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Webinars offer novel educational opportunities beyond those of traditional, in-person experiences. BRAINterns is an open-access webinar-based education platform created to replace opportunities lost during the coronavirus disease 2019 pandemic. This program previously showed the efficacy of webinars to expand access to careers in medicine, and in particular, neurosurgery. BRAINterns 2.0 was established to assess the durability of Web-based learning.A modified 4-week webinar series was held during July 2021. A retrospective exit survey was distributed to participants and responses analyzed.A total of 16,045 people registered for BRAINterns 2.0, representing 103 countries. Survey responses were received from 3765 participants (23% response rate). New, first-time registrants comprised 66% of participants, with the rest being returning participants. A total of 342 students participated in a dedicated module delivered entirely in Spanish. Females represented 81% of respondents. Participants identified that desirable elements of the program were opportunities to hear from women (53%) and people of color (44%) in health care. Participants heard about the series through TikTok (n = 1251; 33%), Instagram (n = 1109; 29%), Facebook (n = 637; 17%), and word of mouth (n = 708; 19%) with assistance from an ambassador program.Webinar-based education programs continue to be of interest to students in an increasingly digital world. Social media, and specifically the use of educational ambassadors, are effective to improve visibility of educational programs across a diverse population of students. Understanding the desires of participants is critical to building a successful online education platform.

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PDF file - 1076K, Immunofluorescence staining of GBM CSCs cultured in the presence of serum and absence of EGF and bFGF (S1); Tumors formed from CSC-seeded PLG scaffold implantation exhibit clinical features of human GBM (S2); Vascular characteristics of tumors formed from PLG scaffold implantation (S3); CSC differentiation is impaired by 3-D hCMEC paracrine signaling cues (S4); Control experiments evaluating IL-8-induced chemotaxis and gene expression in CSCs (S5); Targeted knockdown of CXCR2 in GBM CSCs (S6); Tumor vascularization was not affected by siRNA-knockdown of IL-8 in CSCs (S7).

Glioblastoma multiforme contains a subpopulation of cancer stem–like cells (CSC) believed to underlie tumorigenesis and therapeutic resistance. Recent studies have localized CSCs in this disease adjacent to endothelial cells (EC) in what has been termed a perivascular niche, spurring investigation into the role of EC–CSC interactions in glioblastoma multiforme pathobiology. However, these studies have been limited by a lack of in vitro models of three-dimensional disease that can recapitulate the relevant conditions of the niche. In this study, we engineered a scaffold-based culture system enabling brain endothelial cells to form vascular networks. Using this system, we showed that vascular assembly induces CSC maintenance and growth in vitro and accelerates tumor growth in vivo through paracrine interleukin (IL)-8 signaling. Relative to conventional monolayers, endothelial cells cultured in this three-dimensional system not only secreted enhanced levels of IL-8 but also induced CSCs to upregulate the IL-8 cognate receptors CXCR1 and CXCR2, which collectively enhanced CSC migration, growth, and stemness properties. CXCR2 silencing in CSCs abolished the tumor-promoting effects of endothelial cells in vivo, confirming a critical role for this signaling pathway in GMB pathogenesis. Together, our results reveal synergistic interactions between endothelial cells and CSCs that promote the malignant properties of CSCs in an IL-8–dependent manner. Furthermore, our findings underscore the relevance of tissue-engineered cell culture platforms to fully analyze signaling mechanisms in the tumor microenvironment. Cancer Res; 73(23); 7079–89. ©2013 AACR.

Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood–brain barrier disruption (BBBD). Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan–Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively). Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7–78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7–48.3 cm3). Median PFS was 11.5 months (95% CI 7.7–25.9) with 6, 12, 24 and 60 month PFS estimated to be 91.3% (95% CI 69.5–97.8), 47.4% (26.3–65.9), 32.5% (14.4–52.2) and 5.4% (0.4–21.8), respectively. Median OS was 23.1 months (95% CI 12.2–36.9) with 12, 24, and 36 month OS as 77.3% (95% CI 53.6–89.9), 45.0% (22.3–65.3) and 32.1% (12.5–53.8), respectively. Repeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

