Predictive power of non-invasive mp-MRI markers for clinically significant prostate cancer

Abstract Background Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. Methods Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. Results The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963–0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929–0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956–0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980–0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947–0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. Conclusions The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.

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The Prostate Health Index aids multi-parametric MRI in diagnosing significant prostate cancer

Scientific Reports ◽

10.1038/s41598-020-78428-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yu-Hua Fan ◽

Po-Hsun Pan ◽

Wei-Ming Cheng ◽

Hsin-Kai Wang ◽

Shu-Huei Shen ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Biopsy ◽

Predictive Power ◽

Transrectal Ultrasound ◽

Health Index ◽

Prostate Imaging ◽

Prostate Biopsies ◽

Prostate Health Index ◽

Clinically Significant ◽

Prostate Health

AbstractTo evaluate the performance of the Prostate Health Index (PHI) in magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion prostate biopsy for the detection of clinically significant prostate cancer (csPCa). We prospectively enrolled 164 patients with at least one Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) ≥ 3 lesions who underwent MRI-TRUS fusion prostate biopsy. Of the PSA-derived biomarkers, the PHI had the best performance in predicting csPCa (AUC 0.792, CI 0.707–0.877) in patients with PI-RADS 4/5 lesions. Furthermore, the predictive power of PHI was even higher in the patients with PI-RADS 3 lesions (AUC 0.884, CI 0.792–0.976). To minimize missing csPCa, we used a PHI cutoff of 27 and 7.4% of patients with PI-RADS 4/5 lesions could have avoided a biopsy. At this level, 2.0% of cases with csPCa would have been missed, with sensitivity and NPV rates of 98.0% and 87.5%, respectively. However, the subgroup of PI-RADS 3 was too small to define the optimal PHI cutoff. PHI was the best PSA-derived biomarker to predict csPCa in MRI-TRUS fusion prostate biopsies in men with PI-RADS ≥ 3 lesions, especially for the patients with PI-RADS 3 lesions who gained the most value.

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Prediction of prostate cancer grade using fractal analysis of perfusion MRI: retrospective proof-of-principle study

European Radiology ◽

10.1007/s00330-021-08394-8 ◽

2021 ◽

Author(s):

Florian Michallek ◽

Henkjan Huisman ◽

Bernd Hamm ◽

Sefer Elezkurtaj ◽

Andreas Maxeiner ◽

...

Keyword(s):

Prostate Cancer ◽

Fractal Dimension ◽

Diagnostic Accuracy ◽

Fractal Analysis ◽

Tumor Grade ◽

Perfusion Mri ◽

Non Invasive ◽

Clinically Significant ◽

Cancer Grading ◽

Group 1

Abstract Objectives Multiparametric MRI has high diagnostic accuracy for detecting prostate cancer, but non-invasive prediction of tumor grade remains challenging. Characterizing tumor perfusion by exploiting the fractal nature of vascular anatomy might elucidate the aggressive potential of a tumor. This study introduces the concept of fractal analysis for characterizing prostate cancer perfusion and reports about its usefulness for non-invasive prediction of tumor grade. Methods We retrospectively analyzed the openly available PROSTATEx dataset with 112 cancer foci in 99 patients. In all patients, histological grading groups specified by the International Society of Urological Pathology (ISUP) were obtained from in-bore MRI-guided biopsy. Fractal analysis of dynamic contrast-enhanced perfusion MRI sequences was performed, yielding fractal dimension (FD) as quantitative descriptor. Two-class and multiclass diagnostic accuracy was analyzed using area under the curve (AUC) receiver operating characteristic analysis, and optimal FD cutoffs were established. Additionally, we compared fractal analysis to conventional apparent diffusion coefficient (ADC) measurements. Results Fractal analysis of perfusion allowed accurate differentiation of non-significant (group 1) and clinically significant (groups 2–5) cancer with a sensitivity of 91% (confidence interval [CI]: 83–96%) and a specificity of 86% (CI: 73–94%). FD correlated linearly with ISUP groups (r2 = 0.874, p < 0.001). Significant groupwise differences were obtained between low, intermediate, and high ISUP group 1–4 (p ≤ 0.001) but not group 5 tumors. Fractal analysis of perfusion was significantly more reliable than ADC in predicting non-significant and clinically significant cancer (AUCFD = 0.97 versus AUCADC = 0.77, p < 0.001). Conclusion Fractal analysis of perfusion MRI accurately predicts prostate cancer grading in low-, intermediate-, and high-, but not highest-grade, tumors. Key Points • In 112 prostate carcinomas, fractal analysis of MR perfusion imaging accurately differentiated low-, intermediate-, and high-grade cancer (ISUP grade groups 1–4). • Fractal analysis detected clinically significant prostate cancer with a sensitivity of 91% (83–96%) and a specificity of 86% (73–94%). • Fractal dimension of perfusion at the tumor margin may provide an imaging biomarker to predict prostate cancer grading.

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Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients

Frontiers in Medicine ◽

10.3389/fmed.2021.721554 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jinan Guo ◽

Xuhui Zhang ◽

Taolin Xia ◽

Heather Johnson ◽

Xiaoyan Feng ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Clinical Significance ◽

Treatment Decision ◽

Urine Test ◽

Newly Diagnosed ◽

Grade Group ◽

Non Invasive ◽

Insignificant Cancer ◽

Clinically Significant

Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available.Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups.Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892–0.942) in the retrospective cohort (n = 520), AUC of 0.959 (95% CI 0.935–0.983) in the prospective cohort (n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort (n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1–3 cancer subgroups.Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.

