Fluorescein Guidance in Glioblastoma Resection

Roberts, David W.; Olson, Jonathan D.

doi:10.1056/nejmicm1611258

Cited by 11 publications

(8 citation statements)

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“…6 In addition to evaluating whether the homogenizing process is suitable to obtain at least similar optical properties values by using dissected tissue samples, or whether the interference is too harsh to the tissue's structure, a simplification and thus timesaving aspect of the tissue preparation process accompanied by an increase of reproducibility should be tested. In particular the method of homogenizing is very interesting for small, heterogeneous, or traumatized samples from biopsies or resections (e.g., cholesteatoma 41 and glioblastoma 42 ). As the optical properties of ex vivo samples highly depend on the storage conditions and further processing 7,11,32,43 and may thus decidedly differ from those of in vivo tissue, future work should be focused on the relation between these two kinds of state of tissue conditions.…”

Section: Introductionmentioning

confidence: 99%

Investigation of optical properties of dissected and homogenized biological tissue

et al. 2018

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Knowledge of tissue optical properties, in particular the absorption μ a and the reduced scattering coefficient μ 0 s , is required for diagnostic and therapeutic applications in which the light distribution during treatment has to be known. As it is generally very difficult to obtain this information with sufficient accuracy in vivo, optical properties are often approximately determined on ex vivo tissue samples. In this case, the obtained optical properties may strongly depend on the sample preparation. The extent of the expectable preparationdependent differences was systematically investigated in comparative measurements on dissected and homogenized porcine tissue samples (liver, lung, brain, and muscle). These measurements were performed at wavelengths 520, 635, 660, and 785 nm, using a dual-step reflectance device and at a spectral range of 515 to 800 nm with an integrating sphere setup. In a third experiment, the density of tissue samples (dissected and homogenized) was investigated, as the characteristic of the packaging of internal tissue structures strongly influences the absorption and scattering. The standard errors of the obtained absorption and reduced scattering coefficients were found to be reduced in case of homogenized tissue. Homogenizing the tissues also allows a much easier and faster sample preparation, as macroscopic internal tissue structures are destroyed in the homogenized tissue so that a planar tissue sample with well-defined thickness can easily and accurately be prepared by filling the tissue paste into a cuvette. Consequently, a better reproducibility result was obtained when using homogenized samples. According to the density measurements accomplished for dissected and homogenized tissue samples, all types of tissues, except lung, showed a decrease in the density due to the homogenization process. The presented results are in good agreement for μ 0 s regardless of the preparation procedure, whereas μ a differs, probably influenced by blood content and dehydration. Because of faster and easier preparation and easier sample positioning, homogenization prior to measurement seems to be suitable for investigating the optical properties ex vivo. Additionally, by means of using the homogenization process, the sample size and thickness do not need to be particularly large, as is the case for most biopsies from the OR.

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Section: Introductionmentioning

confidence: 99%

Investigation of optical properties of dissected and homogenized biological tissue

et al. 2018

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“…23 Recent observations during our own clinical study of NaFl showed extensive accumulation of the dye outside the vessels shortly after administration, potentially confounding tumor identification. 15 Previous preclinical studies of NaFl in the blood and normal brains of rodents point to a possible explanation for the observed behavior in human brain. Delori et al have reported that NaFl binds to blood proteins only weakly, resulting in the presence of both free and bound forms of the dye in the circulation, 3 while Yen et al and others have reported the presence of NaFl in normal rodent brain tissue, suggesting that the contrast agent crosses the protective barriers in the brain at measureable concentrations.…”

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confidence: 99%

Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma

Folaron¹,

Strawbridge²,

Samkoe

et al. 2019

Journal of Neurosurgery

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OBJECTIVE The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood-brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB. This study aims to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, the authors examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents. METHODS Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts. RESULTS Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%. CONCLUSIONS Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma.

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“…As a matter of fact, some areas, such as dura mater, circumventricular organs and choroid plexus, due to the lack of BBB, appears intensively fluorescent ( 35 ). In addition, although the presence of FS fluorescence in normal brain parenchyma close to tumor tissue has been occasionally shown and considered a consequence of direct surgical manipulation ( 33 , 39 – 41 ), it has been suggested that the application of a strict intraoperative protocol of FS injection could significantly limit this event ( 35 ).…”

Section: Fluorescein Sodiummentioning

confidence: 99%

Fluorescence-Guided Surgery: A Review on Timing and Use in Brain Tumor Surgery

et al. 2021

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Fluorescence-guided surgery (FGS) allows surgeons to have improved visualization of tumor tissue in the operating room, enabling maximal safe resection of malignant brain tumors. Over the past two decades, multiple fluorescent agents have been studied for FGS, including 5-aminolevulinic acid (5-ALA), fluorescein sodium, and indocyanine green (ICG). Both non-targeted and targeted fluorescent agents are currently being used in clinical practice, as well as under investigation, for glioma visualization and resection. While the efficacy of intraoperative fluorescence in studied fluorophores has been well established in the literature, the effect of timing on fluorophore administration in glioma surgery has not been as well depicted. In the past year, recent studies of 5-ALA use have shown that intraoperative fluorescence may persist beyond the previously studied window used in prior multicenter trials. Additionally, the use of fluorophores for different brain tumor types is discussed in detail, including a discussion of choosing the right fluorophore based on tumor etiology. In the following review, the authors will describe the temporal nature of the various fluorophores used in glioma surgery, what remains uncertain in FGS, and provide a guide for using fluorescence as a surgical adjunct in brain tumor surgery.

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Fluorescein Guidance in Glioblastoma Resection

Cited by 11 publications

References 0 publications

Investigation of optical properties of dissected and homogenized biological tissue

Investigation of optical properties of dissected and homogenized biological tissue

Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma

Fluorescence-Guided Surgery: A Review on Timing and Use in Brain Tumor Surgery

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