Intramedullary Spinal Cord Tumors: Whole-Genome Sequencing to Assist Management and Prognosis.

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth's penalized likelihood approach was used to account for the low event rates. Fisher's exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors.

United States regulatory approval of medical devices used for endovascular neurosurgery: A two-decade review of FDA regulatory files.

BACKGROUND: The evolution of neuroendovascular technologies has progressed substantially. Over the last two decades, the introduction of new endovascular devices has facilitated treatment for more patients, and as a result, the regulatory environment concerning neuroendovascular devices has evolved rapidly in response. OBJECTIVE: To examine trends in the approval of neuroendovascular devices by the United States Food and Drug Administration (FDA) over the last 20 years. METHODS: Open-access US FDA databases were queried between January 2000 and December 2022 for all devices approved by the Neurological Devices Advisory Committee. Neuroendovascular devices were manually classified and grouped by category. Device approval data, including approval times, approval pathway, and presence of predicate devices, were examined. RESULTS: A total of 3186 neurological devices were approved via various US FDA pathways during the study period. 320 (10.0%) corresponded to neuroendovascular devices, of which 301 (94.1%) were approved via the 510(k) pathway. The percentage of 510(k) pathway neuroendovascular devices increased from 6.9% to 14.3% of all neuro devices before and after 2015, respectively. There was an increase in approval times for neuroendovascular devices cleared after 2015. CONCLUSION: Over the last two decades, the neuroendovascular device armamentarium has rapidly expanded, especially after positive stroke trials in 2015. Regulatory approval times are significantly affected by device category, generation, company size, and company location, and a vast majority are approved by the 510(k) pathway. These results can guide further innovation in the endovascular device space and may act as a roadmap for future regulatory planning.

External Ventricular Drain Training in Medical Students Improves Procedural Accuracy and Attitudes Toward Virtual Reality.

OBJECTIVE: Neurosurgery residents face a learning curve at the beginning of residency. Virtual reality (VR) training may alleviate challenges through an accessible, reusable, anatomical model. METHODS: Medical students performed external ventricular drain placements in VR to characterize the learning curve from novice to proficient. Distance from catheter to foramen of Monro and location with respect to ventricle were recorded. Changes in attitudes toward VR were assessed. Neurosurgery residents performed external ventricular drain placements to validate proficiency benchmarks. Resident and student impressions of the VR model were compared. RESULTS: Twenty-one students with no neurosurgical experience and 8 neurosurgery residents participated. Student performance improved significantly from trial 1 to 3 (15 mm [12.1-20.70] vs. 9.7 [5.8-15.3], P = 0.02). Student attitudes regarding VR utility improved significantly posttrial. The distance to foramen of Monro was significantly shorter for residents than for students in trial 1 (9.05 [8.25-10.73] vs. 15 [12.1-20.70], P = 0.007) and trial 2 (7.45 [6.43-8.3] vs. 19.5 [10.9-27.6], P = 0.002). By trial 3 there was no significant difference (10.1 [8.63-10.95 vs. 9.7 [5.8-15.3], P = 0.62). Residents and students provided similarly positive feedback for VR in resident curricula, patient consent, preoperative practice and planning. Residents provided more neutral-to-negative feedback regarding skill development, model fidelity, instrument movement, and haptic feedback. CONCLUSIONS: Students showed significant improvement in procedural efficacy which may simulate resident experiential learning. Improvements in fidelity are needed before VR can become a preferred training technique in neurosurgery.

External Ventricular Drain Placement Teleproctoring Using a Novel Camera-Projector Navigation System: A Proof-of-Concept Study.