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MicroRNA-940 as a Potential Serum Biomarker for Prostate Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.628094 ◽

2021 ◽

Vol 11 ◽

Author(s):

Smrithi Rajendiran ◽

Sayantan Maji ◽

Ahmed Haddad ◽

Yair Lotan ◽

Rajesh R. Nandy ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Characteristic Curve ◽

Specific Antigen ◽

Cancer Prognosis ◽

High Survival ◽

Non Invasive ◽

Non Coding Rnas ◽

Clinically Significant ◽

Culture Supernatants

Prostate cancer is one of the leading causes of death despite an astoundingly high survival rate for localized tumors. Though prostate specific antigen (PSA) test, performed in conjunction with digital rectal examinations, is reasonably accurate, there are major caveats requiring a thorough assessment of risks and benefits prior to conducting the test. MicroRNAs, a class of small non-coding RNAs, are stable molecules that can be detected in circulation by non-invasive methods and have gained importance in cancer prognosis and diagnosis in the recent years. Here, we investigate circulating miR-940, a miRNA known to play a role in prostate cancer progression, in both cell culture supernatants as well as patient serum and urine samples to determine the utility of miR-940 as a new molecular marker for prostate cancer detection. We found that miR-940 was significantly higher in serum from cancer patients, specifically those with clinically significant tumors (GS ≥ 7). Analysis of receiver operating characteristic curve demonstrated that miR-940 in combination with PSA had a higher area under curve value (AUC: 0.818) than the miR-940 alone (AUC: 0.75) for the diagnosis of prostate cancer. This study provides promising results suggesting the use of miR-940 for prostate cancer diagnosis.

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Expression of Urokinase and Its Receptor in Invasive and Non-Invasive Prostate Cancer Cell Lines

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646340 ◽

1992 ◽

Vol 68 (06) ◽

pp. 662-666 ◽

Cited By ~ 38

Author(s):

W Hollas ◽

N Hoosein ◽

L W K Chung ◽

A Mazar ◽

J Henkin ◽

...

Keyword(s):

Prostate Cancer ◽

Steady State ◽

Cell Surface ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Lncap Cells ◽

Prostate Cancer Cell Lines ◽

Non Invasive

SummaryWe previously reported that extracellular matrix invasion by the prostate cancer cell lines, PC-3 and DU-145 was contingent on endogenous urokinase being bound to a specific cell surface receptor. The present study was undertaken to characterize the expression of both urokinase and its receptor in the non-invasive LNCaP and the invasive PC-3 and DU-145 prostate cells. Northern blotting indicated that the invasive PC-3 cells, which secreted 10 times more urokinase (680 ng/ml per 106 cells per 48 h) than DU-145 cells (63 ng/ml per 106 cells per 48 h), had the most abundant transcript for the plasminogen activator. This, at least, partly reflected a 3 fold amplification of the urokinase gene in the PC-3 cells. In contrast, urokinase-specific transcript could not be detected in the non-invasive LNCaP cells previously characterized as being negative for urokinase protein. Southern blotting indicated that this was not a consequence of deletion of the urokinase gene. Crosslinking of radiolabelled aminoterminal fragment of urokinase to the cell surface indicated the presence of a 51 kDa receptor in extracts of the invasive PC-3 and DU-145 cells but not in extracts of the non-invasive LNCaP cells. The amount of binding protein correlated well with binding capacities calculated by Scatchard analysis. In contrast, the steady state level of urokinase receptor transcript was a poor predictor of receptor display. PC-3 cells, which were equipped with 25,000 receptors per cell had 2.5 fold more steady state transcript than DU-145 cells which displayed 93,000 binding sites per cell.

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Investigations into the Clinical Utility of Latex D-Dimer in the Diagnosis of Deep Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651178 ◽

1993 ◽

Vol 69 (01) ◽

pp. 008-011 ◽

Cited By ~ 22

Author(s):

Cedric J Carter ◽

D Lynn Doyle ◽

Nigel Dawson ◽

Shauna Fowler ◽

Dana V Devine

Keyword(s):

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Lower Limb ◽

Clinical Utility ◽

Rapid Test ◽

Fibrin Degradation Product ◽

Current Form ◽

Non Invasive ◽

Clinically Significant ◽

D Dimer

SummaryThe serial use of non-invasive tests has been shown to be a safe method of managing outpatients who are suspected of having lower limb deep venous thrombosis (DVT). Objective testing has shown that the majority of these outpatients do not have venous thrombosis. A rapid test to exclude DVT in these patients, without the need for expensive and inconvenient serial non-invasive vascular testing, would have practical and economic advantages.Studies measuring the fibrin degradation product D-dimer using enzyme-linked immunoassays (EIA) in patients with veno-graphically proven DVT suggest that it should be possible to exclude this condition by the use of one of the rapid latex bead D-dimer tests.We have examined 190 patients with suspected DVT using both a latex and an EIA D-dimer assay. The latex D-dimer test used in this study was negative in 7 of the 36 proven cases of DVT. This sensitivity of only 80% is not sufficient to allow this type of assay, in its current form, to be used as an exclusion test for DVT. The same plasma samples were tested with an EIA assay. This information was used to mathematically model the effects of selecting a range of D-dimer discriminant cut off points for the diagnosis of DVT. These results indicate that 62% of suspected clinically significant DVT could have this diagnosis excluded, with a 98% sensitivity, if the rapid latex or equivalent D-dimer test could be reformulated to measure less than 185 ng/ml of D-dimer.

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