Dr. Parker is currently a PGY6 Neurosurgery Resident at Stanford. He has focused his training and research on minimally invasive treatments for epilepsy and movement disorders in Adults and Children. He has focused his training to develop expertise in open microsurgical resection techniques, laser interstitial thermal therapy (LITT), focused ultrasound (MRgFUS), Deep Brain Stimulation (DBS), Responsive Neurostimulation (RNS), electrocorticography (ECoG), stereo-electro-encephalography (SEEG), and robotic-assisted surgery.
Dr. Parker completed a year long enfolded fellowship in Adult and Pediatric Epilepsy & Functional Surgery with Dr. Gerald Grant and Dr. Casey Halpern. Guided by his surgical mentors, Dr. Parker has utilized state of the art approaches to improve epilepsy surgery by combing SEEG, 3D printing, whole brain tractography, and navigated operative exoscopes to guide safe surgical resections of epileptic foci. Dr. Parker's research revolves around optimizing SEEG techniques for intracranial evaluation of epileptic foci and clinically-relevant brain mapping via understanding the role of white matter in seizure propagation.
- Adult and Pediatric Epilepsy
- Stereo-electro-encephalography (SEEG)
- Adult and Pediatric Movement Disorders
- Deep Brain Stimulation (DBS)
- Responsive Neurostimulation (RNS)
- Electrocorticography (ECoG)
- Brain Mapping (awake craniotomy)
- Microsurgical Resection (epileptic focus, temporal lobectomy, callosotomy, hemispehectomy, and disconnection procedures)
- Tumor Associated Epilepsy
Honors & Awards
Tashia and John Morgridge Endowed Postdoctoral Fellow in Pediatric Translational Medicine, Stanford Maternal & Child Health Research Institute (2019-2020)
Henry Newman Award, Best Clinical Paper, San Francisco Neurological Society (2017)
Alden Harken Basic Science Research Award, University of Colorado, Department of Surgery (2015)
Inductee, Alpha Omega Alpha (2015)
Christopher G Reed Biologist Award, Dartmouth College (2008)
AB, Dartmouth College, Biology with High Honors (2008)
PhD, University of Colorado, Anschutz Medical Campus, Cancer Biology (2013)
MD, University of Colorado, School of Medicine, Medicine (2015)
Current Clinical Interests
- Adult and Pediatric Epilepsy Surgery
- Adult and Pediatric Movement Disorders
Electrophysiologic Signatures of Cortical and White Matter Stimulation
2019 American Epilepsy Society Seed Grant
Stanford / Maternal & Child Health Research Institute
- Gerald Grant, Professor of Neurosurgery , Stanford / LPCH
- Brenda Porter, Professor of Neurology, Stanford / LPCH
Anticipatory human subthalamic area beta-band power responses to dissociable tastes correlate with weight gain.
Neurobiology of disease
The availability of enticing sweet, fatty tastes is prevalent in the modern diet and contribute to overeating and obesity. In animal models, the subthalamic area plays a role in mediating appetitive and consummatory feeding behaviors, however, its role in human feeding is unknown. We used intraoperative, subthalamic field potential recordings while participants (n = 5) engaged in a task designed to provoke responses of taste anticipation and receipt. Decreased subthalamic beta-band (15-30 Hz) power responses were observed for both sweet-fat and neutral tastes. Anticipatory responses to taste-neutral cues started with an immediate decrease in beta-band power from baseline followed by an early beta-band rebound above baseline. On the contrary, anticipatory responses to sweet-fat were characterized by a greater and sustained decrease in beta-band power. These activity patterns were topographically specific to the subthalamic nucleus and substantia nigra. Further, a neural network trained on this beta-band power signal accurately predicted (AUC ≥ 74%) single trials corresponding to either taste. Finally, the magnitude of the beta-band rebound for a neutral taste was associated with increased body mass index after starting deep brain stimulation therapy. We provide preliminary evidence of discriminatory taste encoding within the subthalamic area associated with control mechanisms that mediate appetitive and consummatory behaviors.
