include the use of genomics, transcriptomics, proteomics, metabolomics, epigenomics and phenomics data to unravel the complexity of a disease-associated biological network, to predict prognostic biomarkers, and to identify new targeted drugs for individual cancer patients. We review the impact of multi-omics data in the framework of systems biology in the era of precision medicine, emphasising the combination of molecular imaging modalities with highthroughput techniques and the new treatments that target metabolic pathways involved in prostate cancer.

EDIL3 promotes epithelial\u2013mesenchymal transition and paclitaxel resistance through its interaction with integrin \u03b1V\u03b23 in cancer cells

Epithelial–mesenchymal transition (EMT) has recently been associated with tumor progression, metastasis, and chemotherapy resistance in several tumor types. We performed a differential gene expression analysis comparing paclitaxel-resistant vs. paclitaxel-sensitive breast cancer cells that showed the upregulation of EDIL3 (EGF Like Repeats and Discoidin I Like Domains Protein 3). This gene codifies an extracellular matrix protein that has been identified as a novel regulator of EMT, so we studied its role in tumor progression and paclitaxel response. Our results demonstrated that EDIL3 expression levels were increased in paclitaxel-resistant breast and prostate cancer cells, and in subsets of high-grade breast and prostate tumors. Moreover, we observed that EDIL3 modulated the expression of EMT markers and this was impaired by cilengitide, which blocks the EDIL3–integrin αVβ3 interaction. EDIL3 knockdown reverted EMT and sensitized cells to paclitaxel. In contrast, EDIL3 overexpression or the culture of cells in the presence of EDIL3-enriched medium induced EMT and paclitaxel resistance. Adding cilengitide resensitized these cells to paclitaxel treatment. In summary, EDIL3 may contribute to EMT and paclitaxel resistance through autocrine or paracrine signaling in cancer cells. Blockade of EDIL3–integrin αVβ3 interaction by cilengitide restores sensitivity to paclitaxel and reverts EMT in paclitaxel-resistant cancer cells. Combinations of cilengitide and taxanes could be beneficial in the treatment of subsets of breast and prostate cancers.

Genomic and Clinicopathologic Characterization of ATM-deficient Prostate Cancer.

The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized. We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes. ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables. ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.

Targeted Metabolomics Analyses Reveal Specific Metabolic Alterations in High-Grade Prostate Cancer Patients.

Prostate cancer (PCa) is a hormone-dependent tumor characterized by an extremely heterogeneous prognosis. Despite recent advances in partially uncovering some of the biological processes involved in its progression, there is still an urgent need for identifying more accurate and specific prognostic procedures to differentiate between disease stages. In this context, targeted approaches, focused on mapping dysregulated metabolic pathways, could play a critical role in identifying the mechanisms driving tumorigenesis and metastasis. In this study, a targeted analysis of the nuclear magnetic resonance-based metabolomic profile of PCa patients with different tumor grades, guided by transcriptomics profiles associated with their stages, was performed. Serum and urine samples were collected from 73 PCa patients. Samples were classified according to their Gleason score (GS) into low-GS (GS < 7) and high-GS PCa (GS ≥ 7) groups. A total of 36 metabolic pathways were found to be dysregulated in the comparison between different PCa grades. Particularly, the levels of glucose, glycine and 1-methlynicotinamide, metabolites involved in energy metabolism and nucleotide synthesis were significantly altered between both groups of patients. These results underscore the potential of targeted metabolomic profiling to characterize relevant metabolic changes involved in the progression of this neoplastic process.

Radio-pathomic mapping model generated using annotations from five pathologists reliably distinguishes high-grade prostate cancer.

.Purpose: Our study predictively maps epithelium density in magnetic resonance imaging (MRI) space while varying the ground truth labels provided by five pathologists to quantify the downstream effects of interobserver variability.Approach: Clinical imaging and postsurgical tissue from 48 recruited prospective patients were used in our study. Tissue was sliced to match the MRI orientation and whole-mount slides were stained and digitized. Data from 28 patients ( slides) were sent to five pathologists to be annotated. Slides from the remaining 20 patients ( slides) were annotated by one of the five pathologists. Interpathologist variability was measured using Krippendorff’s alpha. Pathologist-specific radiopathomic mapping models were trained using a partial least-squares regression using MRI values to predict epithelium density, a known marker for disease severity. An analysis of variance characterized intermodel means difference in epithelium density. A consensus model was created and evaluated using a receiver operator characteristic classifying high grade versus low grade and benign, and was statistically compared to apparent diffusion coefficient (ADC).Results: Interobserver variability ranged from low to acceptable agreement (0.31 to 0.69). There was a statistically significant difference in mean predicted epithelium density values () between the five models. The consensus model outperformed ADC (areas under the curve = 0.80 and 0.71, respectively, ).Conclusion: We demonstrate that radiopathomic maps of epithelium density are sensitive to the pathologist annotating the dataset; however, it is unclear if these differences are clinically significant. The consensus model produced the best maps, matched the performance of the best individual model, and outperformed ADC.

