Showing papers by "James T. Rutka published in 2020"

Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition

Abstract: PURPOSEChildren with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in the...

Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas.

Abstract: BACKGROUND Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. METHODS We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers. RESULTS Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma-like tumors could stratify these tumors into low and high risk (P = 0.0014). CONCLUSION The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

Online Impact and Presence of a Specialized Social Media Team for the Journal of Neurosurgery: Descriptive Analysis.

Abstract: Background: Social media use continues to gain momentum in academic neurosurgery. To increase journal impact and broaden engagement, many scholarly publications have turned to social media to disseminate research. The Journal of Neurosurgery Publishing Group (JNSPG) established a dedicated, specialized social media team (SMT) in November 2016 to provide targeted improvement in digital outreach. Objective: The goal of this study was to examine the impact of the JNSPG SMT as measured by increased engagement. Methods: We analyzed various metrics, including impressions, engagements, retweets, likes, profile clicks, and URL clicks, from consecutive social media posts from the JNSPG’s Twitter and Facebook platforms between February 1, 2015 and February 28, 2019. Standard descriptive statistics were utilized. Results: Between February 2015 and October 2016, when a specialized SMT was created, 170 tweets (8.1 tweets/month) were posted compared to 3220 tweets (115.0 tweets/month) between November 2016 and February 2019. All metrics significantly increased, including the impressions per tweet (mean 1646.3, SD 934.9 vs mean 4605.6, SD 65,546.5; P=.01), engagements per tweet (mean 35.2, SD 40.6 vs mean 198.2, SD 1037.2; P<.001), retweets (mean 2.5, SD 2.8 vs mean 10.5, SD 15.3; P<.001), likes (mean 2.5, SD 4.0 vs mean 18.0, SD 37.9; P<.001), profile clicks (mean 1.5, SD 2.0 vs mean 5.2, SD 43.3; P<.001), and URL clicks (mean 13.1, SD 14.9 vs mean 38.3, SD 67.9; P<.001). Tweets that were posted on the weekend compared to weekdays had significantly more retweets (mean 9.2, SD 9.8 vs mean 13.4, SD 25.6; P<.001), likes (mean 15.3, SD 17.9 vs mean 23.7, SD 70.4; P=.001), and URL clicks (mean 33.4, SD 40.5 vs mean 49.5, SD 117.3; P<.001). Between November 2015 and October 2016, 49 Facebook posts (2.3 posts/month) were sent compared to 2282 posts (81.5 posts/month) sent between November 2016 and February 2019. All Facebook metrics significantly increased, including impressions (mean 5475.9, SD 5483.0 vs mean 8506.1, SD 13,113.9; P<.001), engagements (mean 119.3, SD 194.8 vs mean 283.8, SD 733.8; P<.001), and reach (mean 2266.6, SD 2388.3 vs mean 5344.1, SD 8399.2; P<.001). Weekend Facebook posts had significantly more impressions per post (mean 7967.9, SD 9901.0 vs mean 9737.8, SD 19,013.4; P=.03) and a higher total reach (mean 4975.8, SD 6309.8 vs mean 6108.2, SD 12,219.7; P=.03) than weekday posts. Conclusions: Social media has been established as a crucial tool for the propagation of neurosurgical research and education. Implementation of the JNSPG specialized SMT had a demonstrable impact on increasing the online visibility of social media content.

How technology is driving the landscape of epilepsy surgery.

