scholarly journals A Multivariate Diagnostic Model Based on Urinary EpCAM-CD9-Positive Extracellular Vesicles for Prostate Cancer Diagnosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yibei Dai ◽  
Yiyun Wang ◽  
Ying Cao ◽  
Pan Yu ◽  
Lingyu Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Extracellular Vesicles ◽  
Diagnostic Performance ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Area Under The Curve ◽  
Diagnostic Model ◽  
Model Based ◽  
Applied Machine Learning ◽  
Trus Biopsy

IntroductionProstate cancer (PCa) is one of the most frequently diagnosed cancers and the leading cause of cancer death in males worldwide. Although prostate-specific antigen (PSA) screening has considerably improved the detection of PCa, it has also led to a dramatic increase in overdiagnosing indolent disease due to its low specificity. This study aimed to develop and validate a multivariate diagnostic model based on the urinary epithelial cell adhesion molecule (EpCAM)-CD9–positive extracellular vesicles (EVs) (uEVEpCAM-CD9) to improve the diagnosis of PCa.MethodsWe investigated the performance of uEVEpCAM-CD9 from urine samples of 193 participants (112 PCa patients, 55 benign prostatic hyperplasia patients, and 26 healthy donors) to diagnose PCa using our laboratory-developed chemiluminescent immunoassay. We applied machine learning to training sets and subsequently evaluated the multivariate diagnostic model based on uEVEpCAM-CD9 in validation sets.ResultsResults showed that uEVEpCAM-CD9 was able to distinguish PCa from controls, and a significant decrease of uEVEpCAM-CD9 was observed after prostatectomy. We further used a training set (N = 116) and constructed an exclusive multivariate diagnostic model based on uEVEpCAM-CD9, PSA, and other clinical parameters, which showed an enhanced diagnostic sensitivity and specificity and performed excellently to diagnose PCa [area under the curve (AUC) = 0.952, P < 0.0001]. When applied to a validation test (N = 77), the model achieved an AUC of 0.947 (P < 0.0001). Moreover, this diagnostic model also exhibited a superior diagnostic performance (AUC = 0.917, P < 0.0001) over PSA (AUC = 0.712, P = 0.0018) at the PSA gray zone.ConclusionsThe multivariate model based on uEVEpCAM-CD9 achieved a notable diagnostic performance to diagnose PCa. In the future, this model may potentially be used to better select patients for prostate transrectal ultrasound (TRUS) biopsy.

scholarly journals Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease

2020 ◽  
Vol 7 (6) ◽  
pp. e866 ◽  
Author(s):  
Elena Vacchi ◽  
Jacopo Burrello ◽  
Dario Di Silvestre ◽  
Alessio Burrello ◽  
Sara Bolis ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Diagnostic Performance ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Machine Learning Algorithms ◽  
Supervised Machine Learning ◽  
Diagnostic Model ◽  
Surface Markers ◽  
Model Based ◽  
Immune Profiling

ObjectiveTo develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform.MethodsPlasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort.ResultsDistinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations.ConclusionsImmune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP.

scholarly journals Independent Validation of a Diagnostic Noninvasive 3-MicroRNA Ratio Model (uCaP) for Prostate Cancer in Cell-Free Urine

2019 ◽  
Vol 65 (4) ◽  
pp. 540-548 ◽  
Author(s):  
Jacob Fredsøe ◽  
Anne K I Rasmussen ◽  
Emma B Laursen ◽  
Yunpeng Cai ◽  
Kenneth A Howard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Biopsy ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Area Under The Curve ◽  
Extracellular Vesicle ◽  
Urine Samples ◽  
Ratio Model ◽  
Psa Testing ◽  
Diagnostic Potential