View details for DOI 10.1016/j.nbd.2021.105348
View details for PubMedID 33781923
Interobserver Agreement for the CT Severity Grading Scales for Acute Traumatic Brain Injury (TBI).
Journal of neurotrauma
PURPOSE: To determine the interobserver variability among providers of different specialties and levels of experience across five established computed tomography (CT) scoring systems for acute traumatic brain injury (TBI).MATERIALS & METHODS: One hundred cases were selected at random from a retrospective population of adult patients transported to our emergency department and subjected to a non-contrast head CT due to suspicion for TBI. Eight neuroradiologists and neurosurgeons in trainee (residents and fellows) and attending roles independently scored each non-contrast head CT scan on the Marshall, Rotterdam, Helsinki, Stockholm and NeuroImaging Radiological Interpretation System (NIRIS) head CT scales. Interobserver variability of scale scores - overall and by specialty and level of training - was quantified using the intraclass correlation coefficient (ICC), and agreement with respect to National Institutes of Health Common Data Elements (NIH CDEs) was assessed using Cohen's kappa.RESULTS: All CT severity scoring systems showed high interobserver agreement as evidenced by high ICCs, ranging from 0.75 - 0.89. For all scoring systems, neuroradiologists (ICC range from 0.81 - 0.94) tended to have higher interobserver agreement than neurosurgeons (ICC range from 0.63 - 0.76). For all scoring systems, attendings (ICC range from 0.76 - 0.89) had similar interobserver agreement to trainees (ICC range from 0.73 - 0.89). Agreement with respect to NIH CDEs was high for ascertaining presence/absence of hemorrhage, skull fracture, and mass effect, with estimated kappa statistics of least 0.89.CONCLUSION: Acute TBI CT scoring systems demonstrate high interobserver agreement. These results provide scientific rigor for future use of these systems for the classification of acute TBI.
View details for DOI 10.1089/neu.2019.6871
View details for PubMedID 31996087
Postoperative outcomes following pediatric intracranial electrode monitoring: A case for stereoelectroencephalography (SEEG).
Epilepsy & behavior : E&B
2020; 104 (Pt A): 106905
For patients with medically refractory epilepsy, intracranial electrode monitoring can help identify epileptogenic foci. Despite the increasing utilization of stereoelectroencephalography (SEEG), the relative risks or benefits associated with the technique when compared with the traditional subdural electrode monitoring (SDE) remain unclear, especially in the pediatric population. Our aim was to compare the outcomes of pediatric patients who received intracranial monitoring with SEEG or SDE (grids and strips).We retrospectively studied 38 consecutive pediatric intracranial electrode monitoring cases performed at our institution from 2014 to 2017. Medical/surgical history and operative/postoperative records were reviewed. We also compared direct inpatient hospital costs associated with the two procedures.Stereoelectroencephalography and SDE cohorts both showed high likelihood of identifying epileptogenic zones (SEEG: 90.9%, SDE: 87.5%). Compared with SDE, SEEG patients had a significantly shorter operative time (118.7 versus 233.4 min, P < .001) and length of stay (6.2 versus 12.3 days, P < .001), including days spent in the intensive care unit (ICU; 1.4 versus 5.4 days, P < .001). Stereoelectroencephalography patients tended to report lower pain scores and used significantly less narcotic pain medications (54.2 versus 197.3 mg morphine equivalents, P = .005). No complications were observed. Stereoelectroencephalography and SDE cohorts had comparable inpatient hospital costs (P = .47).In comparison with subdural electrode placement, SEEG results in a similarly favorable clinical outcome, but with reduced operative time, decreased narcotic usage, and superior pain control without requiring significantly higher costs. The potential for an improved postoperative intracranial electrode monitoring experience makes SEEG especially suitable for pediatric patients.
View details for DOI 10.1016/j.yebeh.2020.106905
View details for PubMedID 32028127
Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation.