Abstract: This article emphasizes the role of the technological progress in changing the landscape of epilepsy surgery and provides a critical appraisal of robotic applications, laser interstitial thermal therapy, intraoperative imaging, wireless recording, new neuromodulation techniques, and high-intensity focused ultrasound. Specifically, (a) it relativizes the current hype in using robots for stereo-electroencephalography (SEEG) to increase the accuracy of depth electrode placement and save operating time; (b) discusses the drawback of laser interstitial thermal therapy (LITT) when it comes to the need for adequate histopathologic specimen and the fact that the concept of stereotactic disconnection is not new; (c) addresses the ratio between the benefits and expenditure of using intraoperative magnetic resonance imaging (MRI), that is, the high technical and personnel expertise needed that might restrict its use to centers with a high case load, including those unrelated to epilepsy; (d) soberly reviews the advantages, disadvantages, and future potentials of neuromodulation techniques with special emphasis on the differences between closed and open-loop systems; and (e) provides a critical outlook on the clinical implications of focused ultrasound, wireless recording, and multipurpose electrodes that are already on the horizon. This outlook shows that although current ultrasonic systems do have some limitations in delivering the acoustic energy, further advance of this technique may lead to novel treatment paradigms. Furthermore, it highlights that new data streams from multipurpose electrodes and wireless transmission of intracranial recordings will become available soon once some critical developments will be achieved such as electrode fidelity, data processing and storage, heat conduction as well as rechargeable technology. A better understanding of modern epilepsy surgery will help to demystify epilepsy surgery for the patients and the treating physicians and thereby reduce the surgical treatment gap.

Feasibility of awake craniotomy in the pediatric population.

Abstract: Background Awake craniotomy with direct cortical stimulation and mapping is the gold standard for resection of lesions near eloquent brain areas, as it can maximize the extent of resection while minimizing the risk of neurological damage. In contrast to the adult population, only small series of awake craniotomies have been reported in children. Aims The aim of our study is to establish the feasibility of awake craniotomy in the pediatric population. Methods We performed a retrospective observational study of children undergoing a supratentorial awake craniotomy between January 2009 and April 2019 in a pediatric tertiary care center. Our primary outcome was feasibility of awake craniotomy, defined as the ability to complete the procedure without conversion to general anesthesia. Our secondary outcomes were the incidence of serious intraoperative complications and the mapping completion rate. Results Thirty procedures were performed in 28 children: 12 females and 16 males. The median age was 14 years (range 7-17). The primary diagnosis was tumor (83.3%), epilepsy (13.3%), and arterio-venous malformation (3.3%). The anesthetic techniques were asleep-awake-asleep (96.7%) and conscious sedation (3.3%), all cases supplemented with scalp block and pin-site infiltration. Awake craniotomy was feasible in 29 cases (96.7%), one patient converted to general anesthesia due to agitation. Serious complications occurred in six patients: agitation (6.7%), seizures (3.3%), increased intracranial pressure (3.3%), respiratory depression (3.3%), and bradycardia (3.3%). All complications were quickly resolved and without major consequences. Cortical mapping was completed in 96.6% cases. New neurological deficits occurred in six patients (20%)-moderate in one case and mild in 5-being all absent at 6 months of follow-up. Conclusion Awake craniotomy with intraoperative mapping can be successfully performed in children. Adequate patient selection and close cooperation between neurosurgeons, anesthesiologists, neuropsychologists, and neurophysiologists is paramount. Further studies are needed to determine the best anesthetic technique in this population group.

In situ tissue pathology from spatially encoded mass spectrometry classifiers visualized in real time through augmented reality

Abstract: Integration between a hand-held mass spectrometry desorption probe based on picosecond infrared laser technology (PIRL-MS) and an optical surgical tracking system demonstrates in situ tissue pathology from point-sampled mass spectrometry data. Spatially encoded pathology classifications are displayed at the site of laser sampling as color-coded pixels in an augmented reality video feed of the surgical field of view. This is enabled by two-way communication between surgical navigation and mass spectrometry data analysis platforms through a custom-built interface. Performance of the system was evaluated using murine models of human cancers sampled in situ in the presence of body fluids with a technical pixel error of 1.0 ± 0.2 mm, suggesting a 84% or 92% (excluding one outlier) cancer type classification rate across different molecular models that distinguish cell-lines of each class of breast, brain, head and neck murine models. Further, through end-point immunohistochemical staining for DNA damage, cell death and neuronal viability, spatially encoded PIRL-MS sampling is shown to produce classifiable mass spectral data from living murine brain tissue, with levels of neuronal damage that are comparable to those induced by a surgical scalpel. This highlights the potential of spatially encoded PIRL-MS analysis for in vivo use during neurosurgical applications of cancer type determination or point-sampling in vivo tissue during tumor bed examination to assess cancer removal. The interface developed herein for the analysis and the display of spatially encoded PIRL-MS data can be adapted to other hand-held mass spectrometry analysis probes currently available.

CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

Abstract: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of “stemness” itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

Detection of epileptogenic focus using advanced dynamic statistical parametric mapping with magnetoencephalography in a patient with MRI-negative focal cortical dysplasia type IIB

Abstract: Advanced dynamic statistical parametric mapping (AdSPM) with magnetoencephalography (MEG) was used to identify MRI-negative epileptogenic lesions in this report. A 15-year-old girl had MRI-negative and pharmacology-resistant focal-onset epilepsy. She experienced two types of seizures. Type I consisted of her arousal from sleep, staring, and a forced head-turning movement to the left, followed by secondary generalization. Type II began with an aura of dizziness followed by staring and postictal headache with fatigue. Scalp video-electroencephalography (EEG) captured two type I seizures originating from the right frontocentral region. MEG showed scattered dipoles over the right frontal region. AdSPM identified the spike source at the bottom of the right inferior frontal sulcus. Intracranial video-EEG captured one type I seizure, which originated from the depth electrode at the bottom of the sulcus and correlated with the AdSPM spike source. Accordingly, the patient underwent resection of the middle and inferior frontal gyri, including the AdSPM-identified spike source. Histopathological examination revealed that the patient had focal cortical dysplasia type IIB. To date, the patient has been seizure free for 2 years while receiving topiramate treatment. This is the first preliminary report to identify MRI-negative epilepsy using AdSPM. Further investigation of AdSPM would be valuable for cases of MRI-negative focal epilepsy.

Utility of invasive electroencephalography in children 3 years old and younger with refractory epilepsy.

Abstract: OBJECTIVE Early surgical intervention for pediatric refractory epilepsy is increasingly advocated as surgery has become safer and data have demonstrated improved outcomes with early seizure control. There is concern that the risks associated with staged invasive electroencephalography (EEG) in very young children outweigh the potential benefits. Here, the authors present a cohort of children with refractory epilepsy who were referred for invasive monitoring, and they evaluate the role and safety of staged invasive EEG in those 3 years old and younger. METHODS The authors conducted a retrospective review of children 3 years and younger with epilepsy, who had been managed surgically at two institutions between 2001 and 2015. A cohort of pediatric patients older than 3 years of age was used for comparison. Demographics, seizure etiology, surgical management, surgical complications, and adverse events were recorded. Statistical analysis was completed using Stata version 13. A p < 0.05 was considered statistically significant. Fisher's exact test was used to compare proportions. RESULTS Ninety-four patients (45 patients aged ≤ 3 [47.9%]) and 208 procedures were included for analysis. Eighty-six procedures (41.3%) were performed in children younger than 3 years versus 122 in the older cohort (58.7%). Forty-two patients underwent grid placement (14 patients aged ≤ 3 [33.3%]); 3 of them developed complications associated with the implant (3/42 [7.14%]), none of whom were among the younger cohort. Across all procedures, 11 complications occurred in the younger cohort versus 5 in the older patients (11/86 [12.8%] vs 5/122 [4.1%], p = 0.032). Two adverse events occurred in the younger group versus 1 in the older group (2/86 [2.32%] vs 1/122 [0.82%], p = 0.571). Following grid placement, 13/14 younger patients underwent guided resections compared to 20/28 older patients (92.9% vs 71.4%, p = 0.23). CONCLUSIONS While overall complication rates were higher in the younger cohort, subdural grid placement was not associated with an increased risk of surgical complications in that population. Invasive electrocorticography informs management in very young children with refractory, localization-related epilepsy and should therefore be used when clinically indicated.

