{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:05:29Z","timestamp":1778497529210,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main effects [i.e., PSA, age, histological evidence of glandular inflammation (GI)] was built after testing the accuracy by calibration plots and Hosmer-Lemeshow test for goodness of fit. PSA thresholds were derived by assuming a diagnostic sensitivity of 95% (rule-out) and 80% (rule-in) for overall and advanced\/poorly differentiated PCa. In patients without GI, serum PSA concentrations \u2264 4.1 (&lt;65 years old) and \u22643.7 \u03bcg\/L (\u226565 years old) excluded an advanced PCa (defined as Gleason score \u2265 7 at biopsy), with a negative predictive value of 95.1% [95% confidence interval (CI): 83.0\u201398.7] and 88.8% (CI: 80.2\u201393.9), respectively, while PSA &gt; 5.7 (&lt;65) and &gt;6.1 \u03bcg\/L (\u226565) should address biopsy referral. In presence of GI, PSA did not provide a valid estimate for risk of advanced cancer because of its higher variability and the low pre-test probability of PCa. The proposed PSA thresholds may support biopsy decision except for patients with asymptomatic prostatitis who cannot be pre-biopsy identified.<\/jats:p>","DOI":"10.3390\/cancers13143381","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T11:36:44Z","timestamp":1625571404000},"page":"3381","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Definition of Outcome-Based Prostate-Specific Antigen (PSA) Thresholds for Advanced Prostate Cancer Risk Prediction"],"prefix":"10.3390","volume":"13","author":[{"given":"Simona","family":"Ferraro","sequence":"first","affiliation":[{"name":"Unit\u00e0 Operativa Patologia Clinica, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Bussetti","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Patologia Clinica, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niccol\u00f2","family":"Bassani","sequence":"additional","affiliation":[{"name":"Statistical Consultant, Flat 5 Hazel Court Avenue, Hitchin SG4 9SJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta Simona","family":"Rossi","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Anatomia Patologica, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo Piero","family":"Incarbone","sequence":"additional","affiliation":[{"name":"Urologia, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Anatomia Patologica, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Maggioni","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Anatomia Patologica, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Via F. Sforza 35, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Letterio","family":"Runza","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Anatomia Patologica, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Via F. Sforza 35, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0958-5354","authenticated-orcid":false,"given":"Ferruccio","family":"Ceriotti","sequence":"additional","affiliation":[{"name":"Laboratorio Analisi, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico Via F. Sforza 35, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7147-3433","authenticated-orcid":false,"given":"Mauro","family":"Panteghini","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Patologia Clinica, ASST Fatebenefratelli-Sacco, Ospedale \u2018Luigi Sacco\u2019, Via GB Grassi 74, 20157 Milano, Italy"},{"name":"Dipartimento di Scienze Biomediche e Cliniche \u2018Luigi Sacco\u2019, Universit\u00e0 Degli Studi di Milano, 20157 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1093\/clinchem\/hvab002","article-title":"Serum prostate-specific antigen testing for early detection of prostate cancer: Managing the gap between clinical and laboratory practice","volume":"67","author":"Ferraro","year":"2021","journal-title":"Clin. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.juro.2013.04.119","article-title":"Early detection of prostate cancer: AUA guideline","volume":"190","author":"Carter","year":"2013","journal-title":"J. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.eururo.2019.04.033","article-title":"Structured population-based prostate-specific antigen screening for prostate cancer: The European Association of Urology Position in 2019","volume":"76","author":"Gandaglia","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1373\/clinchem.2018.287094","article-title":"Redesigning prostate cancer screening strategies to reduce overdiagnosis","volume":"65","author":"Vickers","year":"2019","journal-title":"Clin. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3322\/caac.20066","article-title":"American Cancer Society PCa Advisory Committee","volume":"60","author":"Wolf","year":"2010","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1373\/clinchem.2018.293514","article-title":"Perspective on prostate cancer screening","volume":"65","author":"Carlsson","year":"2019","journal-title":"Clin. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.eururo.2008.05.022","article-title":"The comparability of models for predicting the risk of a positive prostate biopsy with prostate-specific antigen alone: A systematic review","volume":"54","author":"Kattan","year":"2008","journal-title":"Eur. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1093\/annonc\/mdu525","article-title":"Do prostate cancer risk models improve the predictive accuracy of PSA screening? A meta-analysis","volume":"26","author":"Louie","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e034661","DOI":"10.1136\/bmjopen-2019-034661","article-title":"Prediction models for prostate cancer to be used in the primary care setting: A systematic review","volume":"10","author":"Aladwani","year":"2020","journal-title":"BMJ Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1093\/clinchem\/hvaa268","article-title":"Verification of harmonization of serum total and free prostate-specific antigen (PSA) measurements and implications for medical decisions","volume":"67","author":"Ferraro","year":"2021","journal-title":"Clin. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1373\/clinchem.2005.059170","article-title":"Interchangeability of measurements of total anfree prostate-specific antigen in serum with 5 frequently used assay combinations: An update","volume":"52","author":"Stephan","year":"2006","journal-title":"Clin. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1515\/cclm-2018-1252","article-title":"Prostate cancer screening: Guidelines review and laboratory issues","volume":"57","author":"Filella","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1093\/annonc\/mdv038","article-title":"Letter to the editor concerning \u2018Do prostate cancer risk models improve the predictive accuracy of PSA screening? A meta-analysis\u2019","volume":"26","author":"Carlsson","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/S0022-5347(05)64668-X","article-title":"Percent free prostate-specific antigen in the total prostate-specific antigen 2 to 4 ng.\/mL range does not substantially increase the number of biopsies needed to detect clinically significant prostate cancer compared to the 4 to 10 ng.\/mL. range","volume":"168","author":"Haese","year":"2002","journal-title":"J. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4033","DOI":"10.1200\/JCO.2014.58.5547","article-title":"Markers for the early detection of prostate cancer: Some principles for statistical reporting and interpretation","volume":"32","author":"Vickers","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/j.annonc.2020.05.028","article-title":"A multi-cancer detection test: Focus on the positive predictive value","volume":"31","author":"Fiala","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_17","unstructured":"(2021, April 29). Statistics Canada, Canadian Cancer Registry (CCR) Database (July 2011 File) (CANSIM Table 103-0550). Rates for ICD-O-3 Primary Sites of Cancer, by Sex, Canada, Provinces and Territories, Annual. Prostate Cancer, Incidence Rates Per 100,000, by Age Group, Canada. Available online: https:\/\/www150.statcan.gc.ca\/n1\/pub\/82-624-x\/2011001\/article\/chart\/11596-09-chart9-eng.htm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3322\/caac.20118","article-title":"Prediction models in cancer care","volume":"61","author":"Vickers","year":"2011","journal-title":"CA Cancer J. Clin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0090-4295(99)00185-5","article-title":"Use of percentage of free prostate-specific antigen to identify men at high risk of prostate cancer when PSA-levels are 2.51\u20134 ng\/mL and digital rectal examination is not suspicious for prostate cancer: An alternative model","volume":"54","author":"Catalona","year":"1999","journal-title":"Urology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1503\/cmaj.060955","article-title":"Prostate-specific antigen in the early detection of prostate cancer","volume":"176","author":"Thompson","year":"2007","journal-title":"CMAJ"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.clgc.2016.12.022","article-title":"A systematic review and meta-analysis of the diagnostic accuracy of prostate health index and 4-kallikrein panel score in predicting overall and high-grade prostate cancer","volume":"15","author":"Russo","year":"2017","journal-title":"Clin. Genitourin Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1056\/NEJMoa031918","article-title":"Prevalence of prostate cancer among men with a prostate-specific antigen level <or =4.0 ng per milliliter","volume":"350","author":"Thompson","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.6004\/jnccn.2018.7055","article-title":"Evaluation of new tests and interventions for prostate cancer management: A systematic review","volume":"16","author":"Olleik","year":"2018","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1097\/MOU.0000000000000321","article-title":"What\u2019s new in screening in 2015?","volume":"26","author":"Carlsson","year":"2016","journal-title":"Curr. Opin. