RT Journal Article SR Electronic T1 Factors for differential outcome across cancers in clinical molecular-targeted fluorescence imaging JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP jnumed.121.263674 DO 10.2967/jnumed.121.263674 A1 Quan Zhou A1 Nynke S. van den Berg A1 Wenying Kang A1 Jacqueline Pei A1 Naoki Nishio A1 Stan van Keulen A1 Myrthe A. Engelen A1 Yu-Jin Lee A1 Marisa Hom A1 Johana C. M. Vega Leonel A1 Zachary Hart A1 Hannes Vogel A1 Romain Cayrol A1 Brock A. Martin A1 Mark Roesner A1 Glenn Shields A1 Natalie Lui A1 Melanie Hayden Gephart A1 Roan C. Raymundo A1 Grace Yi A1 Monica Granucci A1 Gerald A. Grant A1 Gordon Li A1 Eben L. Rosenthal YR 2022 UL http://jnm.snmjournals.org/content/early/2022/03/24/jnumed.121.263674.abstract AB Clinical imaging performance using a fluorescent antibody was compared across three cancers to elucidate physical and biological factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors. Methods: Thirty-one patients with high-grade glioma (HGG, n = 5), head-and-neck squamous cell carcinoma (HNSCC, n = 23) or lung adenocarcinoma (LAC, n = 3) were systemically infused with 50 mg panitumumab-IRDye800, 1 – 3 days prior to surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, where imaging device settings and operating room lighting conditions were tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surface. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histological structures. Integrity of the blood-brain barrier (BBB) was examined via tight junction protein (claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biological variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue. Results: Optimally acquired at the lowest gain for tumor detection with ambient light, intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold and 1.4-fold in HGG, HNSCC and LAC, respectively. Tissue surface fluorescence target-to-background ratio correlated with margin size and identified 78 – 97% of at-risk resection margins ex vivo. In 4 µm-thick tissue sections, fluorescence detected tumor with 0.85 – 0.89 areas under the receiver operating characteristic curves. Preferential breakdown of BBB in HGG improved tumor specificity of intratumoral antibody distribution relative to that of EGFR (96% vs 80%) despite its reduced concentration (3.9 ng/mg tissue) compared to HNSCC (8.1 ng/mg) and LAC (6.3 ng/mg). Cellular EGFR expression, tumor cell density, plasma antibody concentration and delivery barrier were independently associated with local intratumoral panitumumab-IRDye800 concentration with 0.62 goodness-of-fit of prediction. Conclusion: In multi-cancer clinical imaging of receptor-ligand based molecular probe, plasma antibody concentration, delivery barrier, as well as intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density, led to heterogeneous intratumoral antibody accumulation and spatial distribution while tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.