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Damian A. Almiron Bonnin, Matthew C. Havrda, Myung Chang Lee, Linton Evans, Cong Ran, David C. Qian, Lia X. Harrington, Pablo A. Valdes, Chao Cheng, Chris I. Amos, Brent T. Harris, Keith D. Paulsen, David W. Roberts and Mark A. Israel

OBJECTIVE

5-aminolevulinic acid (5-ALA)–induced protoporphyrin IX (PpIX) fluorescence is an effective surgical adjunct for the intraoperative identification of tumor tissue during resection of high-grade gliomas. The use of 5-ALA-induced PpIX fluorescence in glioblastoma (GBM) has been shown to double the extent of gross-total resection and 6-month progression-free survival. The heterogeneity of 5-ALA-induced PpIX fluorescence observed during surgery presents a technical and diagnostic challenge when utilizing this tool intraoperatively. While some regions show bright fluorescence after 5-ALA administration, other regions do not, despite that both regions of the tumor may be histopathologically indistinguishable. The authors examined the biological basis of this heterogeneity using computational methods.

METHODS

The authors collected both fluorescent and nonfluorescent GBM specimens from a total of 14 patients undergoing surgery and examined their gene expression profiles.

RESULTS

In this study, the authors found that the gene expression patterns characterizing fluorescent and nonfluorescent GBM surgical specimens were profoundly different and were associated with distinct cellular functions and different biological pathways. Nonfluorescent tumor tissue tended to resemble the neural subtype of GBM; meanwhile, fluorescent tumor tissue did not exhibit a prominent pattern corresponding to known subtypes of GBM. Consistent with this observation, neural GBM samples from The Cancer Genome Atlas database exhibited a significantly lower fluorescence score than nonneural GBM samples as determined by a fluorescence gene signature developed by the authors.

CONCLUSIONS

These results provide a greater understanding regarding the biological basis of differential fluorescence observed intraoperatively and can provide a basis to identify novel strategies to maximize the effectiveness of fluorescence agents.

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Georg Widhalm, Jonathan Olson, Jonathan Weller, Jaime Bravo, Seunggu J. Han, Joanna Phillips, Shawn L. Hervey-Jumper, Susan M. Chang, David W. Roberts and Mitchel S. Berger

OBJECTIVE

In patients with suspected diffusely infiltrating low-grade gliomas (LGG), the prognosis is dependent especially on extent of resection and precision of tissue sampling. Unfortunately, visible 5-aminolevulinic acid (5-ALA) fluorescence is usually only present in high-grade gliomas (HGGs), and most LGGs cannot be visualized. Recently, spectroscopic probes were introduced allowing in vivo quantitative analysis of intratumoral 5-ALA–induced protoporphyrin IX (PpIX) accumulation. The aim of this study was to intraoperatively investigate the value of visible 5-ALA fluorescence and quantitative PpIX analysis in suspected diffusely infiltrating LGG.

METHODS

Patients with radiologically suspected diffusely infiltrating LGG were prospectively recruited, and 5-ALA was preoperatively administered. During resection, visual fluorescence and absolute tissue PpIX concentration (CPpIX) measured by a spectroscopic handheld probe were determined in different intratumoral areas. Subsequently, corresponding tissue samples were safely collected for histopathological analysis. Tumor diagnosis was established according to the World Health Organization 2016 criteria. Additionally, the tumor grade and percentage of tumor cells were investigated in each sample.

RESULTS

All together, 69 samples were collected from 22 patients with histopathologically confirmed diffusely infiltrating glioma. Visible fluorescence was detected in focal areas in most HGGs (79%), but in none of the 8 LGGs. The mean CPpIX was significantly higher in fluorescing samples than in nonfluorescing samples (0.693 μg/ml and 0.008 μg/ml, respectively; p < 0.001). A significantly higher mean percentage of tumor cells was found in samples with visible fluorescence compared to samples with no fluorescence (62% and 34%, respectively; p = 0.005), and significant correlation of CPpIX and percentage of tumor cells was found (r = 0.362, p = 0.002). Moreover, high-grade histology was significantly more common in fluorescing samples than in nonfluorescing samples (p = 0.001), whereas no statistically significant difference in mean CPpIX was noted between HGG and LGG samples. Correlation between maximum CPpIX and overall tumor grade was highly significant (p = 0.005). Finally, 14 (40%) of 35 tumor samples with no visible fluorescence and 16 (50%) of 32 LGG samples showed significantly increased CPpIX (cutoff value: 0.005 μg/ml).

