Incidence of radiographic and clinically significant pneumothorax or hemothorax after thoracic discectomy via mini-open lateral retropleural approach without prophylactic chest tube placement.

OBJECTIVE: The mini-open lateral retropleural (MO-LRP) approach is an effective option for surgically treating thoracic disc herniations, but the approach raises concerns for pneumothorax (PTX). However, chest tube placement causes insertion site tenderness, necessitates consultation services, increases radiation exposure (requires multiple radiographs), delays the progression of care, and increases narcotic requirements. This study examined the incidence of radiographic and clinically significant PTX and hemothorax (HTX) after the MO-LRP approach, without the placement of a prophylactic chest tube, for thoracic disc herniation. METHODS: This study was a single-institution retrospective evaluation of consecutive cases from 2017 to 2022. Electronic medical records were reviewed, including postoperative chest radiographs, radiology and operative reports, and postoperative notes. The presence of PTX or HTX was determined on chest radiographs obtained in all patients immediately after surgery, with interval radiographs if either was present. The size was categorized as large (≥ 3 cm) or small (< 3 cm) based on guidelines of the American College of Chest Physicians. PTX or HTX was considered clinically significant if it required intervention. RESULTS: Thirty patients underwent thoracic discectomy via the MO-LRP approach. All patients were included. Twenty patients were men (67%), and 10 (33%) were women. The patients ranged in age from 25 to 74 years. The most commonly treated level was T11-12 (n = 11, 37%). Intraoperative violation of parietal pleura occurred in 5 patients (17%). No patient had prophylactic chest tube placement. Fifteen patients (50%) had PTX on postoperative chest radiographs; 2 patients had large PTXs, and 13 had small PTXs. Both patients with large PTXs had expansion on repeat radiographs and were treated with chest tube insertion. Of the 13 patients with a small PTX, 1 required 100% oxygen using a nonrebreather mask; the remainder were asymptomatic. One patient, who had no abnormal findings on the immediate postoperative chest radiograph, developed an incidental HTX on postoperative day 6 and was treated with chest tube insertion. Thus, 3 patients (10%) required a chest tube: 2 for expanding PTX and 1 for delayed HTX. CONCLUSIONS: Most patients who undergo thoracic discectomy via the MO-LRP approach do not develop clinically significant PTX or HTX. PTX and HTX in this patient population should be treated with a chest tube only when there are postoperative clinical and radiographic indications.

Anatomical Reduction of Spondylolisthesis Through Lateral Lumbar Interbody Fusion With Percutaneous Pedicle Screw Fixation: An Intraoperative Technical Note.

BACKGROUND: Surgical management of lumbar spondylolisthesis requires neural decompression, stabilization, and alignment restoration. Minimally invasive spine approaches offer a wide variety of advantages for spondylolisthesis management. This intraoperative note describes the treatment of L4-L5 lumbar spondylolisthesis with lateral lumbar interbody fusion (LLIF) and percutaneous pedicle screw fixation (PSF). METHODS: The surgical technique for treating L4-L5 lumbar spondylolisthesis using a minimally invasive approach with LLIF and percutaneous PSF is described. This operative technique is illustrated with figures, and an intraoperative case example of its application is described. RESULTS: LLIF with percutaneous PSF can be a safe, effective, and reliable option for treating lumbar spondylolisthesis when applied with appropriate surgical technique in a selected patient population. This technique is a valuable addition to the range of available spine surgical options. CONCLUSIONS: LLIF with percutaneous PSF can be an effective technique for treating lumbar L4-L5 spondylolisthesis.

Two-Level Anterior Cervical Discectomy and Fusion Performed Using a Three-Dimensional Exoscope.

