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The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma ( P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma., Competing Interests: Competing interests statement:Z.O. is the founder of PurSpec Technologies, which is developing miniature mass spectrometry systems.

Purpose: High-grade gliomas (HGG) are aggressive cancers, and their recurrence is inevitable, despite advances in treatment options. While repeated tumor resection has been shown to increase survival rate, its impact on quality of life is not clearly defined. To address this gap, we compared quality of life (QoL) changes in HGG patients who underwent first-time (FTR) versus repeat surgical resections (RSR) for management of recurrence., Methods: Forty-four adults with HGG who underwent tumor resection were included in this study and classified into either the FTR group (n = 23) or the RSR group (n = 21). All patients completed comprehensive neuropsychological evaluations that included the Functional Assessment of Cancer Therapy-General (FACT-G) and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scales, pre-operatively and at two weeks post-operatively., Results: There was no difference between the FTR and RSR groups in any of the QoL indices (all p > .05), except for improved emotional well-being and worsened social well-being, suggesting minimal detrimental effects of repeat surgeries on QoL in comparison to first time surgery., Conclusions: These results suggest that repeated resection is a viable strategy in certain cases for management of HGG recurrence, with similar impact on QoL as observed in patients undergoing first time surgery. These encouraging outcomes provide useful insight to guide treatment strategies and patient and clinician decision making to optimize surgical and functional outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intraoperative electrocorticography (iECoG) is used as an adjunct to localize the epileptogenic zone during surgical resection of brain tumors in patients with focal epilepsies. It also enables monitoring of after-discharges and seizures with EEG during functional brain mapping with electrical stimulation. When seizures or after-discharges are present, they complicate accurate interpretation of the mapping strategy to outline the brain's eloquent function and can affect the surgical procedure. Recurrent seizures during surgery requires urgent treatment and, when occurring during awake craniotomy, often leads to premature termination of brain mapping due to post-ictal confusion or sedation from acute rescue therapy. There are mixed results in studies on efficacy with iECoG in patients with epilepsy and brain tumors influencing survival and functional outcomes following surgery. Commercially available electrode arrays have inherent limitations. These could be improved with customization potentially leading to greater precision in safe and maximal resection of brain tumors. Few studies have assessed customized electrode grid designs as an alternative to commercially available products. Higher density electrode grids with intercontact distances less than 1 cm improve spatial delineation of electrophysiologic sources, including epileptiform activity, electrographic seizures, and afterdischarges on iECoG during functional brain mapping. In response to the shortcomings of current iECoG grid technologies, we designed and developed a novel higher-density hollow circular electrode grid array. The 360-degree iECoG monitoring capability allows continuous EEG recording during surgical intervention through the aperture with and without electrical stimulation mapping. Compared with linear strip electrodes that are commonly used for iECoG during surgery, the circular grid demonstrates significant benefits in brain tumor surgery. This includes quicker recovery of post-operative motor deficits (2.4 days versus 9 days, p = 0.05), more extensive tumor resection (92.0% versus 77.6%, p = 0.003), lesser reduction in Karnofsky Performance scale postoperatively (-2 versus -11.6, p = 0.007), and more sensitivity to recording afterdischarges. In this narrative review, we discuss the advantages and disadvantages of commercially available recording devices in the operating room and focus on the usefulness of the higher-density circular grid., (© 2023 IOP Publishing Ltd.)

Objective: To identify risk factors for developing glioblastoma (GBM) related preoperative (PRS) and postoperative seizures (POS). Also, we aimed to analyze the impact of PRS and POS on survival in a GBM cohort according to the revised 2021 WHO glioma classification., Methods: We performed a single-center retrospective cohort study of patients with GBM (according to the 2021 World Health Organization Classification) treated at Mayo Clinic Florida between January 2018 and July 2022. Seizures were stratified into preoperative seizures (PRS) and postoperative seizures (POS, >7 days after surgery). Associations between patients' characteristics and overall survival with PRS and POS were assessed., Results: One hundred nineteen adults (mean =60.9 years), 49 (41.2 %) females, were identified. The rates of PRS and POS in the cohort were 35.3 % (n = 42) and 37.8 % (n = 45), respectively. Patients with PRS were younger (p = 0.035) and were likely to undergo intraoperative electrocorticography. The incidence of PRS (p = 0.049) and POS (p<0.001) was lower among patients with tumors located in the occipital location. PRS increased the risk of POS after adjusting for age and sex (RR: 2.59, CI = 1.44-4.65, p = 0.001). There was no association between PRS or POS and other patient-related factors, including several tumor molecular markers (TMMs) examined. PRS (p = 0.036), POS (p<0.001), and O6-Methylguanine-DNA Methyltransferase (MGMT) promotor methylation status (p = 0.032) were associated with longer survival time., Conclusions: PRS and POS are associated with non-occipital tumor location and longer survival time in patients with GBM. While younger ages predicted PRS, PRS predicted POS. Well-designed prospective studies with larger sample sizes are needed to clarify the influence of TMMs in the genesis of epileptic seizures in patients with GBM., Competing Interests: Declaration of Competing Interest Drs. Feyissa, Sanchez-Boluarte, Moniz-Garcia, Chaichana, Sherman, Freund, Middlebrooks, Tatum, Sirven, and Quinones-Hinojosa report no disclosures relevant to the manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

While there is strong evidence from lesion and functional imaging studies implicating the left anterior temporal pole (LTP) in naming unique entities, less is known about white matter tracts in category-specific naming. We present evidence that implicates the uncinate fasciculus (UF) in proper noun naming. First, we describe two patients with left LTP gliomas who developed category specific worsening in proper noun naming in real time during awake surgery when the UF was surgically involved . We then describe a third case involving targeted electrical stimulation of the UF using stereo-electroencephalography (sEEG) that resulted in category specific naming disturbance for proper nouns..

Purpose of Review: Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically., Recent Findings: Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials., (© 2022. The Author(s).)

