The Use of Spectroscopy Handheld Tools in Brain Tumor Surgery: Current Evidence and Techniques

The fundamental principle in the operative treatment of brain tumors involves achieving maximal safe resection in order to improve postoperative outcomes. At present, challenges in visualizing microscopic disease and residual tumor remain an impediment to complete tumor removal. Spectroscopic tools have the theoretical advantage of accurate tissue identification, coupled with the potential for manual intraoperative adjustments to improve visualization of remaining tumor tissue that would otherwise be difficult to detect. The current evidence and techniques for handheld spectroscopic tools in surgical neuro-oncology are explored here

Stereotactic Laser Interstitial Thermal Therapy for Recurrent High-Grade Gliomas

BACKGROUND: The value of maximal safe cytoreductive surgery in recurrent high-grade gliomas (HGGs) is gaining wider acceptance. However, patients may harbor recurrent tumors that may be difficult to access with open surgery. Laser interstitial thermal therapy (LITT) is emerging as a technique for treating a variety of brain pathologies, including primary and metastatic tumors, radiation necrosis, and epilepsy. OBJECTIVE: To review the role of LITT in the treatment of recurrent HGGs, for which current treatments have limited efficacy, and to discuss the possible role of LITT in the disruption of the blood-brain barrier to increase delivery of chemotherapy locoregionally. METHODS: A MEDLINE search was performed to identify 17 articles potentially appropriate for review. Of these 17, 6 reported currently commercially available systems and as well as magnetic resonance thermometry to monitor the ablation and, thus, were thought to be most appropriate for this review. These studies were then reviewed for complications associated with LITT. Ablation volume, tumor coverage, and treatment times were also reviewed. RESULTS: Sixty-four lesions in 63 patients with recurrent HGGs were treated with LITT. Frontal (n = 34), temporal (n = 14), and parietal (n = 16) were the most common locations. Permanent neurological deficits were seen in 7 patients (12%), vascular injuries occurred in 2 patients (3%), and wound infection was observed in 1 patient (2%). Ablation coverage of the lesions ranged from 78% to 100%. CONCLUSION: Although experience using LITT for recurrent HGGs is growing, current evidence is insufficient to offer a recommendation about its role in the treatment paradigm for recurrent HGGs. ABBREVIATIONS: BBB, blood-brain barrierFDA, US Food and Drug AdministrationGBM, glioblastoma multiformeHGG, high-grade gliomaLITT, laser interstitial thermal therapy

Current knowledge on the immune microenvironment and emerging immunotherapies in diffuse midline glioma

Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature in critical areas of the brain, the prognosis of DMG remains dismal. DMGs are characterized by unique phenotypic heterogeneity and histological features. Mutations of H3K27M, TP53, and ACVR1 drive DMG tumorigenesis. Histological artifacts include pseudopalisading necrosis and vascular endothelial proliferation. Mouse models that recapitulate human DMG have been used to study key driver mutations and the tumor microenvironment. DMG consists of a largely immunologically cold tumor microenvironment that lacks immune cell infiltration, immunosuppressive factors, and immune surveillance. While tumor-associated macrophages are the most abundant immune cell population, there is reduced T lymphocyte infiltration. Immunotherapies can stimulate the immune system to find, attack, and eliminate cancer cells. However, it is critical to understand the immune microenvironment of DMG before designing immunotherapies since differences in the microenvironment influence treatment efficacy. To this end, our review aims to overview the immune microenvironment of DMG, discuss emerging insights about the immune landscape that drives disease pathophysiology, and present recent findings and new opportunities for therapeutic discovery

Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey

OBJECTIVE Antiepileptic drugs (AEDs) are often administered prophylactically following brain tumor resection. With conflicting evidence and unestablished guidelines, however, the nature of this practice among tumor surgeons is unknown. METHODS On November 24, 2015, a REDCap (Research Electronic Database Capture) survey was sent to members of the AANS/CNS Section on Tumors to query practice patterns. RESULTS Responses were received from 144 individuals, including 18.8% of board-certified neurosurgeons surveyed (across 86 institutions, 16 countries, and 5 continents). The majority reported practicing in an academic setting (85%) as a tumor specialist (71%). Sixty-three percent reported always or almost always prescribing AED prophylaxis postoperatively in patients with a supratentorial brain tumor without a prior seizure history. Meanwhile, 9% prescribed occasionally and 28% rarely prescribed AED prophylaxis. The most common agent was levetiracetam (85%). The duration of seizure prophylaxis varied widely: 25% of surgeons administered prophylaxis for 7 days, 16% for 2 weeks, 21% for 2 to 6 weeks, and 13% for longer than 6 weeks. Most surgeons (61%) believed that tumor pathology influences epileptogenicity, with high-grade glioma (39%), low-grade glioma (31%), and metastases (24%) carrying the greatest seizure risk. While the majority used prophylaxis, 62% did not believe or were unsure if prophylactic AEDs reduced seizures postoperatively. The vast majority (82%) stated that a well-designed randomized trial would help guide their future clinical decision making. CONCLUSIONS Wide knowledge and practice gaps exist regarding the frequency, duration, and setting of AED prophylaxis for seizure-naive patients undergoing brain tumor resection. Acceptance of universal practice guidelines on this topic is unlikely until higher-level evidence supporting or refuting the value of modern seizure prophylaxis is demonstrated