Frontiers in human neuroscience
2020; 14: 191
Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3-4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.
View details for DOI 10.3389/fnhum.2020.00191
View details for PubMedID 32676015
View details for PubMedCentralID PMC7333679
Contemporaneous evaluation of patient experience, surgical strategy, and seizure outcomes in patients undergoing stereoelectroencephalography or subdural electrode monitoring.
Intracranial electrographic localization of the seizure onset zone (SOZ) can guide surgical approaches for medically refractory epilepsy patients, especially when the presurgical workup is discordant or functional cortical mapping is required. Minimally invasive stereotactic placement of depth electrodes, stereoelectroencephalography (SEEG), has garnered increasing use, but limited data exist to evaluate its postoperative outcomes in the context of the contemporaneous availability of both SEEG and subdural electrode (SDE) monitoring. We aimed to assess the patient experience, surgical intervention, and seizure outcomes associated with these two epileptic focus mapping techniques during a period of rapid adoption of neuromodulatory and ablative epilepsy treatments.We retrospectively reviewed 66 consecutive adult intracranial electrode monitoring cases at our institution between 2014 and 2017. Monitoring was performed with either SEEG (n = 47) or SDEs (n = 19).Both groups had high rates of SOZ identification (SEEG 91.5%, SDE 88.2%, P = .69). The majority of patients achieved Engel class I (SEEG 29.3%, SDE 35.3%) or II outcomes (SEEG 31.7%, SDE 29.4%) after epilepsy surgery, with no significant difference between groups (P = .79). SEEG patients reported lower median pain scores (P = .03) and required less narcotic pain medication (median = 94.5 vs 594.6 milligram morphine equivalents, P = .0003). Both groups had low rates of symptomatic hemorrhage (SEEG 0%, SDE 5.3%, P = .11). On multivariate logistic regression, undergoing resection or ablation (vs responsive neurostimulation/vagus nerve stimulation) was the only significant independent predictor of a favorable outcome (adjusted odds ratio = 25.4, 95% confidence interval = 3.48-185.7, P = .001).Although both SEEG and SDE monitoring result in favorable seizure control, SEEG has the advantage of superior pain control, decreased narcotic usage, and lack of routine need for intensive care unit stay. Despite a heterogenous collection of epileptic semiologies, seizure outcome was associated with the therapeutic surgical modality and not the intracranial monitoring technique. The potential for an improved postoperative experience makes SEEG a promising method for intracranial electrode monitoring.
View details for DOI 10.1111/epi.16762
View details for PubMedID 33236777
Adverse Events and Bundled Costs after Cranial Neurosurgical Procedures: Validation of the LACE Index Across 40,431 Admissions and Development of the LACE-Cranial Index.
Anticipating post-discharge complications following neurosurgery remains difficult. The LACE index, based on four hospitalization descriptors, stratifies patients by risk of 30-day post-discharge adverse events but has not been validated in a procedure-specific manner in neurosurgery. Our study sought to explore the utility of the LACE index in cranial neurosurgery population and to develop an enhanced model, LACE-Cranial.The Optum Clinformatics Database was used to identify cranial neurosurgery admissions (2004-2017). Procedures were grouped as trauma/hematoma/ICP, open vascular, functional/pain, skull base, tumor, or endovascular. Adverse events were defined as post-discharge death/readmission. LACE-Cranial was developed using a logistic regression framework incorporating an expanded feature set in addition to the original LACE components.A total of 40,431 admissions were included. Predictions of 30-day readmissions was best for skull-base (AUC=0.636) and tumor (AUC=0.63) admissions but was generally poor. Predictive ability of 30-day mortality was best for functional/pain admissions (AUC=0.957) and poorest for trauma/hematoma/ICP admissions (AUC=0.613). Across procedure types except for functional/pain, a high-risk LACE score was associated with higher post-discharge bundled payment costs. Incorporating features identified to contribute independent predictive value, the LACE-Cranial model achieved procedure-specific 30-day mortality AUCs ranging from 0.904 to 0.98. Prediction of 30-day and 90-day readmissions was also improved, with tumor and skull base cases achieving 90-day readmission AUCs of 0.718 and 0.717, respectively.While the unmodified LACE index demonstrates inconsistent classification performance, the enhanced LACE-Cranial model offers excellent prediction of short-term post-discharge mortality across procedure groups and significantly improved anticipation of short-term post-discharge readmissions.