CONCLUSIONS

Visible 5-ALA fluorescence is able to detect focal intratumoral areas of malignant transformation, and additional quantitative PpIX analysis is especially useful to visualize mainly LGG tissue that usually remains undetected by conventional fluorescence. Thus, both techniques will support the neurosurgeon in achieving maximal safe resection and increased precision of tissue sampling during surgery for suspected LGG.

Clinical trial registration no.: NCT01116661 (clinicaltrials.gov)

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Margaret Folaron, Rendall Strawbridge, Kimberley S. Samkoe, Caroline Filan, David W. Roberts and Scott C. Davis

OBJECTIVE

The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood-brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB. This study aims to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, the authors examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.

METHODS

Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.

RESULTS

Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.

CONCLUSIONS

Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma.

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David W. Roberts, Jonathan D. Olson, Linton T. Evans, Kolbein K. Kolste, Stephen C. Kanick, Xiaoyao Fan, Jaime J. Bravo, Brian C. Wilson, Frederic Leblond, Mikael Marois and Keith D. Paulsen

OBJECTIVE

The objective of this study was to detect 5-aminolevulinic acid (ALA)-induced tumor fluorescence from glioma below the surface of the surgical field by using red-light illumination.

METHODS

To overcome the shallow tissue penetration of blue light, which maximally excites the ALA-induced fluorophore protoporphyrin IX (PpIX) but is also strongly absorbed by hemoglobin and oxyhemoglobin, a system was developed to illuminate the surgical field with red light (620–640 nm) matching a secondary, smaller absorption peak of PpIX and detecting the fluorescence emission through a 650-nm longpass filter. This wide-field spectroscopic imaging system was used in conjunction with conventional blue-light fluorescence for comparison in 29 patients undergoing craniotomy for resection of high-grade glioma, low-grade glioma, meningioma, or metastasis.

RESULTS

Although, as expected, red-light excitation is less sensitive to PpIX in exposed tumor, it did reveal tumor at a depth up to 5 mm below the resection bed in 22 of 24 patients who also exhibited PpIX fluorescence under blue-light excitation during the course of surgery.

CONCLUSIONS

Red-light excitation of tumor-associated PpIX fluorescence below the surface of the surgical field can be achieved intraoperatively and enables detection of subsurface tumor that is not visualized under conventional blue-light excitation.

Clinical trial registration no.: NCT02191488 (clinicaltrials.gov)

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Jennifer Hong, Atman Desai, Vijay M. Thadani and David W. Roberts

OBJECTIVE

Vagal nerve stimulation (VNS) and corpus callosotomy (CC) have both been shown to be of benefit in the treatment of medically refractory epilepsy. Recent case series have reviewed the efficacy of VNS in patients who have undergone CC, with encouraging results. There are few data, however, on the use of CC following VNS therapy.

METHODS

The records of all patients at the authors' center who underwent CC following VNS between 1998 and 2015 were reviewed. Patient baseline characteristics, operative details, and postoperative outcomes were analyzed.

RESULTS

Ten patients met inclusion criteria. The median follow-up was 72 months, with a minimum follow-up of 12 months (range 12–109 months). The mean time between VNS and CC was 53.7 months. The most common reason for CC was progression of seizures after VNS. Seven patients had anterior CC, and 3 patients returned to the operating room for a completion of the procedure. All patients had a decrease in the rate of falls and drop seizures; 7 patients experienced elimination of drop seizures. Nine patients had an Engel Class III outcome, and 1 patient had a Class IV outcome. There were 3 immediate postoperative complications and 1 delayed complication. One patient developed pneumonia, 1 developed transient mutism, and 1 had persistent weakness in the nondominant foot. One patient presented with a wound infection.

CONCLUSIONS

The authors demonstrate that CC can help reduce seizures in patients with medically refractory epilepsy following VNS, particularly with respect to drop attacks.

