{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:37Z","timestamp":1787028577519,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While standard anti- vascular endothelial growth factor (VEGF) therapy, with or without photodynamic therapy (PDT), is effective for patients with polypoidal choroidal vasculopathy (PCV), not all achieve optimal visual outcomes. This study aimed to compare fortified (double the dose and the volume of the standard one) anti-VEGF combined with PDT versus fortified anti-VEGF monotherapy and to investigate biomolecular profiles and disease relationships among PCV, neovascular age-related macular degeneration (nvAMD), and central serous chorioretinopathy (CSCR). The goal was to identify novel pathways to inform future therapeutic strategies, including hypoxia-inducible factors (HIF)-1\u03b1 inhibitors. This retrospective cohort study included 23 eyes with indocyanine green-confirmed type C PCV. One eye treated with transpupillary thermotherapy was not included in the following two groups. Patients received either combined therapy (PDT + fortified-dose anti-VEGF; n = 12) or fortified-dose anti-VEGF monotherapy (n = 10). Primary outcomes were changes in best-corrected visual acuity\u00a0(BCVA) and central retinal thickness\u00a0(CRT). Secondary outcomes included injection burden and recurrence. Exploratory analyses examined aqueous biomarkers, including VEGF, placental growth factor (PlGF), \u03b2-catenin, HIF-1\u03b1, and Wnt1 across PCV, CSCR, and nvAMD to identify novel therapeutic targets.\u00a0Significant (p\u00a0= 0.003\/p = 0.005) median CRT reduction was similar (p\u00a0= 0.468) between groups (combined\/monotherapy: 137.5 \u00b5m\/106.5 \u00b5m). BCVA (median [Q1, Q3]) change in logarithm of the minimum angle of resolution (LogMAR) was not statistically significant (p = 0.279), with 0.25 [0.00, 0.98] in the combined group versus 0.00 [\u22120.03, 0.28] in the monotherapy group. Treatment burden of anti-VEGFs per person per year was lower with combined therapy (1.16 \u00b1 0.47# PDT + 2.81 \u00b1 0.92# anti-VEGF injections) compared with monotherapy (4.61 \u00b1 1.49# injections). Six eyes demonstrated recurrence at a mean of 15.5 months. Incomplete regression of polyps and branching vascular networks was observed in all eyes. Exploratory biomarker analysis revealed significantly (p &lt; 0.05) higher VEGF and PlGF levels in nvAMD compared with PCV. nvAMD also demonstrated significantly (p &lt; 0.05) higher\u00a0\u03b2-catenin and lower HIF-1\u03b1 levels relative to PCV and CSCR, while no significant biomarker differences were observed between PCV and CSCR.\u00a0Combined therapy or monotherapy with fortified anti-VEGFs reduced treatment burden and achieved significant anatomical improvement but did not yield superior functional outcomes, highlighting the therapeutic difficulty of type C PCV. Biomarker profiling revealed shared hypoxia-related mechanisms between PCV and CSCR, with elevated HIF-1\u03b1 compared to nvAMD indicating a \u201cpreliminary\u201d possible role for HIF-1\u03b1 inhibitors. Differential expression of these biomarkers highlights additional molecular pathways that may inform future targeted interventions.<\/jats:p>","DOI":"10.3390\/ijms27031224","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T11:14:07Z","timestamp":1769426047000},"page":"1224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined Therapy Versus Fortified Anti-VEGF Monotherapy in Type C Polypoidal Choroidal Vasculopathy: Long-Term Outcomes and Exploratory Biomarker Insights"],"prefix":"10.3390","volume":"27","author":[{"given":"Windsor Wen-Jin","family":"Chao","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine, Aston University, Birmingham B4 7ET, UK"},{"name":"Department of Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard Wen-Haur","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Aston University, Birmingham B4 7ET, UK"},{"name":"Department of Medical Education, Leeds University, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiao-Ming","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan"},{"name":"Department of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"van Dijk, E.H.C., Holtz, J.K., Sirks, M.J., Larsson, J.M.E., Diederen, R.M.H., Schlingemann, R.O., Boon, C.J.F., and Subhi, Y. 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