title: SimultaneousIn VivoFluorescent Markers for Perfusion, Protoporphyrin Metabolism, and EGFR Expression for Optically Guided Identification of Orthotopic Glioma.
abstract: Purpose:While extent of tumor resection is an important predictor of outcome in glioma, margin delineation remains challenging due to lack of inherent contrast between tumor and normal parenchyma. Fluorescence-guided surgery is promising for its ability to enhance contrast through exogenous fluorophores; however, the specificity and sensitivity of the underlying contrast mechanism and tumor delivery and uptake vary widely across approved and emerging agents.Experimental Design:Rats with orthotopic F98 wild-type and F98 EGFR-positive (EGFR+) gliomas receivedin vivoadministration of IRDye680RD, 5-aminioleuvulinic acid, and ABY-029-markers of perfusion, protoporphyrin metabolism, and EGFR expression, respectively.Ex vivoimaging demonstrates the contrast mechanism-dependent spatial heterogeneity and enables within-animal comparisons of tumor-to-background ratio (TBR).Results:Generally, ABY-029 outperformed PpIX in F98EGFRorthotopic tumor margins and core (50% and 60% higher TBR, respectively). PpIX outperformed ABY-029 in F98wtmargins by 60% but provided equivalent contrast in the bulk tumor. IRDye680RD provided little contrast, having an average TBR of 1.7 ± 0.2. The unique spatial patterns of each agent were combined into a single metric, the multimechanistic fluorescence-contrast index (MFCI). ABY-029 performed best in EGFR+tumors (91% accuracy), while PpIX performed best in wild-type tumors (87% accuracy). Across all groups, ABY-029 and PpIX performed similarly (80% and 84%, respectively) but MFCI was 91% accurate, supporting multiagent imaging when tumor genotype was unknown.Conclusions:Human use of ABY-029 for glioma resection should enhance excision of EGFR+tumors and could be incorporated into current PpIX strategies to further enhance treatment in the general glioma case.Clin Cancer Res; 23(9); 2203-12. ©2016 AACR.
authors: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire. Jonathan.T.Elliott@dartmouth.edu.
authors: Jonathan T
authors: JT
authors: Elliott
authors: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
authors: Kayla
authors: K
authors: Marra
authors: Department of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: Linton T
authors: LT
authors: Evans
authors: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
authors: Scott C
authors: SC
authors: Davis
authors: Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors: Kimberley S
authors: KS
authors: Samkoe
authors: Preclinical Research, Affibody AB, Solna, Sweden.
authors: Joachim
authors: J
authors: Feldwisch
authors: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
authors: Keith D
authors: KD
authors: Paulsen
authors: Department of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: David W
authors: DW
authors: Roberts
authors: Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire.
authors: Brian W
authors: BW
authors: Pogue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000601:surgery*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage; D011524:Protoporphyrins / Q000008:administration & dosage*; D051381:Rats; D020535:Video-Assisted Surgery
chemical_list: D005456:Fluorescent Dyes; D010446:Peptide Fragments; D011524:Protoporphyrins; C028025:protoporphyrin IX; C512478:EGFR protein, human; D066246:ErbB Receptors