View details for DOI 10.1016/j.wneu.2020.10.103
View details for PubMedID 33127572
Anatomic and Thermometric Analysis of Cranial Nerve Palsy after Laser Amygdalohippocampotomy for Mesial Temporal Lobe Epilepsy.
Operative neurosurgery (Hagerstown, Md.)
BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive therapy for treating medication-resistant mesial temporal lobe epilepsy. Cranial nerve (CN) palsy has been reported as a procedural complication, but the mechanism of this complication is not understood.OBJECTIVE: To identify the cause of postoperative CN palsy after LITT.METHODS: Four medial temporal lobe epilepsy patients with CN palsy after LITT were identified for comparison with 22 consecutive patients with no palsy. We evaluated individual variation in the distance between CN III and the uncus, and CN IV and the parahippocampal gyrus using preoperative T1- and T2-weighted magnetic resonance (MR) images. Intraoperative MR thermometry was used to estimate temperature changes.RESULTS: CN III (n=2) and CN IV palsies (n=2) were reported. On preoperative imaging, the majority of identified CN III (54%) and CN IV (43%) were located within 1 to 2 mm of the uncus and parahippocampal gyrus tissue border, respectively. Affected CN III and CN IV were more likely to be found<1 mm of the tissue border (PCNIII=.03, PCNIV<.01; chi-squared test). Retrospective assessment of thermal profile during ablation showed higher temperature rise along the mesial temporal lobe tissue border in affected CNs than unaffected CNs after controlling for distance (12.9°C vs 5.8°C; P=.03; 2-sample t-test).CONCLUSION: CN palsy after LITT likely results from direct heating of the respective CN running at extreme proximity to the mesial temporal lobe. Low-temperature thresholds set at the border of the mesial temporal lobe in patients whose CNs are at close proximity may reduce this risk.
View details for DOI 10.1093/ons/opz279
View details for PubMedID 31555820
Simulating Episode-Based Bundled Payments for Cranial Neurosurgical Procedures.
BACKGROUND: Episode-based bundled payments were introduced by Medicare in 2013 as the Bundled Payments for Care Improvement (BPCI) in order to improve care coordination and cost efficiency. BPCI has not yet been applied to cranial neurosurgical procedures.OBJECTIVE: To determine projected values of episode-based bundled payments when applied to common cranial neurosurgical procedures using retrospective data from a large database.METHODS: We performed a large retrospective observational study using the MarketScan administrative database to project bundled payment payments for 4 groups of common cranial neurosurgical procedures.RESULTS: We identified 15 276 procedures that met our inclusion criteria. We observed significant variability between groups, with 90-d bundle projected payments ranging from $58,200 for craniotomy for meningioma to $102,073 for craniotomy for malignant glioma. We also found significant variability in projected bundled payments within each class of operation. On average, payment for the index hospitalization accounted for 85% of projected payments for a 30-d bundle and 70.5% of projected payments for a 90-d bundle. Multivariable analysis showed that hospital readmission, discharge to postacute care facilities, venous-thrombo-embolism, medical comorbidities, adjuvant therapies, and payer status significantly contributed to projected cranial bundle payments.CONCLUSION: For the first time, to our knowledge, we project the values of episode-based bundled payments for common vascular and tumor cranial operations. As previously identified in orthopedic procedures, there is significant variability in total bundle payments within each cranial procedure. Compared to spine and orthopedic procedures, postdischarge care significantly impacts total bundle payments in cranial neurosurgery.
