{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:48:01Z","timestamp":1782452881554,"version":"3.54.5"},"reference-count":14,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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":["Int J of Urology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate inflammatory biomarkers (neutrophil\u2010to\u2010lymphocyte ratio [NLR], C\u2010reactive protein [CRP]) as continuous variables and assess linearity and the proportional hazards (PH) assumption, including time\u2010varying effects, in metastatic renal cell carcinoma (mRCC) treated with first\u2010line immune checkpoint inhibitor (ICI)\u2010based combinations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter retrospective study included 151 patients with mRCC. Log\u2010transformed NLR and CRP were tested for linearity (quadratic terms) and PH (Schoenfeld residuals). Multivariable Cox regression was adjusted for International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor count and treatment regimen. Time\u2010varying effects were assessed using marker \u00d7 log(time) interactions and 12\u2010month landmark analyses; incremental discrimination beyond IMDC was evaluated using Harrell's concordance index.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Log\u2010transformed NLR and CRP showed no statistically significant evidence of nonlinearity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.211 and\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.055, respectively). NLR showed evidence of PH violation for all outcomes, whereas CRP did not. On multivariable analysis, NLR remained associated with overall survival (OS; adjusted hazard ratio [HR] 2.10, 95% confidence interval 1.26\u20133.49,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.005) and cancer\u2010specific survival (adjusted HR 2.04, 1.20\u20133.47,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.009). Landmark analysis suggested a stronger OS association during 0\u201312\u2009months (HR 2.61, 1.49\u20134.59) than after 12\u2009months (0.93, 0.37\u20132.34). Adding NLR to IMDC modestly improved OS discrimination (\u0394C\u2010index +0.038, bootstrap\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.052).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Log\u2010transformed inflammatory markers showed no statistically significant evidence of nonlinearity. NLR showed exploratory evidence of time\u2010varying prognostic associations, with stronger discrimination during earlier follow\u2010up.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iju.70536","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:59:37Z","timestamp":1780905577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prognostic Value of Inflammatory Biomarkers as Continuous Variables in Metastatic Renal Cell Carcinoma: Linearity Assessment, Proportional Hazards Assumption Testing, and Time\u2010Varying Effects"],"prefix":"10.1111","volume":"33","author":[{"given":"Shugo","family":"Yajima","sequence":"first","affiliation":[{"name":"Department of Urology National Cancer Center Hospital East  Chiba Japan"},{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-8083","authenticated-orcid":false,"given":"Soichiro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-8338","authenticated-orcid":false,"given":"Shohei","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-9887","authenticated-orcid":false,"given":"Hiroyuki","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2580-7460","authenticated-orcid":false,"given":"Akihiro","family":"Hirakawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Urology Saitama Cancer Center  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Department of Urology Saitama Cancer Center  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3632-2901","authenticated-orcid":false,"given":"Hajime","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaharu","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Urology Cancer Institute Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Numao","sequence":"additional","affiliation":[{"name":"Department of Urology Cancer Institute Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Yonese","sequence":"additional","affiliation":[{"name":"Department of Urology Cancer Institute Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9297-2664","authenticated-orcid":false,"given":"Akinori","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Urology Dokkyo Medical University Saitama Medical Center  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7261-0188","authenticated-orcid":false,"given":"Kazutaka","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Urology Dokkyo Medical University Saitama Medical Center  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0230-6367","authenticated-orcid":false,"given":"Masaya","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Urology Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7888-0085","authenticated-orcid":false,"given":"Fumitaka","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Urology Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Masuda","sequence":"additional","affiliation":[{"name":"Department of Urology National Cancer Center Hospital East  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhisa","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Urology Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1712126"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1816714"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1816047"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2026982"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.2217\/imt\u20102018\u20100175"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2011.145"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010001564"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2331"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.332.7549.1080"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/17588359211019642"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12055\u2010020\u201001108\u20107"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.55.2208"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/81.3.515"}],"container-title":["International Journal of Urology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/iju.70536","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/iju.70536","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/iju.70536","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:18:41Z","timestamp":1782451121000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/iju.70536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":14,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1111\/iju.70536"],"URL":"https:\/\/doi.org\/10.1111\/iju.70536","archive":["Portico"],"relation":{},"ISSN":["0919-8172","1442-2042"],"issn-type":[{"value":"0919-8172","type":"print"},{"value":"1442-2042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2026-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70536"}}