Factors for Differential Outcome Across Cancers in Clinical Molecule-Targeted Fluorescence Imaging.

in Journal of nuclear medicine : official publication, Society of Nuclear Medicine by Quan Zhou, Nynke S van den Berg, Wenying Kang, Jacqueline Pei, Naoki Nishio, Stan van Keulen, Myrthe A Engelen, Yu-Jin Lee, Marisa Hom, Johana C M Vega Leonel, Zachary Hart, Hannes Vogel, Romain Cayrol, Brock A Martin, Mark Roesner, Glenn Shields, Natalie Lui, Melanie Hayden Gephart, Roan C Raymundo, Grace Yi, Monica Granucci, Gerald A Grant, Gordon Li, Eben L Rosenthal

TLDR

  • The study compared the use of a special dye called panitumumab-IRDye800 to help doctors see cancer tumors during surgery across three types of cancer.
  • The study found that the dye worked better in certain cancers, like high-grade glioma, than others, and that factors like protein levels and dye delivery influenced its effectiveness.

Abstract

Clinical imaging performance using a fluorescent antibody was compared across 3 cancers to elucidate physical and biologic factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors.Thirty-one patients with high-grade glioma (HGG,= 5), head-and-neck squamous cell carcinoma (HNSCC,= 23), or lung adenocarcinoma (LAC,= 3) were systemically infused with 50 mg of panitumumab-IRDye800 1-3 d before surgery. Intraoperative open-field fluorescent images of the surgical field were acquired, with imaging device settings and operating room lighting conditions being tested on tissue-mimicking phantoms. Fluorescence contrast and margin size were measured on resected specimen surfaces. Antibody distribution and EGFR immunoreactivity were characterized in macroscopic and microscopic histologic structures. The integrity of the blood-brain barrier was examined via tight junction protein (Claudin-5) expression with immunohistochemistry. Stepwise multivariate linear regression of biologic variables was performed to identify independent predictors of panitumumab-IRDye800 concentration in tissue.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 blood-brain barrier 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 of tissue) compared with 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.In multicancer clinical imaging of a receptor-ligand-based molecular probe, plasma antibody concentration, delivery barrier, and intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density led to heterogeneous intratumoral antibody accumulation and spatial distribution whereas tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.

Overview

  • The study aimed to investigate the physical and biologic factors contributing to differential translation of epidermal growth factor receptor (EGFR) expression to macroscopic fluorescence in tumors across three cancers.
  • Thirty-one patients with high-grade glioma, head-and-neck squamous cell carcinoma, and lung adenocarcinoma received systemic infusions of panitumumab-IRDye800 before surgery, followed by intraoperative open-field fluorescent imaging and specimen analysis.
  • The primary objective was to identify the determinants of panitumumab-IRDye800 concentration in tissue using stepwise multivariate linear regression of biologic variables.

Comparative Analysis & Findings

  • Intraoperative fluorescence imaging enhanced tissue-size dependent tumor contrast by 5.2-fold, 3.4-fold, and 1.4-fold in high-grade glioma, head-and-neck squamous cell carcinoma, and lung adenocarcinoma, respectively.
  • Fluorescence target-to-background ratio correlated with margin size and identified 78%-97% of at-risk resection margins ex vivo.
  • Tumor size, resection margin, and intraoperative imaging settings substantially influenced macroscopic tumor contrast.

Implications and Future Directions

  • The study's findings suggest that plasma antibody concentration, delivery barrier, and intratumoral EGFR expression driven by cellular biomarker expression and tumor cell density contribute to heterogeneous intratumoral antibody accumulation and spatial distribution.
  • Future research directions could focus on investigating novel approaches to optimize the delivery and accumulation of molecular probes in tumors, potentially enhancing the diagnostic value of fluorescence imaging.
  • The study's results may have implications for the development of personalized therapies targeting EGFR, particularly in high-grade glioma, where the blood-brain barrier's preferential breakdown improved tumor specificity of intratumoral antibody distribution.
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