Intraoperative near-infrared imaging with receptor-specific versus passive delivery of fluorescent agents in pituitary adenomas

Abstract

OBJECTIVEIntraoperative molecular imaging with tumor-targeted fluorescent dyes can enhance resection rates. In contrast to visible-light fluorophores (e.g., 5-aminolevulinic-acid), near-infrared (NIR) fluorophores have increased photon tissue penetration and less contamination from tissue autofluorescence. The second-window ICG (SWIG) technique relies on passive accumulation of indocyanine green (ICG) in neoplastic tissues. OTL38, conversely, targets folate receptor overexpression in nonfunctioning pituitary adenomas. In this study, we compare the properties of these 2 modalities for NIR imaging of pituitary adenomas to better understand the potential for NIR imaging in neurosurgery.METHODSA total of 39 patients with pituitary adenomas were enrolled between June 2015 and January 2018 in 2, sequential, IRB-approved studies. Sixteen patients received systemic ICG infusions 24 hours prior to surgery, and another 23 patients received OTL38 infusions 2–3 hours prior to surgery. NIR fluorescence signal-to-background ratio (SBR) was recorded during and after resection. Immunohistochemistry was performed on the 23 adenomas resected from patients who received OTL38 to assess expression of folate receptor–alpha (FRα).RESULTSAll 16 adenomas operated on after ICG administration demonstrated strong NIR fluorescence (mean SBR 4.1 ± 0.69 [SD]). There was no statistically significant difference between the 9 functioning and 7 nonfunctioning adenomas (p = 0.9). After administration of OTL38, the mean SBR was 1.7 ± 0.47 for functioning adenomas, 2.6 ± 0.91 for all nonfunctioning adenomas, and 3.2 ± 0.53 for the subset of FRα-overexpressing adenomas. Tissue identification with white light alone for all adenomas demonstrated 88% sensitivity and 90% specificity. SWIG demonstrated 100% sensitivity but only 29% specificity for both functioning and nonfunctioning adenomas. OTL38 was 75% sensitive and 100% specific for all nonfunctioning adenomas, but when assessment was limited to the 9 FRα-overexpressing adenomas, the sensitivity and specificity of OTL38 were both 100%.CONCLUSIONSIntraoperative imaging with NIR fluorophores demonstrates highly sensitive detection of pituitary adenomas. OTL38, a folate-receptor–targeted fluorophore, is highly specific for nonfunctioning adenomas but has no utility in functioning adenomas. SWIG, which relies on passive diffusion into neoplastic tissue, is applicable to both functioning and nonfunctioning pituitary adenomas, but it is less specific than targeted fluorophores. Thus, targeted and nontargeted NIR fluorophores play important, yet distinct, roles in intraoperative imaging. Selectively and intelligently using either agent has the potential to greatly improve resection rates and outcomes for patients with intracranial tumors.

Confocal Laser Endomicroscopy Assessment of Pituitary Tumor Microstructure: A Feasibility Study

“…Although this study used fluorescein as the fluorescent dye for CLE, other fluorophores have the potential to aid in the visualization of pituitary adenomas. Other studies have assessed the efficacy of two near-infrared (700–850-nm) fluorophores in pituitary adenoma resections: indocyanine green (ICG) and OTL38 (On Target Laboratories, West Lafayette, IN, USA) [ 26 , 27 , 28 ]. ICG, a dye frequently used in neurosurgery, can be applied in a technique known as second-window ICG, which uses the enhanced vascular permeability of pituitary adenomas to allow for intraoperative imaging.…”

Applications of indocyanine green in brain tumor surgery: review of clinical evidence and emerging technologies

“…Using tumor pathology as the gold standard, SWIG demonstrated higher sensitivity and a negative predictive value but lower specificity and a positive predictive value compared with visualization under white light; these test characteristics were later corroborated in intracranial metastases, meningiomas, and pituitary adenomas. [18][19][20] Enhanced sensitivity and a negative predictive value may give neurosurgeons more confidence in detecting remaining neoplastic tissue and thus facilitating gross-total resection (GTR).…”

Dual‐agent fluorescent labeling of soft‐tissue sarcomas improves the contrast based upon targeting both interstitial and cellular components of the tumor milieu

“…Indocyanine green (ICG) is a longstanding, untargeted intravascular probe with FDA approval that has historically been used to facilitate intraoperative perfusion mapping 2 . More recently, ICG imaging that is performed 24‐hours after administration, or during its “second window,” has proven useful in multiple cancer‐centered clinical trials by exploiting the enhanced permeability and retention (EPR) effect 3,17‐21 . Unlike molecularly targeted agents, ICG and other perfusion agents collect in the interstitial spaces of the tumor, and fluorescence contrast arises from the differential of tissue clearance rather than differences in molecular expression.…”

“…2 More recently, ICG imaging that is performed 24-hours after administration, or during its "second window," has proven useful in multiple cancer-centered clinical trials by exploiting the enhanced permeability and retention (EPR) effect. 3,[17][18][19][20][21] Unlike molecularly targeted agents, ICG and other perfusion agents collect in the interstitial spaces of the tumor, and fluorescence contrast arises from the differential of tissue clearance rather than differences in molecular expression. In addition, ICG has been found to localize in necrotic regions of normal tissue through association with lipoproteins and phosphoproteins.…”