Dual-modality GRPR targeting PET and optical image-guided surgery in lower grade glioma using ⁶⁸Ga-IRDye800CW-BBN

Objectives: Lower grade gliomas (WHO grades II and III) are currently diffused disease with variability of tumor behaviors and of challenge to distinguish the margins in white-light microscope. The currently used fluorescence-guided surgery (FGS) with the aid of 5-ALA is still limited because of the low sensitivity and the lack of relevant prediction preoperatively. An integrated dual-modality approach combining preoperative PET imaging with intraoperative optical guidance that target the same tumor biomarker might solve this problem. The aim of this study was to explore a novel gastrin-releasing peptide receptor (GRPR) targeting ⁶⁸Ga-IRDye800CW-BBN dual-modality PET and optical imaging in patients with lower grade gliomas, to assess the sensitivity and specificity of intraoperative IRDye800CW-BBN fluorescence.

Methods: Thirty-three consecutive patients (M 14, F 19, Age 29-62y) with suspected lower grade gliomas on contrast-enhanced MRI were enrolled. Cohort 1 included 10 patients who underwent both preoperative ⁶⁸Ga-NOTA-Aca-BBN PET and the following intraoperative IRDye800CW-BBN FGS. Cohort 2 included 23 patients with IRDye800CW-BBN FGS. PET/CT or PET/MRI were performed at 30 min after injection of ⁶⁸Ga-NOTA-Aca-BBN (1.85 MBq per kilogram of body weight) intravenously and all patients received intravenous injection of 1.0 mg or 2.0 mg IRDye800CW-BBN diluted in 1.0 mL sterile water at 16-20 h before the surgery. Blood count, biochemistry test, any allergy or discomforts were recorded for safety assessment. Semi-quantitative analysis weas used for PET imaging assessment. Intraoperatively multiple fluorescence guided samples were confirmed with H&E and GRPR immunohistochemical staining. Results: No allergy or clinically significant changes were noticed. Mild nausea and sinus tachycardia were reported but disappeared within 20 min. In cohort 1, 8 in 10 patients showed positive lesions on both ⁶⁸Ga-NOTA-Aca-BBN PET and IRDye800CW-BBN intraoperative fluorescence imaging, with pathological confirmation as anaplastic oligoastrocytoma (n=6) and astrocytoma (n=2). The SUVmax and SUVmean on PET were 1.11 ± 0.56 and 0.69 ± 0.34, and tumor-to-background ratios were 25.41 ± 16.09 and 15.87 ± 9.78, respectively. The preoperative MRI showed partial enhancement in the 6 WHO grade III gliomas and patchy enhancement in the 2 WHO grade II gliomas with positive fluorescence. The other 2 patients were negative on both PET and fluorescence with pathologically confirmed anaplastic astrocytoma and astrocytoma, respectively. In cohort 2, 9 in 10 patients with gliomas of WHO grade III and 4 in 13 with WHO grade II were positive on the intraoperative fluorescence imaging. The accuracy of predicting intraoperative FGS feasibility using MRI enhancement as a surrogate indicator was 78.3% (18/23). The overall sensitivity of fluorescence was 94.1% (16/17) in WHO grade III and 37.5% (6/16) in WHO grade II gliomas. A total of 76 samples from 22 patients showing overall positive fluorescence were obtained, including 53 regional samples with positive fluorescence and 23 regional negative samples. The sensitivity and specificity were 89.3% and 69.6%. The immunohistochemical staining result showed positive GRPR expression in all fluorescence positive samples. The enhancement volume was completely resected in all patients, except two patients with eloquence grade III lesions. Conclusions: This study demonstrated the feasibility of a novel dual-modality ⁶⁸Ga-IRDye800CW-BBN PET/NIRF imaging in patients with lower grade gliomas. IRDye800CW-BBN intraoperative optical image may be of great value in guiding precise surgery in lower grade gliomas patients. The preoperative PET also has potential to choose the optimal lower grade gliomas patients with IRDye800CW-BBN FGS which might allow more extent of maximal safe resection.

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