Abstract BACKGROUND Detection of prostate cancer (PC) based on serum prostate-specific antigen (PSA) testing leads to many unnecessary prostate biopsies, overdiagnosis, and overtreatment of clinically insignificant tumors. Thus, novel and more accurate molecular biomarkers are required. METHODS Using reverse transcription quantitative PCR, we measured the concentrations of 45 preselected microRNAs (miRNAs) in extracellular vesicle-enriched cell-free urine samples from 4 independent patient cohorts from Spain and Denmark, including 758 patients with clinically localized PC, 289 noncancer controls with benign prostatic hyperplasia (BPH), and 233 patients undergoing initial transrectal ultrasound (TRUS)-guided prostate biopsy owing to PC suspicion (101 with benign and 132 with malignant outcome). Diagnostic potential was assessed by ROC and decision curve analysis. RESULTS We identified and successfully validated 8 upregulated and 21 downregulated miRNAs in urine from PC patients. Furthermore, we validated a previously identified 3-miRNA diagnostic ratio model, uCaP (miR-222–3p*miR-24–3p/miR-30c-5p). High uCaP scores were distinctive of PC in urine samples from BPH vs PC patients in 3 independent cohorts [area under the curve (AUC) = 0.84, 0.71, 0.72]. Additionally, uCaP predicted TRUS biopsy results with greater accuracy than PSA (AUC uCaP = 0.644; AUC PSA = 0.527) for patients within the diagnostic gray zone (PSA ≤ 10 ng/mL). CONCLUSIONS We successfully validated a urine-based diagnostic 3-miRNA signature for PC (uCaP) in 3 independent patient cohorts from 2 countries. In the future, the simple and noninvasive uCaP test may be used to help more accurately select patients for prostate biopsy. Prospective clinical validation is warranted.

scholarly journals Profiling of Circulating microRNAs in Prostate Cancer Reveals Diagnostic Biomarker Potential

Diagnostics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 188 ◽  
Author(s):  
Jacob Fredsøe ◽  
Anne K. I. Rasmussen ◽  
Peter Mouritzen ◽  
Marianne T. Bjerre ◽  
Peter Østergren ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Minimally Invasive ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Digital Rectal Examination ◽  
Area Under The Curve ◽  
Diagnostic Tools ◽  
Test Set ◽  
Localized Disease ◽  
Clinically Significant

Early detection of prostate cancer (PC) is paramount as localized disease is generally curable, while metastatic PC is generally incurable. There is a need for improved, minimally invasive biomarkers as current diagnostic tools are inaccurate, leading to extensive overtreatment while still missing some clinically significant cancers. Consequently, we profiled the expression levels of 92 selected microRNAs by RT-qPCR in plasma samples from 753 patients, representing multiple stages of PC and non-cancer controls. First, we compared plasma miRNA levels in patients with benign prostatic hyperplasia (BPH) or localized prostate cancer (LPC), versus advanced prostate cancer (APC). We identified several dysregulated microRNAs with a large overlap of 59 up/down-regulated microRNAs between BPH versus APC and LPC versus APC. Besides identifying several novel PC-associated dysregulated microRNAs in plasma, we confirmed the previously reported upregulation of miR-375 and downregulation of miR-146a-5p. Next, by randomly splitting our dataset into a training and test set, we identified and successfully validated a novel four microRNA diagnostic ratio model, termed bCaP (miR-375*miR-33a-5p/miR-16-5p*miR-409-3p). Combined in a model with prostate specific antigen (PSA), digital rectal examination status, and age, bCaP predicted the outcomes of transrectal ultrasound (TRUS)-guided biopsies (negative vs. positive) with greater accuracy than PSA alone (Training: area under the curve (AUC), model = 0.84; AUC, PSA = 0.63. Test set: AUC, model = 0.67; AUC, PSA = 0.56). It may be possible in the future to use this simple and minimally invasive bCaP test in combination with existing clinical parameters for a more accurate selection of patients for prostate biopsy.

scholarly journals Affinity Captured Urinary Extracellular Vesicles Provide mRNA and miRNA Biomarkers for Improved Accuracy of Prostate Cancer Detection: A Pilot Study