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Kimon Bekelis, Joanna S. Kerley-Hamilton, Amy Teegarden, Craig R. Tomlinson, Rachael Kuintzle, Nathan Simmons, Robert J. Singer, David W. Roberts, Manolis Kellis and David A. Hendrix

OBJECTIVE

The molecular mechanisms behind cerebral aneurysm formation and rupture remain poorly understood. In the past decade, microRNAs (miRNAs) have been shown to be key regulators in a host of biological processes. They are noncoding RNA molecules, approximately 21 nucleotides long, that posttranscriptionally inhibit mRNAs by attenuating protein translation and promoting mRNA degradation. The miRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled.

METHODS

A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and miRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix miRNA microarrays were used to analyze miRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets.

RESULTS

Overall, 7 unruptured cerebral aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple miRNAs were significantly differentially expressed, with miR-21 (fold change 16.97) being the most upregulated, and miR-143–5p (fold change −11.14) being the most downregulated. From these, miR-21, miR-143, and miR-145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms.

CONCLUSIONS

This analysis identified differentially expressed genes and miRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for miRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed.

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Xiaoyao Fan, David W. Roberts, Timothy J. Schaewe, Songbai Ji, Leslie H. Holton, David A. Simon and Keith D. Paulsen

OBJECTIVE

Preoperative magnetic resonance images (pMR) are typically coregistered to provide intraoperative navigation, the accuracy of which can be significantly compromised by brain deformation. In this study, the authors generated updated MR images (uMR) in the operating room (OR) to compensate for brain shift due to dural opening, and evaluated the accuracy and computational efficiency of the process.

METHODS

In 20 open cranial neurosurgical cases, a pair of intraoperative stereovision (iSV) images was acquired after dural opening to reconstruct a 3D profile of the exposed cortical surface. The iSV surface was registered with pMR to detect cortical displacements that were assimilated by a biomechanical model to estimate whole-brain nonrigid deformation and produce uMR in the OR. The uMR views were displayed on a commercial navigation system and compared side by side with the corresponding coregistered pMR. A tracked stylus was used to acquire coordinate locations of features on the cortical surface that served as independent positions for calculating target registration errors (TREs) for the coregistered uMR and pMR image volumes.

RESULTS

The uMR views were visually more accurate and well aligned with the iSV surface in terms of both geometry and texture compared with pMR where misalignment was evident. The average misfit between model estimates and measured displacements was 1.80 ± 0.35 mm, compared with the average initial misfit of 7.10 ± 2.78 mm between iSV and pMR, and the average TRE was 1.60 ± 0.43 mm across the 20 patients in the uMR image volume, compared with 7.31 ± 2.82 mm on average in the pMR cases. The iSV also proved to be accurate with an average error of 1.20 ± 0.37 mm. The overall computational time required to generate the uMR views was 7–8 minutes.

CONCLUSIONS

This study compensated for brain deformation caused by intraoperative dural opening using computational model–based assimilation of iSV cortical surface displacements. The uMR proved to be more accurate in terms of model-data misfit and TRE in the 20 patient cases evaluated relative to pMR. The computational time was acceptable (7–8 minutes) and the process caused minimal interruption of surgical workflow.

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Pablo A. Valdés, David W. Roberts, Fa-Ke Lu, PhD and Alexandra Golby

Biomedical optics is a broadly interdisciplinary field at the interface of optical engineering, biophysics, computer science, medicine, biology, and chemistry, helping us understand light–tissue interactions to create applications with diagnostic and therapeutic value in medicine. Implementation of biomedical optics tools and principles has had a notable scientific and clinical resurgence in recent years in the neurosurgical community. This is in great part due to work in fluorescence-guided surgery of brain tumors leading to reports of significant improvement in maximizing the rates of gross-total resection. Multiple additional optical technologies have been implemented clinically, including diffuse reflectance spectroscopy and imaging, optical coherence tomography, Raman spectroscopy and imaging, and advanced quantitative methods, including quantitative fluorescence and lifetime imaging. Here we present a clinically relevant and technologically informed overview and discussion of some of the major clinical implementations of optical technologies as intraoperative guidance tools in neurosurgery.