Objective: The authors' goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma after gross-total resection (GTR)., Methods: The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed., Results: In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01-2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13-1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27-0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52-0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98-0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35-0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45-1.21; p = 0.234)., Conclusions: SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

Introduction: This study compares the postsurgical course of frontotemporal craniotomies conducted "awake" under regional anesthesia (RA) versus "asleep" under general anesthesia (GA) to investigate postoperative recovery, pain, opioid use, and anesthesia-related side effects., Methods: We retrospectively reviewed craniotomies for supratentorial, intra-axial tumors with frontotemporal exposure. Chronic opioid use and emergent cases were excluded. Primary outcomes included pain scores on a 0-10 numerical rating scale, opioid use as oral morphine milligram equivalence, first time to opioid use, nausea, and sedation on the Richmond Agitation and Sedation Scale (RASS). Secondary outcomes included postoperative seizures, Karnofsky Performance Scale (KPS) status, and hospital length of stay (LOS)., Results: A total of 91 patients met inclusion criteria: 56 underwent a craniotomy under RA versus 35 under GA. Demographics and operative characteristics were similar between cohorts. A significant reduction in both postoperative pain and opioid use was observed among RA versus GA (first postoperative pain score 2 vs. 5, P < 0.01; postoperative day [POD] 0 median pain score 2.5 vs. 4, P < 0.01; POD 0 mean opioid in mg 14.49 vs. 24.43, P < 0.01). The time until patients requested opioids for pain after surgery was prolonged for RA versus GA [mean 7.23 vs. 3.42 hours, P < 0.01). Somnolence (RASS < 0) on POD 0 was significantly reduced among RA versus GA, with 23% versus 43%. Both cohorts had equivocal postsurgical outcomes such as seizures, KPS, and hospital LOS., Conclusions: Frontotemporal craniotomy under RA during awake craniotomies provides better pain control, a reduction in opioid use, and less somnolence in the early postoperative period., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The field of neurosurgery has witnessed a dramatic increase in the use of stereotactic radiosurgery (SRS) as a modality to treat various cranial and spinal pathologies. However, studies have consistently demonstrated disparities in SRS training. Accordingly, the present study represents a cross-sectional analysis of current SRS training and practice patterns., Methods: An online survey was utilized to collect data from participants. Two-sided t-tests were used in order to compare frequency tables for statistically significant differences between groups. Qualitative analyses were performed by modified thematic analyses, employing open and axial coding., Results: A total of 67 participants completed the online survey (16.4% response rate). The majority of participants were neurosurgery attendings (58.2%), followed by neurosurgery residents (25.4%). The majority of participants reported that resident exposure to SRS was gained primarily through non-SRS focused rotations (52.2%). The survey found that exposure to tumor cases was most frequent, followed by functional, vascular, and spine indications. The majority of participants (49.3%) indicate that residents are not competent or exhibit a low level of competency in SRS at the completion of neurosurgical residency. Qualitative analyses demonstrated that respondents believe SRS is a critical modality in current cranial neurosurgical care and that increased training is needed., Conclusions: This study provides a multi-national analysis of SRS residency training and practice patterns, and aims to stimulate improvement in SRS in training worldwide. Enhanced resident training in SRS must include wider exposure to vascular, neoplastic, functional and pediatric indications for SRS.

Background and Importance: In the setting of intracranial neoplasms, EWSR1-cAMP Response Element-Binding Protein (CREB) transcription factor family fusions have been described in myxoid mesenchymal tumors, extremely rare entities with a close histopathologic and immunologic resemblance to myxoid subtype angiomatoid fibrous histiocytomas (AFH). Controversy exists on whether these central nervous system lesions are a subtype of myxoid AFH or a completely separate entity, which entitles a distinct clinical behavior and, consequently, a different approach to management. Upon review of the literature, only 14 cases of intracranial tumors harboring an EWSR1-CREB family fusion were identified, with only 3 cases presenting in middle-aged adults, none of which reported an EWSR1-CREM fusion mutation. Significant variability in reported radiographic and histopathological characteristics, as well as in clinical outcomes, was noted. Their similarity with other soft tissue tumors, added to the scarce information on its clinical behavior, represents a great diagnostic and therapeutic challenge to the treating physician., Clinical Presentation: We present a rare case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor/myxoid subtype AFH presenting as persistent headaches in a 36-yr-old woman with radiographic evidence of rapid growth and extensive vasogenic edema, for which she underwent surgical resection., Conclusion: This represents a unique case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor presenting in adulthood, with evidence of aggressive behavior., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Minimally invasive surgery using tubular retractors was developed to minimize injury of surrounding brain during the removal of deep-seated lesions. No evidence supports the superiority of any available tubular retraction system in the treatment of these lesions. We conducted a systematic review and meta-analysis to evaluate outcomes and complications after the resection of deep-seated lesions with tubular retractors and among available systems., Methods: A PRISMA compliant systematic review was conducted on PubMed, Embase, and Scopus to identify studies in which tubular retractors were used to resect deep-seated brain lesions in patients ≥18 years old., Results: The search strategy yielded 687 articles. Thirteen articles complying with inclusion criteria and quality assessment were included in the meta-analysis. A total of 309 patients operated on between 2008 and 2018 were evaluated. The most common lesions were gliomas (n = 127), followed by metastases (n = 101) and meningiomas (n = 19). Four different tubular retractors were used: modified retractors (n = 121, 39.1%); METRx (n = 60, 19.4%); BrainPath (n = 92, 29.7%); and ViewSite Brain Access System (n = 36,11.7%). Estimated gross total resection rate was 75% (95% confidence interval, 69%-80%; I 2  = 9%), whereas the estimated complication rate was 9% (95% confidence interval: 6%-14%; I 2  = 0%). None of the different brain retraction systems was found to be superior regarding extent of resection or complications on multiple comparisons (P > 0.05)., Conclusions: Tubular retractors represent a promising tool to achieve maximum safe resection of deep-seated brain lesions. However, there does not seem to be a statistically significant difference in extent of resection or complication rates among tubular retraction systems., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Three-dimensional (3D) printing is a powerful tool for replicating patient-specific anatomic features for education and surgical planning. The advent of "desktop" 3D printing has created a cost-effective and widely available means for institutions with limited resources to implement a 3D-printing workflow into their clinical applications. The ability to physically manipulate the desired components of a "dynamic" 3D-printed model provides an additional dimension of anatomic understanding. There is currently a gap in the literature describing a cost-effective and time-efficient means of creating dynamic brain tumor 3D-printed models., Methods: Using free, open-access software (3D Slicer) for patient imaging to Standard Tessellation Language file conversion, as well as open access Standard Tessellation Language editing software (Meshmixer), both intraaxial and extraaxial brain tumor models of patient-specific pathology are created., Results: A step-by-step methodology and demonstration of the software manipulation techniques required for creating cost-effective, multidimensional brain tumor models for patient education and surgical planning are exhibited using a detailed written guide, images, and a video display., Conclusions: In this technical note, we describe in detail the specific functions of free, open-access software and desktop 3D printing techniques to create dynamic and patient-specific brain tumor models for education and surgical planning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Intraoperative stimulation (IS) mapping has become the preferred standard treatment for eloquent tumors as it permits a more accurate identification of functional areas, allowing surgeons to achieve higher extents of resection (EOR) and decrease postoperative morbidity. For lesions adjacent to the perirolandic area and descending motor tracts, mapping can be done with both awake craniotomy (AC) and under general anesthesia (GA)., Objective: We aimed to determine which anesthetic protocol-AC vs. GA-provides better patient outcomes by comparing EOR and postoperative morbidity for surgeries using IS mapping in gliomas located near or in motor areas of the brain., Methods: A systematic literature search was carried out to identify relevant studies from 1983 to 2019. Seven databases were screened. A total of 2351 glioma patients from 17 studies were analyzed., Results: A random-effects meta-analysis revealed a trend towards a higher mean EOR in AC [90.1% (95% C.I. 85.8-93.8)] than with GA [81.7% (95% C.I. 72.4-89.7)] (p = 0.06). Neurological deficits were divided by timing and severity for analysis. There was no significant difference in early neurological deficits [20.9% (95% C.I. 4.1-45.0) vs. 25.4% (95% C.I. 13.6-39.2)] (p = 0.74), late neurological deficits [17.1% (95% C.I. 0.0-50.0) vs. 3.8% (95% C.I. 1.1-7.6)] (p = 0.06), or in non-severe [28.4% (95% C.I. 0.0-88.5) vs. 20.1% (95% C.I. 7.1-32.2)] (p = 0.72), and severe morbidity [2.6% (95% C.I. 0.0-15.5) vs. 4.5% (95% C.I. 1.1-9.6)] (p = 0.89) between patients who underwent AC versus GA, respectively., Conclusion: Mapping during resection of gliomas located in or near the perirolandic area and descending motor tracts can be safely carried out with both AC and GA.