2020 ◽  
Vol 21 (21) ◽  
pp. 8330
Author(s):  
Michelle Davey ◽  
Sami Benzina ◽  
Marc Savoie ◽  
Guy Breault ◽  
Anirban Ghosh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Minimally Invasive ◽  
Extracellular Vesicles ◽  
Prostate Cancer Screening ◽  
Quantitative Polymerase Chain Reaction ◽  
Specific Antigen ◽  
Area Under The Curve ◽  
Test Accuracy ◽  
Expression Ratio ◽  
Tissue Biopsy

Serum prostate-specific antigen (sPSA) testing has helped to increase early detection of and decrease mortality from prostate cancer. However, since sPSA lacks specificity, an invasive prostate tissue biopsy is required to confirm cancer diagnosis. Using urinary extracellular vesicles (EVs) as a minimally invasive biomarker source, our goal was to develop a biomarker panel able to distinguish prostate cancer from benign conditions with high accuracy. We enrolled 56 patients in our study, 28 negative and 28 positive for cancer based on tissue biopsy results. Using our Vn96 peptide affinity method, we isolated EVs from post-digital rectal exam urines and used quantitative polymerase chain reaction to measure several mRNA and miRNA targets. We identified a panel of seven mRNA biomarkers whose expression ratio discriminated non-cancer from cancer with an area under the curve (AUC) of 0.825, sensitivity of 75% and specificity of 84%. We also identified two miRNAs whose combined score yielded an AUC of 0.744. A model pairing the seven mRNA and two miRNA panels yielded an AUC of 0.843, sensitivity of 79% and specificity of 89%. Addition of EV-derived PCA3 levels and clinical characteristics to the biomarker model further improved test accuracy. An AUC of 0.955, sensitivity of 86% and specificity of 93% were obtained. Hence, Vn96-isolated urinary EVs are a clinically applicable and minimally invasive source of mRNA and miRNA biomarkers with potential to improve on the accuracy of prostate cancer screening and diagnosis.

scholarly journals Performance of a Single Assay for Both Type III and Type VI TMPRSS2:ERG Fusions in Noninvasive Prediction of Prostate Biopsy Outcome

2008 ◽  
Vol 54 (12) ◽  
pp. 2007-2017 ◽  
Author(s):  
Jarrod P Clark ◽  
Kristofer W Munson ◽  
Jessie W Gu ◽  
Katarzyna Lamparska-Kupsik ◽  
Kevin G Chan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Digital Rectal Examination ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Gleason Grade ◽  
Type Iii ◽  
Standard Curve ◽  
Institutional Review

Abstract Background: TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. Methods: We collected expressed prostatic secretion (EPS) under an institutional review board-approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. Results: Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728–0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740–0.948, P < 0.001). Conclusions: Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens.

scholarly journals A multicentre randomised controlled trial assessing whether MRI-targeted biopsy is non-inferior to standard transrectal ultrasound guided biopsy for the diagnosis of clinically significant prostate cancer in men without prior biopsy: a study protocol

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e017863 ◽  
Author(s):  
Veeru Kasivisvanathan ◽  
Fatima Jichi ◽  
Laurence Klotz ◽  
Arnauld Villers ◽  
Samir S Taneja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Alternative Pathway ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Digital Rectal Examination ◽  
Classical Pathway ◽  
Targeted Biopsy ◽  
Ultrasound Guided ◽  
Trus Biopsy ◽  
Clinically Significant

