Microdose fluorescence imaging of ABY-029 on an operating microscope adapted by custom illumination and imaging modules

Elliott, Jonathan T.; DSouza, Alisha V.; Marra, Kayla; Pogue, Brian W.; Roberts, David W.; Paulsen, Keith D.

doi:10.1364/boe.7.003280

Cited by 23 publications

(29 citation statements)

References 13 publications

(6 reference statements)

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“…Much of the cutting-edge research in FGS focuses on imaging-targeted or environment-sensitive agents; 2,6,12,16,18 however, there is still substantial interest and research in nonspecific agents that exploit the vascular abnormalities found in most tumors, such as NaFl and indocyanine green. 13,22 These agents often already have a clinical foothold in other indications, have a safety record, and are envisioned as stand-alone or complementary tools for FGS.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…We have an extensive history of using both of these instruments for in vivo and ex vivo small rodent preclinical imaging studies using ABY-029. 27,28,31,32,[46][47][48][49] Furthermore, the Odyssey CLx will be used in the clinical trial of ABY-029 in sarcoma resection (NCT03154411) to obtain high-resolution images of resected tissue that could be up to several centimeters thick; thus, comparison of the depth of imaging of these systems is clinically applicable.…”

Section: Discussionmentioning

confidence: 99%

Development and evaluation of a connective tissue phantom model for subsurface visualization of cancers requiring wide local excision

et al. 2017

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Wide local excision (WLE) of tumors with negative margins remains a challenge because surgeons cannot directly visualize the mass. Fluorescence-guided surgery (FGS) may improve surgical accuracy; however, conventional methods with direct surface tumor visualization are not immediately applicable, and properties of tissues surrounding the cancer must be considered. We developed a phantom model for sarcoma resection with the near-infrared fluorophore IRDye 800CW and used it to iteratively define the properties of connective tissues that typically surround sarcoma tumors. We then tested the ability of a blinded surgeon to resect fluorescent tumor-simulating inclusions with ∼1-cm margins using predetermined target fluorescence intensities and a Solaris open-air fluorescence imaging system. In connective tissue-simulating phantoms, fluorescence intensity decreased with increasing blood concentration and increased with increasing intralipid concentrations. Fluorescent inclusions could be resolved at ≥1-cm depth in all inclusion concentrations and sizes tested. When inclusion depth was held constant, fluorescence intensity decreased with decreasing volume. Using targeted fluorescence intensities, a blinded surgeon was able to successfully excise inclusions with ∼1-cm margins from fat- and muscle-simulating phantoms with inclusion-to-background contrast ratios as low as 2∶1. Indirect, subsurface FGS is a promising tool for surgical resection of cancers requiring WLE.

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“…Smaller targeting agents -incorporating peptides, protein scaffolds, or antibody-fragments -with improved pharmacokinetic properties and specificity, have also been developed and are undergoing evaluation [25][26][27][28][29]. For example, fluorescent peptides have been clinically translated that were shown to improve the detection of polyps and neoplastic lesions in humans during an endoscopic examination at early time points [30][31].…”

Section: Fluorescence-guided Surgerymentioning

confidence: 99%

Emerging Intraoperative Imaging Modalities to Improve Surgical Precision

et al. 2018

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Intraoperative imaging (IOI) is performed to guide delineation and localization of regions of surgical interest. While oncological surgical planning predominantly utilizes x-ray computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US), intraoperative guidance mainly remains on surgeon interpretation and pathology for confirmation. Over the past decades however, intraoperative guidance has evolved significantly with the emergence of several novel imaging technologies, including fluorescence-, Raman, photoacoustic-, and radio-guided approaches. These modalities have demonstrated the potential to further optimize precision in surgical resection and improve clinical outcomes for patients. Not only can these technologies enhance our understanding of the disease, they can also yield large imaging datasets intraoperatively that can be analyzed by deep learning approaches for more rapid and accurate pathological diagnosis. Unfortunately, many of these novel technologies are still under preclinical or early clinical evaluation. Organizations like the Intra-Operative Imaging Study Group of the European Society for Molecular Imaging (ESMI) support interdisciplinary interactions with the aim to improve technical capabilities in the field, an approach that can succeed only if scientists, engineers, and physicians work closely together with industry and regulatory bodies to resolve roadblocks to clinical translation. In this review, we provide an overview of a variety of novel IOI technologies, discuss their challenges, and present future perspectives on the enormous potential of IOI for oncological surgical navigation.

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Microdose fluorescence imaging of ABY-029 on an operating microscope adapted by custom illumination and imaging modules

Cited by 23 publications

References 13 publications

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

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

Development and evaluation of a connective tissue phantom model for subsurface visualization of cancers requiring wide local excision

Emerging Intraoperative Imaging Modalities to Improve Surgical Precision

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