Introduction: 20.8% of the United States population and 67% of the European population speak two or more languages. Intraoperative different languages, mapping, and localization are crucial. This investigation aims to address three questions between BL and ML patients: (1) Are there differences in complications (i.e. seizures) and DECS techniques during intra-operative brain mapping? (2) Is EOR different? and (3) Are there differences in the recovery pattern post-surgery?, Methods: Data from 56 patients that underwent left-sided awake craniotomy for tumors infiltrating possible dominant hemisphere language areas from September 2016 to June 2019 were identified and analyzed in this study; 14 BL and 42 ML control patients. Patient demographics, education level, and the age of language acquisition were documented and evaluated. fMRI was performed on all participants., Results: 0 (0%) BL and 3 (7%) ML experienced intraoperative seizures (P = 0.73). BL patients received a higher direct DECS current in comparison to the ML patients (average = 4.7, 3.8, respectively, P = 0.03). The extent of resection was higher in ML patients in comparison to the BL patients (80.9 vs. 64.8, respectively, P = 0.04). The post-operative KPS scores were higher in BL patients in comparison to ML patients (84.3, 77.4, respectively, P = 0.03). BL showed lower drop in post-operative KPS in comparison to ML patients (- 4.3, - 8.7, respectively, P = 0.03)., Conclusion: We show that BL patients have a lower incidence of intra-operative seizures, lower EOR, higher post-operative KPS and tolerate higher DECS current, in comparison to ML patients.

Purpose: Glioblastoma multiforme (GBM) is a common and aggressive malignancy associated with poor prognosis. Characteristics and treatment of long-term survivors are of particular interest in efforts to improve outcomes. Therefore, the objective of this study was to examine trends and prognostic factors for 3-year survival from a national database., Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with cranial GBM from 2004 to 2013 and with 3-year follow-up. Trends in 3-year and overall survival, patient characteristics, tumor properties, and treatment modalities were examined. Multivariable logistic regression was utilized to investigate the association of these factors with 3-year survival. Predictor importance analysis was conducted using a metric defined as Wald χ 2 penalized by degrees of freedom., Results: A total of 88,919 GBM patients with 3-year follow-up were identified. Overall, 8757 (9.8%) patients survived ≥ 3 years. Three-year survival significantly improved from 8.0 to 10.5% (p < 0.001) from 2004 to 2013. Trimodal treatment administration also significantly increased from 38.7 to 55.9% (p < 0.001). During this span, patients increasingly presented as older (p = 0.040), without private insurance (p < 0.001), and with a higher comorbidity index (p < 0.001). On multivariable regression, factors such as trimodal treatment (p < 0.001), younger age (p < 0.001), and MGMT methylation (p < 0.001) were significantly associated with increased odds of 3-year survival. Predictor importance analysis indicated that MGMT methylation, age, and treatment modality were the most significant relative determinants of 3-year survival., Conclusion: These findings illustrate an improved 3-year survival rate for GBM patients from 2004 to 2013 with a concurrent increase in trimodal treatment administration despite more adverse patient presenting characteristics.

Introduction: Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities., Methods: A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation., Results: The central tendency of median overall survival (MOS) was 13.5 months (2.3-29.6) and cumulative 5-year survival was 5.8% (0.01%-29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3-28) vs 15.6 (3.8-29.6) months, P < 0.001]. In clinical trials, bevacizumab [18.2 (10.6-23.0) months], tumor treating fields (TTF) [20.7 (20.5-20.9) months], and vaccines [19.2 (15.3-26.0) months] reported the highest central measure of median survival., Conclusion: Coadministration with radiotherapy and temozolomide provided a statistically significant increase in survival for patients suffering from glioblastoma. However, the natural history for GBM remains poor. Therapies including TTF pooled values of MOS and provide means of prolonging the survival of GBM patients.

Objective: To evaluate intraoperative use of a novel high-density circular grid in detecting after-discharges (AD) on electrocorticography (ECoG) during functional brain mapping (FBM)., Methods: FBM during glioma surgery (10/2016 to 5/2019) recorded ADs using a 22-channel circular grid compared to conventional strip electrodes. ADs were analyzed for detection, duration, amplitude, morphology, histology, direction, and clinical signs., Results: Thirty-two patients (mean age 54.2 years; r = 30-75) with glioma (WHO grade II-IV; 20 grade IV) had surgery. ADs during FBM were more likely in patients with wild-type as opposed to IDH-1 mutants (p < 0.0001) using more contacts compared with linear strip electrodes (p = 0.0001). More sensors tended to be involved in ADs detected by the circular grid vs strips (6.61 vs 3.43; p = 0.16) at lower stimulus intensity (3.14 mA vs 4.13 mA; p = 0.09). No difference in the number of cortical stimulations before resection was present (38.9 mA vs 47.9 mA; p = 0.26). ADs longer than 10 seconds were 32.5 seconds (circular grid) vs 58.4 (strips) (p = 0.12)., Conclusions: High-density circular grids detect ADs in 360 degrees during FBM for glioma resection. Provocation of ADs was more likely in patients with wild-type than IDH-1 mutation., Significance: Circular grids offer high-resolution ECoG during intraoperative FBM for detection of ADs., Competing Interests: Declaration of Competing Interest Drs. Quinones-Hinojosa, ReFaey and Tatum, have filed a patent application disclosing this device and technology., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting., Methods: Biodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells., Results: For anisotropic micelles, uptake efficiency was ~100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (~1.8-fold greater, p ≤ 0.001) and 24 hrs (~2.1-fold greater, p ≤ 0.0001)., Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer., Competing Interests: A.Q.H. was supported by the Mayo Clinic Professorship and a Clinician Investigator award. J.J.G. was supported by the Bloomberg~Kimmel Institute for Cancer Immunotherapy. J.K. received fellowship support from Samsung Scholarship. The authors report no other conflicts of interest in this work., (© 2019 Shamul et al.)

