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Background Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved chemotherapies. Computational drug repositioning is an expanding approach to identify pharmacotherapies for clinical trials. Objective To identify FDA-approved compounds for repurposing in chordoma. Methods Previously identified highly differentially expressed genes from chordoma tissue samples at our institution were compared with pharmacogenomic interactions in the Comparative Toxicogenomics Database (CTD) using ksRepo, a drug-repositioning platform. Compounds selected by ksRepo were then validated in CH22 and UM-Chor1 human chordoma cells in Vitro. Results A total of 13 chemical compounds were identified in silico from the CTD, and 6 were selected for preclinical validation in human chordoma cell lines based on their clinical relevance. Of these, 3 identified drugs are FDA-approved chemotherapies for other malignancies (cisplatin, cytarabine, and lucanthone). Cytarabine, a deoxyribonucleic acid polymerase inhibitor approved for the treatment of various leukemias, exhibited a significant concentration-dependent effect against CH22 and UM-Chor1 cells when compared to positive (THZ1) and negative (venetoclax) controls. Tretinoin exhibited a significant concentration-dependent cytotoxic effect in CH22, sacral chordoma-derived cell lines but to a much lesser extent in UM-Chor1, a cell line derived from skull base chordoma. Conclusion Cytarabine administration reduces the viability of human chordoma cells. The equally effective reduction in viability seen with tretinoin seems to be cell line dependent. Based on our findings, we recommend the evaluation of cytarabine and tretinoin in an expanded set of human chordoma cell lines and animal models.

Background Preservation of functional integrity during vestibular schwannoma surgery has become critical in the era of patient-centric medical decision-making. Subtotal tumor removal is often necessary when dense adhesions between the tumor and critical structures are present. However, it is unclear what the rate of tumor control is after subtotal resection (STR) and what factors are associated with recurrence. Objective To determine the rate of residual tumor growth after STR and identify clinical and radiographic predictors of tumor progression. Methods A single-institution retrospective study was performed on all sporadic vestibular schwannomas that underwent surgical resection between January 1, 2002 and December 31, 2015. Clinical charts, pathology, radiology, and operative reports were reviewed. Volumetric analysis was performed on all pre- and postoperative MR imaging. Univariate and multivariate logistic regression was performed to identify predictors of the primary endpoint of tumor progression. Kaplan-Meier analysis was performed to compare progression free survival between 2 groups of residual tumor volumes and location. Results In this cohort of 66 patients who underwent primary STR, 30% had documented progression within a median follow up period of 3.1 yr. Greater residual tumor volume (OR 2.0 [1.1-4.0]) and residual disease within the internal auditory canal (OR 3.7 [1.0-13.4]) predicted progression on multivariate analysis. Conclusion These longitudinal data provide insight into the behavior of residual tumor, helping clinicians to determine if and when STR is an acceptable surgical strategy and to anchor expectations during shared medical decision-making consultation with patients.

Background Intraoperative stimulation of the posterior inferior frontal lobe (IFL) induces speech arrest, which is often interpreted as demonstration of essential language function. However, prior reports have described "negative motor areas" in the IFL, sites where stimulation halts ongoing limb motor activity. Objective To investigate the spatial and functional relationship between IFL speech arrest areas and negative motor areas (NMAs). Methods In this retrospective cohort study, intraoperative stimulation mapping was performed to localize speech and motor function, as well as arrest of hand movement, hand posture, and guitar playing in a set of patients undergoing awake craniotomy for dominant hemisphere pathologies. The incidence and localization of speech arrest and motor inhibition was analyzed. Results Eleven patients underwent intraoperative localization of speech arrest sites and inhibitory motor areas. A total of 17 speech arrest sites were identified in the dominant frontal lobe, and, of these, 5 sites (29.4%) were also identified as NMAs. Speech arrest and arrest of guitar playing was also evoked by a single IFL site in 1 subject. Conclusion Inferior frontal gyrus speech arrest sites do not function solely in speech production. These findings provide further evidence for the complexity of language organization, and suggest the need for refined mapping strategies that discern between language-specific sites and inhibitory motor areas.

Background The optimal observation interval after the radiosurgical treatment of a sporadic vestibular schwannoma, prior to salvage intervention, is unknown. Objective To determine an optimal postradiosurgical treatment interval for differentiating between pseudoprogression and true tumor growth by analyzing serial volumetric data. Methods This single-institution retrospective study included all sporadic vestibular schwannomas treated with Gamma Knife radiosurgery (Eketa AB, Stockholm, Sweden; 12-13 Gy) from 2002 to 2014. Volumetric analysis was performed on all available pre- and posttreatment magnetic resonance imaging scans. Tumors were classified as "stable/decreasing," "transient enlargement", or "persistent growth" after treatment, based on incrementally increasing follow-up durations. Results A total of 118 patients included in the study had a median treatment tumor volume of 0.74 cm3 (interquartile range [IQR] = 0.34-1.77 cm3) and a median follow-up of 4.1 yr (IQR = 2.6-6.0 yr). Transient tumor enlargement was observed in 44% of patients, beginning at a median of 1 yr (IQR = 0.6-1.4 yr) posttreatment, with 90% reaching peak volume within 3.5 yr, posttreatment. Volumetric enlargement resolved at a median of 2.4 yr (IQR 1.9-3.6 yr), with 90% of cases resolved at 6.9 yr. Increasing follow-up revealed that many of the tumors initially enlarging 1 to 3 yr after stereotactic radiosurgery ultimately begin to shrink on longer follow-up (45% by 4 yr, 77% by 6 yr). Conclusion Tumor enlargement within ∼3.5 yr of treatment should not be used as a sole criterion for salvage treatment. Patient symptoms and tumor size must be considered, and giving tumors a chance to regress before opting for salvage treatment may be worthwhile.

