{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:32:05Z","timestamp":1787157125182,"version":"build-2736575974"},"reference-count":19,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Anastomotic leakage is a serious complication after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Among patients who develop leakage, early identification of those requiring operative source control remains difficult. This study evaluated the discriminatory performance of early postoperative inflammatory and metabolic biomarkers for subsequent operative source control. Methods: This multicenter retrospective cohort study screened 540 patients who underwent CRS-HIPEC between January 2015 and January 2025. Anastomotic leakage was identified in 51 patients. Four patients underwent reoperation before completion of the postoperative day (POD) 3 laboratory assessment: two for anastomotic leakage and two for postoperative bleeding. Three additional patients were excluded because the clinical or laboratory data required for the primary analyses were unavailable. The final cohort comprised 44 patients, of whom 24 (54.5%) subsequently underwent operative source control for anastomotic leakage and 20 (45.5%) were managed without reoperation through one month. C-reactive protein (CRP), albumin, neutrophil-to-lymphocyte ratio (NLR), white blood cell count, glucose, CRP-to-albumin ratio (CAR), and leukoglycemic index (LGI) were assessed on POD1 and POD3. All POD1 and POD3 laboratory measurements were obtained before operative source control in patients who subsequently underwent reoperation. Discriminatory performance was evaluated using receiver operating characteristic analysis. Post hoc, data-informed Firth penalized logistic regression models were used to explore the associations of POD1 CRP and POD3 NLR with operative source control after adjustment for BMI and HIPEC agent. Results: NLR was significantly higher in patients who subsequently required operative source control on both POD1 (median, 14.9 vs. 9.8; p &lt; 0.001) and POD3 (21.0 vs. 9.8; p &lt; 0.001). The increase in NLR from POD1 to POD3 was also greater in the operative group (median change, 4.8 vs. 1.0; p = 0.009). POD3 NLR showed the highest observed discriminatory performance (area under the curve [AUC], 0.901; 95% confidence interval [CI], 0.810\u20130.992), while POD1 NLR (AUC, 0.834; 95% CI, 0.717\u20130.951) and POD1 CRP (AUC, 0.798; 95% CI, 0.649\u20130.947) also showed good observed discrimination. POD3 CRP-to-albumin ratio showed moderate discrimination, whereas POD3 LGI showed more limited performance. In post hoc exploratory Firth models adjusted for BMI and HIPEC agent, POD1 CRP per 10 mg\/L increase (adjusted odds ratio [aOR], 1.52; 95% CI, 1.10\u20132.56; p = 0.006) and POD3 NLR per 5-unit increase (aOR, 3.91; 95% CI, 1.57\u201320.23; p = 0.001) remained associated with operative source control. All ROC-derived cutoff values and their operating characteristics were data-derived, intended solely for hypothesis generation, and should not be used for clinical decision-making. Conclusions: Within this selected retrospective cohort, POD3 NLR showed the highest observed discriminatory performance and remained associated with subsequent operative source control in a post hoc exploratory adjusted model. POD1 NLR and POD1 CRP also provided exploratory discriminatory information, while the greater increase in NLR from POD1 to POD3 suggests that serial biomarker trajectories warrant further investigation. These findings, including the data-derived cutoff estimates, are intended solely for hypothesis generation and should not be used for clinical decision-making. Prospective external validation is required.<\/jats:p>","DOI":"10.3390\/diagnostics16162647","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:12:58Z","timestamp":1787155978000},"page":"2647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early Postoperative Biomarkers Associated with Subsequent Operative Source Control in Anastomotic Leakage After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multicenter Retrospective Cohort Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0881-1003","authenticated-orcid":false,"given":"Erkan","family":"G\u00fcler","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Mersin University School of Medicine, Mersin 