Second window indocyanine green localizes CNS lymphoma in real time in the operating room: report of two cases.

Intraoperative distinction of lesional tissue versus normal brain parenchyma can be difficult in neurosurgical oncology procedures. We report the successful, real-time visualization of central nervous system (CNS) lymphoma using the 'Second Window Indocyanine Green' (SWIG) method for two patients who underwent craniotomy for pathology that was determined to be large B cell lymphoma. Indocyanine green (ICG), when administered intravenously the day prior to cranial surgery, is a re-purposed fluorophore that may afford safe, immediate visual confirmation of on-target tissue resection, thereby providing a valuable adjunct to intraoperative navigation and decreasing reliance on frozen pathology analysis. These first reported cases of SWIG for lymphoma in the CNS indicate that further study of fluorophores to improve biopsy targeting and yield is warranted.

Near-infrared intraoperative molecular imaging with conventional neurosurgical microscope can be improved with narrow band "boost" excitation.

BACKGROUND: Intraoperative visualization of brain tumors with near-infrared (NIR)-fluorescent dyes is an emerging method for tumor margin approximation but are limited by existing fluorescence detection platforms. We previously showed that a dedicated NIR imaging platform outperformed a state-of-the-art neurosurgical microscope in fluorescence signal characteristics. This study examined whether conventional neurosurgical microscope NIR signal could be improved with the addition of a narrow wavelength excitation source. METHODS: Imaging was conducted with a broad-spectrum neurosurgical microscope and commercial near-infrared module. Addition of an 805-nm laser was used to "boost" NIR excitation of indocyanine green (ICG). In vitro quantification was performed on serial dilutions of ICG. Patients underwent tumor resection with delayed 24-h imaging of ICG infusion. NIR fluorescence of dura, cortex, or tumor was quantified from images prior to (pre-boost) and following added excitation with the laser (post-boost). Signal to background ratio (SBR) of pre- and post-boost was calculated as a readout of image enhancement. RESULTS: In vitro, excitation boost effected a 29% increase in mean SBR in six serial dilutions of ICG. Intraoperative boost was performed in 11 patients including meningioma, glioblastoma multiforme, and metastases. Increase in tumor fluorescence was pronounced under direct tumor visualization. Across all patients, boost excitation resulted in 35% mean improvement from pre-boost SBR (p < 0.001). CONCLUSION: Neurosurgical microscopes remain the preferred method of visualizing tumor during intracranial surgery. However, current modalities for NIR signal detection are suboptimal. We demonstrate that augmentation of a fluorescence microscope module with a focused excitation source is a simple mechanism of improving NIR tumor visualization. CLINICAL TRIAL REGISTRATION: NCT03262636.

Ethical Issues in Intraoperative Neuroscience Research: Assessing Subjects' Recall of Informed Consent and Motivations for Participation.

BackgroundAn increasing number of studies utilize intracranial electrophysiology in human subjects to advance basic neuroscience knowledge. However, the use of neurosurgical patients as human research subjects raises important ethical considerations, particularly regarding informed consent and undue influence, as well as subjects' motivations for participation. Yet a thorough empirical examination of these issues in a participant population has been lacking. The present study therefore aimed to empirically investigate ethical concerns regarding informed consent and voluntariness in Parkinson's disease patients undergoing deep brain stimulator (DBS) placement who participated in an intraoperative neuroscience study.MethodsTwo semi-structured 30-minute interviews were conducted preoperatively and postoperatively via telephone. Interviews assessed participants' motivations for participation in the parent intraoperative study, recall of information presented during the informed consent process, and participants' postoperative reflections on the research study.ResultsTwenty-two participants (mean age = 60.9) completed preoperative interviews at a mean of 7.8 days following informed consent and a mean of 5.2 days prior to DBS surgery. Twenty participants completed postoperative interviews at a mean of 5 weeks following surgery. All participants cited altruism or advancing medical science as "very important" or "important" in their decision to participate in the study. Only 22.7% (n = 5) correctly recalled one of the two risks of the study. Correct recall of other aspects of the informed consent was poor (36.4% for study purpose; 50.0% for study protocol; 36.4% for study benefits). All correctly understood that the study would not confer a direct therapeutic benefit to them.ConclusionEven though research coordinators were properly trained and the informed consent was administered according to protocol, participants demonstrated poor retention of study information. While intraoperative studies that aim to advance neuroscience knowledge represent a unique opportunity to gain fundamental scientific knowledge, improved standards for the informed consent process can help facilitate their ethical implementation.

Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study.

OBJECTIVE: Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS: This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS: The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17-2.68, p = 0.006). CONCLUSIONS: SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

Second-Window Indocyanine Green for Visualization of Hemangioblastoma: A Case Report With Two-Dimensional Operative Video.