Gliomas are molecularly complex neoplasms and require a multidisciplinary approach to treatment. Maximal safe resection is often the initial goal of treatment and extent of resection (EOR) is an important prognostic factor correlating with both progression-free-survival (PFS) and overall survival (OS). Postoperative patient outcome is also a critical and independent prognosticator and high EOR must not be achieved at the expense of good functional outcome. Several intraoperative adjuvant techniques have been developed to help the surgeon push the boundaries of EOR while maintaining safety. Fluorescence-guided surgery for brain tumors is a contemporary adjuvant technique that allows for intraoperative delineation of diseased and normal brain thus improving maximal safe resection. The most extensively used fluorophores are 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SFL). These fluorophores have different spectrophotometric properties, mechanisms of action and considerations for use. Both have demonstrated utility in neurosurgical oncology. They are safe and both are FDA approved for use as surgical adjuncts during resection of primary CNS neoplasms although they have been used with varying success for other tumor types. When combined with other surgical adjuvant strategies such as neuronavigation, intraoperative ultrasound, intraoperative MRI, awake resection and/or electrophysiological mapping/monitoring, fluorescence-guided resection appears to further improve resection quality in regard to EOR and safety. In this article, we review the current knowledge related to both fluorophores for brain tumor resection, their benefits, and pitfalls, as well as the major advantages associated with their use. We also briefly review additional fluorophores in early clinical development. Fluorescence-guided surgery is a novel surgical adjuvant which allows for real-time delineation of neoplastic tissues. The most widely used fluorophores are 5-ALA and SFL. They are safe compounds and there is a large body of evidence suggesting improvement in EOR when these are employed. There are nuances to the use of each; the fluorescence intensity is dose-dependent in either case and the sensitivity and specificity for various tumors vary widely. Additional prospective studies will be necessary to parse the impact of this technique and these fluorophores on survival metrics.

Background: Epithelioid glioblastoma (eGBM) is a very rare histologic variant of glioblastoma that has not been studied in isolation and, therefore, its optimal management has been largely assumed, but not confirmed. The aim of this study was to analyze all reported cases describing the presentation and clinical features to better understand the clinical significance of this histologic diagnosis., Methods: A comprehensive literature search was conducted from 2005 to April 2019 identifying cases of eGBM that satisfied selection criteria for analysis. Survival was investigated using Kaplan-Meier estimations, and then univariate and multivariate logistic regression analyses for primary end point overall survival (OS) and second end point progression-free survival (PFS)., Results: A total cohort of 59 eGBM cases from 28 articles were included for final analysis. Median age of patients at diagnosis was 30 years, with 29 (46%) female patients. When reported, 100% (37/37) cases were IDH1-wild-type and 63% (19/30) were positive for the BRAF V600E mutation by immunohistochemistry. Median OS and PFS were estimated to be 11.0 months (95% confidence interval, 6.5-13.0) and 7.0 months (95% confidence interval, 3.0-10.0), respectively. Surgical extent of resection, radiation therapy, and chemotherapy all predicted superior OS and PFS on multivariate analysis (P < 0.05). No biomarkers prognosticated survival., Conclusions: These findings indicate that the histologic diagnosis of eGBM does not deviate from the clinical course of the broader glioblastoma diagnosis, despite being a unique histologic identity. These results argue against the temptation to deviate from the traditional management paradigm of surgery, radiation, and chemotherapy for glioblastoma based on this histology alone., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is one of the most lethal cancers. Various prognostic factors impact the survival of GBM patients. To further understand this extremely poor prognosis disease, we evaluated the effect of the treatment facility volumes on overall survival (OS) over the years, especially after the approval of multimodality therapy using temozolomide (TMZ) in 2005. National Cancer Data Base (NCDB) was utilized to identify GBM cases from 2004 through 2013 using ICD-O-3 code 9440/3 to identify eligible patients. We focused on studying the association between treatment facility volume and OS after adjusting for the patient-, disease-, and facility-characteristics. A total of 60,672 eligible GBM patients with median age of 65 years, treated at 1166 facilities were included in this analysis. The median annual facility volume was 3 patients/year (range: 0.1-55.1) and median OS was 8.1 months. There was an improvement in OS across all facilities after 2005, when multimodality therapy with TMZ was approved. Treatment at quartile 4 centers (Q4; >7 patients/year) was independently associated with decreased all-cause mortality in a multivariate analysis (Q3 hazard ratio [HR]: 1.11, 95% CI 1.09, 1.13; Q2 HR: 1.15, 95% CI 1.12, 1.19; Q1 HR: 1.25, 95% CI 1.17, 1.33). Treatment facility volume independently affects OS among GBM patients. Factors that are variable in high- and low-volume centers should be addressed to mitigate outcome disparities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Although reoperation likely confers survival benefit for glioblastoma, whether the extent of resection (EOR) of the reoperation affects survival outcome has yet to be thoroughly evaluated in the current temozolomide (TMZ) era. The aim of this meta-analysis was to pool the current literature and evaluate the prognostic significance of reoperation EOR for glioblastoma recurrence in the current TMZ era., Methods: Searches of 7 electronic databases from inception to January 2019 were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There were 1203 articles identified for screening. Prognostic hazard ratios (HRs) for overall survival (OS) derived from multivariate regression analysis were analyzed using meta-analysis of proportions., Results: Nine individual studies satisfied all selection criteria, describing survival in 1507 patients with glioblastoma, including 1335 reoperations for recurrence (89%). When studies incorporated the EOR of index surgery into their analysis, maximal resection at reoperation was significantly prognostic for longer OS (HR, 0.59; 95% confidence interval [CI], 0.43-0.79; I 2  = 0%; P heterogeneity <0.01). When studies did not incorporate the EOR of index surgery into their analysis, maximal resection remained significantly prognostic for longer OS at reoperation (HR, 0.53; 95% CI, 0.45-0.64; I 2  = 5.2%; P heterogeneity <0.01). Based on EOR, radiographic gross total resection (GTR) was the most prognostic EOR definition at reoperation (HR, 0.52; 95% CI, 0.44-0.61; I 2  = 0%; P heterogeneity <0.01)., Conclusions: In the current TMZ era, when reoperation is feasible for recurrent glioblastoma, maximal safe resection appears to confer a significant OS benefit based on the current literature. This benefit is most pronounced with radiographic GTR, and likely irrespective of EOR at index surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To examine the occurrence of glioma-related preoperative seizures (GPS) and post-operative seizure control (PSC) with respect to patients characteristics including five commonly tested tumor molecular markers (TMMs)., Methods: A single-center retrospective cohort study of patients with glioma evaluated at the Mayo Clinic, Florida between 2016 and 2018., Results: 68 adult patients (mean age = 51-years, 45-males) were included. 46 patients had GPS. 57 patients underwent intra-operative electrocorticography during awake craniotomy-assisted glioma resection. All patients underwent glioma resection (53, gross-total resection) with histologies of pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 4), oligodendroglioma (n = 14), anaplastic astrocytoma (n = 16), anaplastic oligodendroglioma (n = 1), and glioblastoma (n = 31). 31 (67%) patients had PSC (median follow-up = 14.5 months; IQR = 7-16.5 months). IDH1 mutation (IDH1 mut ) was present in 32, ARTX retention in 53, MGMT gene promotor methylation in 15, 1p/19q co-deletion in 15, and over-expression of p53 in 19 patients. Patients with IDH1 mut were more likely to have GPS (p = 0.037) and PSC (p = 0.035) compared to patients with IDH1 wild-type. Patients with MGMT gene promoter methylation were also likely to have PSC (p = 0.032). GPS or PSC did not differ by age, sex, extent of surgery, glioma grade, location, and histopathological subtype, p53 expression, ARTX retention, or 1p/19q co-deletion status., Conclusions: GPS and PSC may be associated with IDH1 mutation and MGMT gene promoter methylation status but not other glioma characteristics including tumor grade, location, or histopathology. Prospective studies with larger sample size are needed to clarify the exact mechanisms of GPS and PSC by the various TMMs to identify new treatment targets., (Published by Elsevier Ltd.)