33110, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2193-9984","authenticated-orcid":false,"given":"Kamil","family":"Er\u00f6zkan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3192-4359","authenticated-orcid":false,"given":"Volkan","family":"Sayur","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4086-4316","authenticated-orcid":false,"given":"Sami","family":"Benli","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Mersin University School of Medicine, Mersin 33110, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-025X","authenticated-orcid":false,"given":"Cumhur","family":"\u00d6zcan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mersin University School of Medicine, Mersin 33110, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-2720","authenticated-orcid":false,"given":"Osman","family":"Bozb\u0131y\u0131k","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cemil","family":"\u00c7al\u0131\u015fkan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-1392","authenticated-orcid":false,"given":"Hamza","family":"\u00c7\u0131nar","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Gastrointestinal Surgery, Pamukkale University School of Medicine, Denizli 20010, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1861-8282","authenticated-orcid":false,"given":"Tufan","family":"G\u00fcm\u00fc\u015f","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1634-8365","authenticated-orcid":false,"given":"G\u00fcl\u015fah Selvi","family":"Demirta\u015f","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Denizli State Hospital, Denizli 20010, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7253-5608","authenticated-orcid":false,"given":"Tahsin","family":"\u00c7olak","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, Mersin University School of Medicine, Mersin 33110, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-6561","authenticated-orcid":false,"given":"Taylan \u00d6zg\u00fcr","family":"Sezer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Ege University School of Medicine, \u0130zmir 35100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1245\/s10434-023-14368-5","article-title":"2022 Peritoneal Surface Oncology Group International consensus on HIPEC regimens for peritoneal malignancies: Colorectal cancer","volume":"31","author":"Govaerts","year":"2024","journal-title":"Ann. Surg. Oncol."},{"key":"ref_2","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1016\/j.ejso.2022.05.018","article-title":"Anastomotic leakage after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer","volume":"48","author":"Feenstra","year":"2022","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"publisher","first-page":"107020","DOI":"10.1016\/j.ejso.2023.107020","article-title":"Risk factors for gastrointestinal perforation and anastomotic leak in patients submitted to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy","volume":"49","author":"Nogueiro","year":"2023","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_4","doi-asserted-by":"publisher","first-page":"370","DOI":"10.14744\/tjtes.2023.52358","article-title":"The risk factors for gastrointestinal anastomotic leak after cytoreduction with hyperthermic intraperitoneal chemotherapy","volume":"29","author":"Bisgin","year":"2023","journal-title":"Ulus. Travma Acil Cerrahi Derg."},{"key":"ref_5","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1055\/s-0041-1735271","article-title":"Management of acute anastomotic leaks","volume":"34","author":"Hedrick","year":"2021","journal-title":"Clin. Colon Rectal Surg."},{"key":"ref_6","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1245\/s10434-020-08619-y","article-title":"Predictive ability of C-reactive protein in detecting short-term complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A retrospective cross-sectional study","volume":"28","author":"Oemrawsingh","year":"2021","journal-title":"Ann. Surg. Oncol."},{"key":"ref_7","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.ejso.2021.09.015","article-title":"Inflammatory biomarkers to predict postoperative infectious complications after cytoreductive surgery and HIPEC for peritoneal carcinomatosis","volume":"48","author":"Amroun","year":"2022","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_8","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1007\/s11605-022-05473-z","article-title":"C-reactive protein and procalcitonin levels to predict anastomotic leak after colorectal surgery: Systematic review and meta-analysis","volume":"27","author":"Bona","year":"2023","journal-title":"J. Gastrointest. Surg."