View details for DOI 10.1093/neuros/nyz353
View details for PubMedID 31515558
Robot-assisted versus manual navigated stereoelectroencephalography in adult medically-refractory epilepsy patients.
2019; 159: 106253
Stereoelectroencephalography (SEEG) has experienced a recent growth in adoption for epileptogenic zone (EZ) localization. Advances in robotics have the potential to improve the efficiency and safety of this intracranial seizure monitoring method. We present our institutional experience employing robot-assisted SEEG and compare its operative efficiency, seizure reduction outcomes, and direct hospital costs with SEEG performed without robotic assistance using navigated stereotaxy.We retrospectively identified 50 consecutive adult SEEG cases at our institution in this IRB-approved study, of which 25 were navigated with image guidance (hereafter referred to as "navigated") (02/2014-10/2016) and 25 were robot-assisted (09/2016-12/2017). A thorough review of medical/surgical history and operative records with imaging and trajectory plans was done for each patient. Direct inpatient costs related to each technique were compared.Most common seizure etiologies for patients undergoing navigated and robot-assisted SEEG included non-lesional and benign temporal lesions. Despite having a higher mean number of leads-per-patient (10.2 ± 3.5 versus 7.2 ± 2.6, P = 0.002), robot-assisted cases had a significantly shorter mean operative time than navigated cases (125.5±48.5 versus 173.4±84.3 min, P = 0.02). Comparison of robot-assisted cases over the study interval revealed no significant difference in mean operative time (136.4±51.4 min for the first ten cases versus 109.9±75.8 min for the last ten cases, P = 0.25) and estimated operative time-per-lead (13.4±6.0 min for the first ten cases versus 12.9±7.7 min for the last ten cases, P = 0.86). The mean depth, radial, target, and entry point errors for robot-assisted cases were 2.12±1.89, 1.66±1.58, 3.05±2.02 mm, and 1.39 ± 0.75 mm, respectively. The two techniques resulted in equivalent EZ localization rate (navigated 88 %, robot-assisted 96 %, P = 0.30). Common types of epilepsy surgery performed consisted of implantation of responsive neurostimulation (RNS) device (56 %), resection (19.1 %), and laser ablation (23.8 %) for navigated SEEG. For robot-assisted SEEG, either RNS implantation (68.2 %) or laser ablation (22.7 %) were performed or offered. A majority of navigated and robot-assisted patients who underwent epilepsy surgery achieved either Engel Class I (navigated 36.8 %, robot-assisted 31.6 %) or II (navigated 36.8 %, robot-assisted 15.8 %) outcome with no significant difference between the groups (P = 0.14). Direct hospital cost for robot-assisted SEEG was 10 % higher than non-robotic cases.This single-institutional study suggests that robotic assistance can enhance efficiency of SEEG without compromising safety or precision when compared to image guidance only. Adoption of this technique with uniform safety and efficacy over a short period of time is feasible with favorable epilepsy outcomes.
View details for DOI 10.1016/j.eplepsyres.2019.106253
View details for PubMedID 31855826
- Adjunctive repetitive transcranial magnetic stimulation delivers superior quality of life for focal epilepsy compared to anti-epileptic drugs: A meta-analytic utility prediction study. Brain stimulation 2019
Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion.
2019; 9 (1): 14020
Among high-grade brain tumors, glioblastoma is particularly difficult to treat, in part due to its highly infiltrative nature which contributes to the malignant phenotype and high mortality in patients. In order to better understand the signaling pathways underlying glioblastoma invasion, we performed the first large-scale CRISPR-Cas9 loss of function screen specifically designed to identify genes that facilitate cell invasion. We tested 4,574 genes predicted to be involved in trafficking and motility. Using a transwell invasion assay, we discovered 33 genes essential for invasion. Of the 11 genes we selected for secondary testing using a wound healing assay, 6 demonstrated a significant decrease in migration. The strongest regulator of invasion was mitogen-activated protein kinase 4 (MAP4K4). Targeting of MAP4K4 with single guide RNAs or a MAP4K4 inhibitor reduced migration and invasion in vitro. This effect was consistent across three additional patient derived glioblastoma cell lines. Analysis of epithelial-mesenchymal transition markers in U138 cells with lack or inhibition of MAP4K4 demonstrated protein expression consistent with a non-invasive state. Importantly, MAP4K4 inhibition limited migration in a subset of human glioma organotypic slice cultures. Our results identify MAP4K4 as a novel potential therapeutic target to limit glioblastoma invasion.
