{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T13:45:12Z","timestamp":1785678312661,"version":"3.56.0"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>[\u20102]proPSA(p2PSA)\u2010related indices have demonstrated diagnostic value for detecting prostate cancer (PC) in males with modest increases in prostate\u2010specific antigen levels (PSA) of &lt;\u200910\u2009ng\/mL. However, the \u201cleak point\u201d of p2PSA level in the blood circulation before developing screen\u2010detectable PC remains uncertain. Therefore, this study evaluated the ability of p2PSA\u2010related indices in the years before considering conventional biopsy indications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This case\u2010control study analyzed database and serum bank information from a population\u2010based screening cohort in Gunma Prefecture. The case group included 58 males diagnosed with PC due to increased PSA (4\u201310\u2009ng\/mL) followed serially for 5 years. The control group comprised 58 males without PC based on biopsy who were matched to the case group by adjusted PSA levels (\u00b1\u20092\u2009ng\/mL) and age (\u00b1\u20095 years) at the time of biopsy. p2PSA, free PSA, and PSA were measured from frozen serum samples from 0 to 5 years before biopsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>p2PSA\u2010to\u2010free PSA ratio (%p2PSA) and prostate health index (phi) were significantly higher in the case group than in the control group from five, three, and 3 years before biopsy, respectively. The areas under the receiver operating characteristic curve for predicting PC were 0.437 for PSA, 0.637 for phi, 0.663 for %p2PSA, and 0.618 for free PSA\u2010to PSA ratio (%fPSA) at 3 years before biopsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>p2PSA\u2010related indices showed group\u2010level differences between future PC cases and matched controls before PSA exceeded conventional cut\u2010offs. These findings should be regarded as hypothesis\u2010generating and require validation in prospective studies before clinical application to risk\u2010stratified screening.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pros.70232","type":"journal-article","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T13:07:23Z","timestamp":1785676043000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predictive Value of [\u22122]proPSA\u2010Related Indices for Prostate Cancer Detection Years Before Prostate\u2010Specific Antigen Elevation: Insights From a Five\u2010Year Longitudinal Screening Cohort"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8094-4524","authenticated-orcid":false,"given":"Yoshitaka","family":"Sekine","sequence":"first","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2399-8757","authenticated-orcid":false,"given":"Yuji","family":"Fujizuka","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syun","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4757-4633","authenticated-orcid":false,"given":"Akira","family":"Ohtsu","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8416-2394","authenticated-orcid":false,"given":"Yoshiyuki","family":"Miyazawa","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9514-735X","authenticated-orcid":false,"given":"Seiji","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Nomura","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3735-2769","authenticated-orcid":false,"given":"Kazuto","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Urology Kurosawa Hospital Takasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1448-7273","authenticated-orcid":false,"given":"Kazuhiro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Urology Gunma University Graduate School of Medicine Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"issue":"1","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.eururo.2019.02.009","article-title":"A 16\u2010yr Follow\u2010Up of the European Randomized Study of Screening for Prostate Cancer","volume":"76","author":"Hugosson J.","year":"2019","journal-title":"European Urology"},{"issue":"1","key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.4111\/kju.2012.53.1.50","article-title":"A Prospective Study of Reducing Unnecessary Prostate Biopsy in Patients With High Serum Prostate\u2010Specific Antigen With Consideration of Prostatic Inflammation","volume":"53","author":"Lee A. 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Prostate Cancer Screening Guidelines 2025. Igaku Tosho Shuppan;2025."},{"issue":"6","key":"e_1_2_13_17_1","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.eururo.2013.01.011","article-title":"Serum Isoform [\u20102]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2\u201310 ng\/mL: A Multicentric European Study","volume":"63","author":"Lazzeri M.","year":"2013","journal-title":"European Urology"},{"issue":"6","key":"e_1_2_13_18_1","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/iju.70024","article-title":"Utility of Combining Prostate Health Index and Magnetic Resonance Imaging for the Diagnosis of Prostate Cancer","volume":"32","author":"Sekine Y.","year":"2025","journal-title":"International Journal of Urology"},{"issue":"1","key":"e_1_2_13_19_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/pros.70055","article-title":"Enhancing Prostate Cancer Diagnosis: The Combined Value of PHI and mpMRI","volume":"86","author":"Y\u00e1\u00f1ez\u2010Castillo Y. 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Y.","year":"2003","journal-title":"Urology"},{"issue":"2","key":"e_1_2_13_23_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00432-013-1566-2","article-title":"The Impact of Baseline [\u20102]proPSA\u2010related Indices on the Prediction of Pathological Reclassification at 1 Year During Active Surveillance for Low\u2010Risk Prostate Cancer: The Japanese Multicenter Study Cohort","volume":"140","author":"Hirama H.","year":"2014","journal-title":"Journal of Cancer Research and Clinical Oncology"},{"issue":"8","key":"e_1_2_13_24_1","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/iju.13381","article-title":"Predictive Value of Different Prostate\u2010Specific Antigen\u2010Based Markers in Men With Baseline Total Prostate\u2010Specific Antigen <\u20092.0 ng\/mL","volume":"24","author":"Fujizuka Y.","year":"2017","journal-title":"International Journal of Urology: Official Journal of the Japanese Urological Association"},{"key":"e_1_2_13_25_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.cca.2022.04.992","article-title":"Value of PHI and PHID in the Detection of Intermediate\u2010 and High\u2010Risk Prostate Cancer","volume":"531","author":"Filella X.","year":"2022","journal-title":"Clinica Chimica Acta"},{"issue":"9","key":"e_1_2_13_26_1","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1159\/000517891","article-title":"Comparison of PHI and PHI Density for Prostate Cancer Detection in a Large Retrospective Caucasian Cohort","volume":"106","author":"Peters R.","year":"2022","journal-title":"Urologia Internationalis"},{"issue":"8","key":"e_1_2_13_27_1","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1515\/cclm-2022-0354","article-title":"Prostate Health Index (PHI) as a Reliable Biomarker for Prostate Cancer: A Systematic Review and Meta\u2010Analysis","volume":"60","author":"Agnello L.","year":"2022","journal-title":"Clinical Chemistry and Laboratory Medicine (CCLM)"},{"issue":"1","key":"e_1_2_13_28_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.5534\/wjmh.220223","article-title":"Nomogram Using Prostate Health Index for Predicting Prostate Cancer in the Gray Zone: Prospective, Multicenter Study","volume":"42","author":"Chung J. 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