BACKGROUND AND IMPORTANCE: The proper differentiation of neoplastic tissue from adjacent brain parenchyma can pose a great challenge, especially in eloquent areas of the brain. With the novel technique, "Second-Window Indocyanine Green," injection of a near-infrared fluorophore (ICG) allows for intraoperative visualization of tumors by taking advantage of the compromised vasculature surrounding the tumor. Thus, such a technique may demonstrate utility for hemangioblastomas, which are hypervascular tumors of the central nervous system. CLINICAL PRESENTATION: Here we present the case of a 39-yr-old male with a demonstrated cystic mass in the left cerebellum, with additional edema spreading towards the vermis. A total of 5 mg/kg of ICG was delivered intravenously 24 h prior to the operation. The tumor was approached via the infratentorial suboccipital approach. We observed strong near-infrared fluorescence through the intact dura, consistent with the tumor location. Surgical pathology confirmed a final diagnosis of cerebellar hemangioblastoma. There was complete resection of the tumor, with the patient discharged uneventfully. CONCLUSION: We report the first successful case of fluorescence-guided surgery of a cerebellar hemangioblastoma using near-infrared fluorescence imaging with the Second-Window ICG technique. This joins a growing series of publications that demonstrate the efficacy of a novel application of ICG, a near-infrared fluorophore, in accurate intraoperative visualization of neoplastic tissue. While the use of a dedicated near-infrared platform (ie, the VisionSense Iridium [Visionsense, Philadelphia, Pennsylvania]) yields a higher signal-to-background ratio, a neurosurgical microscope (ie, the Leica OH6 [Leica Microsystems, Wetzlar, Germany]) may also provide a suitable option in cases where fluorescence is very strong.

Second window ICG predicts gross-total resection and progression-free survival during brain metastasis surgery.

OBJECTIVE: Metastases are the most common intracranial malignancies and complete resection can provide relief of neurological symptoms and reduce recurrence. The authors' prospective pilot study in 2017 demonstrated promising results for the application of high-dose, delayed imaging of indocyanine green (ICG), known as second window ICG (SWIG), in patients undergoing surgery for brain metastases. In this prospective cohort study, the authors evaluated intraoperative imaging and clinical outcomes of treatment using SWIG. METHODS: Patients were prospectively enrolled in an approved study of high-dose, delayed ICG (SWIG) and received 5 mg/kg (2014-2018) or 2.5 mg/kg (2018-2019) ICG 24 hours preoperatively. Intraoperatively, near-infrared (NIR) imaging was performed using a dedicated NIR exoscope. NIR images were analyzed and the signal-to-background ratio (SBR) was calculated to quantify fluorescence. Residual fluorescence on the postresection NIR view was compared and correlated to the residual gadolinium enhancement on postoperative MRI. Patient survival and predictive factors were analyzed. RESULTS: In total, 51 intracranial metastases were surgically treated in 47 patients in this cohort. All 51 metastatic tumors demonstrated strong NIR fluorescence (mean SBR 4.9). In tumors ≤ 10 mm from the cortical surface, SWIG with 5 mg/kg ICG produced enhanced transdural tumor visibility (91.3%) compared to 2.5 mg/kg (52.9%; p = 0.0047). Neoplastic margin detection using NIR fluorescence compared to white light improved sensitivity, albeit lowered specificity; however, increasing the SBR cutoff for positive fluorescence significantly improved specificity without sacrificing sensitivity, increasing the overall accuracy from 57.5% to 72.5%. A lack of residual NIR fluorescence after resection was closely correlated with a lack of residual enhancement on postoperative MRI (p = 0.007). Among the 16 patients in whom tumor recurred at the site of surgery, postoperative MRI successfully predicted 8 cases, whereas the postresection NIR view predicted 12 cases. Progression-free survival rate at 12 months was greater for patients without residual NIR fluorescence (38%) than for those without residual enhancement on postoperative MRI (29%). CONCLUSIONS: The current study demonstrates the clinical benefits of the SWIG technique in surgery for patients with brain metastases. Specifically, this technique allows for dose-dependent, transdural localization of neoplasms and improved sensitivity in neoplastic margin detection. Postresection residual fluorescence can be a powerful tool to evaluate extent of resection in conjunction with MRI, and it may guide decisions on brain metastasis management.

Stereotactic Radiosurgery for Differentiated Thyroid Cancer Brain Metastases: An International, Multicenter Study.

Background: Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. Methods: From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). Results: We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1-10 BMs). The median SRS treatment volume was 0.79 cm3 (range: 0.003-38.18 cm3), and the median SRS prescription dose was 20 Gy (range: 8-24 Gy). The median survival after SRS for BMs was 14 months (range: 3-58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452, p = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143-11.904; p = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689-0.945; p = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. Conclusion: The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.

Stereotactic radiosurgery for treatment of radiation-induced meningiomas: a multiinstitutional study.