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1002\/ijc.22956","article-title":"The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: Towards a biologically-based screening strategy","volume":"121","author":"Vickers","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"g2296","DOI":"10.1136\/bmj.g2296","article-title":"Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: Population-based cohort study","volume":"348","author":"Carlsson","year":"2014","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1001\/jama.2018.3712","article-title":"Prostate-specific antigen-based screening for prostate cancer: Evidence report and systematic review for the US Preventive Services Task Force","volume":"319","author":"Fenton","year":"2018","journal-title":"JAMA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S85","DOI":"10.1016\/j.ijantimicag.2007.08.028","article-title":"Epidemiology of prostatitis","volume":"31","author":"Krieger","year":"2008","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1001\/jama.282.3.236","article-title":"NIH consensus definition and classification of prostatitis","volume":"282","author":"Krieger","year":"1999","journal-title":"JAMA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0022-5347(05)63959-6","article-title":"The prevalence of men with National Institutes of Health category IV prostatitis and association with serum prostate specific antigen","volume":"169","author":"Carver","year":"2003","journal-title":"J. Urol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.urology.2004.07.017","article-title":"Prostatitis and prostate cancer: Implications for prostate cancer screening","volume":"64","author":"Kawakami","year":"2004","journal-title":"Urology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.urology.2007.06.1102","article-title":"Association of extent and aggressiveness of inflammation with serum PSA levels and PSA density in asymptomatic patients","volume":"70","author":"Kandirali","year":"2007","journal-title":"Urology"},{"key":"ref_33","first-page":"1071","article-title":"Regression models for prognostic prediction: Advantages, problems, and suggested solutions","volume":"69","author":"Harrell","year":"1985","journal-title":"Cancer Treat. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1056\/NEJMe048003","article-title":"Prostate cancers in men with low PSA levels--must we find them?","volume":"350","author":"Carter","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1111\/j.1464-410X.2012.11481.x","article-title":"Positive predictive value of prostate biopsy indicated by prostate-specific-antigen-based prostate cancer screening: Trends over time in a European randomized trial","volume":"110","author":"Bokhorst","year":"2012","journal-title":"BJU Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cca.2021.01.017","article-title":"Is pre-biopsy serum prostate specific antigen retesting always justified? A study of the influence of individual and analytical factors on decision making for biopsy referral","volume":"516","author":"Ferraro","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1002\/ijc.29538","article-title":"Prevalence of incidental prostate cancer: A systematic review of autopsy studies","volume":"137","author":"Bell","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1001\/jama.294.1.66","article-title":"Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng\/mL or lower","volume":"294","author":"Thompson","year":"2005","journal-title":"JAMA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S0140-6736(16)32401-1","article-title":"Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): A paired validating confirmatory study","volume":"389","author":"Ahmed","year":"2017","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cca.2018.07.043","article-title":"Biological variation estimates for prostate specific antigen from the European Biological Variation Study; consequences for diagnosis and monitoring of prostate cancer","volume":"486","author":"Carobene","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/sj.pcan.4500996","article-title":"PSA reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients","volume":"11","author":"Serretta","year":"2008","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"479","DOI":"10.6004\/jnccn.2019.0023","article-title":"Prostate cancer, version 2.2019, NCCN Clinical Practice Guidelines in Oncology","volume":"17","author":"Mohler","year":"2019","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.eururo.2015.06.046","article-title":"A contemporary prostate cancer grading system: A validated alternative to the Gleason score","volume":"69","author":"Epstein","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_44","unstructured":"Epstein, J.I., and Netto, G.J. (2015). Chapter 4 Inflammatory condition. Biopsy Interpretation of the Prostate, Lippincott Williams & Wilkins. [5th ed.]."},{"key":"ref_45","unstructured":"Brant, R. (2021, April 29). Inference for Means: Comparing Two Independent Samples. Available online: https:\/\/www.stat.ubc.ca\/~rollin\/stats\/ssize\/n2.html."},{"key":"ref_46","first-page":"366","article-title":"Cost-effectiveness of prostate cancer screening: A simulation study based on ERSPC data","volume":"107","author":"Heijnsdijk","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.eururo.2015.09.002","article-title":"Prostate cancer screening biomarkers: An emerging embarrassment of \u2018riches\u2019?","volume":"70","author":"Eggener","year":"2016","journal-title":"Eur. Urol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/14\/3381\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:31Z","timestamp":1760163991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/14\/3381"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,6]]},"references-count":47,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cancers13143381"],"URL":"https:\/\/doi.org\/10.3390\/cancers13143381","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,6]]}}}