Folate receptor overexpression can be visualized in real time during pituitary adenoma endoscopic transsphenoidal surgery with near-infrared imaging

OBJECTIVEPituitary adenomas account for approximately 10% of intracranial tumors and have an estimated prevalence of 15%–20% in the general US population. Resection is the primary treatment for pituitary adenomas, and the transsphenoidal approach remains the most common. The greatest challenge with pituitary adenomas is that 20% of patients develop tumor recurrence. Current approaches to reduce recurrence, such as intraoperative MRI, are costly, associated with high false-positive rates, and not recommended. Pituitary adenomas are known to overexpress folate receptor alpha (FRα), and it was hypothesized that OTL38, a folate analog conjugated to a near-infrared (NIR) fluorescent dye, could provide real-time intraoperative visual contrast of the tumor versus the surrounding nonneoplastic tissues. The preliminary results of this novel clinical trial are presented.METHODSNineteen adult patients who presented with pituitary adenoma were enrolled. Patients were infused with OTL38 2–4 hours prior to surgery. A 4-mm endoscope with both visible and NIR light capabilities was used to visualize the pituitary adenoma and its margins in real time during surgery. The signal-to-background ratio (SBR) was recorded for each tumor and surrounding tissues at various endoscope-to-sella distances. Immunohistochemical analysis was performed to assess the FRα expression levels in all specimens and classify patients as having either high or low FRα expression.RESULTSData from 15 patients (4 with null cell adenomas, 1 clinically silent gonadotroph, 1 totally silent somatotroph, 5 with a corticotroph, 3 with somatotrophs, and 1 somatocorticotroph) were analyzed in this preliminary analysis. Four patients were excluded for technical considerations. Intraoperative NIR imaging delineated the main tumors in all 15 patients with an average SBR of 1.9 ± 0.70. The FRα expression level of the adenomas and endoscope-to-sella distance had statistically significant impacts on the fluorescent SBRs. Additional considerations included adenoma functional status and time from OTL38 injection. SBRs were 3.0 ± 0.29 for tumors with high FRα expression (n = 3) and 1.6 ± 0.43 for tumors with low FRα expression (n = 12; p < 0.05). In 3 patients with immunohistochemistry-confirmed FRα overexpression (2 patients with null cell adenoma and 1 patient with clinically silent gonadotroph), intraoperative NIR imaging demonstrated perfect classification of the tumor margins with 100% sensitivity and 100% specificity. In addition, for these 3 patients, intraoperative residual fluorescence predicted postoperative MRI results with perfect concordance.CONCLUSIONSPituitary adenomas and their margins can be intraoperatively visualized with the preoperative injection of OTL38, a folate analog conjugated to NIR dye. Tumor-to-background contrast is most pronounced in adenomas that overexpress FRα. Intraoperative SBR at the appropriate endoscope-to-sella distance can predict adenoma FRα expression status in real time. This work suggests that for adenomas with high FRα expression, it may be possible to identify margins and to predict postoperative MRI findings.

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

Operative Neurosurgery ◽

10.1093/ons/opy034 ◽

2018 ◽

Vol 16 (1) ◽

pp. 59-70 ◽

Cited By ~ 8

Author(s):

Steve S Cho ◽

Ryan Zeh ◽

John T Pierce ◽

Jun Jeon ◽

MacLean Nasrallah ◽

...

Keyword(s):