Anterior cervical discectomy and fusion (ACDF) is a common neurosurgical procedure. Portions of the procedure, such as the discectomy, foraminotomy, graft placement, and plate placement, are often performed using operating microscopes to maximize visualization and minimize neurovascular injury. Although standard operating microscopes offer superb visualization, they lack ergonomic and educational utility. With modern advancements in digital imaging and stereopsis, there has been a surge of interest in evaluating modern exoscopes for their utility in cranial and spinal neurosurgery.1-3 In Video 1, we demonstrate the use of a commercial three-dimensional exoscope from skin incision through completion of a two-level ACDF. Both the lead surgeon and the assistant surgeon were able to maintain a neutral, ergonomic, and comfortable position throughout the surgery. Furthermore, we tested the utility of this technique in 15 patients undergoing ACDF (2 one-level, 9 two-level, 3 three-level, and 1 four-level). Mean (SD) overall operative time was 118 (34) minutes (2-level ACDF, 110 [12] minutes), and mean (SD) blood loss was 23 (8.0) mL. The Neck Disability Index score and visual analog scale score for neck pain improved significantly at 6 weeks postoperatively (from 59.6 [1.3] to 27.9 [3.0] and from 6.3 [1.0] to 2.5 [0.92], respectively; P < 0.001 for both). Thus, excellent clinical outcomes can be achieved using three-dimensional exoscopes with comparable operative time and blood loss compared with conventional surgical microscopes or loupes. Given the improved ergonomic and teaching potential of exoscopes, the use of three-dimensional exoscopes for neurosurgical and spine surgeries warrants further investigation.

Radiographic and Clinical Outcomes After Stand-Alone Anterior Lumbar Interbody Fusion for Symptomatic L5-S1 Retrolisthesis.

BACKGROUND AND OBJECTIVES: Degenerative lumbar spondylolisthesis is associated with significant pain and disability. The literature on the treatment options and clinical outcomes for lumbar anterolisthesis is robust, but very few reports specifically evaluate lumbar retrolisthesis. This study investigated surgical outcomes for symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 anterior lumbar interbody fusion (ALIF). METHODS: All patients with symptomatic L5-S1 retrolisthesis treated with stand-alone L5-S1 ALIF at a single institution over a 7-year period were identified. Exhaustive nonoperative management had failed for all patients. Patients with previous lumbar fusion were excluded. Preoperative and postoperative radiographic images and patient-reported outcome measures for 20 patients (14 males and 6 females; mean [SD] age, 50.3 [13.7] years) were analyzed. RESULTS: The mean (SD) follow-up was 43.0 (23.7) months (range, 12.1-102.5 months). Patients experienced postoperative improvements in L5-S1 retrolisthesis (P = .048), L5-S1 disk height and angle (P < .001), L5 foraminal height (P < .001), L5-S1 lordosis (P < .001), and lumbar lordosis (P = .01). There were no significant changes in spinopelvic parameters. At the most recent follow-up, minimal clinically important differences in Oswestry Disability Index score, 36-Item Short-Form Survey (SF-36), and numerical rating scale score for leg pain were achieved in 11 of 20 (55%), 7 of 14 (50%), and 7 of 13 (54%) patients, respectively. All patients demonstrated fusion with no graft subsidence at up to 32 months. No patient experienced intraoperative complications, was readmitted, or required a subsequent posterior decompression or fusion because of refractory symptoms. CONCLUSION: In our cohort, stand-alone L5-S1 ALIF was associated with radiographic and clinical improvement in patients with symptomatic L5-S1 retrolisthesis.

Stable Regional and Global Alignment in Patients Treated With Minimally Invasive Lateral Retropleural Thoracic Diskectomy Without Fixation.

BACKGROUND AND OBJECTIVES: Thoracic disk herniations are challenging to treat, and open transthoracic or minimally invasive thoracoscopic approaches are associated with significant morbidity, substantial costs, and steep learning curves. The minimally invasive lateral retropleural thoracic diskectomy (MIS-LRP-TD) approach is straightforward and is associated with lower perioperative morbidity. With MIS-LRP-TD, the overlying rib, ipsilateral pedicle, ligamentum flavum, posterior longitudinal ligament, and posterior third of the adjacent vertebral bodies are resected. Adjunct fixation is typically not performed, eliminating hardware-related complications and costs. This radiographic study investigates long-term global and thoracic spine alignment after MIS-LRP-TD without fixation. METHODS: This study was a single-institution, retrospective evaluation of all patients who underwent MIS-LRP-TD without fixation between November 7, 2017 and July 19, 2022. Preoperative and the most recent postoperative radiographs were used to determine the C7 plumb line to central sacral vertical line, thoracic Cobb angle (TCA), segmental Cobb angle, C7 to sagittal vertical axis, thoracic kyphosis, and segmental kyphosis. RESULTS: In total, 22 patients with 24 disk herniations underwent MIS-LRP-TD without fixation. The mean (SD) radiographic follow-up was 12.9 (11.2) months. Overall, no significant differences were seen in C7 plumb line to central sacral vertical line (P = .65), C7 to sagittal vertical axis (P = .99), thoracic kyphosis (P = .30), TCA (P = .28), segmental kyphosis (P = .27), or segmental Cobb angle (P = .56) at follow-up. One patient demonstrated a >5° change in TCA but remained asymptomatic. CONCLUSION: Despite requiring extensive resection of the middle column and ipsilateral costovertebral joint at the index level, MIS-LRP-TD without adjunct fixation does not lead to significant global, regional, or segmental deformity. Thus, MIS-LRP-TD appears to be a safe, effective treatment approach for challenging thoracic disk herniations.