Objective: Traditionally, extent of resection (EOR) has been seen as a surgical parameter that can predict survival outcomes of surgically managed WHO grade II gliomas. The aim of this study was to evaluate if such an influence was potentially affected by 1p/19q codeletion status based on a national cancer registry., Patient and Methods: All adults diagnosed with grade II gliomas between the years 2004 to 2014 were queried from the National Cancer Database (NCDB). The population was then divided based on 1p/19q codeletion status, and then Kaplan-Meier, univariate and multivariate Cox regression analyses were utilized to evaluate the prognostic effect of EOR., Results: In total, 1,498 grade II gliomas satisfied inclusion for analysis, with the 1p/19q non-codeleted in 705 (47%) cases, and codeletion in 793 (53%) cases. When the cohort was divided based on codeletion status, Kaplan-Meier modelling and univariate regression analyses indicated that gross total resection (GTR) was significantly associated with greater 5-overall survival (OS) in both 1p/19q non-codeleted and codeletion groups. Upon multivariate analysis which incorporated adjuvant therapy status, the significance of GTR was only retained in the 1p/19q non-codeletion group after post-hoc adjustment., Conclusion: Our findings indicate that the survival impact of GTR in grade II gliomas may be affected by 1p/19q codeletion status within the first five years after surgery based on overall survival. Therefore, molecular diagnostics have potential clinical application in surgery outcomes, and validation of the reported findings will assist in surgical planning if such an association can be thoroughly established., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is no clear consensus regarding the optimal treatment for glioblastoma (GBM) in the elderly. Hypofractionated radiation therapy (hRT) has emerged as a viable and comparable radiation regime compared to standard radiation therapy (sRT), however the survival effect of temozolomide (TMZ) with hRT is uncertain. The aim of this meta-analysis was to evaluate survival outcomes of hRT + TMZ vs sRT + TMZ in this specific demographic., Methods: Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The progression free survival (PFS) and overall survival (OS) metrics were then extracted and pooled by meta-analysis evaluating mean difference (MD)., Results: A total of 7 individual comparative studies describing hRT + TMZ vs sRT + TMZ (n = 917) respectively satisfied inclusion criteria. Meta-analysis by random-effects modelling indicated that compared to sRT + TMZ, hRT + TMZ resulted in comparable PFS (MD 0.3 months; 95% CI - 2.4 to 2.9; I 2  = 91.7%; P-effect = 0.85) and significantly shorter OS (MD - 3.5 months; 95% CI - 6.3 to - 0.6; I 2  = 98.9%; P-effect = 0.02). Subgroup analysis between age definitions of elderly of > 65 vs > 70 years old both demonstrated the same significant trend with no statistical difference between the groups., Conclusion: The combination of hRT + TMZ is feasible in well-selected elderly GBM cases, and appears to confer a statistically comparable PFS compared to sRT + TMZ. However, expectations that the OS with hRT + TMZ is comparable to that of sRT + TMZ in all elderly GBM presentations should be tempered. It is likely a specific subgroup of elderly GBM patients will benefit greatly from the addition of TMZ to hRT, and greater investigation is needed to identify their characteristics.

Purpose: This study seeks to ascertain whether different primary tumor types have a propensity for brain metastases (BMs) in different cerebral vascular territories and cerebral edema., Methods: Consecutive adult patients who underwent surgical resection of a BM at a tertiary care institution between 2001 and 2011 were retrospectively reviewed. Only patients with the most common primary cancers (lung, breast, skin-melanoma, colon, and kidney) were included. Preoperative MRIs were reviewed to classify all tumors by cerebral vascular territory (anterior cerebral artery-ACA, lenticulostriate, middle cerebral artery-MCA, posterior cerebral artery-PCA, posterior fossa, and watershed), and T2-weighted FLAIR widths were measured. Chi square analyses were performed to determine differences in cerebral vascular distribution by primary tumor type, and one-way ANOVA analyses were performed to determine FLAIR signal differences., Results: 669 tumors from 388 patients were classified from lung (n = 316 BMs), breast (n = 144), melanoma (n = 119), renal (n = 47), and colon (n = 43). BMs from breast cancer were less likely to be located in PCA territory (n = 18 [13%]; χ 2  = 6.10, p = 0.01). BMs from melanoma were less likely to be located in cerebellar territory (n = 11 [9%]; χ 2  = 14.1, p < 0.001), and more likely to be located in lateral (n = 5 [4%]; χ 2  = 4.56, p = 0.03) and medial lenticulostriate territories (n = 2 [2%]; χ 2  = 6.93, p = 0.009). BMs from breast and melanoma had shorter T2-FLAIR widths, with an average [IQR] of 47.2 [19.6-69.2] mm (p = 0.01) and 41.2 [14.4-62.7] mm (p = 0.002) respectively. Conversely, BMs from renal cancer had longer T2-FLAIR widths (64.2 [43.6-80.8] mm, p = 0.002)., Conclusions: These findings suggest that different primary tumor types could have propensities for different cerebral vascular territories and cerebral edema.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 μm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