OBJECTIVE: Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. METHODS: From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. RESULTS: Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4-195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3-45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028-65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. CONCLUSIONS: SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

Surface-Registration Frameless Stereotactic Navigation Is Less Accurate During Prone Surgeries: Intraoperative Near-Infrared Visualization Using Second Window Indocyanine Green Offers an Adjunct.

BACKGROUND: Frameless neuronavigation allows neurosurgeons to visualize and relate the position of surgical instruments to intracranial pathologies based on preoperative tomographic imaging. However, neuronavigation can often be inaccurate. Multiple factors have been proposed as potential causes, and new technologies are needed to overcome these challenges. OBJECTIVE: To evaluate the accuracy of neuronavigation systems compared to near-infrared (NIR) fluorescence imaging using Second Window Indocyanine Green, a novel technique, and to determine factors that lead to neuronavigation errors. METHODS: A retrospective analysis was conducted on 56 patients who underwent primary resections of intracranial tumors. Patients received 5 mg/kg ICG approximately 24 h preoperatively. Intraoperatively, neuronavigation was used to plan craniotomies to place the tumors in the center. After craniotomy, NIR imaging visualized tumor-specific NIR signals. The accuracy of neuronavigation and NIR fluorescence imaging for delineating the tumor boundary prior to durotomy was compared. RESULTS: The neuronavigation centers and NIR centers were 23.0 ± 7.7 % and 2.6 ± 1.1 % deviated from the tumor centers, respectively, relative to the craniotomy sizes. In 12 cases, significant changes were made to the planned durotomy based on NIR imaging. Patient position was a significant predictor of neuronavigation inaccuracy on both univariate and multivariate analysis, with the prone position having significantly higher inaccuracy (29.2 ± 8.1 %) compared to the supine (16.2 ± 8.1 %, p value < 0.001) or the lateral (17.9 ± 5.1 %, p value = 0.003) positions. CONCLUSION: Patient position significantly affects neuronavigation accuracy. Intraoperative NIR fluorescence imaging before durotomy offers an opportunity to readjust the neuronavigation image space to better align with the patient space.

Second Window Indocyanine Green (SWIG) Near Infrared Fluorescent Transventricular Biopsy of Pineal Tumor.

BACKGROUND: Second Window Indocyanine Green (SWIG) is a novel technique for real-time, intraoperative tumor visualization using a high-dose infusion of indocyanine green (ICG) 24 hours before surgery. Due to pathologic diversity found in the pineal region, tissue diagnosis in patients with pineal region mass is essential to optimize further clinical management. CASE DESCRIPTION: We present the case of a 75-year-old woman with known pineal region mass for 18 years, who presented with progressive classic signs and symptoms of obstructive hydrocephalus over the past 6 months. Preoperative imaging confirmed a contrast-enhancing pineal region tumor, which appeared to be obstructing the aqueduct of Sylvius, causing proximal obstructive hydrocephalus. We delivered 5 mg/kg of ICG intravenously 24 hours before the surgery. The patient underwent an endoscopic third ventriculostomy and a biopsy of the pineal lesion. The tumor demonstrated clear near-infrared fluorescence, which was distinct from surrounding third ventricle floor and ependyma. The signal-to-background ratio was 2.9. The final pathology report revealed a World Health Organization grade I pineocytoma. CONCLUSIONS: We report on a novel application of near-infrared fluorescence for tumor identification of pineal region tumors, using the "SWIG technique."

Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas.

PURPOSE: Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA. PROCEDURES: Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and H&E images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence. RESULTS: In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence. CONCLUSION: Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections. CLINICAL TRIAL: NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1 ).

Near-Infrared Imaging with Second-Window Indocyanine Green in Newly Diagnosed High-Grade Gliomas Predicts Gadolinium Enhancement on Postoperative Magnetic Resonance Imaging.

PURPOSE: Intraoperative molecular imaging with tumor-targeting fluorophores offers real-time detection of neoplastic tissue. The second window indocyanine green (SWIG) technique relies on passive accumulation of indocyanine green (ICG), a near-infrared fluorophore, in neoplastic tissues. In this study, we explore the ability of SWIG to detect neoplastic tissue and to predict postoperative magnetic resonance imaging (MRI) findings intraoperatively. PROCEDURES: Retrospective data were collected from 36 patients with primary high-grade gliomas (HGG) enrolled as part of a larger trial between October 2014 and October 2018. Patients received systemic ICG infusions at 2.5-5 mg/kg 24 h preoperatively. Near-infrared fluorescence was recorded throughout the case and from biopsy specimens. The presence/location of residual SWIG signal after resection was compared to the presence/location of residual gadolinium enhancement on postoperative MRI. The extent of resection was not changed based on near-infrared imaging. RESULTS: All 36 lesions demonstrated strong near-infrared fluorescence (signal-to-background = 6.8 ± 2.2) and 100 % of tumors reaching the cortex were visualized before durotomy. In 78 biopsy specimens, near-infrared imaging demonstrated higher sensitivity and accuracy than white light for diagnosing neoplastic tissue intraoperatively. Furthermore, near-infrared imaging predicted gadolinium enhancement on postoperative MRI with 91 % accuracy, with visualization of residual enhancement as small as 0.3 cm3. Patients with no residual near-infrared signal after resection were significantly more likely to have complete resection on postoperative MRI (p value < 0.0001). CONCLUSIONS: Intraoperative imaging with SWIG demonstrates highly sensitive detection of HGG tissue in real time. Furthermore, post-resection near-infrared imaging correlates with postoperative MRI. Overall, our findings suggest that SWIG can provide surgeons with MRI-like results in real time, potentially increasing resection rates.

