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

2018 ◽  
Vol 16 (1) ◽  
pp. 59-70 ◽  
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.

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

2019 ◽  
Vol 131 (6) ◽  
pp. 1974-1984 ◽  
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.

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

2018 ◽  
Vol 129 (2) ◽  
pp. 390-403 ◽  
Author(s):  
John Y. K. Lee ◽  
Steve S. Cho ◽  
Ryan Zeh ◽  
John T. Pierce ◽  
Maria Martinez-Lage ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Real Time ◽  
Pituitary Adenomas ◽  
Near Infrared ◽  
Folate Receptor ◽  
Mri Findings ◽  
Null Cell ◽  
Postoperative Mri ◽  
Visual Contrast ◽  
Nir 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.

scholarly journals Detection of early neoplasia in Barrett’s esophagus using lectin-based near-infrared imaging: an ex vivo study on human tissue

Endoscopy ◽  
2018 ◽  
Vol 50 (06) ◽  
pp. 618-625 ◽  
Author(s):  
André Neves ◽  
Massimiliano Di Pietro ◽  
Maria O’Donovan ◽  
Dale Waterhouse ◽  
Sarah Bohndiek ◽  
...  
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Near Infrared ◽  
Infrared Imaging ◽  
Ex Vivo ◽  
Sampling Error ◽  
Nir Light ◽  
Nir Imaging ◽  
Nir Fluorescence ◽  
Nir Dye

Abstract Background and study aims Endoscopic surveillance for Barrett’s esophagus (BE) is limited by long procedure times and sampling error. Near-infrared (NIR) fluorescence imaging minimizes tissue autofluorescence and optical scattering. We assessed the feasibility of a topically applied NIR dye-labeled lectin for the detection of early neoplasia in BE in an ex vivo setting. Methods Consecutive patients undergoing endoscopic mucosal resection (EMR) for BE-related early neoplasia were recruited. Freshly collected EMR specimens were sprayed at the bedside with fluorescent lectin and then imaged. Punch biopsies were collected from each EMR under NIR light guidance. We compared the fluorescence intensity from dysplastic and nondysplastic areas within EMRs and from punch biopsies with different histological grades. Results 29 EMR specimens were included from 17 patients. A significantly lower fluorescence was found for dysplastic regions across whole EMR specimens (P < 0.001). We found a 41 % reduction in the fluorescence of dysplastic compared to nondysplastic punch biopsies (P < 0.001), with a sensitivity and specificity for dysplasia detection of 80 % and 82.9 %, respectively. Conclusion Lectin-based NIR imaging can differentiate dysplastic from nondysplastic Barrett’s mucosa ex vivo.

scholarly journals Feasibility of sentinel lymph node detection by near-infrared endoscopy in squamous cell carcinoma of the oral cavity: a pilot study

2020 ◽  
Author(s):  
Matti Sievert ◽  
Miguel Goncalves ◽  
Markus Eckstein ◽  
Heinrich Iro ◽  
Michael Koch
Keyword(s):  
Squamous Cell Carcinoma ◽  
Lymph Node ◽  
Sentinel Lymph Node ◽  
Oral Cavity ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Near Infrared ◽  
Elective Neck Dissection ◽  
Fluorescence Signal ◽  
Nir Fluorescence

Abstract Background Near-Infrared (NIR) fluorescence imaging is a novel technique for intraoperative sentinel lymph node (SLN) identification. It has demonstrated promising results in several surgical specialties. The study aims to evaluate the feasibility of identifying the SLN by indocyanine green (ICG) enhanced NIR endoscopy in squamous cell carcinoma of the oral cavity (OCSCC). Methods Five patients with (cT1-3N0) OCSCC were included. We injected 1–1.25 ml of ICG (5 mg/ml) at four to five points around the primary. After the elevation of a platysma flap and posterior retraction of the sternocleidomastoid muscle, fluorescence images were taken with the IMAGE1 S™ NIR/ICG system to define the SLN(s). We sampled fluorescence marked SLN(s) stratified to lymph node levels, followed by level-specified elective neck dissection. Results The detection of at least one uni- or bilateral SLN (range 1–4) was possible in every case. The fluorescence signal occurred, on average, 4.8 ± 2.6 minutes after injection. There was no case of neck metastasis in SLN (0/13) and non-SLN (0/189). No adverse reactions to ICG occurred. Conclusions Our first results are confirming the concept of SLN concerning OCSCC after the application of real-time NIR fluorescence endoscopy. However, this has to be verified by more extended studies.

