115 [89Zr]Zr-DFO-avelumab PET/CT in early stage NSCLC patients Imaging assessment Contrast enhanced (ce)CT and 18F-FDG PET/CT At baseline, a [18F]FDG PET/CT and cacti of the chest was obtained, except when recent scan (<6 weeks prior to enrolment) was available. [18F]FDG PET/CT was performed according to European Association of Nuclear Medicine (EANM) guidelines version 1.016. Response assessment of CT lesions was performed according to RECIST 1.117 and according to PERCIST18 for [18F]FDG PET/ CT, in clinically available image analysis software Agfa Enterprise Imaging. [89Zr]Zr-DFO-avelumab PET/CT The quantification of [89Zr]Zr-DFO-avelumab PET/CT uptake in tumor lesions was performed by placing a 3D-sphere of at least 10 mm in [18F]FDG-positive lesions using Accurate tool software developed in IDL version 8.4 (Harris Geospatial Solutions, Bloomfield, USA))19. This was done for all [18F]FDG-positive lesions, irrespective of visual [89Zr]Zr-DFO-avelumab uptake. The SUV max and SUVpeak were used for tumor tracer-uptake; SUVmean to measure tracer uptake in healthy organs and blood pool. To correct for variable concentrations of circulating [89Zr]Zr-DFO-avelumab, tumor-to-blood (TTB) ratios were reported as SUVpeak tumor / SUVmean blood. Pathology PD-L1 immunohistochemistry Fresh cytological of histological material was available for all NSCLC patients. PD-L1 staining was performed using the DAKO 22C3 antibody on all available histological samples PD-L1 expression was reported as a percentage of tumor cells showing positive cell membrane staining and a score of <1, 1-49 or ≥50. The same analysis was performed on the surgical specimen. Pathological response Surgical specimens were evaluated by a dedicated pathologist for various histopathological features, including percentage of residual viable tumor cells, necrosis and fibrosis. Pathological response percentage was interpreted as the tumor nodule (100%) minus the percentage of viable tumor cells. A decrease of 90% vital tumor cells was considered major pathologic response (MPR) 20,21. Statistical analyses The clinical course of disease of patients with early-stage NSCLC was visualized in a swimmer’s plot and pathological response was depicted in a waterfall plot. Differences in tracer-uptake and TTB ratios between dose groups were tested for significance using a two-sided Kruskal Wallis. Spearman correlations were performed to correlate [89Zr]Zr-DFO-avelumab SUVpeak and TTB ratio to PD-L1 expression, pathological response, number/ratio of infiltrating immune cells, and [18F]FDG SUVpeak. Statistical analyses were performed using SPSS Statistics for windows version 22.0. Differences with a p-value of 0.05 or less were considered significant. 6
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