Predictive Value ◽

Pituitary Adenomas ◽

Near Infrared ◽

Folate Receptor ◽

P Value ◽

Fluorescence Signal ◽

Postoperative Mri ◽

Nir Fluorescence ◽

Residual Neoplasm ◽

Nir Dye

Abstract BACKGROUND Surgical resection is the primary treatment for nonfunctional (NF) pituitary adenomas, but gross-total resection is difficult to achieve in all cases. NF adenomas overexpress folate receptor alpha (FRα). OBJECTIVE To test the hypothesis that we could target FRα for highly sensitive and specific intraoperative detection of NF adenomas using near-infrared (NIR) imaging. METHODS Fourteen patients with NF pituitary adenoma were infused with the folate analog NIR dye OTL38 preoperatively. NIR fluorescence signal-to-background ratio (SBR) was recorded for each tumor during resection of the adenomas. Extent of surgery was not modified based on the presence or absence of fluorescence. Immunohistochemistry was performed to assess FRα expression in all specimens. Magnetic resonance imaging (MRI) was performed postoperatively to assess residual neoplasm. RESULTS Nine adenomas overexpressed FRα and fluoresced with a NIR SBR of 3.2 ± 0.52, whereas the 5 non-FRα-overexpressing adenomas fluoresced with an SBR of 1.5 ± 0.21. Linear regression demonstrated a significant correlation between intraoperative SBR and the FRα expression (P-value < .001). Analysis of 14 margin samples revealed that the surgeon's impression of the tissue had 83% sensitivity, 100% specificity, 100% positive predictive value, and 89% negative predictive value, while NIR fluorescence had 100% for all values. NIR fluorescence accurately predicted postoperative MRI results in 78% of FRα-overexpressing patients. CONCLUSION Preoperative injection of folate-tagged NIR dye provides strong signal and visualization of NF pituitary adenomas. It is 100% sensitive and specific for detecting margin neoplasm and can predict postoperative MRI findings. Our results suggest that NIR fluorescence may be superior to white-light visualization alone and may improve resection rates in NF pituitary adenomas.

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

Journal of Neurosurgery ◽

10.3171/2018.7.jns181642 ◽

2019 ◽

Vol 131 (6) ◽

pp. 1974-1984 ◽

Cited By ~ 8

Author(s):

Steve S. Cho ◽

Jun Jeon ◽

Love Buch ◽

Shayoni Nag ◽

MacLean Nasrallah ◽

...

Keyword(s):

Pituitary Adenomas ◽

Near Infrared ◽

Fluorescent Dyes ◽

Folate Receptor ◽

Intraoperative Imaging ◽

Fluorescence Signal ◽

Nonfunctioning Pituitary Adenomas ◽

Nir Imaging ◽

Nir Fluorescence ◽

Significant Difference

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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Fluorescence-guided craniotomy of glioblastoma using panitumumab-IRDye800

Neurosurgical Focus: Video ◽

10.3171/2021.10.focvid21201 ◽

2022 ◽

Vol 6 (1) ◽

pp. V9

Keyword(s):

Near Infrared ◽

Ex Vivo ◽

Growth Factor Receptor ◽

Tumor Removal ◽

En Bloc ◽

Postoperative Mri ◽

Visual Contrast ◽

Resected Tumor ◽

Epidermal Growth ◽

Egfr Antibody

A contrast-enhancing lesion in the left temporal lobe of a 72-year-old woman was biopsied and diagnosed as glioblastoma. Near-infrared (NIR)–labeled epidermal growth factor receptor (EGFR) antibody, panitumumab-IRDye800, was infused 52 hours before craniotomy without pretreatment. Tumor fluorescence was detected through intact dura, and the visual contrast between disease and peritumoral healthy brain was enhanced after tumor exposure. Residual cancerous tissue was identified with strong fluorescence in resection cavity after en bloc tumor removal. Minimal fluorescence remained in the final wound bed, likely from nonenhancing tumor. Fluorescence was heterogeneously distributed at the infiltrative margin in resected tumor pieces imaged ex vivo. Postoperative MRI confirmed gross-total resection. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21201

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Co-expression of intermediate filaments glial fibrillary acidic protein and cytokeratin in pituitary adenoma

Pituitary ◽

10.1007/s11102-020-01087-3 ◽

2020 ◽

Author(s):

Nina Wiesnagrotzki ◽

Christian Bernreuther ◽

Wolfgang Saeger ◽

Jörg Flitsch ◽

Markus Glatzel ◽

...

