FMISO-PET and immunohistochemistry verified tumor oxygenation, stemness, and immunosupportive microenvironment after preoperative neoadjuvant bevacizumab for newly diagnosed glioblastoma

Abstract

Background Gadolinium-enhanced magnetic resonance imaging and T2-weighted imaging/fluid-attenuated inversion recovery imaging are used to determine the efficacy of bevacizumab (Bev) against glioblastoma (GBM). Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) reflects hypoxia in the tumor microenvironment (TME). This study compared FMISO-PET findings for alterations in tumor oxygenation in the TME of GBM during Bev treatment. Materials and Methods We retrospectively reviewed data from 7 patients with newly diagnosed IDH (isocitrate dehydrogenase)-wildtype GBM who underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) followed by radiation therapy and temozolomide, and subsequently underwent surgical resection. Re-operation was performed for recurrence. FMISO-PET was performed at each time point. Four patients who underwent tumor resection after FMISO-PET without any preoperative interventions were also included as a Control group. Surgically obtained tumor tissues were analyzed for expression of a marker of hypoxia (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-1, PD-L1) by immunohistochemistry (IHC). Results All 3 patients treated with preoperative chemoradiotherapy showed reduced FMISO accumulation (maximum tumor-to-blood ratio and hypoxic volume) and decreases in CA9 and FOXM1 compared with Controls. Two cases in the preoperative neo-Bev group showed recurrence with increasing FMISO accumulation. IHC showed increased CA9- and FOXM1-positive cells at recurrence in both cases. A trend toward fewer CA9-positive cells was seen in patients with low FMISO accumulation both with and without neo-Bev (r = 0.90, p = 0.006). Expressions of immunoregulatory molecules tended to be lower after neo-Bev compared with the Control group and increased at recurrence, but these differences were not significant. Conclusion FMISO-PET effectively visualized improvements in TME oxygenation after preoperative chemoradiotherapy including Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, suggests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.