Supplemental Digital Content is Available in the Text., BACKGROUND: Recent findings associated with resting-state cortical networks have provided insight into the brain's organizational structure. In addition to their neuroscientific implications, the networks identified by resting-state functional magnetic resonance imaging (rs-fMRI) may prove useful for clinical brain mapping. OBJECTIVE: To demonstrate that a data-driven approach to analyze resting-state networks (RSNs) is useful in identifying regions classically understood to be eloquent cortex as well as other functional networks. METHODS: This study included 6 patients undergoing surgical treatment for intractable epilepsy and 7 patients undergoing tumor resection. rs-fMRI data were obtained before surgery and 7 canonical RSNs were identified by an artificial neural network algorithm. Of these 7, the motor and language networks were then compared with electrocortical stimulation (ECS) as the gold standard in the epilepsy patients. The sensitivity and specificity for identifying these eloquent sites were calculated at varying thresholds, which yielded receiver-operating characteristic (ROC) curves and their associated area under the curve (AUC). RSNs were plotted in the tumor patients to observe RSN distortions in altered anatomy. RESULTS: The algorithm robustly identified all networks in all patients, including those with distorted anatomy. When all ECS-positive sites were considered for motor and language, rs-fMRI had AUCs of 0.80 and 0.64, respectively. When the ECS-positive sites were analyzed pairwise, rs-fMRI had AUCs of 0.89 and 0.76 for motor and language, respectively. CONCLUSION: A data-driven approach to rs-fMRI may be a new and efficient method for preoperative localization of numerous functional brain regions. ABBREVIATIONS: AUC, area under the curve BA, Brodmann area BOLD, blood oxygen level dependent ECS, electrocortical stimulation fMRI, functional magnetic resonance imaging ICA, independent component analysis MLP, multilayer perceptron MP-RAGE, magnetization-prepared rapid gradient echo ROC, receiver-operating characteristic rs-fMRI, resting-state functional magnetic resonance imaging RSN, resting-state network

OBJECTIVE Electrocortical stimulation (ECS) has long been established for delineating eloquent cortex in extraoperative mapping. However, ECS is still coarse and inefficient in delineating regions of functional cortex and can be hampered by afterdischarges. Given these constraints, an adjunct approach to defining motor cortex is the use of electrocorticographic (ECoG) signal changes associated with active regions of cortex. The broad range of frequency oscillations are categorized into 2 main groups with respect to sensorimotor cortex: low-frequency bands (LFBs) and high-frequency bands (HFBs). The LFBs tend to show a power reduction, whereas the HFBs show power increases with cortical activation. These power changes associated with activated cortex could potentially provide a powerful tool in delineating areas of speech cortex. We explore ECoG signal alterations as they occur with activated region of speech cortex and its potential in clinical brain mapping applications. METHODS We evaluated 7 patients who underwent invasive monitoring for seizure localization. Each had extraoperative ECS mapping to identify speech cortex. Additionally, all subjects performed overt speech tasks with an auditory or a visual cue to identify associated frequency power changes in regard to location and degree of concordance with ECS results. RESULTS Electrocorticographic frequency alteration mapping (EFAM) had an 83.9% sensitivity and a 40.4% specificity in identifying any language site when considering both frequency bands and both stimulus cues. Electrocorticographic frequency alteration mapping was more sensitive in identifying the Wernicke area (100%) than the Broca area (72.2%). The HFB is uniquely suited to identifying the Wernicke area, whereas a combination of the HFB and LFB is important for Broca localization. CONCLUSION The concordance between stimulation and spectral power changes demonstrates the possible utility of EFAM as an adjunct method to improve the efficiency and resolution of identifying speech cortex.

Background The emerging insight into resting-state cortical networks has been important in our understanding of the fundamental architecture of brain organization. These networks, which were originally identified with functional magnetic resonance imaging, are also seen in the correlation topography of the infraslow rhythms of local field potentials. Because of the fundamental nature of these networks and their independence from task-related activations, we posit that, in addition to their neuroscientific relevance, these slow cortical potential networks could play an important role in clinical brain mapping. Objective To assess whether these networks would be useful in identifying eloquent cortex such as sensorimotor cortex in patients both awake and under anesthesia. Methods This study included 9 subjects undergoing surgical treatment for intractable epilepsy. Slow cortical potentials were recorded from the cortical surface in patients while awake and under propofol anesthesia. To test brain-mapping utility, slow cortical potential networks were identified with data-driven (seed-independent) and anatomy-driven (seed-based) approaches. With electrocortical stimulation used as the gold standard for comparison, the sensitivity and specificity of these networks for identifying sensorimotor cortex were calculated. Results Networks identified with a data-driven approach in patients under anesthesia and awake were 90% and 93% sensitive and 58% and 55% specific for sensorimotor cortex, respectively. Networks identified with systematic seed selection in patients under anesthesia and awake were 78% and 83% sensitive and 67% and 60% specific, respectively. Conclusion Resting-state networks may be useful for tailoring stimulation mapping and could provide a means of identifying eloquent regions in patients while under anesthesia.