scholarly journals A Targeted Folate Receptor-α Near-infrared Fluorescent Agent Used for in Vitro Diagnosis of Endometrial Cytology

2020 ◽  
Author(s):  
Dongxin Liang ◽  
Xiaoqian Tuo ◽  
Lanbo Zhao ◽  
Kailu Zhang ◽  
Yiran Wang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Efficient Method ◽  
Predictive Value ◽  
Near Infrared ◽  
Folate Receptor ◽  
Intraoperative Imaging ◽  
False Negative ◽  
Endometrial Cytology ◽  
In Vitro Diagnosis

Abstract Background Endometrial cancer is the second-most prevalent cancer after breast cancer. Endometrial cytology test is a new diagnosis method for endometrial lesions. However, some unresolved issues limited the application of endometrial cytology test (ECT) in early diagnosis and screening of endometrial cancer. Evidence suggests that FRα is overexpressed in various solid tumors such as endometrial cancer, breast carcinoma, ovarian cancer and so on. Based on the expression of FR-α, the agent used in intraoperative imaging, FRα-targeting antibody drugs and diagnosis were developed previously. Nevertheless, research regarding agents used in the diagnosis of endometrial cancer is rarely carried out yet. Methods To obtain a promising and efficient method for in vitro and screening diagnosis of endometrial cytology, we performed the synthesis and evaluation of the new near-infrared targeting fluorescent dye folic acid-ZW800-1 (ZW-FA) and to explore its potential feasibility for in vitro diagnosis of endometrial cancer. Characterisation and Folate receptor-α (FR-α) targeting verification of ZW-FA were performed first and 92 patients were recruited, after liquid-based cytology preparations, during a 15-month period. ZW-FA and Hematoxylin-Eosin (H&E) staining were performed on all cytological slides successively; the histological diagnoses were regarded as the gold standard for ROC curve analysis. Results The cut-off value of ZW-FA fluorescence intensity is 62.9745; the sensitivity (Se), specificity (Sp), false-negative rate (FNR), false-positive rate (FPR), positive predictive value (PV+) percentage and negative predictive value (PV–) of the ZW-FA method are 84.6%, 85.2%, 15.4%,14.8%, 93.2% and 69.7%, respectively. Conclusions ZW-FA is potentially efficient for in vitro diagnosis of endometrial lesions based on the FR-α expression level of different endometrial lesions. This research offers a promising and efficient method for in vitro and screening diagnosis of endometrial cytology. Trial registration: ChiCTR1800020123. Registered December 15, 2018.

scholarly journals A targeted folate receptor-α near-infrared fluorescent agent used for in vitro diagnosis of endometrial cytology

2020 ◽  
Author(s):  
Dongxin Liang ◽  
Xiaoqian Tuo ◽  
Lanbo Zhao ◽  
Kailu Zhang ◽  
Yiran Wang ◽  
...  
Keyword(s):  
Predictive Value ◽  
Near Infrared ◽  
Folate Receptor ◽  
False Positive Rate ◽  
False Negative ◽  
False Negative Rate ◽  
Roc Curve Analysis ◽  
Fluorescent Agent ◽  
In Vitro Diagnosis

AbstractThe aim of this study is to perform the synthesis and evaluation of the new near-infrared targeting fluorescent dye folic acid-ZW800-1 (ZW-FA) and to explore its potential feasibility for in vitro diagnosis of endometrial cancer. Characterisation and Folate receptor-α (FR-α) targeting verification of ZW-FA were performed first and 92 patients were recruited, after liquid-based cytology preparations, during a 15-month period. ZW-FA and Hematoxylin-Eosin (H&E) staining were performed on all cytological slides successively; the histological diagnoses were regarded as the gold standard for ROC curve analysis. The cut-off value of ZW-FA fluorescence intensity is 62.9745; the sensitivity (Se), specificity (Sp), false-negative rate (FNR), false-positive rate (FPR), positive predictive value (PV+) percentage and negative predictive value (PV–) of the ZW-FA method are 84.6%, 85.2%, 15.4%,14.8%, 93.2% and 69.7%, respectively. ZW-FA is potentially efficient for in vitro diagnosis of endometrial lesions based on the FR-α expression level of different endometrial lesions.