Clinical Utility of 4Kscore ® , ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer

We aimed to evaluate 4Kscore® and ExosomeDx™ with multiparametric magnetic resonance imaging in the detection of high grade prostate cancer and number of biopsies avoided. Patients had 1 liquid biomarker test with or without multiparametric magnetic resonance imaging. High grade prostate cancer was defined as Gleason grade group 2 or greater. The overall number of avoided biopsies (with Gleason grade 1 or less), and number of missed Gleason grade 2 or greater cancer among the biopsied patients, were determined. Of the 783 patients in the overall cohort 419 (53.5%) underwent biopsy. 4Kscore and ExosomeDx scores higher than the manufacturers' cut point were associated with PI-RADS™ scores 3 to 5 and Gleason grade 2 or greater prostate cancer. Limiting biopsy to the men with liquid biomarker scores above the manufacturers' cut point would have resulted avoiding 29.5% to 39.9% unnecessary biopsies overall, while missing 4.0% to 4.8% Gleason grade 2 or greater prostate cancer in the biopsy group. Screening algorithms with up-front liquid biomarker testing followed by multiparametric magnetic resonance imaging if the biomarker is above the manufacturers' cut point, then followed by biopsy if the multiparametric magnetic resonance imaging is positive or if 4Kscore 20 or greater or ExosomeDx 19 or greater would have missed 4.8% to 5.6% of Gleason grade 2 or greater prostate cancer in the biopsy group while avoiding 39.4% to 43.0% biopsies and 29.5% to 39.9% multiparametric magnetic resonance imaging overall. Similar algorithms with up-front multiparametric magnetic resonance imaging followed by liquid biomarker testing for negative multiparametric magnetic resonance imaging would have missed 2.4% of Gleason grade 2 or greater prostate cancer in the biopsy group but only avoided 17.2% 19.3% biopsies overall. Screening algorithms with up-front liquid biomarker testing followed by multiparametric magnetic resonance imaging and biopsy at certain biomarker thresholds could reduce unnecessary biopsies, multiparametric magnetic resonance imaging and overdetection of Gleason grade 1 prostate cancer.

A urine-based Exosomal gene expression test stratifies risk of high-grade prostate Cancer in men with prior negative prostate biopsy undergoing repeat biopsy

BackgroundInitial prostate biopsy often fails to identify prostate cancer resulting in patient anxiety, especially when clinical features such as prostate specific antigen (PSA) remain elevated, leading to the need for repeat biopsies. Prostate biomarker tests, such as the ExoDx™ Prostate (IntelliScore), or EPI test, have been shown to provide individualized risk assessment of clinically significant prostate cancer at initial biopsy; however, the performance in the repeat biopsy setting is not well established.MethodsAs part of a previous prospective clinical validation study evaluating the performance of the EPI test, we collected first-catch, non-DRE urine samples across 22 sites from men with at least one prior negative biopsy scheduled to undergo a repeat prostate biopsy to rule out prostate cancer. All men were 50 years or older with a PSA 2–10 ng/mL. Exosomal mRNA was extracted and expression of three genomic markers, PCA3, ERG and SPDEF was measured. The resulting EPI score was correlated with biopsy results.Results229 men with a prior negative biopsy underwent repeat biopsies. ExoDx Prostate demonstrated good performance ruling out high-grade (Grade group 2, GG2, or higher) prostate cancer (HGPCa) using the previously validated 15.6 cut point in the initial biopsy setting. The EPI test yielded an NPV of 92% independent of other clinical features and would have avoided 26% of unnecessary biopsies while missing only five patients with HGPCa (2.1%). Furthermore, the EPI test provided additional information at a cut-point of 20 and 29.6 with an NPV of 94%, potentially delaying 35 and 61% of unnecessary biopsies, respectively. AUC curves and Net Health Benefit Analyses demonstrated superior performance of ExoDx Prostate over PSA and clinical only risk calculators, i.e. ERSPC.ConclusionsThe EPI test provided good performance using the 15.6 cut-point for ruling out HGPCa / GG2 or higher in men undergoing a repeat prostate biopsy with a PSA of 2–10 ng/ml. Furthermore, the test utilizes gene expression data independent of clinical features to predict the likelihood of HGPCa / GG2 on a subsequent needle biopsy.

Biomarkers in previous histologically negative prostate biopsies can be helpful in repeat biopsy decision-making processes.

To evaluate whether the addition of biomarkers to traditional clinicopathological parameters may help to increase the accurate prediction of prostate re‐biopsy outcome. A training cohort with 98 patients and a validation cohort with 72 patients were retrospectively recruited into our study. Immunohistochemical analysis was used to evaluate the immunoreactivity of a group of biomarkers in the initial negative biopsy normal‐looking tissues of the training and validation cohorts. p‐STAT3, Mcm2, and/or MSR1 were selected out of 10 biomarkers to construct a biomarker index for predicting cancer and high‐grade prostate cancer (HGPCa) in the training cohort based on the stepwise logistic regression analysis; these biomarkers were then validated in the validation cohort. In the training cohort study, we found that the biomarker index was independently associated with the re‐biopsy outcomes of cancer and HGPCa. Moreover supplementing the biomarker index with traditional clinical‐pathological parameters can improve the area under the receiver operating characteristic curve of the model from 0.722 to 0.842 and from 0.735 to 0.842, respectively, for predicting cancer and HGPCa at re‐biopsy. In the decision‐making analysis, we found the model supplemented with the biomarker index can improve patients’ net benefit. The application of the model to clinical practice, at a 10% risk threshold, would reduce the number of biopsies by 34.7% while delaying the diagnosis of 7.8% cancers and would reduce the number of biopsies by 73.5% while delaying the diagnosis of 17.8% HGPCas. Taken together, supplementing the biomarker index with clinicopathological parameters may help urologists in re‐biopsy decision‐making processes.