Circulating PDIA4, MMP-2, MMP-9, and Claudin-2 in Vitamin D-Deficient Patients with Brain Tumors: An Exploratory...

Background/Objectives: Extracellular matrix remodeling, cellular stress responses, and blood-brain/blood-tumor barrier-related alterations are important processes involved in brain tumor biology. This exploratory cross-sectional pilot study evaluated circulating circulating protein disulfide isomerase A4 (PDIA4), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and claudin-2 (CLDN2) concentrations in vitamin D-deficient patients with different brain tumor entities and aimed to provide preliminary effect-size estimates for future studies. Methods: A total of 62 vitamin D-deficient participants were included, comprising patients with glioblastoma (GBM; n = 15), brain metastases (n = 20), and meningioma (n = 8) and surgical controls with degenerative spine disease (n = 19). Serum biomarker concentrations were measured using enzyme-linked immunosorbent assays. Global between-group effect sizes were estimated using η², while exploratory pairwise comparisons and associations with tumor size were assessed using non-parametric methods. Effect-size estimates were prioritized, with p-values reported to provide complementary inferential context. Results: The largest global between-group effect-sizes were observed for CLDN2 (η² = 0.35) and MMP-2 (η² = 0.22), whereas the estimated effects were small for MMP-9 (η² = 0.05) and negligible for PDIA4 (η² = 0.00). Exploratory pairwise comparisons indicated lower serum MMP-2 concentrations in patients with GBM than in surgical controls and lower CLDN2 concentrations in patients with GBM and brain metastases than in controls. Positive exploratory associations were observed between tumor size and PDIA4 concentration in the GBM group (Spearman's rho = 0.56; 95% CI: 0.02-0.90) and between tumor size and MMP-2 concentration in patients with brain metastases (rho = 0.46; 95% CI: 0.01-0.90). Conclusions: These preliminary effect-size estimates, together with the exploratory correlations with tumor size, may inform biomarker selection and sample-size planning in future prospective studies. The findings should not be interpreted as robust diagnostic or prognostic evidence and require validation in larger, independent, and well-controlled cohorts.