Keyword(s):

Pituitary Adenoma ◽

Recurrence Rate ◽

Intermediate Filaments ◽

Pituitary Adenomas ◽

Medical Center ◽

Tumor Stem Cells ◽

Null Cell ◽

Lower Recurrence Rate ◽

Folliculostellate Cells ◽

Prognostic Data

Abstract Purpose To analyze the co-expression of the intermediate filaments GFAP and cytokeratin in 326 pituitary adenomas with regard to the distribution pattern, the subtype of the adenoma and clinical prognostic data. Methods Tissue from 326 pituitary adenomas and 13 normal anterior pituitaries collected in the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, between 2006 and 2009 was investigated by immunohistochemistry, immunofluorescence and electron microscopy. Results Co-expression of intermediate filaments GFAP and cytokeratin was associated with hormone expression in 62/278 cases (22%), but only found in 2/48 (4%) of null cell adenomas (p < 0.01). Simultaneous co-expression of GFAP and cytokeratin in the same cells was demonstrated in 26 out of 326 pituitary adenomas and in all 13 pituitaries. In pituitary intermediate filaments were demonstrated in a larger area of the cytoplasm than in adenoma (p < 0.01), however, overlapping expression was seen in 2.6% of the total area in both, pituitary and adenoma. Congenially, cells with overlapping expression were found near vessels and in follicles. Furthermore, adenomas with cellular co-expression of GFAP and cytokeratin were associated with a lower recurrence rate (7.7%) compared to adenomas without co-expression of intermediate filaments (17.8%). Conclusions Cellular co-expression of the intermediate filaments GFAP and cytokeratin in pituitary adenomas and the pituitary was demonstrated and shown to be associated with hormone expression and low recurrence rate. The results are discussed with regard to the biology of folliculostellate cells, neural transformation and tumor stem cells. This study may complement the understanding of pituitary adenoma biology.

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Second window ICG predicts postoperative MRI gadolinium enhancement in high grade gliomas and brain metastases

Neurosurgical Focus: Video ◽

10.3171/2021.10.focvid21204 ◽

2022 ◽

Vol 6 (1) ◽

pp. V8

Keyword(s):

Brain Metastases ◽

Near Infrared ◽

Prospective Trial ◽

High Grade ◽

Gadolinium Enhancement ◽

Postoperative Mri ◽

Nir Imaging ◽

Residual Neoplasm ◽

High Grade Gliomas ◽

Higher Sensitivity

A prospective trial evaluating the utility of second window indocyanine green (SWIG) in predicting postoperative MRI gadolinium enhancement was performed on high-grade gliomas (HGGs) and brain metastases. Compared to white light alone, SWIG demonstrated a higher sensitivity, negative predictive value, and accuracy in predicting residual neoplasm on MRI. The specificity of SWIG for predicting MRI enhancement was higher in HGGs than brain metastases. Clinically, near-infrared (NIR) imaging was better able to predict tumor recurrence than postoperative MRI. These results illustrate how SWIG is able to take advantage of gadolinium-like distribution properties to extravasate into the tumor microenvironment, enabling guidance in surgical resection. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21204

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Identification of Abnormal Biliary Anatomy Utilizing Real-Time Near-Infrared Cholangiography: A Report of Two Cases

Case Reports in Gastrointestinal Medicine ◽

10.1155/2017/8628206 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

Joseph Bozzay ◽

Diego Vicente ◽

Elliot M. Jessie ◽

Carlos J. Rodriguez

Keyword(s):

Decision Making ◽

Real Time ◽

Near Infrared ◽

Imaging System ◽

Biliary Tree ◽

Biliary Duct ◽

Biliary Anatomy ◽

Nir Imaging ◽

Intraoperative Detection ◽

Fluorescence Imaging System

Biliary duct anomalies are commonly encountered during laparoscopic cholecystectomy. Advancements in the field of surgery allow for enhanced intraoperative detection of these abnormalities. Fluorophore injection and near-infrared (NIR) imaging can provide real-time intraoperative anatomic feedback without intraoperative delays and ionizing radiation. This report details two cases where the PINPOINT Endoscopic Fluorescence Imaging System (NOVADAQ, Ontario, Canada) was used to identify anomalies of the biliary tree and guide operative decision-making.

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Dual-channel near-infrared fluorescent probe for real-time tracking of endogenous γ-glutamyl transpeptidase activity

Chemical Communications ◽

10.1039/c8cc07376g ◽

2018 ◽

Vol 54 (87) ◽

pp. 12393-12396 ◽

Cited By ~ 12

Author(s):

Bing Bai ◽

Chenxu Yan ◽

Yutao Zhang ◽

Zhiqian Guo ◽

Wei-Hong Zhu

Keyword(s):

Real Time ◽

Fluorescent Probe ◽

Near Infrared ◽

Dual Channel ◽

Nir Imaging ◽

Real Time Tracking ◽

Glutamyl Transpeptidase

We developed a curcuminoid difluoroboron-based fluorescent probe for tracking endogenous GGT activity with dual-channel light-up near-infrared (NIR) imaging.

