5-aminolevulinic acid, fluorescein sodium, and indocyanine green for glioma margin detection: analysis of operating wide-field and confocal microscopy in glioma models of various grades

Evgenii Belykh, The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.Follow
Liudmila Bardonova, The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.Follow
Irakliy Abramov, The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.Follow
Vadim A. Byvaltsev, Department of Neurosurgery, Irkutsk State Medical University, Irkutsk, Russia.
Talgat Kerymbayev, Department of Neurosurgery, JSC "National Scientific Center of Neurosurgery", Nur-Sultan, Kazakhstan.
Kwanha Yu, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, United States.
Debbie R. Healey, Department of Research Imaging, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.Follow
Ernesto Luna-Melendez, Department of Neurosurgery, Irkutsk State Medical University, Irkutsk, Russia.
Benjamin Deneen, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, United States.
Shwetal Mehta, Ivy Brain Tumor Research Center, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
James K. Liu, Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ, United States.
Mark C. Preul, The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.

Document Type

Article

Abstract

INTRODUCTION: Surgical resection remains the first-line treatment for gliomas. Several fluorescent dyes are currently in use to augment intraoperative tumor visualization, but information on their comparative effectiveness is lacking. We performed systematic assessment of fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), and indocyanine green (ICG) fluorescence in various glioma models using advanced fluorescence imaging techniques. METHODS: Four glioma models were used: GL261 (high-grade model), GB3 (low-grade model), and an electroporation model with and without red fluorescence protein (IUE +RFP and IUE -RFP, respectively) (intermediate-to-low-grade model). Animals underwent 5-ALA, FNa, and ICG injections and craniectomy. Brain tissue samples underwent fluorescent imaging using a wide-field operative microscope and a benchtop confocal microscope and were submitted for histologic analysis. RESULTS: Our systematic analysis showed that wide-field imaging of highly malignant gliomas is equally efficient with 5-ALA, FNa, and ICG, although FNa is associated with more false-positive staining of the normal brain. In low-grade gliomas, wide-field imaging cannot detect ICG staining, can detect FNa in only 50% of specimens, and is not sensitive enough for PpIX detection. With confocal imaging of low-intermediate grade glioma models, PpIX outperformed FNa. DISCUSSION: Overall, compared to wide-field imaging, confocal microscopy significantly improved diagnostic accuracy and was better at detecting low concentrations of PpIX and FNa, resulting in improved tumor delineation. Neither PpIX, FNa, nor ICG delineated all tumor boundaries in studied tumor models, which emphasizes the need for novel visualization technologies and molecular probes to guide glioma resection. Simultaneous administration of 5-ALA and FNa with use of cellular-resolution imaging modalities may provide additional information for margin detection and may facilitate maximal glioma resection.

Keywords

5-aminolevulinic acid, fluorescein sodium, fluorescence guided surgery, glioma, indocyanine green, laser scanning microscopy, protoporphyrin IX

Publication Date

1-1-2023

Publication Title

Frontiers in oncology

ISSN

2234-943X

Volume

13

First Page

1156812

PubMed ID

37287908

Digital Object Identifier (DOI)

10.3389/fonc.2023.1156812

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