{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:59:54Z","timestamp":1780898394100,"version":"3.54.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>This study aimed to assess the prognostic values of the S-GRAS model and two of the most frequently used inflammation-based scores \u2013 neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) \u2013 and to characterise the potential interaction between the two measures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and methods<\/jats:title>\n                    <jats:p>In this single-centre, retrospective, observational cohort analysis, 67 adult patients with histologically confirmed adrenocortical carcinoma (ACC) were analysed. The S-GRAS score and the inflammation-based markers were evaluated using Kaplan-Meier survival analysis with log-rank tests, univariate and multivariate Cox proportional hazards regressions. Discriminative ability was assessed using Harrell\u2019s C-index, later compared with likelihood ratio tests. An interaction analysis was conducted by constructing a multivariate regression with mean-centred variables and their interaction term.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>External validation on the S-GRAS scoring system demonstrated the superior discriminative ability of the model (C-index=0.765) compared to its constituents. Our sub-analysis on 42 patients identified NLR as a significant predictor of mortality (HR\u00a0=\u00a03.1; p=0.008), whilst PLR failed to reach statistical significance. Our interaction analysis revealed a significant synergistic interaction between S-GRAS and NLR (HR\u00a0=\u00a01.177, p=0.009). While both S-GRAS (C-index=0.803) and NLR (C-index=0.722) was found to be a significant predictor of survival, their joint application demonstrated superior prognostic discrimination (C-index=0.822) over their individual use (p=0.006 and p&amp;lt;0.001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NLR provides independent and complementary predictive value to the well-established S-GRAS score, and their combination offers superior discrimination over each marker alone. A synergistic interaction between the two metrics is the most prominent in high-risk patient groups. External validation confirms the prognostic robustness of the S-GRAS score.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1733138","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:35:52Z","timestamp":1780896952000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["S-GRAS score and the complementary prognostic value of neutrophil-to-lymphocyte ratio in adrenocortical carcinoma: evidence for a synergistic interaction"],"prefix":"10.3389","volume":"17","author":[{"given":"Erik","family":"B\u00e9nyei","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"Huszty","sequence":"additional","affiliation":[{"name":"Department of Surgery, Transplantation and Gastroenterology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Laki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Jakab","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"Kiss","sequence":"additional","affiliation":[{"name":"Medical Imaging Centre, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila Krist\u00f3f","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Forensic and Insurance Medicine, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Borka","sequence":"additional","affiliation":[{"name":"Department of Pathology, Forensic and Insurance Medicine, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Uhlyarik","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Eitler","sequence":"additional","affiliation":[{"name":"Department of Surgery, Transplantation and Gastroenterology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Igaz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]},{"name":"Department of Endocrinology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"T\u0151ke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikl\u00f3s","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2014.08.018","article-title":"A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage i\/ii disease","volume":"156","author":"Asare","year":"2014","journal-title":"Surgery"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2013.02.034","article-title":"Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993","volume":"49","author":"Kerkhofs","year":"2013","journal-title":"Eur J Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2856","article-title":"Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma","volume":"99","author":"Else","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1530\/eje-13-0519","article-title":"Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center","volume":"169","author":"Ayala-Ramirez","year":"2013","journal-title":"Eur J Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2023.100759","article-title":"Adrenocortical carcinoma: diagnosis, prognostic classification and treatment of localized and advanced disease","volume":"37","author":"Lib\u00e9","year":"2023","journal-title":"Cancer Treat Res Commun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14163904","article-title":"The overall survival and progression-free survival in patients with advanced adrenocortical cancer is increased after the multidisciplinary team evaluation","volume":"14","author":"Tizianel","year":"2022","journal-title":"Cancers Bsl"},{"key":"B7","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s12894-015-0038-1","article-title":"Survival and prognostic factors for adrenocortical carcinoma: a single institution experience","volume":"15","author":"Loncar","year":"2015","journal-title":"BMC Urol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvac112","article-title":"Prognostic factors in advanced adrenocortical carcinoma: summary of a national referral center's 20 years of experience","volume":"6","author":"Arnon","year":"2022","journal-title":"J Endocr Soc"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08660.x","article-title":"External validation of a nomogram predicting mortality in patients with adrenocortical carcinoma","volume":"104","author":"Zini","year":"2009","journal-title":"BJU Int"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2147\/cmar.S187169","article-title":"Nomograms to predict overall survival and cancer-specific survival in patients with adrenocortical carcinoma","volume":"10","author":"Li","year":"2018","journal-title":"Cancer Manag Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2015.4516","article-title":"Nomograms to predict recurrence-free and overall survival after curative resection of adrenocortical carcinoma","volume":"151","author":"Kim","year":"2016","journal-title":"JAMA Surg"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s40880-019-0426-0","article-title":"A nomogram for individualized estimation of survival among adult patients with adrenocortical carcinoma after surgery: a retrospective analysis and multicenter validation study","volume":"39","author":"Kong","year":"2019","journal-title":"Cancer Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv329","article-title":"Prognostic factors in stage iii-iv adrenocortical carcinomas (acc): an European network for the study of adrenal tumor (ensat) study","volume":"26","author":"Lib\u00e9","year":"2015","journal-title":"Ann Oncol Off J Eur Soc For Med Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3182","article-title":"Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection","volume":"100","author":"Beuschlein","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2559","article-title":"The role of surgery in the management of recurrent adrenocortical carcinoma","volume":"98","author":"Erdogan","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2013.11.006","article-title":"Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer","volume":"65","author":"Berruti","year":"2014","journal-title":"Eur