Circulating Angiopoietin-1/Angiopoietin-2 ratio may reflect pre- and post-treatment vascular states in Glioblastoma and improve discrimination between tumor recurrence and radiation necrosis.

PURPOSE: Distinguishing Glioblastoma (GBM) recurrence from radiation-induced injury, including radiation necrosis (RN), remains a major clinical challenge in neuro-oncology. Because angiogenesis reflects dynamic vascular remodeling, we investigated whether longitudinal assessment of circulating angiogenic mediators, particularly the Angiopoietin-1 to Angiopoietin-2 ratio (Ang-1/Ang-2), could improve discrimination between disease progression and RN.

METHODS

In this prospective observational study, 42 patients with newly diagnosed GBM underwent peripheral blood (serum) sampling at index surgery and at reoperation. Circulating angiogenic and inflammatory mediators were quantified using a multiplex bead-based assay. Imaging findings were integrated with histopathological confirmation at reoperation (n = 21).

RESULTS

Baseline Ang-1/Ang-2 ratios were lower (median 3) in patients whose first post-treatment event was RN (n = 11) than in those developing tumor recurrence (median 7, p = 0.028). Higher Ang-1/Ang-2 were associated with reduced RN risk (HR 0.75, p = 0.031). Longitudinally, Ang-1 levels declined following chemoradiotherapy (median change − 9235 pg/mL; p = 0.002), resulting in reduced Ang-1/Ang-2 (p = 0.004). At reoperation, recurrent tumors exhibited higher peripheral Ang-1/Ang-2 than RN (median 2.36 vs. 1.48; p = 0.023). Correlation network analyses of peripheral mediators revealed dense, synchronized signaling in RN and modular network organization with reduced global synchronization in recurrence. The addition of Ang-1/Ang-2 provided a possible incremental explanatory value over advanced imaging alone (ROC 0.94 vs. 0.73; p = 0.055).

CONCLUSIONS

Peripheral assessment of the Ang-1/Ang-2 ratio may capture a compressed systemic signal reflecting the underlying vascular state beyond the blood-brain barrier. By encoding the balance between vascular stabilization and destabilization within the angiopoietin-Tie2 axis, this ratio provides biologically meaningful information and represents a mechanistically grounded biomarker.