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

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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).

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Abbreviations

5-ALA:

Delta-aminolevulinic-acid

FGS:

Fluorescence-guided surgery

H&E:

Hematoxylin and eosin

HGG:

High-grade glioma

ICG:

Indocyanine green

MRI:

Magnetic resonance imaging

NIR:

Near-infrared

NPV:

Negative predictive value

PpIX:

Protoporphyrin-IX

ROC:

Receiver operating characteristic

ROI:

Region of interest

SBR:

Signal to background ratio

SWIG:

Second Window Indocyanine Green

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Conflict of interest

JYKL has had stock options in VisionSense in the past. No other authors declare that they disclosures or conflicts of interest.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding

Financial Support: Supported in part by the National Institutes of Health R01 CA193556 (SS), and the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (JYKL). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000003 (JYKL). In addition, research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880 (SSC). Authorship Statement

All authors have read and approved this manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Steve S. Cho, Clare W. Teng, Andrew I. Yang, Emma De Ravin, Love Buch, Carrie Li, Yash Singh & John Y. K. Lee

  2. Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Steve S. Cho, Clare W. Teng, Emma De Ravin & Carrie Li

  3. Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Saad Sheikh & Jay Dorsey

  4. Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

    Joseph Georges & Denah Appelt

  5. Department of Neurosurgery, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

    Joseph Georges

  6. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Edward J. Delikatny

  7. Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA

    E. James Petersson

  8. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Andrew Tsourkas

  9. Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Sunil Singhal

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  1. Steve S. Cho
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Correspondence to John Y. K. Lee.

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All animal procedures were conducted according to a protocol approved by the Institutional Animal Care and Use Committee at the University of Pennsylvania (#805979) and NIH and ARRIVE guidelines. The clinical trial was approved by the University of Pennsylvania’s Institutional Review Board (NCT02710240).

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Cho, S.S., Sheikh, S., Teng, C.W. et al. Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas. Mol Imaging Biol 22, 1266–1279 (2020). https://doi.org/10.1007/s11307-020-01504-w

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