Intraoperative Fluorescence Diagnosis in the Brain: A Systematic Review and Suggestions for Future Standards on Reporting Diagnostic Accuracy and Clinical Utility

BACKGROUND: Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations. METHODS: A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies. RESULTS: Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported. CONCLUSIONS: Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here

[18F]Fluciclovine PET discrimination between high- and low-grade gliomas

Abstract Background The ability to accurately and non-invasively distinguish high-grade glioma from low-grade glioma remains a challenge despite advances in molecular and magnetic resonance imaging. We investigated the ability of fluciclovine (18F) PET as a means to identify and distinguish these lesions in patients with known gliomas and to correlate uptake with Ki-67. Results Sixteen patients with a total of 18 newly diagnosed low-grade gliomas (n = 6) and high grade gliomas (n = 12) underwent fluciclovine PET imaging after histopathologic assessment. Fluciclovine PET analysis comprised tumor SUVmax and SUVmean, as well as metabolic tumor thresholds (1.3*, 1.6*, 1.9*) to normal brain background (TBmax, and TBmean). Comparison was additionally made to the proliferative status of the tumor as indicated by Ki-67 values. Fluciclovine uptake greater than normal brain parenchyma was found in all lesions studied. Time activity curves demonstrated statistically apparent flattening of the curves for both high-grade gliomas and low-grade gliomas starting 30 min after injection, suggesting an influx/efflux equilibrium. The best semiquantitative metric in discriminating HGG from LGG was obtained utilizing a metabolic 1 tumor threshold of 1.3* contralateral normal brain parenchyma uptake to create a tumor: background (TBmean1.3) cutoff of 2.15 with an overall sensitivity of 97.5% and specificity of 95.5%. Additionally, using a SUVmax > 4.3 cutoff gave a sensitivity of 90.9% and specificity of 97.5%. Tumor SUVmean and tumor SUVmax as a ratio to mean normal contralateral brain were both found to be less relevant predictors of tumor grade. Both SUVmax (R = 0.71, p = 0.0227) and TBmean (TBmean1.3: R = 0.81, p = 0.00081) had a high correlation with the tumor proliferative index Ki-67. Conclusions Fluciclovine PET produces high-contrast images between both low-grade and high grade gliomas and normal brain by visual and semiquantitative analysis. Fluciclovine PET appears to discriminate between low-grade glioma and high-grade glioma, but must be validated with a larger sample size

Intraoperative fluorescence diagnosis in the brain: a systematic review and suggestions for future standards on reporting diagnostic accuracy and clinical utility

Background Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations. Methods A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies. Results Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported. Conclusions Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here

A Systematic Pipeline for the Objective Comparison of Whole-Brain Spectroscopic MRI with Histology in Biopsy Specimens from Grade 3 Glioma

The diagnosis, prognosis, and management of patients with gliomas are largely dictated by the pathological analysis of tissue biopsied from a selected region within the lesion. However, the heterogeneous and infiltrative nature of gliomas make it difficult to identify the optimal region for biopsy with conventional magnetic resonance imaging (MRI). This is particularly true for low-grade gliomas, which are often nonenhancing tumors. To improve the management of patients with such tumors, neuro-oncology requires an imaging modality that can specifically identify a tumor\u27s most anaplastic/aggressive region(s) for biopsy targeting. The addition of metabolic mapping using spectroscopic MRI (sMRI) to supplement conventional MRI could improve biopsy targeting and, ultimately, diagnostic accuracy. Here, we describe a pipeline for the integration of state-of-the-art, high-resolution, whole-brain 3-dimensional sMRI maps into a stereotactic neuronavigation system for guiding biopsies in gliomas with nonenhancing components. We also outline a machine-learning method for automated histological analysis that generates normalized, quantitative metrics describing tumor infiltration in immunohistochemically stained tissue specimens. As a proof of concept, we describe the combination of these 2 techniques in a small cohort of patients with grade 3 glioma. With this work, we aim to present a systematic pipeline to stimulate histopathological image validation of advanced MRI techniques, such as sMRI