An amphiphilic block copolymer conjugated with carborane and a NIR fluorescent probe for potential imaging-guided BNCT therapy

2016 ◽  
Vol 7 (26) ◽  
pp. 4411-4418 ◽  
Author(s):  
Zheng Ruan ◽  
Le Liu ◽  
Liyi Fu ◽  
Tao Xing ◽  
Lifeng Yan
Keyword(s):  
Block Copolymer ◽  
Fluorescent Probe ◽  
Triblock Copolymer ◽  
Near Infrared ◽  
Chain Transfer ◽  
Fluorescence Probe ◽  
Reversible Addition ◽  
Nir Fluorescence ◽  
Ring Open ◽  
Nir Dye

A carborane-containing triblock copolymer conjugated with a near infrared (NIR) fluorescence probe has been synthesized via reversible addition fragmentation chain transfer (RAFT), ring open polymerization (ROP), and conjugations of a cyanine NIR dye.

scholarly journals Macrophage as cellular vehicles for delivery of nanoparticles

2014 ◽  
Vol 07 (03) ◽  
pp. 1450023 ◽  
Author(s):  
Song Feng ◽  
Sisi Cui ◽  
Jing Jin ◽  
Yueqing Gu
Keyword(s):  
Central Nervous System ◽  
Near Infrared ◽  
Folate Receptor ◽  
Drug Carriers ◽  
Chemotherapeutic Agents ◽  
Tumor Bearing ◽  
The Central Nervous System ◽  
Clearing Rate ◽  
Nir Dye

Treatment of malignant brain tumors continues to challenge scientists and clinicians alike. Location of these tumors within the central nervous system (CNS), which is considered a "privileged" organ, can prevent the penetration of chemotherapeutic agents through the blood–brain barrier (BBB). To overcome this limitation, nanoparticles are taken up and transported by macrophage and then delivered directly into the CNS. In this study, we used macrophage to uptake the folate-targeted bifunctional micelles loaded with near-infrared (NIR) dye ICG-Der-01 and investigate the dynamic bio-distributions of macrophage after intravenous injection into tumor-bearing mice. In vitro cellular experiments by confocal microscopy indicated that the uptake of micelles in macrophage was greatly enhanced due to the folate receptor overexpression. Dynamic bio-distributions of macrophage showed a rapid clearing rate through the liver intestine pathway. In conclusion, macrophage could potentially be used as nanoparticle drug carriers and require further investigation.

scholarly journals Validation of a Three-Dimensional Head and Neck Spheroid Model to Evaluate Cameras for NIR Fluorescence-Guided Cancer Surgery

2021 ◽  
Vol 22 (4) ◽  
pp. 1966
Author(s):  
Claire Egloff-Juras ◽  
Ilya Yakavets ◽  
Victoria Scherrer ◽  
Aurélie Francois ◽  
Lina Bezdetnaya ◽  
...  
Keyword(s):  
Head And Neck ◽  
Near Infrared ◽  
Tumor Model ◽  
Resection Margins ◽  
Fluorescence Signal ◽  
Multicellular Tumor Spheroid ◽  
Guided Surgery ◽  
Nir Fluorescence ◽  
Fluorescence Guided Surgery

Near-infrared (NIR) fluorescence-guided surgery is an innovative technique for the real-time visualization of resection margins. The aim of this study was to develop a head and neck multicellular tumor spheroid model and to explore the possibilities offered by it for the evaluation of cameras for NIR fluorescence-guided surgery protocols. FaDu spheroids were incubated with indocyanine green (ICG) and then included in a tissue-like phantom. To assess the capability of Fluobeam® NIR camera to detect ICG in tissues, FaDu spheroids exposed to ICG were embedded in 2, 5 or 8 mm of tissue-like phantom. The fluorescence signal was significantly higher between 2, 5 and 8 mm of depth for spheroids treated with more than 5 µg/mL ICG (p < 0.05). The fluorescence intensity positively correlated with the size of spheroids (p < 0.01), while the correlation with depth in the tissue-like phantom was strongly negative (p < 0.001). This multicellular spheroid model embedded in a tissue-like phantom seems to be a simple and reproducible in vitro tumor model, allowing a comparison of NIR cameras. The ideal configuration seems to be 450 μm FaDu spheroids incubated for 24 hours with 0.05 mg/ml of ICG, ensuring the best stability, toxicity, incorporation and signal intensity.

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