Objective To replace educational opportunities lost during the coronavirus disease 2019 (COVID-19) pandemic, the Department of Neurosurgery at Lenox Hill Hospital produced an open-access webinar series (“BRAINterns”) that covered a broad range of health care topics with a focus on neurosurgery. Methods This 8-week webinar series ran from July 1 to August 28, 2020. An optional exit survey was distributed to participants. Data were analyzed to characterize and better understand trends among a global cohort of participants. Results A total of 16,484 people registered for BRAINterns, and 6675 took the survey (40.5% response rate). Responders represented 87 countries, of which the majority were from the United States and Canada (90.48%, n = 6039). Responders were primarily female (82.9%, n = 5521). Racial and ethnic representation was majority Asian (42%, n = 2798), followed by White (22.7%, n = 1514), Hispanic/Latino (16.2%, n = 1080), and Black and African American (7.7%, n = 516). Participants reported hearing about BRAINterns through various social media platforms (72.18%, n = 4818)—the most popular was TikTok (33.4%, n = 2232). Overall, 93.4% of participants reported that the course was a good use of their time during the pandemic, and 86.7% reported that the course helped replace lost opportunities. Conclusions These data demonstrate that webinar-based education is an effective method of expanding access to careers in medicine and in particular, neurosurgery, to traditionally underrepresented populations. Social media can be a powerful tool to combat barriers to early exposure and vastly improve diversity within the field.

Background The major difficulty in treating glioblastoma stems from the intrinsic privileged nature of the brain. This complicates therapy, as many traditionally potent chemotherapeutics cannot access their target sites in the brain. Several techniques have been investigated to overcome this barrier and facilitate drug delivery. However, these techniques have inherent shortcomings related to the delivery system, the drug itself, or its bioactivity. Periosteal flaps and temporoparietal fascial flaps (TPFFs) are widely used options because they have predictable vasculature and a wide rotational arc. These flaps are not restricted by the blood-brain barrier, as they derive their vascular supply from branches of the external carotid artery, which can be readily identified with Doppler ultrasound. We hypothesized that transposition of a vascularized TPFF to the walls of a resected tumor surgical cavity may bring autologous tissue not restricted by the blood-brain barrier in close vicinity of the resected tumor bed microenvironment. This offers a nonselective, long-lasting gateway to target the residual tumor cells nesting in the brain adjacent to the tumor. Case Description A 47-year-old, right-handed woman with newly diagnosed multifocal glioblastoma underwent excision of the tumor and TPFF placement. This illustrative case report represents the first case of the use of this novel surgical technique with radiologic follow-up. Conclusions The blood-brain barrier is identified as a major barrier for effective drug delivery in glioblastoma. This study demonstrates the feasibility of the TPFF technique to bypass this barrier and help facilitate the goal of improving drug delivery.

Deep learning represents end-to-end machine learning in which feature selection from images and classification happen concurrently. This articles provides updates on how deep learning is being applied to the study of glioma and its genetic heterogeneity. Deep learning algorithms can detect patterns in routine and advanced MR imaging that elude the eyes of neuroradiologists and make predictions about glioma genetics, which impact diagnosis, treatment response, patient management, and long-term survival. The success of these deep learning initiatives may enhance the performance of neuroradiologists and add greater value to patient care by expediting treatment.

Background Anatomic compression of the optic nerve secondary to a dolichoectatic cerebrovascular compression is a rare clinical entity. Because of the limited number of published cases and variable clinical presentation, the natural history remains ambiguous and no consensus exists regarding management. In addition, there is an ongoing debate regarding whether a dolichoectatic cerebral blood vessel can actually cause optic neuropathy, or it merely represents an incidental finding. As a result, it is thought that a diagnosis of compressive optic neuropathy from an adjacent dolichoectatic internal carotid artery (ICA) should be considered only after other possible etiologies are excluded. Although this might seem straightforward, the clinical scenario becomes complex if the patient is also found to have additional incidental pituitary lesions. Such coexistence has not been reported previously in the literature. Case Description A 52-year-old left-handed man presented to us with intermittent headache and painless progressive visual deterioration in the right eye for 1 month. Screening magnetic resonance imaging (MRI) scan revealed a 9-mm eccentrically placed pituitary adenoma with right optic nerve compression because of dolichoectatic ICA. He underwent microvascular decompression of the right optic nerve. On follow-up, significant vision improvement was noticed and MRI scan revealed no change in the size of the pituitary adenoma. Conclusions The compression of the optic nerve by dolichoectatic ICA is commonly thought to be a diagnosis of exclusion. However, the presence of a coexisting pathology should not prompt the exclusion in every case and a case-based approach is highly recommended to correctly manage this rare clinical condition.

