Challenges in diagnostics of Prostate cancer

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and it is one of the leading causes of men’s cancer deaths in the developed countries. It can be considered as a continuum of neoplasms with aggressiveness ranging from cancers with no effect on the patients’ life expectancy to highly aggressive cancers. Contrary to all other solid-organ cancers, PCa diagnosis is not traditionally based on imaging or visual examination (e.g. endoscopy), but systematic biopsies. Convincing evidence of prostate MRIs’ high sensitivity in detecting clinically significant PCa (CSPCa) and tendency to discriminate insignificant PCas have recently been published. However, the role of imaging is still under debate. Additionally, infectious prostate biopsy complications have increased lately, which has been suspected to have risen from a globally increasing antibiotic resistance e.g. an increased resistance to an antibiotic prophylaxis. In the first substudy, we prospectively investigated the prevalence of transrectal prostate biopsy complications. The rate of complications was low, even though intestinal bacterial antibiotic resistance for prophylaxis was significant. In the second substudy, we prospectively determined the prevalence and risk factors for antibiotic resistance of intestinal Escherichia coli in men undergoing prostate biopsies. A rate of fluoroquinolone resistant Escherichia coli was 13% while international traveling was a significant risk factor. In the third substudy, we externally validated an optimal combination strategy of PSA density and MRI score for selecting men to prostate biopsies. Like in the study to be validated, PSA density has only a minor additional value to the MRI score. In the fourth substudy, we investigated an impact of prostate MRI in an initial PCa diagnostics. In a prospective study cohort using prebiopsy prostate MRI, the rate of CSPCa was significantly higher in initial biopsies and significantly few CSPCa were diagnosed during the follow-up comparing to a cohort with traditional PCa diagnostics. In the fifth substudy, we analyzed performance measures of MRI in CSPCa diagnostics. In the substudy, MRI demonstrated an excellent negative predictive value in ruling out CSPCa. As a conclusion, prebiopsy prostate MRI should be performed to all men in a suspicion of localized prostate cancer. A biopsy decision should be based on men’s individual risk for having significant PCa in the patient level. From a point of view of an individual man, the most significant risk for an unnecessary biopsy could be a diagnosis of insignificant PCa, not a lethal complication.Haasteet eturauhassyövän diagnostiikassa Eturauhassyöpä (PCa) on miesten yleisin syöpä ja toiseksi yleisin syöpäkuolemien aiheuttaja kehittyneissä maissa. Sitä voidaan pitää jatkumona merkityksettömistä ja elinajanennusteeseen vaikuttamattomista syövistä erittäin aggressiivisiin syöpiin. Toisin kuin muiden kiinteiden elinten syöpien suhteen, PCa:ää ei perinteisesti ole diagnosoitu kuvantamisen tai tähystystutkimusten/inspektion perusteella vaan systemaattisilla biopsioilla. MRI:sta on viime aikoina julkaistu vakuuttavaa näyttöä sen korkeasta herkkyydestä kliinisesti merkittävien eturauhassyöpien (CSPCa) suhteen ja taipumuksesta jättää merkityksettömät syövät löytämättä. Kuvantamisella ei kuitenkaan ole vielä vakiintunutta roolia diagnostiikassa. Lisäksi eturauhasbiopsioista seuraavien infektioiden määrä on lisääntynyt, minkä epäillään johtuvan maailmanlaajuisesti lisääntyneestä antibioottiresistenssistä eli toisin sanoen lisääntyneestä resistenssistä profylaktiselle antibiootille. Ensimmäisessä osatyössä tutkimme eturauhasbiopsioiden komplikaatioita prospektiivisessa aineistossa, joita todettiin vähän huolimatta merkittävästä antibioottiresistenssistä annetulle profylaksialle. Toisessa osatyössä tutkimme prospektiivisesti suoliston Escherichia colin antibioottiresistenssin vallitsevuutta ja sen riskitekijöitä eturauhasbiopsioitavilla miehillä. Tutkimuksessa fluorokinoloniresistentti Escherichia coli todettiin 13 %:lla. Ulkomaanmatkailu oli tälle merkittävä riskitekijä. Kolmannessa osatyössä validoimme optimaalista strategiaa PSA tiheyden ja MRI tuloksen yhdistelmälle biopsoitavien miesten valinnassa. Kuten validoitavassa tutkimuksessa, PSA tiheyden tuoma lisäarvo oli vähäinen. Neljännessä osatyössä tutkimme MRI:n vaikutusta CSPCa:n primääridiagnostiikassa. Prospektiivisessa aineistossa MRI kuvattuja miehiä, CSPCa:n määrä ensimmäisissä biopsioissa oli merkittävästi korkeampi ja seurannassa todettujen CSPCa:n määrä merkittävästi alempi verrattuna perinteisellä diagnostiikalla tutkittuihin. Viidennessä osatyössä tutkimme MRI:n tehokkuusarvoja CSPCa:n diagnostiikassa. Totesimme MRI:n negatiivisen ennustearvon olevan erinomainen CSPCa:n poissulussa. Yhteenvetona, MRI pitäisi tehdä ennen biopsioita kaikille miehille, joilla epäillään paikallista PCa:ää. Päätös biopsioista tulisi perustua yksilölliseen riskiin potilaskohtaisesti merkittävälle PCa:lle. Yksittäisen miehen näkökulmasta, mahdollisesti oleellisin riski tarpeettomilla biopsioilla on merkityksettömän PCa:n diagnoosi, ei hengenvaarallinen biopsiakomplikaatio