The resection of insular gliomas remains a neurosurgical challenge due to the close proximity of functionally-important cortical, white matter tracts, and vasculature structures. More recently, the feasibility of resection has gained traction, however, there is a lack of consolidated neurological deficit metrics. Thus, the aim of this study was to determine the incidences of neurological deficits following insular glioma resection to better guide selection algorithms and resource allocations. Searches of seven electronic databases from inception to August 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted and pooled using meta-analysis of proportions. Meta-regression was used to identify potential sources of heterogeneity. Nineteen observational studies reported the neurological outcomes of 890 insular glioma patients. The pooled incidences of new temporary and permanent motor deficits were 11% (95% CI, 6-17%) and 4% (95% CI, 2-7%) respectively, and new temporary and permanent language deficits were 11% (95% CI, 6-17%) and 2% (95% CI, 0-4%) respectively. Single-surgeon series reported significantly lower incidences of both permanent motor (2% vs 7%; P < 0.001) and language (1% vs 3%; P = 0.03) deficits. The incidences of motor and language neurological deficits following insular glioma resection have been quantified, and will assist in determining the suitability and appropriateness of pursuing surgical resection for insular glioma. We note that permanent neurological deficits are lowest when reported by series describing outcomes of a single surgeon, indicating most optimal outcomes may be best achieved after intense training and/or greater experience., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation. Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis., Results: Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations ( R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff., Conclusions: APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity., (©2018 American Association for Cancer Research.)

Object: It is becoming well-established that increasing extent of resection with decreasing residual volume is associated with delayed recurrence and prolonged survival for patients with glioblastoma (GBM). These prior studies are based on evaluating the contrast-enhancing (CE) tumour and not the surrounding fluid attenuated inversion recovery (FLAIR) volume. It therefore remains unclear if the resection beyond the CE portion of the tumour if it translates into improved outcomes for patients with GBM., Methods: Adult patients who underwent resection of a primary glioblastoma at a tertiary care institution between January 1, 2007 and December 31, 2012 and underwent radiation and temozolomide chemotherapy were retrospectively reviewed. Pre and postoperative MRI images were measured for CE tumour and FLAIR volumes. Multivariate proportional hazards were used to assess associations with both time to recurrence and death. Values with p < 0.05 were considered statistically significant., Results: 245 patients met the inclusion criteria. The median [IQR] preoperative CE and FLAIR tumour volumes were 31.9 [13.9-56.1] cm 3 and 78.3 [44.7-115.6] cm 3 , respectively. Following surgery, the median [IQR] postoperative CE and FLAIR tumour volumes were 1.9 [0-7.1] cm 3 and 59.7 [29.7-94.2] cm 3 , respectively. In multivariate analyses, the postoperative FLAIR volume was not associated with recurrence and/or survival (p > 0.05). However, the postoperative CE tumour volume was significantly associated with both recurrence [HR (95%CI); 1.026 (1.005-1.048), p = 0.01] and survival [HR (95%CI); 1.027 (1.007-1.032), p = 0.001]. The postoperative FLAIR volume was also not associated with recurrence and/or survival among patients who underwent gross total resection of the CE portion of the tumour as well as those who underwent supratotal resection., Conclusions: In this study, the volume of CE tumour remaining after resection is more important than FLAIR volume in regards to recurrence and survival for patients with GBM.

Purpose: To investigate clinical characteristics and patterns of care among patients with central neurocytomas in a large cohort of patients., Methods: The National Cancer Database (NCDB) was queried to identify patients with biopsy confirmed neurocytoma from 2004 to 2015. Patterns of care were described and univariable and multivariable models were performed to investigate the impact of prognostic factors on overall survival., Results: Among 223,404 patients with brain tumors in the NCDB, 868 patients were diagnosed with biopsy-proven neurocytoma and analyzed (0.4% or approximately 75 patients annually). Median age at diagnosis was 31 years and median tumor size was 4-5 cm. Diagnosis was similar between male (49.5%) and female (50.5%). Regarding location, 622 (72%) tumors were intraventricular, 168 (19%) were extra-ventricular, and 78 (9%) overlapping or unspecified. Five-year overall survival among all patients was 89%. On multivariable analysis tumor location, extent of resection, and use of radiation, were not predictive for improved survival (each p > 0.05); however, patient age (p < 0.001), WHO grade (p < 0.001), and medical comorbidity scores (p = 0.002) were independently associated with overall survival., Conclusion: Patients with central neurocytoma often present as young adults with sizable tumor burden and are well managed with surgery alone. Considering their favorable survival, efforts to improve tumor control should be carefully weighed against the long-term risks associated with adjuvant therapy like radiation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background:  Perirolandic motor area gliomas present invasive eloquent region tumors within the precentral gyrus that are difficult to resect without causing neurologic deficits., Study Aims:  This study evaluates the role of awake craniotomy and motor mapping on neurologic outcome and extent of resection (EOR) of tumor in the perirolandic motor region. It also analyzes preoperative risk factors for intraoperative seizures., Methods:  We evaluated 57 patients who underwent an awake craniotomy for a perirolandic motor area eloquent region glioma. Patients who had positive mapping (PM) or intraoperative identification of motor regions in the cortex using direct cortical stimulation were compared with patients with no positive motor mapping following direct cortical stimulation and negative mapping (NM). Preoperative risks, intraoperative seizures, perioperative outcomes, tumor characteristics, and EOR were also compared. A logistic regression model was used to evaluate the predictors for intraoperative seizures in this patient cohort., Results:  Overall, 33 patients were in the PM cohort; 24 were in the NM cohort. Our study showed an 8.8% incidence of intraoperative seizures during cortical and subcortical mapping for awake craniotomies in the perirolandic motor area, none of which aborted the case. PM patients had significantly more intraoperative and postoperative seizures (15.5% and 30.3%, respectively) compared with the NM patients (0% and 8.3%, respectively; p  = 0.046 and 0.044). New transient postoperative motor deficits were found more often in the PM group (51.5%) versus the NM group (12.5%; p  = 0.002). A univariate logistic regression showed that PM (odds ratio [OR]: 1.16; 95% confidence interval [CI], 1.01-1.34; p  = 0.035) and preoperative tumor volume (OR: 0.998; 95% CI, 0.996-0.999; p  = 0.049) were significant predictors for intraoperative seizures in patients with perirolandic gliomas., Conclusion:  Awake craniotomies in the perirolandic motor region can be safely performed with a similar incidence of intraoperative seizures as reported for the language cortex. PM in this region may increase the likelihood of perioperative seizures or motor deficits compared with NM. Craniotomies that minimize cortical exposure for perirolandic gliomas that may not localize motor regions can still allow for extensive tumor resection with a good postoperative outcome., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To examine the relationship between high-frequency oscillations (HFOs) and the presence of preoperative seizures, World Health Organization tumor grade, and isocitrate dehydrogenase 1 (IDH1) mutational status in gliomas., Methods: We retrospectively studied intraoperative electrocorticography recorded in 16 patients with brain tumor (12 presenting with seizures) who underwent awake craniotomy and surgical resection between September 2016 and June 2017. The number and distribution of HFOs were determined and quantified visually and with an automated HFO detector., Results: Five patients had low-grade (1 with grade I and 4 with grade II) and 11 had high-grade (6 with grade III and 5 with grade IV) brain tumors. An IDH1 mutation was found in 6 patients. Patients with a history of preoperative seizures were more likely to have HFOs than those without preoperative seizures (9 of 12 vs 0 of 4, p = 0.02). The rate of HFOs was higher in patients with IDH1 mutant (mean 7.2 per minute) than IDH wild-type (mean 2.3 per minute) genotype ( p = 0.03)., Conclusions: HFOs are common in brain tumor-related epilepsy, and HFO rate may be a useful measure of epileptogenicity in gliomas. Our findings further support the notion that IDH1 mutant genotype is more epileptogenic than IDH1 wild-type genotype gliomas., (© 2018 American Academy of Neurology.)

Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle-based DDSs aiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an in-depth review of nanotherapeutic systems that are intended to bypass the blood-brain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner. WIREs Nanomed Nanobiotechnol 2018, 10:e1479. doi: 10.1002/wnan.1479 This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2017 Wiley Periodicals, Inc.)

Purpose: Pathological assessment using World Health Organization (WHO) criteria is the gold standard for diagnosis of gliomas. However, the accuracy of diagnosis is limited by tissue sampling, particularly for infiltrating, heterogeneous tumours. We assessed the accuracy of amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI)-guided tissue sampling to identify regions of high-grade glioma via radiographic-histopathologic correlation in patients with newly suspected glioma., Patients and Methods: Twenty-four patients with previously undiagnosed gliomas underwent a volumetric APTw MRI prior to their first neurosurgical procedure. A total of 70 specimens were collected via APTw image-directed stereotactic biopsy. Cellularity, necrosis, proliferation and glioma WHO grade were analysed for all specimens and correlated with corresponding APTw signal intensities., Results: Thirty-three specimens displayed grade-II pathology, 14 grade-III, 15 grade-IV, and eight specimens revealed only peritumoural oedema. Multiple glioma grades were found within a single lesion in six patients. APTw signal intensities of the biopsied sites and the maximum APTw values across all biopsied sites in each patient were significantly higher for high-grade versus low-grade specimens. APTw signal intensities were significantly positively correlated with cellularity (R = 0.757) and proliferation (R = 0.538). Multiple linear regression analysis showed that tumour cellularity and proliferation index were the best predictors of APTw signal intensities., Conclusion: APTw imaging identified tumour areas of higher cellularity and proliferation, allowing identification of high-grade regions within heterogeneous gliomas. APTw imaging can be readily translated for more widespread use and can assist diagnostic neurosurgical procedures by increasing the accuracy of tumour sampling in patients with infiltrating gliomas., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The authors investigate the role of extent of resection (EOR) and genetic markers on patient outcome and survival for LGGs. We conducted a retrospective cohort between 2005 and 2015, of 109 adult patients who underwent surgery for a LGG by a single surgeon. Volumetric computations of MRI studies were conducted to evaluate the EOR, and genetic markers (IDH1, 1p/19q co-deletion, and p53) were assessed and their effects on survival and neurological outcome were evaluated. The median EOR was 88.1%. Permanent postoperative neurological deficits were seen in 4.6% of patients. EOR was a significant predictor for both overall survival (OS) (hazard ratio [HR] = 0.979, 95% CI 0.961-0.980, p = 0.029) and progression free survival (PFS) (HR = 0.982, 95% CI 0.968-0.997, p = 0.018). Malignant progression free survival (MPFS) was predicted by the 1p/19q co-deletion (HR = 0.148, 95% CI 0.019-1.148, p = 0.048). Patients with EOR of 100% had a significantly better OS than EOR less than 90% (p = 0.038). Patients with an EOR of at least 76% had a better OS than EOR less than 76% (p = 0.025). Patients with an EOR of at least 71% had a better PFS than EOR less than 71% (p = 0.030). Preoperative tumor volume was found to have significant association with EOR (R 2  = 0.049, p = 0.031). Increased EOR is associated with improved OS and PFS survival outcomes, while 1p/19q co-deletion provides improved MPFS. Understanding both surgical resections and molecular markers of the tumor are important for effective management of LGG patients.

Background: Insular gliomas are challenging tumors to surgically resect owing to the anatomy surrounding them. This study evaluates the role of extent of resection (EOR) and molecular markers in surgical outcome and survival for insular gliomas., Methods: Seventy-four patients who had undergone initial resection for insular glioma by the same surgeon between 2006 and 2016 were analyzed. Low-grade gliomas (LGGs) (grade II) and high-grade gliomas (HGGs) (grade III/IV) were analyzed for the prognostic role of volumetric EOR and molecular markers in patient survival outcomes., Results: The cohort included 25 patients with LGGs (33.8%) and 49 patients with HGGs (66.2%). Median EOR was 91.7% (range, 10%-100%). New permanent postoperative deficits were found in 2.7% of patients. Patients with LGGs with ≥90% EOR had 5-year survival of 100%, and patients with <90% EOR had 5-year survival of 80%. Patients with HGGs with ≥90% EOR had 2-year survival of 83.7%, and patients with <90% EOR had 2-year survival of 43.8%. For LGGs, EOR was predictive of overall survival (P = 0.017), progression-free survival (PFS) (P = 0.039), and malignant PFS (P = 0.014), whereas 1p/19q codeletion was predictive of PFS (P = 0.014). For HGGs, EOR was predictive of overall survival (P = 0.020) and PFS (P = 0.024). Preoperative tumor volume most significantly affected EOR for insular gliomas (R 2  = 0.053, P = 0.048)., Conclusions: Extensive resections of insular gliomas can be achieved with low morbidity and can improve overall survival and PFS. In this series of LGGs, EOR was associated with longer malignant PFS, and 1p/19q codeletion was predictive of PFS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

