Peer-Review ReportIntraoperative Fluorescence-Guided Resection of High-Grade Gliomas: A Comparison of the Present Techniques and Evolution of Future Strategies
Introduction
Gliomas account for nearly 80% of primary malignant brain tumors, contributing to approximately 13,000 deaths and 18,000 new cases annually in the United States (58). This devastating disease accounts for more years of life lost than any other type of tumor (58). Glioblastoma multiforme (GBM) is the most common type of glioma and carries a very poor prognosis. The current standard of care results in an average life expectancy of 14 months after diagnosis (58). The extent of resection in patients with GBM primarily determines the length of life expectancy. Improving intraoperative visualization and detection of residual tumor is vital to improving patients' prognosis 2, 52. Unfortunately, the heterogeneity, similarity of tumor appearance under the operating microscope to the surrounding brain parenchyma, and diffusely infiltrative behavior of high-grade gliomas make complete tumor resection challenging and difficult to achieve 2, 15, 51. Traditional imaging techniques do not permit a complete intraoperative identification of residual tumor cells. The tumor-brain interface may be difficult to identify for selective tumor removal sparing surrounding brain parenchyma 2, 15, 52.
Resection of these gliomas can be facilitated by the application of fluorescence and computer-assisted neuroimaging modalities to provide more precise localization and removal of the tumor 2, 15, 47, 51, 52, 82. Several techniques that use fluorescent biomarkers have been investigated as a means to improve intraoperative navigation and identification of residual tumor. These developments permit improved identification of tumor tissue, facilitating gross total resection (GTR) assessed via the use of contrast-enhanced T1-weighted imaging (65); there has been no significant improvement, however, offered in patients' long-term prognosis 2, 15, 51, 52, 58. The aim of this study was to provide a review and analysis of the advantages and limitations of intraoperative fluorescence-guided resection of high-grade gliomas and provide an insight for similar future studies.
Section snippets
Methods
A systematic evidence-based review of the relevant published literature was completed. A Medline search was performed using the key words “fluorescence,” “intraoperative fluorescence-guided resection,” “intraoperative image-guided resection,” and “brain glioma.” These articles were filtered for those published in English, on human subjects, and dates from 1960 until present. This initial search revealed 267 articles. Each abstract and article was reviewed, and the reference lists from select
Basic Mechanisms of Fluorescence
Electromagnetic radiation can excite electrons in atoms or molecules from their ground state (S0) to a greater energy state (S1). Excitation energy between 1.5 eV and 3.5 eV is required for aromatic organic molecules; this corresponds to wavelengths between 800 nm and 300 nm. Fluorescence occurs when electrons relax from their S1 to S0 state by emitting photons of light. Excitation light is of lower wavelength (i.e., greater frequency and higher energy) and the corresponding fluorescent
Discussion
In the literature, evidence demonstrates that extent of resection has an impact in progression-free survival and overall survival, but no Class I data are available. Lacroix et al. (35) retrospectively analyzed a database of 416 patients with GBM. They concluded that an extent of resection (EOR) of 98% or greater was associated with a survival advantage (median survival 13 months vs. 8.8 for <98%, P < 0.0001). Sanai et al. (53) retrospectively reviewed a series of 500 patients with GBM. They
Conclusions
The extent of resection in high-grade gliomas has been shown to positively affect patient prognosis. Several fluorescence contrast techniques have been implemented over the past few decades, including detection of fluorescence lifetimes (e.g., FLIM, TR-LIFS) and fluorescence intensities (e.g., 5-ALA, fluorescein sodium, hypericin, ICG). These agents have shown considerable promise in detecting residual tumor intraoperatively. Among these novel methods, currently 5-ALA and fluorescein sodium may
Acknowledgments
The authors sincerely appreciate the help of Roland Guckler from Zeiss Meditech for his review of the technical aspects of the manuscript.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.