IntroductionThe classical pathway for the diagnosis of prostate cancer is transrectal ultrasound-guided (TRUS) biopsy of the prostate initiated on the basis of a raised prostate-specific antigen (PSA). An alternative pathway is to perform multi-parametricMRI (MPMRI) to localise cancer and to use this information to influence the decision for, and conduct of, a subsequent biopsy, known as an MPMRI-targeted biopsy. An MPMRI pathway has been shown to detect a similar or greater amount of clinically significant cancer as TRUS biopsy but has several advantages, including the potential to biopsy fewer men with fewer cores.MethodsThis is a pragmatic, international, multicentre, parallel group randomised study in which men are allocated in a 1:1 ratio to an MPMRI or TRUS biopsy pathway. This study will assess whether an MPMRI-targeted biopsy approach is non-inferior to a standard TRUS biopsy approach in the diagnosis of clinically significant cancer.Men in the MRI arm will undergo targeted biopsy of suspicious areas only and no biopsy will be carried out if the MRI is non-suspicious. Men in the TRUS biopsy will undergo a standard 10–12-core TRUS biopsy. The main inclusion criteria are a serum PSA ≤20 ng/mL, a digital rectal examination finding of T2 or less and no prior prostate biopsy.The primary outcome is the proportion of men with clinically significant cancer detected. A sample size of at least 470 patients is required. Key secondary outcomes include the proportion of clinically insignificant cancer detected.Ethics and disseminationEthical approval was obtained from the National Research Ethics Committee East Midlands, Leicester (15/EM/0188). Results of this study will be disseminated through national and international papers. The participants and relevant patient support groups will be informed about the results of the study.Registration detailsNCT02380027; Pre-results

scholarly journals What is the risk of prostate cancer mortality following negative systematic TRUS-guided biopsies? A systematic review

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e040965
Author(s):  
Sandra Miriam Kawa ◽  
Signe Benzon Larsen ◽  
John Thomas Helgstrand ◽  
Peter Iversen ◽  
Klaus Brasso ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Data Extraction ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Population Based ◽  
Free Text ◽  
Medical Subject Headings ◽  
Prognostic Information ◽  
Prostate Biopsies

ObjectiveTo investigate the risk of prostate cancer-specific mortality (PCSM) following initial negative systematic transrectal ultrasound-guided (TRUS) prostate biopsies.DesignSystematic review.Data sourcesPubMed and Embase were searched using a string combination with keywords/Medical Subject Headings terms and free text in the search builder. Date of search was 13 April 2020.Study selectionStudies addressing PCSM following initial negative TRUS biopsies. Randomised controlled trials and population-based studies including men with initial negative TRUS biopsies reported in English from 1990 until present were included.Data extractionData extraction was done using a predefined form by two authors independently and compared with confirm data; risk of bias was assessed using the Newcastle–Ottawa Scale for cohort studies when applicable.ResultsFour eligible studies were identified. Outcomes were reported differently in the studies as both cumulative incidence and Kaplan-Meier estimates have been used. Regardless of the study differences, all studies reported low estimated incidence of PCSM of 1.8%–5.2% in men with negative TRUS biopsies during the following 10–20 years. Main limitation in all studies was limited follow-up.ConclusionOnly a few studies have investigated the risk of PCSM following initial negative biopsies and all studies included patients before the era of MRI of the prostate. However, the studies point to the fact that the risk of PCSM is low following initial negative TRUS biopsies, and that the level of prostate-specific antigen before biopsies holds prognostic information. This may be considered when advising patients about the need for further diagnostic evaluation.PROSPERO registration numberCRD42019134548.

scholarly journals Prostate Cancer Liquid Biopsy Biomarkers’ Clinical Utility in Diagnosis and Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3373
Author(s):  
Milena Matuszczak ◽  
Jack A. Schalken ◽  
Maciej Salagierski
Keyword(s):  
Prostate Cancer ◽  
Liquid Biopsy ◽  
Current Knowledge ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Transrectal Ultrasound ◽  
Digital Rectal Examination ◽  
Cost Effective ◽  
Non Invasive ◽  
Diagnosis And Prognosis

Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level in the blood serum. PSA is a marker produced by prostate cells, not just cancer cells. Therefore, an elevated PSA level may be associated with other symptoms such as benign prostatic hyperplasia or inflammation of the prostate gland. Due to this marker’s low specificity, a common problem is overdiagnosis, which leads to unnecessary biopsies and overtreatment. This is associated with various treatment complications (such as bleeding or infection) and generates unnecessary costs. Therefore, there is no doubt that the improvement of the current procedure by applying effective, sensitive and specific markers is an urgent need. Several non-invasive, cost-effective, high-accuracy liquid biopsy diagnostic biomarkers such as Progensa PCA3, MyProstateScore ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed in recent years. This article compares current knowledge about them and their potential application in clinical practice.

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