Detection of Prostate Cancer Using Biparametric Prostate MRI, Radiomics, and Kallikreins : A Retrospective Multicenter Study of Men With a Clinical Suspicion of Prostate Cancer

Background Accurate detection of clinically significant prostate cancer (csPCa), Gleason Grade Group >= 2, remains a challenge. Prostate MRI radiomics and blood kallikreins have been proposed as tools to improve the performance of biparametric MRI (bpMRI). Purpose To develop and validate radiomics and kallikrein models for the detection of csPCa. Study Type Retrospective. Population A total of 543 men with a clinical suspicion of csPCa, 411 (76%, 411/543) had kallikreins available and 360 (88%, 360/411) did not take 5-alpha-reductase inhibitors. Two data splits into training, validation (split 1: single center, n = 72; split 2: random 50% of pooled datasets from all four centers), and testing (split 1: 4 centers, n = 288; split 2: remaining 50%) were evaluated. Field strength/Sequence A 3 T/1.5 T, TSE T2-weighted imaging, 3x SE DWI. Assessment In total, 20,363 radiomic features calculated from manually delineated whole gland (WG) and bpMRI suspicion lesion masks were evaluated in addition to clinical parameters, prostate-specific antigen, four kallikreins, MRI-based qualitative (PI-RADSv2.1/IMPROD bpMRI Likert) scores. Statistical Tests For the detection of csPCa, area under receiver operating curve (AUC) was calculated using the DeLong's method. A multivariate analysis was conducted to determine the predictive power of combining variables. The values of P-value < 0.05 were considered significant. Results The highest prediction performance was achieved by IMPROD bpMRI Likert and PI-RADSv2.1 score with AUC = 0.85 and 0.85 in split 1, 0.85 and 0.83 in split 2, respectively. bpMRI WG and/or kallikreins demonstrated AUCs ranging from 0.62 to 0.73 in split 1 and from 0.68 to 0.76 in split 2. AUC of bpMRI lesion-derived radiomics model was not statistically different to IMPROD bpMRI Likert score (split 1: AUC = 0.83, P-value = 0.306; split 2: AUC = 0.83, P-value = 0.488). Data Conclusion The use of radiomics and kallikreins failed to outperform PI-RADSv2.1/IMPROD bpMRI Likert and their combination did not lead to further performance gains. Level of Evidence 1 Technical Efficacy Stage 2Peer reviewe

How to read biparametric MRI in men with a clinical suspicious of prostate cancer: Pictorial review for beginners with public access to imaging, clinical and histopathological database

Prostate Magnetic Resonance Imaging (MRI) is increasingly being used in men with a clinical suspicion of prostate cancer (PCa). Performing prostate MRI without the use of an intravenous contrast (IV) agent in men with a clinical suspicion of PCa can lead to reduced MRI scan time. Enabling a large array of different medical providers (from mid-level to specialized radiologists) to evaluate and potentially report prostate MRI in men with a clinical suspicion of PCa with a high accuracy could be one way to enable wide adoption of prostate MRI in men with a clinical suspicion of PCa. The aim of this pictorial review is to provide an insight into acquisition, quality control and reporting of prostate MRI performed without IV contrast agent in men with a clinical suspicion of PCa, aimed specifically at radiologists starting reporting prostate MRI, urologists, urology/radiology residents and mid-level medical providers without experience in reporting prostate MRI. Free public access (http://petiv.utu.fi/improd/and http://petiv.utu.fi/multiimprod/) to complete datasets of 161 and 338 men is provided. The imaging datasets are accompanied by clinical, laboratory and histopathological findings. Several topics are simplified in order to provide a solid base for the development of skills needed for an unsupervised review and potential reporting of prostate MRI in men with a clinical suspicion of PCa. The current review represents the first step towards enabling a large array of different medical providers to review and report accurately prostate MRI performed without IV contrast agent in men with a clinical suspicion of PCa