},{"key":"ref_9","doi-asserted-by":"publisher","first-page":"102201","DOI":"10.1016\/j.amsu.2021.102201","article-title":"Neutrophil-to-lymphocyte ratio vs C-reactive protein as early predictors of anastomotic leakage after colorectal surgery: A retrospective cohort study","volume":"64","author":"Gielis","year":"2021","journal-title":"Ann. Med. Surg."},{"key":"ref_10","doi-asserted-by":"publisher","unstructured":"Mu\u017eina, D., Kopljar, M., Bili\u0107, Z., Ladika Davidovi\u0107, B., Glav\u010di\u0107, G., Jankovi\u0107, S., and Ma\u010dki\u0107, M. (2024). The value of C-reactive protein and peritoneal cytokines as early predictors of anastomotic leak after colorectal surgery. Diagnostics, 14.","DOI":"10.3390\/diagnostics14182101"},{"key":"ref_11","doi-asserted-by":"publisher","unstructured":"Zhang, F., Qiao, S., Yao, N., Li, C., Weber, M.C., Jefferies, B., Friess, H., Reischl, S., and Neumann, P.A. (2022). Anastomotic rings and inflammation values as biomarkers for leakage of stapled circular colorectal anastomoses. Diagnostics, 12.","DOI":"10.3390\/diagnostics12122902"},{"key":"ref_12","doi-asserted-by":"publisher","first-page":"484","DOI":"10.21470\/1678-9741-2020-0349","article-title":"Prognostic value of the leuko-glycaemic index in the postoperative period of coronary artery bypass grafting","volume":"36","author":"Seoane","year":"2021","journal-title":"Braz. J. Cardiovasc. Surg."},{"key":"ref_13","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1245\/s10434-025-18712-9","article-title":"The clinical presentation of anastomotic leakage compared between CRS-HIPEC and conventional colorectal surgery","volume":"33","author":"Cats","year":"2026","journal-title":"Ann. Surg. Oncol."},{"key":"ref_14","doi-asserted-by":"publisher","unstructured":"Niemann, B.R., Murthy, J., Breinholt, C., Swords, J., Stevens, A., Garland-Kledzik, M., Mayers, K., Groves, E., Train, K., and Murken, D. (2025). Postoperative C-reactive protein trend is a more accurate predictor of anastomotic leak than absolute values alone. J. Clin. Med., 14.","DOI":"10.3390\/jcm14092931"},{"key":"ref_15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1515\/pp-2022-0203","article-title":"Early postoperative CRP predicts major complications following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy","volume":"8","author":"Kartik","year":"2023","journal-title":"Pleura Peritoneum"},{"key":"ref_16","doi-asserted-by":"publisher","unstructured":"Roux, A., David, V., Bardet, S.M., Auditeau, E., Durand Fontanier, S., and Taibi, A. (2022). Predictive value of C-reactive protein levels for the early and later detection of postoperative complications after cytoreductive surgery and HIPEC. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.943522"},{"key":"ref_17","doi-asserted-by":"publisher","unstructured":"Tan, F., Xu, K., Qi, X., Gao, P., Liu, M., Yao, Z., Zhang, N., Yang, H., Zhang, C., and Xing, J. (2023). Neutrophil-to-lymphocyte ratio as an early predictor of symptomatic anastomotic leakage in patients after rectal cancer surgery: A propensity score-matched analysis. J. Pers. Med., 13.","DOI":"10.3390\/jpm13010093"},{"key":"ref_18","doi-asserted-by":"publisher","unstructured":"Haghi, S.E., Khanzadeh, M., Sarejloo, S., Mirakhori, F., Hernandez, J., Dioso, E., Goutnik, M., Lucke-Wold, B., Ghaedi, A., and Khanzadeh, S. (2024). Systematic review of the significance of neutrophil to lymphocyte ratio in anastomotic leak after gastrointestinal surgeries. BMC Surg., 24.","DOI":"10.1186\/s12893-023-02292-0"},{"key":"ref_19","doi-asserted-by":"publisher","first-page":"101621","DOI":"10.1016\/j.suronc.2021.101621","article-title":"C reactive protein to albumin ratio (CAR) as predictor of anastomotic leakage in colorectal surgery","volume":"38","author":"Paliogiannis","year":"2021","journal-title":"Surg. Oncol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/16\/2647\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:14:13Z","timestamp":1787156053000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/16\/2647"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":19,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["diagnostics16162647"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16162647","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}