View details for DOI 10.1038/s41598-019-50160-w
View details for PubMedID 31570734
Stereotactic laser ablation for completion corpus callosotomy.
Journal of neurosurgery. Pediatrics
Completion corpus callosotomy can offer further remission from disabling seizures when a prior partial corpus callosotomy has failed and residual callosal tissue is identified on imaging. Traditional microsurgical approaches to section residual fibers carry risks associated with multiple craniotomies and the proximity to the medially oriented motor cortices. Laser interstitial thermal therapy (LITT) represents a minimally invasive approach for the ablation of residual fibers following a prior partial corpus callosotomy. Here, the authors report clinical outcomes of 6 patients undergoing LITT for completion corpus callosotomy and characterize the radiological effects of ablation.A retrospective clinical review was performed on a series of 6 patients who underwent LITT completion corpus callosotomy for medically intractable epilepsy at Stanford University Medical Center and Lucile Packard Children's Hospital at Stanford between January 2015 and January 2018. Detailed structural and diffusion-weighted MR images were obtained prior to and at multiple time points after LITT. In 4 patients who underwent diffusion tensor imaging (DTI), streamline tractography was used to reconstruct and evaluate tract projections crossing the anterior (genu and rostrum) and posterior (splenium) parts of the corpus callosum. Multiple diffusion parameters were evaluated at baseline and at each follow-up.Three pediatric (age 8-18 years) and 3 adult patients (age 30-40 years) who underwent completion corpus callosotomy by LITT were identified. Mean length of follow-up postoperatively was 21.2 (range 12-34) months. Two patients had residual splenium, rostrum, and genu of the corpus callosum, while 4 patients had residual splenium only. Postoperative complications included asymptomatic extension of ablation into the left thalamus and transient disconnection syndrome. Ablation of the targeted area was confirmed on immediate postoperative diffusion-weighted MRI in all patients. Engel class I-II outcomes were achieved in 3 adult patients, whereas all 3 pediatric patients had Engel class III-IV outcomes. Tractography in 2 adult and 2 pediatric patients revealed time-dependent reduction of fractional anisotropy after LITT.LITT is a safe, minimally invasive approach for completion corpus callosotomy. Engel outcomes for completion corpus callosotomy by LITT were similar to reported outcomes of open completion callosotomy, with seizure reduction primarily observed in adult patients. Serial DTI can be used to assess the presence of tract projections over time but does not classify treatment responders or nonresponders.
View details for DOI 10.3171/2019.5.PEDS19117
View details for PubMedID 31374542
Intratumoral heterogeneity of endogenous tumor cell invasive behavior in human glioblastoma.
2018; 8 (1): 18002
Intratumoral genetic heterogeneity is a widely accepted characteristic of human cancer, including the most common primary malignant brain tumor, glioblastoma. However, the variability in biological behaviors amongst cells within individual tumors is not well described. Invasion into unaffected brain parenchyma is one such behavior, and a leading mechanism of tumor recurrence unaddressed by the current therapeutic armamentarium. Further, providing insight into variability of tumor cell migration within individual tumors may inform discovery of novel anti-invasive therapeutics. In this study, ex vivo organotypic slice cultures from EGFR-wild type and EGFR-amplified patient tumors were treated with the EGFR inhibitor gefitinib to evaluate potential sub-population restricted intratumoral drug-specific responses. High-resolution time-lapse microscopy and quantitative path tracking demonstrated migration of individual cells are punctuated by intermittent bursts of movement. Elevation of population aggregate mean speeds were driven by subpopulations of cells exhibiting frequent high-amplitude bursts, enriched within EGFR-amplified tumors. Treatment with gefitinib specifically targeted high-burst cell subpopulations only in EGFR-amplified tumors, decreasing bursting frequency and amplitude. We provide evidence of intratumoral subpopulations of cells with enhanced migratory behavior in human glioblastoma, selectively targeted via EGFR inhibition. These data justify use of direct human tumor slice cultures to investigate patient-specific therapies designed to limit tumor invasion.