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Terrance M. Darcey, Erik J. Kobylarz, Michael A. Pearl, Patricia J. Krauss, Stephanie A. Ferri, David W. Roberts and David F. Bauer

OBJECTIVE

The purpose of this study was to develop safe, site-specific procedures for placing and leaving subdermal needle leads for intraoperative monitoring (IOM) during intraoperative MRI procedures.

METHODS

The authors tested a variety of standard subdermal needle electrodes designed and FDA-approved for IOM in the conventional operating room. Testing was used to determine the conditions necessary to avoid thermal injury and significant image artifacts with minimal disruption of IOM and MRI procedures. Phantom testing was performed with a fiber optic (lead) temperature monitoring system and was followed by testing of leads placed in a healthy volunteer. The volunteer testing used electrode placements typical of standard IOM cases, together with radiofrequency (RF) coil placement and imaging sequences routinely employed for these case types. Lead length was investigated to assess heating effects for electrodes placed within the RF coil.

RESULTS

The authors found that conventional stainless steel (SS) and platinum/iridium (Pt/Ir) subdermal needles can be used safely without significant heating when placed outside the RF coil, and this accounts for the majority or entirety of electrode placements. When placed within the RF coil, Pt/Ir leads produced minimal image artifacts, while SS leads produced potentially significant artifacts. In phantom testing, significant heating was demonstrated in both SS and Pt/Ir leads placed within the RF coil, but only during high-resolution T2-weighted scanning. This problem was largely, but not completely, eliminated when leads were shortened to 25 cm. Human testing was unremarkable except for nonpainful heating detected in a few electrodes during thin-slice (1.5 mm) FLAIR scanning. Transient irritation (skin reddening along the needle tract) was noted at 2 of the electrodes with detectable heating.

CONCLUSIONS

The authors were satisfied with the safety of their site-specific procedures and have begun with off-label use (following institutional review board approval and obtaining patient informed consent) of tested monitoring leads in cases that combine IOM and MRI. The authors recommend that all facilities perform their own site-specific testing of monitoring leads before proceeding with their routine use.

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Xiaoyao Fan, David W. Roberts, Songbai Ji, Alex Hartov and Keith D. Paulsen

OBJECT

Fiducial-based registration (FBR) is used widely for patient registration in image-guided neurosurgery. The authors of this study have developed an automatic fiducial-less registration (FLR) technique to find the patient-to-image transformation by directly registering 3D ultrasound (3DUS) with MR images without incorporating prior information. The purpose of the study was to evaluate the performance of the FLR technique when used prospectively in the operating room and to compare it with conventional FBR.

METHODS

In 32 surgical patients who underwent conventional FBR, preoperative T1-weighted MR images (pMR) with attached fiducial markers were acquired prior to surgery. After craniotomy but before dural opening, a set of 3DUS images of the brain volume was acquired. A 2-step registration process was executed immediately after image acquisition: 1) the cortical surfaces from pMR and 3DUS were segmented, and a multistart sum-of-squared-intensity-difference registration was executed to find an initial alignment between down-sampled binary pMR and 3DUS volumes; and 2) the alignment was further refined by a mutual information-based registration between full-resolution grayscale pMR and 3DUS images, and a patient-to-image transformation was subsequently extracted.

RESULTS

To assess the accuracy of the FLR technique, the following were quantified: 1) the fiducial distance error (FDE); and 2) the target registration error (TRE) at anterior commissure and posterior commissure locations; these were compared with conventional FBR. The results showed that although the average FDE (6.42 ± 2.05 mm) was higher than the fiducial registration error (FRE) from FBR (3.42 ± 1.37 mm), the overall TRE of FLR (2.51 ± 0.93 mm) was lower than that of FBR (5.48 ± 1.81 mm). The results agreed with the intent of the 2 registration techniques: FBR is designed to minimize the FRE, whereas FLR is designed to optimize feature alignment and hence minimize TRE. The overall computational cost of FLR was approximately 4–5 minutes and minimal user interaction was required.

CONCLUSIONS

Because the FLR method directly registers 3DUS with MR by matching internal image features, it proved to be more accurate than FBR in terms of TRE in the 32 patients evaluated in this study. The overall efficiency of FLR in terms of the time and personnel involved is also improved relative to FBR in the operating room, and the method does not require additional image scans immediately prior to surgery. The performance of FLR and these results suggest potential for broad clinical application.