BACKGROUND: Teleproctoring is an emerging method of bedside clinical teaching; however, its feasibility has been limited by the available technologies. The use of novel tools that incorporate 3-dimensional environmental information and feedback might offer better bedside teaching options for neurosurgical procedures, including external ventricular drain placement. METHODS: A platform with a camera-projector system was used to proctor medical students on placing external ventricular drains on an anatomic model as a proof-of-concept study. Three-dimensional depth information of the model and surrounding environment was captured by the camera system and provided to the proctor who could provide projected annotations in a geometrically compensated manner onto the head model in real time. The medical students were randomized to identify Kocher's point on the anatomic model with or without the navigation system. The time required to identify Kocher's point and the accuracy were measured as a proxy for determining the effectiveness of the navigation proctoring system. RESULTS: Twenty students were enrolled in the present study. Those in the experimental group identified Kocher's point an average of 130 seconds faster than did the control group (P < 0.001). The mean diagonal distance from Kocher's point was 8.0 ± 4.29 mm for the experimental group compared with 23.6 ± 21.98 mm for the control group (P = 0.053). Of the 10 students randomized to the camera-projector system arm, 70% were accurate to within 1 cm of Kocher's point compared with 40% of the control arm (P > 0.05). CONCLUSIONS: Camera-projector systems for bedside procedure proctoring and navigation are a viable and valuable technology. We demonstrated its viability for external ventricular drain placement as a proof-of-concept. However, the versatility of this technology indicates that that it could be useful for a variety of even more complex neurosurgical procedures.

Permanent Cerebrospinal Fluid Diversion in Adults With Posterior Fossa Tumors: Incidence and Predictors.

BACKGROUND: Posterior fossa tumors (PFTs) can cause hydrocephalus. Hydrocephalus can persist despite resection of PFTs in a subset of patients requiring permanent cerebrospinal fluid (CSF) diversion. Characteristics of this patient subset are not well defined. OBJECTIVE: To define preoperative and postoperative variables that predict the need for postoperative CSF diversion in adult patients with PFTs. METHODS: We surveyed the CNS (Central Nervous System) Tumor Outcomes Registry at Emory (CTORE) for patients who underwent PFT resection at 3 tertiary-care centers between 2006 and 2019. Demographic, radiographic, perioperative, and dispositional data were analyzed using univariate and multivariate models. RESULTS: We included 617 patients undergoing PFT resection for intra-axial (57%) or extra-axial (43%) lesions. Gross total resection was achieved in 62% of resections. Approximately 13% of patients required permanent CSF diversion/shunting. Only 31.5% of patients who required pre- or intraop external ventricular drain (EVD) placement needed permanent CSF diversion. On logistic regression, size, transependymal flow, use of perioperative EVD, postoperative intraventricular hemorrhage (IVH), and surgical complications were predictors of permanent CSF diversion. Preoperative tumor size was only independent predictor of postoperative shunting in patients with subtotal resection. In patients with intra-axial tumors, transependymal flow (P = .014), postoperative IVH (P = .001), surgical complications (P = .013), and extent of resection (P = .03) predicted need for shunting. In extra-axial tumors, surgical complications were the major predictor (P = .022). CONCLUSION: Our study demonstrates that presence of preoperative hydrocephalus in patients with PFT does not necessarily entail the need for permanent CSF diversion. We report the major predictive factors for needing permanent CSF diversion.

Meningioma: A Review of Epidemiology, Pathology, Diagnosis, Treatment, and Future Directions.

Meningiomas are the most common intracranial tumor, making up more than a third of all primary central nervous system (CNS) tumors. They are mostly benign tumors that can be observed or preferentially treated with gross total resection that provides good outcomes. Meningiomas with complicated histology or in compromising locations has proved to be a challenge in treating and predicting prognostic outcomes. Advances in genomics and molecular characteristics of meningiomas have uncovered potential use for more accurate grading and prediction of prognosis and recurrence. With the study and detection of genomic aberrancies, specific biologic targets are now being trialed for possible management of meningiomas that are not responsive to standard surgery and radiotherapy treatment. This review summarizes current epidemiology, etiology, molecular characteristics, diagnosis, treatments, and current treatment trials.

Implementation and evaluation of eight virtual surgical electives for medical students during the COVID-19 pandemic.