View details for PubMedID 30573757
A Human Glioblastoma Organotypic Slice Culture Model for Study of Tumor Cell Migration and Patient-specific Effects of Anti-Invasive Drugs
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
Glioblastoma (GBM) continues to carry an extremely poor clinical prognosis despite surgical, chemotherapeutic, and radiation therapy. Progressive tumor invasion into surrounding brain parenchyma represents an enduring therapeutic challenge. To develop anti-migration therapies for GBM, model systems that provide a physiologically relevant background for controlled experimentation are essential. Here, we present a protocol for generating slice cultures from human GBM tissue obtained during surgical resection. These cultures allow for ex vivo experimentation without passaging through animal xenografts or single cell cultures. Further, we describe the use of time-lapse laser scanning confocal microscopy in conjunction with cell tracking to quantitatively study the migratory behavior of tumor cells and associated response to therapeutics. Slices are reproducibly generated within 90 min of surgical tissue acquisition. Retrovirally-mediated fluorescent cell labeling, confocal imaging, and tumor cell migration analyses are subsequently completed within two weeks of culture. We have successfully used these slice cultures to uncover genetic factors associated with increased migratory behavior in human GBM. Further, we have validated the model's ability to detect patient-specific variation in response to anti-migration therapies. Moving forward, human GBM slice cultures are an attractive platform for rapid ex vivo assessment of tumor sensitivity to therapeutic agents, in order to advance personalized neuro-oncologic therapy.
View details for PubMedID 28784966
Cost-effectiveness of focused ultrasound, radiosurgery, and DBS for essential tremor.
Essential tremor remains a very common yet medically refractory condition. A recent phase 3 study demonstrated that magnetic resonance-guided focused ultrasound thalamotomy significantly improved upper limb tremor. The objectives of this study were to assess this novel therapy's cost-effectiveness compared with existing procedural options.Literature searches of magnetic resonance-guided focused ultrasound thalamotomy, DBS, and stereotactic radiosurgery for essential tremor were performed. Pre- and postoperative tremor-related disability scores were collected from 32 studies involving 83 magnetic resonance-guided focused ultrasound thalamotomies, 615 DBSs, and 260 stereotactic radiosurgery cases. Utility, defined as quality of life and derived from percent change in functional disability, was calculated; Medicare reimbursement was employed as a proxy for societal cost. Medicare reimbursement rates are not established for magnetic resonance-guided focused ultrasound thalamotomy for essential tremor; therefore, reimbursements were estimated to be approximately equivalent to stereotactic radiosurgery to assess a cost threshold. A decision analysis model was constructed to examine the most cost-effective option for essential tremor, implementing meta-analytic techniques.Magnetic resonance-guided focused ultrasound thalamotomy resulted in significantly higher utility scores compared with DBS (P < 0.001) or stereotactic radiosurgery (P < 0.001). Projected costs of magnetic resonance-guided focused ultrasound thalamotomy were significantly less than DBS (P < 0.001), but not significantly different from radiosurgery.Magnetic resonance-guided focused ultrasound thalamotomy is cost-effective for tremor compared with DBS and stereotactic radiosurgery and more effective than both. Even if longer follow-up finds changes in effectiveness or costs, focused ultrasound thalamotomy will likely remain competitive with both alternatives. © 2017 International Parkinson and Movement Disorder Society.