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High-resolution18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging for pituitary adenoma detection in Cushing disease

Journal of Neurosurgery ◽

10.3171/2014.10.jns14911 ◽

2015 ◽

Vol 122 (4) ◽

pp. 791-797 ◽

Cited By ~ 24

Author(s):

Prashant Chittiboina ◽

Blake K. Montgomery ◽

Corina Millo ◽

Peter Herscovitch ◽

Russell R. Lonser

Keyword(s):

Pituitary Adenoma ◽

High Resolution ◽

Pituitary Adenomas ◽

Imaging Modality ◽

Spin Echo ◽

Mri Findings ◽

Cushing Disease ◽

Standardized Uptake Values ◽

Adenoma Detection ◽

Corticotroph Adenomas

OBJECT High-resolution PET (hrPET) performed using a high-resolution research tomograph is reported as having a resolution of 2 mm and could be used to detect corticotroph adenomas through uptake of18F-fluorodeoxyglucose (18F-FDG). To determine the sensitivity of this imaging modality, the authors compared18F-FDG hrPET and MRI detection of pituitary adenomas in Cushing disease (CD). METHODS Consecutive patients with CD who underwent preoperative18F-FDG hrPET and MRI (spin echo [SE] and spoiled gradient recalled [SPGR] sequences) were prospectively analyzed. Standardized uptake values (SUVs) were calculated from hrPET and were compared with MRI findings. Imaging findings were correlated to operative and histological findings. RESULTS Ten patients (7 females and 3 males) were included (mean age 30.8 ± 19.3 years; range 11–59 years). MRI revealed a pituitary adenoma in 4 patients (40% of patients) on SE and 7 patients (70%) on SPGR sequences.18F-FDG hrPET demonstrated increased18F-FDG uptake consistent with an adenoma in 4 patients (40%; adenoma size range 3–14 mm). Maximum SUV was significantly higher for18F-FDG hrPET–positive tumors (difference = 5.1, 95% CI 2.1–8.1; p = 0.004) than for18F-FDG hrPET–negative tumors.18F-FDG hrPET positivity was not associated with tumor volume (p = 0.2) or dural invasion (p = 0.5). Midnight and morning ACTH levels were associated with18F-FDG hrPET positivity (p = 0.01 and 0.04, respectively) and correlated with the maximum SUV (R = 0.9; p = 0.001) and average SUV (R = 0.8; p = 0.01). All18F-FDG hrPET–positive adenomas had a less than a 180% ACTH increase and18F-FDG hrPET–negative adenomas had a greater than 180% ACTH increase after CRH stimulation (p = 0.03). Three adenomas were detected on SPGR MRI sequences that were not detected by18F-FDG hrPET imaging. Two adenomas not detected on SE (but no adenomas not detected on SPGR) were detected on18F-FDG hrPET. CONCLUSIONS While18F-FDG hrPET imaging can detect small functioning corticotroph adenomas and is more sensitive than SE MRI, SPGR MRI is more sensitive than18F-FDG hrPET and SE MRI in the detection of CD-associated pituitary adenomas. Response to CRH stimulation can predict18F-FDG hrPET–positive adenomas in CD.

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Kinetics analysis of indocyanine green based on a novel mouse model to distinguish between tumor and inflammation

Analytical Methods ◽

10.1039/c9ay01906e ◽

2019 ◽

Vol 11 (44) ◽

pp. 5704-5710 ◽

Cited By ~ 2

Author(s):

Diya Xie ◽

Yuxin Wang ◽

Ziyang Wang ◽

Jianquan Wang ◽

Hao Han ◽

...

Keyword(s):

Mouse Model ◽

Indocyanine Green ◽

Real Time ◽

Near Infrared ◽

Tumor Resection ◽

Kinetics Analysis ◽

Nir Imaging

Near-infrared (NIR) imaging with indocyanine green (ICG) has been proven to be feasible for the visualization of tumor and enables real-time guidance during tumor resection.

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