Background The coronavirus disease 2019 (COVID-19) pandemic has infected more than 13 million people on a global scale and claimed more than half million deaths across 213 countries and territories. While the focus is currently on recovery from the pandemic, the disease has significantly changed the way we practice medicine and neurosurgery in New York City and the United States. Apart from the emergency cases, several health systems across the country have similarly started to perform elective surgeries. Although COVID-19 screening and testing guidelines have been proposed and adopted by many hospitals, these may not adequately protect the operating room personnel who are in proximity to the patient for prolonged periods. There are concerning reports of especially high transmission rates of COVID-19 in transmucosal head and neck procedures conducted by otolaryngologists and neurosurgeons, despite attempts at wearing what constitutes appropriate personal protective equipment. Methods Here, we describe a simple technique of additional draping that can be used for all cranial, endonasal, spinal, and neurointerventional cases to limit the transmission of coronavirus. Results The proposed technique offers a simple, commonly available, cost-effective alternative that avoids the use of additional retractor systems. Moreover, this technique can be used in all neurosurgical procedures. Conclusions With the rising concerns regarding airborne spread of the virus, we expect that these precautions will prove highly useful as we enter the recovery phase of this pandemic and hospitals attempt to prevent a return to widespread infection. In addition, its availability and cost effectiveness make this technique especially attractive to practical use in centers with limited resources.

Background Spontaneous spinal cerebrospinal fluid (CSF) leak is an increasingly recognized condition responsible for spontaneous intracranial hypotension. A host of connective tissue disorders and mechanical factors may precipitate the condition. Conservative treatment has limited efficacy, and many patients with persistent symptoms ultimately require epidural blood patch (EBP). However, about 23%–44% of patients experience recurrence of symptoms after EBP. Unidentified or multiple sites of CSF leaks are thought to be responsible for the failure of EBP. Using our previously published technique, we treated a patient who developed a large spontaneous CSF leak in her cervicothoracic spine after a boxing class, offering further evidence of the utility of the technique for select patients. Case Description A 28-year-old woman was referred to our center with recurrent, severe headaches and associated nausea and vomiting. She underwent EBP 3 times with no resolution of her symptoms. A right-side partial C7-T1 hemilaminotomy was performed to identify a large meningocele filled with CSF. After dissection, dural sealant was applied using an angled needle with a syringe to buttress the meningocele to allow for normalization of the hydrostatic pressure. At 5-month follow-up, her symptoms have resolved with no headaches and paresthesias in upper limbs. Conclusions Commonplace events, such as a boxing/sparring class, may precipitate a spontaneous spinal CSF leak. Our minimally invasive surgical approach can be safely used in patients with spontaneous intracranial hypotension with recurrent symptoms, no identified leak site, and prior failed attempts of EBP.

TikTok is a social media platform that has gained popularity and become a powerful engine to disseminate public health and medical information. To date, no study has characterized the qualities of popular TikTok videos related to neurosurgery, or assessed biases in the content of these videos.The TikTok web browser application was queried using "#neurosurgery" to identify neurosurgery-related videos. The top 100 videos meeting inclusion criteria were analyzed and video characteristics determined. Bias was assessed by the DISCERN scoring system using 3 independent reviewers. A Kruskal-Wallis H test was used to correlate video popularity with video characteristics and to correlate bias with creator and video type.The 100 videos evaluated totaled 8.8 million likes, 104,718 comments, and 100,856 shares. The oldest video was posted February 2020 and the most recent March 2022. Videos were most commonly entertaining (Neurosurgical content on TikTok contains a high degree of bias across all creator and video types. Entertaining videos are associated with the highest numbers of likes but also the greatest bias. These data may be used to guide institutions and neurosurgeons to grow interest in the field of neurosurgery and disseminate unbiased information while expanding their social media presence.

Brain tumors account for over 20% of childhood cancers and are the biggest cancer killer in children and young adults. Several initiatives over the past 40 years have tried to identify more effective drug treatments, but with very limited success. This is largely due to the bloodâ brain barrier, which restricts the entry of many drugs into the brain. In this review, we describe the main techniques that are being developed to enhance brain tumor drug delivery and explore the preclinical brain tumor models that are essential for translational development of these techniques. We also identify existing approved drugs that, if coupled with an efficient delivery method, could have potential as brain tumor treatments. Bringing this information together is part of a funded initiative to highlight drug delivery as a research strategy to overcome the current challenges for children diagnosed with brain tumors., This review was written on behalf of the Children's Brain Tumor Drug Delivery Consortium, which is funded by Children with Cancer UK, grant number 16-244. This review was also supported by Maryland's Cancer Moonshot Initiative in Pediatric Cancer Research, grant number Project 4'.

Background: Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system .Objective: Assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM.Methods: Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study.Results: Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Conclusion: Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients.