Validation of IMPROD biparametric MRI in men with clinically suspected prostate cancer: A prospective multi-institutional trial

Background: Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption.Methods and findings: The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score >= 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings.Conclusions: IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.</p

Validation of IMPROD biparametric MRI in men with clinically suspected prostate cancer : A prospective multi-institutional trial

Background Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption. Methods and findings The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score >= 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings. Conclusions IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.Peer reviewe

The Mount Sinai Prebiopsy Risk Calculator for Predicting any Prostate Cancer and Clinically Significant Prostate Cancer: Development of a Risk Predictive Tool and Validation with Advanced Neural Networking, Prostate Magnetic Resonance Imaging Outcome Database, and European Randomized Study of Screening for Prostate Cancer Risk Calculator

Background: The European Association of Urology guidelines recommend the use of imaging, biomarkers, and risk calculators in men at risk of prostate cancer. Risk predictive calculators that combine multiparametric magnetic resonance imaging with prebiopsy variables aid as an individualized decision-making tool for patients at risk of prostate cancer, and advanced neural networking increases reliability of these tools.Objective: To develop a comprehensive risk predictive online web-based tool using magnetic resonance imaging (MRI) and clinical data, to predict the risk of any prostate cancer (PCa) and clinically significant PCa (csPCa) applicable to biopsy-naive men, men with a prior negative biopsy, men with prior positive low-grade cancer, and men with negative MRI.Design, setting, and participants: Institutional review board-approved prospective data of 1902 men undergoing biopsy from October 2013 to September 2021 at Mount Sinai were collected.Outcome measurements and statistical analysis: Univariable and multivariable analyses were used to evaluate clinical variables such as age, race, digital rectal examination, family history, prostate-specific antigen (PSA), biopsy status, Prostate Imaging Reporting and Data System score, and prostate volume, which emerged as predictors for any PCa and csPCa. Binary logistic regression was performed to study the probability. Validation was performed with advanced neural networking (ANN), multi-institutional European cohort (Prostate MRI Outcome Database [PROMOD]), and European Randomized Study of Screening for Prostate Cancer Risk Calculator (ERSPC RC) 3/4.Results and limitations: Overall, 2363 biopsies had complete clinical information, with 57.98% any cancer and 31.40% csPCa. The prediction model was significantly associated with both any PCa and csPCa having an area under the curve (AUC) of 81.9% including clinical data. The AUC for external validation was calculated in PROMOD, ERSPC RC, and ANN for any PCa (0.82 vs 0.70 vs 0.90) and csPCa (0.82 vs 0.78 vs 0.92), respectively. This study is limited by its retrospective design and over-estimation of csPCa in the PROMOD cohort.Conclusions: The Mount Sinai Prebiopsy Risk Calculator combines PSA, imaging and clinical data to predict the risk of any PCa and csPCa for all patient settings. With accurate validation results in a large European cohort, ERSPC RC, and ANN, it exhibits its efficiency and applicability in a more generalized population. This calculator is available online in the form of a free web-based tool that can aid clinicians in better patients counseling and treatment decision-making.Patient summary: We developed the Mount Sinai Prebiopsy Risk Calculator (MSP-RC) to assess the likelihood of any prostate cancer and clinically significant disease based on a combination of clinical and imaging characteristics. MSP-RC is applicable to all patient settings and accessible online. Crown Copyright (C) 2022 Published by Elsevier B.V. on behalf of European Association of Urology.</p

ANO7 is associated with aggressive prostate cancer

Free to read on publisher website Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case–control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09–1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p‐values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E‐06; Stockholm prostate tumor cohort p = 1.53E‐13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03–2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43–237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome

ANO7 is associated with aggressive prostate cancer

Free to read on publisher website Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case–control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09–1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p‐values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E‐06; Stockholm prostate tumor cohort p = 1.53E‐13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03–2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43–237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome

ANO7 is associated with aggressive prostate cancer

Abstract Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case–control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09–1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p‐values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E‐06; Stockholm prostate tumor cohort p = 1.53E‐13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03–2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43–237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome