F-Fluoromisonidazole-Positron Emission Tomography and Immunohistochemistry Verified Tumor Oxygenation, Stemness, and Immunosupportive Microenvironment After Preoperative Neoadjuvant Bevacizumab for Newly Diagnosed Glioblastoma

-BACKGROUND: Cancer stemness and immunosuppres-sive tumor microenvironment (TME) in accordance with tumor oxygenation are variable during bevacizumab (Bev) therapy for glioblastoma (GBM). Positron emission tomog-raphy (PET) using 18F-fluoromisonidazole (FMISO) reflects hypoxic TME. The aim of this study was to compare FMISO-PET and immunohistochemical findings of tumor oxygena-tion in the TME of GBM during Bev treatment. -METHODS: Seven patients with newly diagnosed IDH-wildtype GBM underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) and subsequently underwent surgical resection. Reoperation was performed at the recurrence. FMISO-PET was performed before and after neo-Bev. Four patients who underwent tumor resection without neo-Bev were included as the control group. Expressions of hypoxic markers (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-L1) in tumor tissues were analyzed by immu-nohistochemistry (IHC). -RESULTS: All 3 patients treated with neo-Bev showed decrease in FMISO accumulation in accordance with ex-pressions of CA9 and FOXM1 compared with the control group. Two of these 3 patients at the recurrence showed increase in FMISO accumulation. IHC showed increased CA9-and FOXM1-positive cells in recurrent tumors. Expression of PD-L1 tended to be lower after neo-Bev compared with the control group. -CONCLUSIONS: FMISO-PET effectively visualized TME oxygenation after neo-Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, sug-gests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.