Urol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-020-09562-8","article-title":"Cumulative GRAS score as a predictor of survival after resection for adrenocortical carcinoma: analysis from the U.S. adrenocortical carcinoma database","volume":"28","author":"Baechle","year":"2021","journal-title":"Ann Surg Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1530\/eje-21-0510","article-title":"S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study","volume":"186","author":"Elhassan","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac470","article-title":"Prognostic role of targeted methylation analysis in paraffin-embedded samples of adrenocortical carcinoma","volume":"107","author":"Lippert","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2024.2086","article-title":"The modified S-GRAS scoring system for prognosis in Korean with adrenocortical carcinoma","volume":"39","author":"Baek","year":"2024","journal-title":"Endocrinol Metab Seoul"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/bjsopen\/zrae001","article-title":"Stage, grade, resection status, age, symptoms (S-GRAS) score in predicting survival after resection of adrenocortical carcinomas","volume":"8","author":"Mihai","year":"2024","journal-title":"BJS Open"},{"key":"B22","doi-asserted-by":"publisher","first-page":"16717","DOI":"10.1038\/s41598-017-16955-5","article-title":"The role of the systemic inflammatory response in predicting outcomes in patients with operable cancer: systematic review and meta-analysis","volume":"7","author":"Dolan","year":"2017","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab238","article-title":"Serum inflammation-based scores in endocrine tumors","volume":"106","author":"Marques","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/jso.23982","article-title":"Neutrophil-lymphocyte and platelet-lymphocyte ratio as predictors of disease specific survival after resection of adrenocortical carcinoma","volume":"112","author":"Bagante","year":"2015","journal-title":"J Surg Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-020-05868-6","article-title":"Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as possible prognostic markers for patients undergoing resection of adrenocortical carcinoma","volume":"45","author":"de Jong","year":"2021","journal-title":"World J Surg"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jso.25760","article-title":"Preoperative systemic inflammatory markers are prognostic indicators in recurrent adrenocortical carcinoma","volume":"120","author":"Gaitanidis","year":"2019","journal-title":"J Surg Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1080\/07435800.2020.1870234","article-title":"Neutrophil-lymphocyte ratio as a prognostic marker in adrenocortical carcinoma","volume":"46","author":"Solak","year":"2021","journal-title":"Endocr Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.952418","article-title":"Prognostic factors and mitotane treatment of adrenocortical cancer. Two decades of experience from an institutional case series","volume":"13","author":"T\u0151ke","year":"2022","journal-title":"Front Endocrinol Lausanne"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju124","article-title":"Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis","volume":"106","author":"Templeton","year":"2014","journal-title":"J Natl Cancer Inst"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/ejendo\/lvag046","article-title":"Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study","volume":"194","author":"Mangone","year":"2026","journal-title":"Eur J Endocrinol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.08.2099","article-title":"Adrenocortical carcinomas and Malignant phaeochromocytomas: ESMO-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Fassnacht","year":"2020","journal-title":"Ann Oncol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/eje-18-0608","article-title":"European Society of Endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"179","author":"Fassnacht","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4158\/dscr-2020-0567","article-title":"American Association of Clinical Endocrinology disease state clinical review on the evaluation and management of adrenocortical carcinoma in an adult: a practical approach","volume":"26","author":"Kiseljak-Vassiliades","year":"2020","journal-title":"Endocr Pract"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1530\/ec-22-0114","article-title":"S-GRAS score performs better than a model from SEER for patients with adrenocortical carcinoma","volume":"11","author":"Lin","year":"2022","journal-title":"Endocr Connect"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1530\/eje-22-0173","article-title":"Assessment of prognostic factors in pediatric adrenocortical tumors: a systematic review and evaluation of a modified S-GRAS score","volume":"187","author":"Riedmeier","year":"2022","journal-title":"Eur J Endocrinol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1093\/ejendo\/lvae079","article-title":"Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort\u2014a work from the ENSAT-PACT working group","volume":"191","author":"Riedmeier","year":"2024","journal-title":"Eur J Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15010225","article-title":"Outcome for pediatric adreno-cortical tumors is best predicted by the COG stage and five-item microscopic score\u2014report from the German MET studies","volume":"15","author":"Kuhlen","year":"2023","journal-title":"Cancers"},{"key":"B38","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s12916-020-01817-1","article-title":"Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies","volume":"18","author":"Cupp","year":"2020","journal-title":"BMC Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cca.2018.04.023","article-title":"Platelet-to-lymphocyte ratio in advanced cancer: review and meta-analysis","volume":"483","author":"Li","year":"2018","journal-title":"Clin Chim Acta"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1530\/erc-24-0244","article-title":"Inflammation-based score in pediatric adrenocortical carcinoma","volume":"32","author":"Riedmeier","year":"2025","journal-title":"Endocr Relat Cancer"},{"key":"B41","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s12894-017-0240-4","article-title":"The neutrophil-to-lymphocyte ratio (NLR) predicts adrenocortical carcinoma and is correlated with the prognosis","volume":"17","author":"Mochizuki","year":"2017","journal-title":"BMC Urol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s40618-024-02426-y","article-title":"Inflammation-based scores in a large cohort of adrenocortical carcinoma and adrenocortical adenoma: role of the hormonal secretion pattern","volume":"48","author":"Mangone","year":"2025","journal-title":"J Endocrinol Invest"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1530\/erc-22-0372","article-title":"Inflammation-based scores as predictors of treatment response in advanced adrenocortical carcinoma","volume":"30","author":"Mangone","year":"2023","journal-title":"Endocr Relat Cancer"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1530\/eje-22-0211","article-title":"Subtype-specific pattern of white blood cell differential in endogenous hypercortisolism","volume":"187","author":"Detomas","year":"2022","journal-title":"Eur J Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1733138\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:35:53Z","timestamp":1780896953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1733138\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":44,"alternative-id":["10.3389\/fendo.2026.1733138"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1733138","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]},"article-number":"1733138"}}