Abstract
<title>Abstract</title> <p>Background Despite major advances in immune checkpoint inhibitors and targeted therapies, metastatic cutaneous melanoma remains associated with substantial heterogeneity in clinical outcomes. Easily accessible prognostic biomarkers capable of integrating tumor burden, systemic inflammation, nutritional status, and host-related factors remain an unmet clinical need. We aimed to investigate the prognostic significance of the modified Endothelial Activation and Stress Index (mEASIX), inflammatory–nutritional biomarkers, metastatic patterns, and treatment characteristics in a multicenter real-world cohort of patients with metastatic cutaneous melanoma. Methods This multicenter retrospective study included 142 patients with stage IV cutaneous melanoma. Clinicopathological characteristics, BRAF mutation status, metastatic patterns, first- and second-line treatment strategies, and laboratory parameters were retrospectively reviewed. mEASIX, EASIX, Hemoglobin–Albumin–Lymphocyte–Platelet (HALP) score, Prognostic Nutritional Index (PNI), C-reactive Protein–Albumin Ratio (CAR), and Lymphocyte–C-reactive Protein Ratio (LCR) were calculated from baseline laboratory values. Overall survival (OS) was evaluated using Kaplan–Meier analyses and Cox proportional hazards models. Results A total of 142 patients were included, of whom 71.8% were male. BRAF mutations were detected in 38.0% of patients. Median overall survival for the entire cohort was 18 months. Metastatic pattern significantly influenced survival outcomes. Patients with isolated lymph node metastasis demonstrated the most favorable prognosis, with a median OS of 30 months, whereas patients with combined liver and brain metastases had the poorest outcomes, with a median OS of 15 months. Among the evaluated biomarkers, elevated mEASIX was associated with significantly inferior survival. Patients with high mEASIX demonstrated a median OS of 16 months compared with 31 months in patients with low mEASIX. In multivariable Cox regression analysis, elevated mEASIX remained independently associated with worse survival (HR 1.91, 95% CI 1.24–2.93; p=0.003). Elevated mEASIX remained independently associated with inferior OS, while combined liver and brain metastases independently predicted poor prognosis (HR 2.29, 95% CI 1.16–4.52; p=0.017). Treatment-specific analyses suggested differences in survival across systemic treatment strategies; however, treatment category was not independently associated with overall survival after multivariable adjustment. Conclusions mEASIX is an independent and clinically accessible prognostic biomarker in metastatic cutaneous melanoma. The integration of endothelial dysfunction markers, inflammatory–nutritional indices, metastatic patterns, and treatment characteristics improves risk stratification beyond conventional clinicopathological variables. Patients with elevated mEASIX and combined liver–brain metastases represent a particularly high-risk subgroup that may benefit from closer surveillance and individualized treatment strategies.</p>