Management of hangman's fractures using anchored anterior cervical cages.

Background: Hangman's fractures comprise approximately 20% of C2 fractures and often require surgery to correct significant angulation and/or subluxation. Recently, anchored anterior cervical cages (ACCs) have been used to fuse C2-3 as they reduce the risks of soft-tissue dissection, bone drilling, operative time, and postoperative dysphagia. Methods: This single-center and retrospective study (2012-2019) included 12 patients (3 type I, 6 type II, and 3 type IIa fractures) undergoing C2-3 ACCs (zero profile, half plate, full plate). Preoperative and postoperative radiographic and clinical data were analyzed. Results: The 12 patients demonstrated the following findings: a mean operative time of 106 ± 21 min, blood loss averaging 67 ± 58 mL, and mean length of stay of 9.8 ± 7.7 days (6.4 ± 5.5 days in intensive care). The mean differences in preoperative versus postoperative radiographs showed an increase in disc angle (9.0° ± 9.4° vs. 14.0° ± 7.2°), reduction of subluxation (18.5% ± 13.6% vs. 2.6% ± 6.2%), and maintenance of C2-7 lordosis (14.3° ± 9.5° vs. 14.4° ± 9.5°). All patients demonstrated fusion on dynamic films obtained >6 months postoperatively. In addition, only one patient had Grade 0 subsidence, three had transient postoperative dysphagia, whereas none had either intraoperative complications or 90-day readmissions. Conclusion: ACCs proved to be a viable alternative to traditional anterior cervical discectomy/fusion to treat 12 patients with C2-3 hangman's fractures in this preliminary study.

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.

Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an AA transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here, we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/ß-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

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

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.

Stereotactic-Guided Transcerebellar Cisternoperitoneal Shunt Placement for Idiopathic Intracranial Hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) can cause debilitating symptoms and optic nerve ischemia if untreated. Cerebrospinal fluid diversion is often necessary to reduce intracranial pressure; however, current ventriculoperitoneal and lumboperitoneal shunting techniques have high failure rates in patients with IIH. OBJECTIVE: To describe our experience treating IIH with a novel stereotactic-guided transcerebellar cisternoperitoneal shunt (SGTC-CPS) technique that places the proximal shunt catheter in the posterior cisterna magnum. METHODS: Retrospective perioperative and postoperative data from all patients who underwent SGTC-CPS placement for IIH from March 1, 2015, to December 31, 2020, were analyzed. Patients were positioned as for ventriculoperitoneal shunt placement but with the head turned farther laterally to adequately expose the retrosigmoid space. Using neuronavigation, an opening was made near the transverse-sigmoid junction, and the proximal catheter was inserted transcerebellarly into the posterior foramen magnum. RESULTS: Thirty-two patients underwent SGTC-CPS placement (29 female; mean body mass index, 36.0 ± 7.5; 14 with prior shunt failures). The mean procedure time for shunt placement was 145 minutes. No intraoperative complications occurred, and all patients were discharged uneventfully. At the 6-month follow-up, 81% of patients (21 of 26) had relief of their presenting symptoms. Shunt survival without revision was 86% (25 of 29) at 1 year and 67% (10 of 15) at 3 years, with no infections. CONCLUSION: The SGTC-CPS offers an alternative solution for cerebrospinal fluid diversion in patients with IIH and demonstrates a lower failure rate and more durable symptom relief compared with ventriculoperitoneal or lumboperitoneal shunt placement. Using proper techniques and equipment promotes safe and facile placement of the proximal catheter.

Assessment and Comparison of Three Dimensional Exoscopes for Near-Infrared Fluorescence-Guided Surgery Using Second-Window Indocyanine-Green.