Intraoperative Molecular Imaging with Second Window Indocyanine Green Facilitates Confirmation of Contrast-Enhancing Tissue During Intracranial Stereotactic Needle Biopsy: A Case Series.

BACKGROUND: Stereotactic needle biopsy provides a minimally invasive option for the diagnosis of intracranial lesions but is limited by inconclusive diagnoses on frozen pathology. For rapid pathology, 5-aminovelunic acid and sodium fluorescein have previously demonstrated potential as diagnostic adjuvants. Stereotactic biopsy with near-infrared (NIR) fluorophores has not been reported. We identified 5 representative cases using NIR fluorescent dye indocyanine green (ICG) administered in a high dose, delayed manner. METHODS: Five patients underwent second window indocyanine green (SWIG)-guided stereotactic biopsy for diagnosis of suspected glioma or tumor recurrence. Up to 5 mg/kg ICG was administered approximately 24 hours prior to surgery. Biopsies were conducted in the standard fashion, targeting regions of suspected tumor using intraoperative frameless navigation. Samples were examined intraoperatively under standard visible light and for fluorescence using conventional NIR imaging platforms. Findings were correlated with frozen and final tumor pathology for all cases. RESULTS: A total of 10 biopsy specimens were obtained. Three did not fluoresce and did not demonstrate tumor on preliminary or final pathology, including a non-gadolinium-enhancing sample taken proximal to the final target. The remaining 7 fluoresced, of which 6 contained tumor and 1 contained necrosis. Fluorescence was also noted in a patient with radiation treatment effect. Overall fluorescence characteristics were highly concordant with preliminary and final diagnoses. CONCLUSIONS: SWIG provides rapid intraoperative confirmation of pathologic brain tissue by permeating neoplastic or inflammatory brain tissue via a mechanism similar to that of gadolinium enhancement. SWIG-guided stereotactic biopsy can improve surgical efficiency by enhancing confidence in acquisition of target tissue.

Near-Infrared Optical Contrast of Skull Base Tumors During Endoscopic Endonasal Surgery.

BACKGROUND: Near-infrared (NIR) tumor contrast is achieved through the "second-window ICG" technique, which relies on passive accumulation of high doses of indocyanine green (ICG) in neoplasms via the enhanced permeability and retention effect. OBJECTIVE: To report early results and potential challenges associated with the application of second-window ICG technique in endonasal endoscopic, ventral skull-base surgery, and to determine potential predictors of NIR signal-to-background ratio (SBR) using endoscopic techniques. METHODS: Pituitary adenoma (n = 8), craniopharyngioma (n = 3), and chordoma (n = 4) patients received systemic infusions of ICG (5 mg/kg) approximately 24 h before surgery. Dual-channel endoscopy with visible light and NIR overlay were photodocumented and analyzed post hoc. RESULTS: All tumors (adenoma, craniopharyngioma, chordoma) demonstrated NIR positivity and fluoresced with an average SBR of 3.9 ± 0.8, 4.1 ± 1.7, and 2.1 ± 0.6, respectively. Contrast-enhanced T1 signal intensity proved to be the single best predictor of observed SBR (P = .0003). For pituitary adenomas, the sensitivity, specificity, positive predictive value, and negative predictive value of NIR-guided identification of tumor was 100%, 20%, 71%, and 100%, respectively. CONCLUSION: In this preliminary study of a small set of patients, we demonstrate that second-window ICG can provide NIR optical tumor contrast in 3 types of ventral skull-base tumors. Chordomas demonstrated the weakest NIR signal, suggesting limited utility in those patients. Both nonfunctional and functional pituitary adenomas appear to accumulate ICG, but utility for margin detection for the adenomas is limited by low specificity. Craniopharyngiomas with third ventricular extension appear to be a particularly promising target given the clean brain parenchyma background and strong SBR.

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

OBJECTIVE: Intraoperative 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. METHODS: A 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). RESULTS: All 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%. CONCLUSIONS: Intraoperative 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.