Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas

Steve S. Cho, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Saad Sheikh, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Clare W. Teng, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Joseph Georges, Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA.
Andrew I. Yang, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Emma De Ravin, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Love Buch, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Carrie Li, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Yash Singh, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Denah Appelt, Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA.
Edward J. Delikatny, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
E James Petersson, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Andrew Tsourkas, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Jay Dorsey, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Sunil Singhal, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
John Y. Lee, Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. leejohn@uphs.upenn.edu.

Document Type

Article

Abstract

PURPOSE: Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA. PROCEDURES: Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and H&E images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence. RESULTS: In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence. CONCLUSION: Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections. CLINICAL TRIAL: NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1 ).

Medical Subject Headings

Aminolevulinic Acid (administration & dosage); Animals; Brain Neoplasms (diagnosis); Cell Line, Tumor; Disease Models, Animal; Female; Fluorescent Dyes (chemistry); Glioblastoma (diagnosis); Humans; Indocyanine Green (administration & dosage); Mice, Inbred C57BL; Optical Imaging

Publication Date

10-1-2020

Publication Title

Molecular imaging and biology

E-ISSN

1860-2002

Volume

22

Issue

5

First Page

1266

Last Page

1279

PubMed ID

32514886

Digital Object Identifier (DOI)

10.1007/s11307-020-01504-w

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