Clinical phenotypes and prognostic features of ETMRs (Embryonal Tumor with Multi-layered Rosettes) a new CNS tumor entity: A Rare Brain Tumor Registry study

Abstract: Background ETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease. Methods Primary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses. Findings ETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=<0.001) correlated with improved EFS and OS in multi-variable analyses. EFS and OS for patients treated with only conventional dose chemotherapy (CC) was 0% and respectively 37%+/-14% and 32%+/-13% for patients treated with HDC. Patients with GTR or sub-total resection (STR) treated with HDC and RT had superior EFS (GTR 73%+/-14%, p=0.018; STR 67%+/-19% p=0.009) and OS (GTR 66%+/-17%, p=0.05; STR 67%+/-16%, p=0.005). Amongst 21 long-term survivors (OS 24-202 months); 38%, 24% and 24% respectively received craniospinal, focal or no RT. Interpretation: Prompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.

Three-Dimensional Computed Tomography Reconstruction Unmasks Shunt Disconnection in a Child.

Abstract: An 18-month-old patient with complex postinfectious hydrocephalus presented with suspected shunt malfunction. The infant was vomiting intermittently for over a month, but her clinical appearance was reassuring. She was alert with no focal neurological deficits. The fontanelle was closed and papilledema was absent. Cranial imaging demonstrated ventriculomegaly (Figure 1A) but prior cross-sectional imaging was unavailable for comparative review. The shunt X-rays and axial computerized tomography (CT) did not reveal an obvious shunt disconnection (Figure 1B). We were unable to aspirate cerebrospinal fluid from the shunt, but her symptoms resolved spontaneously soon after admission. A diagnosis of arrested hydrocephalus and a viral illness was suspected. She re-presented with emesis 7 days later. Again, her clinical status was reassuring with no impairment of consciousness or signs of raised intracranial pressure. A repeat CT scan showed stable ventriculomegaly and no obvious shunt disconnection was apparent on repeat X-rays. We elected to explore the shunt in the operating room the day after admission. Intraoperatively, an unexpected disconnection was identified between the proximal ventricular catheter and shunt valve. Correction of this problem quickly led to resolution of the patient’s symptoms. We re-reviewed the preoperative imaging at initial presentation and during her repeat admission but could not visualize the disconnection (Figure 1A and B). However, we retrospectively obtained 3D reconstructions of the CT scans, which clearly demonstrated the disconnection (Figure 2). This case emphasizes the value of obtaining 3D-CT reconstructions in the context of suspected shunt malfunction, especially in the pediatric patient who may not exhibit overt clinical or radiological signs. Earlier identification of the disconnection via 3D-CT imaging may have enhanced decision making, avoided a discharge and readmission, and facilitated prompter treatment. Shunt disconnection is the cause of malfunction in approximately 10% of cases. Diagnosing shunt disconnection with shunt series X-rays may prove difficult as the disconnection may be subtle, as in our case, and the shunt may still be partially functional which can manifest as inconsistent and intermittent symptoms. The negative predictive value of shunt series X-rays is only 22%. 3D visualization of the shunt by reconstruction of a multidetector CT scan provides much better clarity of shunt components. These 3D reformats can be easily generated from the original CT dataset from a multidetector CT available in most imaging departments today and do not require any increased radiation dose. In summary, 3D-CT reconstructions retrospectively proved to be diagnostic of a subtle shunt disconnection in a child with ambiguous clinical and radiological signs of shunt malfunction. In our institution, patients with suspected shunt malfunction who have CT brain imaging on admission are now receiving routine radiological evaluation with 3D-CT reconstructions to facilitate the detection of obscure shunt fractures and disconnections.