BACKGROUND: Eight novel virtual surgery electives (VSEs) were developed and implemented in April-May 2020 for medical students forced to continue their education remotely due to COVID-19. METHODS: Each VSE was 1-2 weeks long, contained specialty-specific course objectives, and included a variety of teaching modalities. Students completed a post-course survey to assess changes in their interest and understanding of the specialty. Quantitative methods were employed to analyze the results. RESULTS: Eighty-three students participated in the electives and 67 (80.7%) completed the post-course survey. Forty-six (68.7%) respondents reported "increased" or "greatly increased" interest in the course specialty completed. Survey respondents' post-course understanding of each specialty increased by a statistically significant amount (p-value = <0.0001). CONCLUSION: This initial effort demonstrated that VSEs can be an effective tool for increasing medical students' interest in and understanding of surgical specialties. They should be studied further with more rigorous methods in a larger population.

Smart Sanitation-Biosensors as a Public Health Tool in Sanitation Infrastructure.

The health of individuals and communities is more interconnected than ever, and emergent technologies have the potential to improve public health monitoring at both the community and individual level. A systematic literature review of peer-reviewed and gray literature from 2000-present was conducted on the use of biosensors in sanitation infrastructure (such as toilets, sewage pipes and septic tanks) to assess individual and population health. 21 relevant papers were identified using PubMed, Embase, Global Health, CDC Stacks and NexisUni databases and a reflexive thematic analysis was conducted. Biosensors are being developed for a range of uses including monitoring illicit drug usage in communities, screening for viruses and diagnosing conditions such as diabetes. Most studies were nonrandomized, small-scale pilot or lab studies. Of the sanitation-related biosensors found in the literature, 11 gathered population-level data, seven provided real-time continuous data and 14 were noted to be more cost-effective than traditional surveillance methods. The most commonly discussed strength of these technologies was their ability to conduct rapid, on-site analysis. The findings demonstrate the potential of this emerging technology and the concept of Smart Sanitation to enhance health monitoring at the individual level (for diagnostics) as well as at the community level (for disease surveillance).

DNX-2401: an investigational drug for the treatment of recurrent glioblastoma.

Introduction: High-grade gliomas (HGG) are extremely aggressive brain malignancies that are fatal. Despite maximal resection, chemotherapy, and radiation, these tumors inevitably recur and present a poor median overall survival (mOS); hence a pressing need for improved treatments.Areas covered: This review assesses DNX-2401 as a treatment of recurrent HGG. Phase I data on efficacy, safety, and tolerability are examined while insights and perspectives on future directions are offered.Expert opinion: This phase I study assessed DNX-2401 in two study groups; one received an intratumoral injection without tumor resection while the second received an intratumoral injection followed by surgical resection 14 days later with a second injection into the resection cavity. In patients that did not receive resection, the mOS was 9.5 months while patients in the resection group had a mOS of 13 months, a promising extension of survival compared to historical controls. Furthermore, this study had numerous long-term survivors living for greater than 2 years. DNX-2401 was well tolerated with no Grade 3/4 adverse events; it provoked an immunologic response to the tumor which may contribute to the complete responses in some patients. Randomized-control trials are necessary and further studies are warranted to identify patients who will benefit most.

Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma.

INTRODUCTION: Glioblastoma and anaplastic astrocytoma are two of the most aggressive and common glioma malignancies in adults. These high-grade gliomas (HGG) universally recur despite aggressive treatment modalities and have a median overall survival (mOS) of approximately 14 months from initial diagnosis. Upon recurrence, there is no standard of care and these patients have a dismal prognosis of around 9 months at time of recurrence. Areas covered: In this article, we assess the newly published phase I data of Toca 511 and Toca FC, a two-drug combination therapy for recurrent HGG (rHGG) tumors, for effectiveness and safety. Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. Furthermore, all responders were complete responses after extended follow-up. The drug is well tolerated for most patients. Responders tended to be young and have high-performance scores prior to beginning therapy, but more studies are necessary to understand the patient profile that receives the most benefit. Randomized-controlled trials are warranted for Toca 511 and Toca FC to confirm drug efficacy.

