Folate Receptor Near-Infrared Optical Imaging Provides Sensitive and Specific Intraoperative Visualization of Nonfunctional Pituitary Adenomas

Cho, Steve S.; Zeh, Ryan; Pierce, J. Thomas; Jeon, Jun; Nasrallah, MacLean P.; Adappa, Nithin D.; Palmer, James N.; Newman, Jason G.; White, Caitlin; Kharlip, Julia; Snyder, Peter J.; Singhal, Sunil; Grady, M. Sean; Lee, John Y.K.

doi:10.1093/ons/opy034

Cited by 23 publications

(15 citation statements)

References 41 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Belykh

Ngo

Farhadi

et al. 2020

JCM

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This is the first study to assess confocal laser endomicroscopy (CLE) use within the transsphenoidal approach and show the feasibility of obtaining digital diagnostic biopsies of pituitary tumor tissue after intravenous fluorescein injection. We confirmed that the CLE probe reaches the tuberculum sellae through the transnasal transsphenoidal corridor in cadaveric heads. Next, we confirmed that CLE provides images with identifiable histological features of pituitary adenoma. Biopsies from nine patients who underwent pituitary adenoma surgery were imaged ex vivo at various times after fluorescein injection and were assessed by a blinded board-certified neuropathologist. With frozen sections used as the standard, pituitary adenoma was diagnosed as “definitively” for 13 and as “favoring” in 3 of 16 specimens. CLE digital biopsies were diagnostic for pituitary adenoma in 10 of 16 specimens. The reasons for nondiagnostic CLE images were biopsy acquisition <1 min or >10 min after fluorescein injection (n = 5) and blood artifacts (n = 1). In conclusion, fluorescein provided sufficient contrast for CLE at a dose of 2 mg/kg, optimally 1–10 min after injection. These results provide a basis for further in vivo studies using CLE in transsphenoidal surgery.

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Section: Discussionmentioning

confidence: 99%

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

Belykh

Ngo

Farhadi

et al. 2020

JCM

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“…In order to avoid this, the surgeon should attempt to visualize areas of suspected NIR fluorescence from a set distance. With the VisionSense Iridium endoscope in transsphenoidal surgeries for pituitary adenomas using a related NIR dye, we demonstrated that having the endoscope at a distance that maintains the distance between the two medial opticocarotid recesses to be <50% of the field of view is ideal for minimizing false-positive NIR signals ( Figures 8E – H ) ( 60 , 61 ). Endoscopes that offer more precise distance measurements could further help the neurosurgeon to acquire more accurate NIR signals.…”

Section: Practical Experiencementioning

confidence: 95%

“…In fact, multiple such conjugates are currently being investigated in preclinical and clinical trials for different intracranial tumors. For instance, folate-receptor overexpression on nonfunctional pituitary adenomas and meningiomas may provide targets for sensitive and specific detection of these tumors in real-time ( 54 , 60 – 62 ). An alternative is to use imaging apparatus with higher resolution for fluorescence, which may better distinguish true areas of fluorescence from areas of false-positive fluorescence.…”

Section: Future Researchmentioning

confidence: 99%

Indocyanine-Green for Fluorescence-Guided Surgery of Brain Tumors: Evidence, Techniques, and Practical Experience

2019

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The primary treatment for brain tumors often involves surgical resection for diagnosis, relief of mass effect, and prolonged survival. In neurosurgery, it is of utmost importance to achieve maximal safe resection while minimizing iatrogenic neurologic deficit. Thus, neurosurgeons often rely on extra tools in the operating room, such as neuronavigation, intraoperative magnetic resonance imaging, and/or intraoperative rapid pathology. However, these tools can be expensive, not readily available, time-consuming, and/or inaccurate. Recently, fluorescence-guided surgery has emerged as a cost-effective method to accurately visualize neoplastic areas in real-time to guide resection. Currently, 5-aminolevulinic-acid (5-ALA) remains the only fluorophore that has been approved specifically for fluorescence-guided tumor resection. Its use has demonstrated improved resection rates and prolonged progression-free survival. However, protoporphyrin-IX, the metabolic product of 5-ALA that accumulates in neoplastic cells, fluoresces in the visible-light range, which suffers from limited tissue penetration and significant auto-fluorescence. Near-infrared fluorescence, on the other hand, overcomes these problems with ease. Since 2012, researchers at our institution have developed a novel technique using indocyanine-green, which is a well-known near-infrared fluorophore used traditionally for angiography. This Second-Window-ICG (SWIG) technique takes advantage of the increased endothelial permeability in peritumoral tissue, which allows indocyanine-green to accumulate in these areas for intraoperative visualization of the tumor. SWIG has demonstrated utility in gliomas, meningiomas, metastases, pituitary adenomas, chordomas, and craniopharyngiomas. The main benefits of SWIG stem from its highly sensitive detection of neoplastic tissue in a wide variety of intracranial pathologies in real-time, which can help neurosurgeons both during surgical resections and in stereotactic biopsies. In this review of this novel technique, we summarize the development and mechanism of action of SWIG, provide evidence for its benefits, and discuss its limitations. Finally, for those interested in near-infrared fluorescence-guided surgery, we provide suggestions for maximizing the benefits while minimizing the limitations of SWIG based on our own experience thus far.

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“…7,8,21 While FRa-targeted tomographic imaging with SPECT is capable of estimating FRa expression levels preoperatively, the cost-to-benefit analysis of preoperatively scanning all patients is unclear. 11 Instead, we have data 3 suggesting that initial NIR SBR of > 2.5 upon tumor exposure may predict FRa overexpression with near-100% probability; thus, a reasonable and affordable approach to using OTL38 clinically might be to administer it to all patients with nonfunctioning adenomas and determine intraoperatively whether each adenoma overexpresses FRa to decide if OTL38 fluorescence would be reliable for that surgery. If the initial SBR prior to resection is < 2.5, resection should proceed using conventional techniques without NIR imaging.…”

Section: Folate-receptor-targeted Imaging Is Highly Sensitive and Specific For Neoplasmmentioning

confidence: 98%

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

Cho

Jeon

Buch³

et al. 2019

Journal of Neurosurgery

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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.

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Folate Receptor Near-Infrared Optical Imaging Provides Sensitive and Specific Intraoperative Visualization of Nonfunctional Pituitary Adenomas

Cited by 23 publications

References 41 publications

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

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

Indocyanine-Green for Fluorescence-Guided Surgery of Brain Tumors: Evidence, Techniques, and Practical Experience

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

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