OBJECTIVE An increased extent of resection (EOR) has been shown to improve overall survival of patients with glioblastoma (GBM) but has the potential for causing a new postoperative neurological deficit. To investigate the impact of surgical neurological morbidity on survival, the authors performed a retrospective analysis of the clinical data from patients with GBM to quantify the impact of a new neurological deficit on the survival benefit achieved with an increased EOR. METHODS The data from all GBM patients who underwent resection at the University of Florida from 2010 to 2015 with postoperative imaging within 72 hours of surgery were included in the study. Retrospective analysis was performed on clinical outcomes and tumor volumes determined on postoperative and follow-up imaging examinations. RESULTS Overall, 115 patients met the inclusion criteria for the study. Tumor volume at the time of presentation was a median of 59 cm 3 (enhanced on T1-weighted MRI scans). The mean EOR (± SD) was 94.2% ± 8.7% (range 59.9%-100%). Almost 30% of patients had a new postoperative neurological deficit, including motor weakness, sensory deficits, language difficulty, visual deficits, confusion, and ataxia. The neurological deficits had resolved in 41% of these patients on subsequent follow-up examinations. The median overall survival was 13.1 months (95% CI 10.9-15.2 months). Using a multipredictor Cox model, the authors observed that increased EOR was associated with improved survival except for patients with smaller tumor volumes (≤ 15 cm 3 ). A residual volume of 2.5 cm 3 or less predicted a favorable overall survival. Developing a postoperative neurological deficit significantly affected survival (9.2 months compared with 14.7 months, p = 0.02), even if the neurological deficit had resolved by the first follow-up. However, there was a trend of improved survival among patients with resolution of a neurological deficit by the first follow-up compared with patients with a permanent neurological deficit. Any survival benefit from achieving a 95% EOR was abrogated by the development of a new neurological deficit postoperatively. CONCLUSIONS Developing a new neurological deficit after resection of GBM is associated with a decrease in overall survival. A careful balance between EOR and neurological compromise needs to be taken into account to reduce the likelihood of neurological morbidity from surgery.

Background: In patients with progressive low-grade glioma (LGG), the presence of new magnetic resonance imaging (MRI) enhancement is commonly used as an indicator of malignant degeneration, but its accuracy in this setting is uncertain., Objective: We characterize the ability of new MRI enhancement to serve as a surrogate for histologic grade in patients with progressive LGG, and to explore the prognostic value of new MRI enhancement, pathologic grade, and extent of resection., Methods: Patients at our institution with World Health Organization grade II glioma diagnosed between 1994 and 2010 and who underwent repeat biopsy or resection at progression were retrospectively reviewed (n = 108). The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were characterized. A multivariable proportional hazards model was used to test associations with overall survival (OS), and Kaplan-Meier curves were constructed to compare OS between patient subsets., Results: The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were 82%, 77%, 92%, and 57%, respectively. In patients without malignant degeneration, new MRI enhancement was associated with inferior median OS (92.5 months vs. not reached; P = 0.03). In patients with malignant degeneration, gross or near total resection was associated with improved median OS (58.8 vs. 28.8 months; P = 0.02)., Conclusion: In patients with progressive LGG, new MRI enhancement and pathologic grade were discordant in greater than 20% of cases. Pathologic confirmation of grade should therefore be attempted, when safe, to dictate management. Beyond functioning as a surrogate for pathologic grade, new MRI enhancement may predict for worse outcomes, a concept that merits prospective investigation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: High-grade astrocytomas of the mesial temporal lobe may pose surgical challenges. Several approaches (trans-sylvian, subtemporal, and transcortical) have been designed to circumnavigate the critical neurovascular structures and white fiber tracts that surround this area. Considering the paucity of literature on the transcortical approach for these lesions, we describe our institutional experience with transcortical approaches to Grade III/IV astrocytomas in the mesial temporal lobe., Methods: Between 1999 and 2009, 23 patients underwent surgery at the Johns Hopkins Medical Institutions for Grade III/IV astrocytomas involving the mesial temporal lobe (without involvement of the temporal neocortex). Clinical notes, operative records, and imaging were reviewed., Results: Thirteen patients had tumors in the dominant hemisphere. All patients underwent surgery via a transcortical approach (14 via the inferior temporal gyrus and 9 via the middle temporal gyrus). Gross total resection was obtained in 92 % of the cohort. Neurological outcomes were: clinically significant stroke (2 patients), new visual deficits (2 patients), new speech deficit (1 patient); seizure control (53 %)., Conclusions: In comparison to reported results in the literature for the transylvian and subtemporal approaches, the transcortical approach may provide the access necessary for a gross total resection with minimal neurological consequences. In our series of patients, there was no statistically significant difference in outcomes between the middle temporal gyrus versus the inferior temporal gyrus trajectories.

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.

Galvanotaxis is a complex process that represents the collective outcome of various contributing mechanisms, including asymmetric ion influxes, preferential activation of voltage-gated channels, and electrophoretic redistribution of membrane components. While a large number of studies have focused on various up- and downstream signaling pathways, little is known about how the surrounding microenvironment may interact and contribute to the directional response. Using a customized galvanotaxis chip capable of carrying out experiments in both two- and three-dimensional microenvironments, we show that cell-extracellular matrix (ECM) interactions modulate the galvanotaxis of brain tumor initiating cells (BTICs). Five different BTICs across three different glioblastoma subtypes were examined and shown to all migrate toward the anode in the presence of a direct-current electric field (dcEF) when cultured on a poly-L-ornithine/laminin coated surface, while the fetal-derived neural progenitor cells (fNPCs) migrated toward the cathode. Interestingly, when embedded in a 3D ECM composed of hyaluronic acid and collagen, BTICs exhibited opposite directional response and migrated toward the cathode. Pharmacological inhibition against a panel of key molecules involved in galvanotaxis further revealed the mechanistic differences between 2- and 3D galvanotaxis in BTICs. Both myosin II and phosphoinositide 3-kinase (PI3K) were found to hold strikingly different roles in different microenvironments.

Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

Objectives: Patients with glioblastoma (GBM) have an inherently shortened survival because of their disease. It has been recently shown that carmustine wafers in addition to other therapies (surgery, temozolomide, and radiation) can further extend survival. There is concern, however, that these therapies may increase infection risk. The goals of this study were to calculate the incidence of postoperative infection, evaluate if carmustine wafers changes the risk of infection and identify factors independently associated with an infection following GBM surgery., Methods: All patients who underwent non-biopsy, surgical resection of an intracranial GBM from 2007 to 2011 at a single institution were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify factors associated with infection, including the use of carmustine wafers. Variables with P < 0.05 were considered statistically significant., Results: Four hundred and one patients underwent resection of an intracranial GBM during the reviewed period, and 21 (5%) patients developed an infection at a median time of 40 [28-286] days following surgery. The incidence of infection was not higher in patients who had carmustine wafers, and this remained true in multivariate analyses to account for differences in treatment cohorts. The factors that remained significantly associated with an increased risk of infection were prior surgery [RR (95% CI); 2.026 (1.473-4.428), P = 0.01], diabetes mellitus [RR (95% CI); 6.090 (1.380-9.354)], P = 0.02], and increasing duration of hospital stay [RR (95% CI); 1.048 (1.006-1.078); P = 0.02], where the greatest risk occurred with hospital stays > 5 days [RR (95% CI); 3.904 (1.003-11.620), P = 0.05]., Discussion: These findings may help guide treatment regimens aimed at minimizing infection for patients with GBM.