Microparticle-mediated sequestration of cell-secreted proteins to modulate chondrocytic differentiation.

Protein delivery is often used in tissue engineering applications to control differentiation processes, but is limited by protein instability and cost. An alternative approach is to control the cellular microenvironment through biomaterial-mediated sequestration of cell-secreted proteins important to differentiation. Thus, we utilized heparin-based microparticles to modulate cellular differentiation via protein sequestration in an in vitro model system of endochondral ossification. Heparin and poly(ethylene-glycol) (PEG; a low-binding material control)-based microparticles were incorporated into ATDC5 cell spheroids or incubated with ATDC5 cells in transwell culture. Reduced differentiation was observed in the heparin microparticle group as compared to PEG and no microparticle-containing groups. To determine if observed changes were due to sequestration of cell-secreted protein, the proteins sequestered by heparin microparticles were analyzed using SDS-PAGE and mass spectrometry. It was found that heparin microparticles bound insulin-like growth factor binding proteins (IGFBP)-3 and 5. When incubated with a small-molecule inhibitor of IGFBPs, NBI 31772, a similar delay in differentiation of ATDC5 cells was observed. These results indicate that heparin microparticles modulated chondrocytic differentiation in this system via sequestration of cell-secreted protein, a technique that could be beneficial in the future as a means to control cellular differentiation processes. STATEMENT OF SIGNIFICANCE: In this work, we present a proof-of-principle set of experiments in which heparin-based microparticles are shown to modulate cellular differentiation through binding of cell-secreted protein. Unlike existing systems that rely on expensive protein with limited half-lives to elicit changes in cellular behavior, this technique focuses on temporal modulation of cell-generated proteins. This technique also provides a biomaterials-based method that can be used to further identify sequestered proteins of interest. Thus, this work indicates that glycosaminoglycan-based biomaterial approaches could be used as substitutes or additions to traditional methods for modulating and identifying the cell-secreted proteins involved in directing cellular behavior.

Core-shell microparticles for protein sequestration and controlled release of a protein-laden core.

Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin-poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can temporally control delivery of protein-laden heparin MPs. Core-shell MPs were fabricated via a re-emulsification technique and the number of heparin MPs per PEG-based shell could be tuned by varying the mass of heparin MPs in the precursor PEG phase. When heparin MPs were loaded with bone morphogenetic protein-2 (BMP-2) and then encapsulated into core-shell MPs, degradable core-shell MPs initiated similar C2C12 cell alkaline phosphatase (ALP) activity as the soluble control, while non-degradable core-shell MPs initiated a significantly lower response (85+19% vs. 9.0+4.8% of the soluble control, respectively). Similarly, when degradable core-shell MPs were formed and then loaded with BMP-2, they induced a ∼7-fold higher C2C12 ALP activity than the soluble control. As C2C12 ALP activity was enhanced by BMP-2, these studies indicated that degradable core-shell MPs were able to deliver a bioactive, BMP-2-laden heparin MP core. Overall, these dynamic core-shell MPs have the potential to sequester, isolate, and then redeliver proteins attached to a heparin core to initiate a cell response, which could be of great benefit to tissue regeneration applications requiring tight temporal control over protein presentation. STATEMENT OF SIGNIFICANCE: Tissue repair requires temporally controlled presentation of potent proteins. Recently, biomaterial-mediated binding (sequestration) of cell-secreted proteins has emerged as a strategy to harness the regenerative potential of naturally produced proteins, but this strategy currently only allows immediate amplification and re-delivery of these signals. The multifunctional, dynamic core-shell heparin-PEG microparticles presented here overcome this limitation by sequestering proteins through a PEG-based shell onto a protein-protective heparin core, temporarily isolating bound proteins from the cellular microenvironment, and re-delivering proteins only after degradation of the PEG-based shell. Thus, these core-shell microparticles have potential to be a novel tool to harness and isolate proteins produced in the cellular environment and then control when proteins are re-introduced for the most effective tissue regeneration and repair.