OBJECTIVE: Compared to microscopes, exoscopes have advantages in field-depth, ergonomics, and educational value. Exoscopes are especially well-poised for adaptation into fluorescence-guided surgery (FGS) due to their excitation source, light path, and image processing capabilities. We evaluated the feasibility of near-infrared FGS using a 3-dimensional (3D), 4 K exoscope with nearinfrared fluorescence imaging capability. We then compared it to the most sensitive, commercially-available near-infrared exoscope system (3D and 960 p). In-vitro and intraoperative comparisons were performed. METHODS: Serial dilutions of indocyanine-green (1-2000 µg/mL) were imaged with the 3D, 4 K Olympus Orbeye (system 1) and the 3D, 960 p VisionSense Iridium (system 2). Near-infrared sensitivity was calculated using signal-to-background ratios (SBRs). In addition, three patients with brain tumors were administered indocyanine-green and imaged with system 1, with two also imaged with system 2 for comparison. RESULTS: Systems 1 and 2 detected near-infrared fluorescence from indocyanine green concentrations of >250 µg/L and >31.3 µg/L, respectively. Intraoperatively, system 1 visualized strong near-infrared fluorescence from two, strongly gadoliniumenhancing meningiomas (SBR=2.4, 1.7). The high-resolution, bright images were sufficient for the surgeon to appreciate the underlying anatomy in the near-infrared mode. However, system 1 was not able to visualize fluorescence from a weakly-enhancing intraparenchymal metastasis. In contrast, system 2 successfully visualized both the meningioma and the metastasis but lacked high resolution stereopsis. CONCLUSION: Three-dimensional exoscope systems provide an alternative visualization platform for both standard microsurgery and near-infrared fluorescent guided surgery. However, when tumor fluorescence is weak (i.e., low fluorophore uptake, deep tumors), highly sensitive near-infrared visualization systems may be required.

The Evolution of 5-Aminolevulinic Acid Fluorescence Visualization: Time for a Headlamp/Loupe Combination.

BACKGROUND: The use of 5-aminolevulinic acid (5-ALA) for intraoperative protoporphyrin IX fluorescent imaging in the resection of malignant gliomas has been demonstrated to improve tumor visualization, increase the extent of resection, and extend progression-free survival. The current technique for visualization of 5-ALA consists of excitation and emission filters built into the operating microscope. However, there are notable limitations to this process, including low quantum yield, expense, and masking of surrounding anatomy. METHODS: We present 3 cases in which 3 separate methods were employed for visualizing fluorescence. The devices reported are 1) a low-cost blue light flashlight, 2) a low-cost headlamp, and 3) the first reported case of the new Designs for Vision REVEAL Fluorescence-Guided Surgery (FGS) 5-ALA fluorescent headlight and loupes. The aim of the study is to provide confirmation that tumor fluorescence can be observed using commercially available products other than the microscope. RESULTS: We demonstrate through 3 intraoperative cases that a variety of devices can produce visible fluorescence of the high-grade tumor and allow for simultaneous real-time visualization of the adjacent brain parenchyma and vasculature. The REVEAL FGS system appears to offer increased fluorescence emission compared with all other methods, including the microscope. CONCLUSIONS: Our study demonstrates the feasibility of using blue/ultraviolet light supplied by a commercially available, inexpensive flashlight or headlamp to visualize 5-ALA fluorescence in high-grade gliomas. We also provide the first documentation of the intraoperative use of the new Designs for Vision REVEAL FGS 5-ALA fluorescent headlight and loupes and report on the experience. Lack of an operative microscope capable of fluorescent illumination should not be a limiting factor in performing fluorescent-guided glioma resection.

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.

Somatostatin Receptor as a Molecular Imaging Target in Human and Canine Cushing Disease.

OBJECTIVES: Fluorescence-guided surgery may improve completeness of resection in transsphenoidal surgery for Cushing disease (CD) by enabling visualization of residual tumor tissue at the margins. In this review we discuss somatostatin receptors (SSTRs) as targets for fluorescence-guided surgery and overview existing SSTR-specific imaging agents. We also compare SSTR expression in normal pituitary and corticotrophinoma tissues from human and canine CD patients to assess canines as a translational model for CD. METHODS: A PubMed literature search was conducted for publications containing the terms canine, somatostatin receptor, Cushing's disease, and corticotroph adenoma. SSTR expression data from each study was documented as the presence or absence of expression or, when possible, the number of tumors expressing a given SSTR subtype within a group of tumors being studied. Studies that used reverse transcription polymerase chain reaction to quantify SSTR expression were selected for additional comparative analysis. RESULTS: SSTR5 is strongly expressed in human corticotroph adenomas and weakly expressed in surrounding pituitary parenchyma, a pattern not conclusively observed in canine patients. SSTR2 mRNA expression is similar in human normal pituitary and corticotrophinoma cells but may be significantly higher in canine normal pituitary tissue than in corticotroph tumoral tissue. Limited data were available on SSTR subtypes 1, 3, and 4. CONCLUSIONS: Further studies must fill the knowledge gaps related to species-specific SSTR expression, so using canine CD as a translational model may be premature. We do conclude that the expression profile of SSTR5 (i.e., high local expression in pituitary adenomas relative to normal surrounding tissues) makes SSTR5 a promising molecular target for FGS.