View details for DOI 10.1002/mds.26997
View details for PubMedID 28370272
Frontal and occipital horn ratio is associated with multifocal intraparenchymal hemorrhages in neonatal shunted hydrocephalus.
Journal of neurosurgery. Pediatrics
2017; 20 (5): 432–38
OBJECTIVE Placement of a cerebrospinal fluid diversion device (i.e., shunt) is a routine pediatric neurosurgical procedure, often performed in the first weeks of life for treatment of congenital hydrocephalus. In the postoperative period, shunt placement may be complicated by subdural, catheter tract, parenchymal, and intraventricular hemorrhages. The authors observed a subset of infants and neonates who developed multifocal intraparenchymal hemorrhages (MIPH) following shunt placement and sought to determine any predisposing perioperative variables. METHODS A retrospective review of the electronic medical record at a tertiary-care children's hospital was performed for the period 1998-2015. Inclusion criteria consisted of shunt placement, age < 30 days, and available pre- and postoperative brain imaging. The following data were collected and analyzed for each case: ventricular size ratios, laboratory values, clinical presentation, shunt and valve type, and operative timing and approach. RESULTS A total of 121 neonates met the inclusion criteria for the study, and 11 patients (9.1%) had MIPH following shunt placement. The preoperative frontal and occipital horn ratio (FOR) was significantly higher in the patients with MIPH than in those without (0.65 vs 0.57, p < 0.001). The change in FOR (∆FOR) after shunt placement was significantly greater in the MIPH group (0.14 vs 0.08, p = 0.04). Among neonates who developed MIPH, aqueductal stenosis was the most common etiology (45%). The type of shunt valve was associated with incidence of MIPH (p < 0.001). Preoperative clinical parameters, including head circumference, bulging fontanelle, and coagulopathy, were not significantly associated with development of MIPH. CONCLUSIONS MIPH represents an underrecognized complication of neonatal shunted hydrocephalus. Markers of severity of ventriculomegaly (FOR) and ventricular response to CSF diversion (∆FOR) were significantly associated with occurrence of MIPH. Choice of shunt and etiology of hydrocephalus were also significantly associated with MIPH. After adjusting for corrected age, etiology of hydrocephalus, and shunt setting, the authors found that ∆FOR after shunting was still associated with MIPH. A prospective study of MIPH prevention strategies and assessment of possible implications for patient outcomes is needed.
View details for PubMedID 28885094
Vocal Tremor: Novel Therapeutic Target for Deep Brain Stimulation.
2016; 6 (4)
Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. Traditional EVT treatments have demonstrated limited success in long-term management of symptoms. However, voice tremor has been noted to decrease in patients receiving deep brain stimulation (DBS) with the targeting of thalamic nuclei. In this study, we describe our multidisciplinary procedure for awake, frameless DBS with optimal stimulation targets as well as acoustic analysis and laryngoscopic assessment to quantify tremor reduction. Finally, we investigate the most recent clinical evidence regarding the procedure.
View details for PubMedID 27735866
Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma.
2013; 15 (8): 1048–57
Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.Migration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
View details for DOI 10.1093/neuonc/not053
View details for PubMedID 23749785
View details for PubMedCentralID PMC3714155
Preoperative evaluation of pineal tumors.
Neurosurgery clinics of North America
2011; 22 (3): 353–58, vii-viii
The role of the neurosurgeon is critical for initiating preoperative evaluation and care for pineal region tumors. Preoperative evaluation of pineal region tumor can be simplified into a checklist: (1) evaluation for emergent surgical intervention due to symptomatic obstructive hydrocephalus or mass effect; (2) development of a focused differential after acquisition of craniospinal MRI, serum and cerebrospinal fluid oncoprotein levels, and cerebrospinal fluid cytology; and (3) decision on whether a biopsy, surgical resection, or both are necessary. Subsequent biopsy or surgical resection is the first step of tumor management and leads to coordination of consultation with medical and radiation oncology.
View details for DOI 10.1016/j.nec.2011.04.003
View details for PubMedID 21801983