{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:40:56Z","timestamp":1785426056969,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dharmais National Cancer Hospital","award":["DP.04.03\/ D.XII.2.3\/ 577 \/2024"],"award-info":[{"award-number":["DP.04.03\/ D.XII.2.3\/ 577 \/2024"]}]},{"DOI":"10.13039\/501100006378","name":"Universitas Indonesia","doi-asserted-by":"crossref","award":["NKB-229\/UN2.RST\/HKP.05.00.2024"],"award-info":[{"award-number":["NKB-229\/UN2.RST\/HKP.05.00.2024"]}],"id":[{"id":"10.13039\/501100006378","id-type":"DOI","asserted-by":"crossref"}]},{"award":["NKB-229\/UN2.RST\/HKP.05.00.2024"],"award-info":[{"award-number":["NKB-229\/UN2.RST\/HKP.05.00.2024"]}],"id":[{"id":"https:\/\/ror.org\/0116zj450","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Hepatocellular carcinoma (HCC) shows a high rate of early recurrence after curative resection, indicating a critical contribution of tumor microenvironment-driven molecular mechanisms. Early recurrence of hepatocellular carcinoma is defined as recurrence within 6 months after curative resection, with a prevalence exceeding 30%. Hypoxia signaling and immune dysregulation have been implicated, yet their compartment-specific relevance remains unclear. Methods: This multicenter nested case\u2013control study included 49 HCC patients to evaluate associations between hypoxia-inducible factor-1 alpha (HIF-1\u03b1), vascular endothelial growth factor (VEGF), tumor-infiltrating lymphocytes (TILs), CD4+ T cells, CD8+ T cells, regulatory T cells (Tregs), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) and early recurrence after resection. TIL density was assessed using hematoxylin and eosin staining, while immunohistochemistry was performed to quantify intratumoral and peritumoral expression of the studied markers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance. Recurrence-free survival (RFS) was analyzed using the Kaplan\u2013Meier, and independent predictors were identified using multivariate Cox proportional hazards regression. Results: Early recurrence occurred in 11 of 49 patients (22.4%) of Child\u2013Pugh A patients. Recurrent tumors were characterized by elevated VEGF expression despite absent HIF-1\u03b1, alongside significant depletion of intratumoral TILs (HR 5.02; 95% CI 1.09\u201323.26), CD4+ (HR 7.68; 95% CI 1.66\u201335.60) and CD8+ cells (HR 6.68; 95% CI 1.77\u201325.23) and reduced peritumoral CD8+ infiltration (HR 4.20; 95% CI 1.11\u201315.91). Multivariable analysis identified low intratumoral CD4+ (HR 7.98; 95% CI 1.63\u201339.07) and reduced peritumoral CD8+ expression (HR 4.98; 95% CI 1.14\u201321.70) as independent predictors, whereas HIF-1\u03b1, VEGF, Treg, PD-1, and PD-L1 were not significantly associated. Conclusions: Early HCC recurrence shows HIF-1\u03b1-independent angiogenesis alongside spatial immune depletion, supporting integrated immune profiling over single angiogenic markers.<\/jats:p>","DOI":"10.3390\/biom16050723","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:46:18Z","timestamp":1779381978000},"page":"723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early Recurrence of HCC Is Driven by Inflammation-Related HIF-1\u03b1 Independent Angiogenesis Rather than Hypoxia-Induced Immune Escape"],"prefix":"10.3390","volume":"16","author":[{"given":"Lianda","family":"Siregar","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rino Alvani","family":"Gani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toar J. M.","family":"Lalisang","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irsan","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Suhendro","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heriawan","family":"Soejono","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siti Boedina","family":"Kresno","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurjati Chairani","family":"Siregar","sequence":"additional","affiliation":[{"name":"Department of Pathological Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Begawan","family":"Bestari","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Universitas Padjajaran, Bandung 40161, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.3748\/wjg.v29.i8.1243","article-title":"Predictors of Early and Late Hepatocellular Carcinoma Recurrence","volume":"29","author":"Nevola","year":"2023","journal-title":"World J. 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