Fluorescence guided surgery for pituitary adenomas.

PURPOSE: Resection of pituitary adenomas presents a number of unique challenges in neuro-oncology. The proximity of these lesions to key vascular and endocrine structures as well as the need to interpret neuronavigation in the context of shifting tumor position increases the complexity of the operation. More recently, substantial advances in fluorescence-guided surgery have been demonstrated to facilitate the identification of numerous tumor types and result in increased rates of complete resection and overall survival. METHODS: A review of the literature was performed, and data regarding the mechanism of the fluorescence agents, their administration, and intraoperative tumor visualization were extracted. Both in vitro and in vivo studies were assessed. The application of these agents to pituitary tumors, their advantages and limitations, as well as future directions are presented here. RESULTS: Numerous laboratory and clinical studies have described the use of 5-ALA, fluorescein, indocyanine green, and OTL38 in pituitary lesions. All of these drugs have been demonstrated to accumulate in tumor cells. Several studies have reported the successful use of the majority of the agents in inducing intraoperative tumor fluorescence. However, their sensitivity and specificity varies across the literature and between functioning and non-functioning adenomas. CONCLUSIONS: At present, numerous studies have shown the feasibility and safety of these agents for pituitary adenomas. However, further research is needed to assess the applicability of fluorescence-guided surgery across different tumor subtypes as well as explore the relationship between their use and postoperative clinical outcomes.

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.

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

Indocyanine green (ICG) is a water-soluble dye that was approved by the FDA for biomedical purposes in 1956. Initially used to measure cardiocirculatory and hepatic functions, ICG's fluorescent properties in the near-infrared (NIR) spectrum soon led to its application in ophthalmic angiography. In the early 2000s, ICG was formally introduced in neurosurgery as an angiographic tool. In 2016, the authors' group pioneered a novel technique with ICG named second-window ICG (SWIG), which involves infusion of a high dose of ICG (5.0 mg/kg) in patients 24 hours prior to surgery. To date, applications of SWIG have been reported in patients with high-grade gliomas, meningiomas, brain metastases, pituitary adenomas, craniopharyngiomas, chordomas, and pinealomas.The applications of ICG have clearly expanded rapidly across different specialties since its initial development. As an NIR fluorophore, ICG has advantages over other FDA-approved fluorophores, all of which are currently in the visible-light spectrum, because of NIR fluorescence's increased tissue penetration and decreased autofluorescence. Recently, interest in the latest applications of ICG in brain tumor surgery has grown beyond its role as an NIR fluorophore, extending into shortwave infrared imaging and integration into nanotechnology. This review aims to summarize reported clinical studies on ICG fluorescence-guided surgery of intracranial tumors, as well as to provide an overview of the literature on emerging technologies related to the utility of ICG in neuro-oncological surgeries, including the following aspects: 1) ICG fluorescence in the NIR-II window; 2) ICG for photoacoustic imaging; and 3) ICG nanoparticles for combined diagnostic imaging and therapy (theranostic) applications.

Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier.

Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss. We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis. Mice lacking either the Wnt co-receptor low-density lipoprotein receptor-related protein 5 (Lrp5-/- ) or the Wnt ligand Norrin (Ndpy/- ) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis. Wnt signaling directly controls the transcription of an endothelium-specific transcytosis inhibitor, major facilitator superfamily domain-containing protein 2a (MFSD2A), in a ß-catenin-dependent manner. MFSD2A overexpression reverses Wnt deficiency-induced transcytosis in endothelial cells and in retinas. Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)-positive caveolae pathway. In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling-deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter. Our findings uncovered the Wnt/ß-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.

Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. METHODS: A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. RESULTS: ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745 nm, em: 800 nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 on day 23 (p = 0.0055). CONCLUSION: A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration.

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 ).