IntroductionRecently, there has been a paradigm shift in the management of hypothalamic hamartoma (HH) from traditional microsurgical techniques to less invasive alternatives such as stereotactic radiosurgery and laser interstitial thermal therapy. However, large and extensive HH may fail to respond to minimally invasive therapies, ultimately necessitating microsurgery.MethodsAll patients who underwent microsurgical resection of a complex HH by the 2 senior authors (D.J.L., H.L.R.) in 2011-2017 were included. Charts were retrospectively reviewed and demographic, clinical, imaging, and outcome data were recorded.Results8 patients, 7 children and 1 adult, with a mean age of 7 years (10 months-27 years), were included. Of those, 2 had failed previous treatments. All 7 children presented with pharmacoresistant gelastic seizures and cognitive dysfunction, 6 exhibited central precocious puberty, and 3 had behavioral problems. Other seizure types affected 6/8 patients. Mean lesion size was 21.6 mm (14-31), all with interpeduncular extension and 5 with intraventricular extension (Delalande type I: 3, type III: 4, type IV: 1). A frontotemporal orbitozygomatic (FTOZ) approach with optic nerve decompression was used in all patients, supplemented by another approach in 3 (endoscopic transventricular: 3, transcallosal: 1). Gross total resection was achieved in 6 patients and subtotal resection in 2. Transient complications occurred in 3 patients (37.5%): self-limited sodium imbalance (n=3), subdural hygroma (n=2). Permanent complications occurred in 2 patients (25%): perforator infarct (n=1), short-term memory loss (n=1). All patients experienced seizure resolution postoperatively with preserved hypothalamic-pituitary axis function. After a mean follow-up of 41 months (2-66), 7 patients remain seizure-free, while 1 has rare recurrent seizures. Cognitive and behavioral symptoms improved significantly in all patients.Conclusion For large HH with interpeduncular extension, microsurgery via the FTOZ approach is a safe and highly effective treatment modality.

The name of author Jason A. Ellis was missing in the intial online publication, and there was a typo in the sixth author's first name. The original article has been corrected.

Background High-dose bevacizumab delivered via super selective intra-arterial cerebral infusion (SIACI) is one promising clinical trial combination for patients with glioblastoma (GBM). Although both continuous intravenous and intra-arterial administration of bevacizumab, and rechallenge with intravenous bevacizumab, have demonstrated improved survival, this is the first description of rechallenging GBM with SIACI of bevacizumab. Case Description We report a case of a 43-year-old woman with recurrent GBM who had received treatment from 3 clinical trials, including a rechallenge with SIACI of bevacizumab. First, she enrolled into a phase I/II trial for patients newly diagnosed with GBM ( NCT01811498 ) and received 3 doses of SIACI bevacizumab over 180 days in addition to standard of care chemotherapy and radiation. Following progression, as indicated on her magnetic resonance imaging scan, she consented for a separate clinical trial for her disease and received 2 cycles of temozolomide with an investigational agent. The patient was removed from the study on tumor progression. Subsequently, she was rechallenged with SIACI of bevacizumab via a third clinical trial ( NCT01269853 ) and then completed 3 intravenous infusions. After completing the third trial, her magnetic resonance imaging scan demonstrated improvement based on Response Assessment In Neuro-Oncology criteria. Conclusions This is the first report to highlight the effect of rechallenging a patient with SIACI of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus intravenous bevacizumab for GBM and further explore theories of bevacizumab resistance.

Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood-brain barrier disruption (BBBD).Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan-Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively).Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7-78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7-48.3 cmRepeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

BACKGROUND AND IMPORTANCE: Data supporting the use of electrocorticography (ECoG) monitoring during electrical stimulation in awake craniotomies for resection of supratentorial neoplasms is robust, but its applicability during active resection is often limited by the inability to keep the array in place. Given the known survival benefit of gross total resection in glioma surgery, novel approaches to surgical monitoring are warranted to maximize safe resection and optimize surgical outcomes in patients with glioblastoma. CLINICAL PRESENTATION: A 68-yr-old right-handed woman presented to the emergency department with confusion. Imaging studies revealed a bifrontal intra-axial brain lesion. She underwent a left-sided awake craniotomy procedure with cortical and subcortical mapping. During surgical resection, multiple electrographic seizures were detected on continuous ECoG monitoring with a customized 22-channel high-density hollow circular array. She remained without clinical evidence of seizures at 3 mo after surgery. CONCLUSION: We report a unique case of serial electrographic seizures detected during continuous intraoperative ECoG monitoring during active surgical resection of a glioblastoma using a novel circular hollow array during an awake craniotomy. The use of continuous ECoG monitoring during active resection may provide additional data, with potential influence in outcomes for patients undergoing resection of high-grade glial neoplasms.

While well-established in other surgical subspecialties, the benefits of extended reality, consisting of virtual reality (VR), augmented reality (AR), and mixed reality (MR) technologies, remains underexplored in neurosurgery despite its increasing utilization. To address this gap, we conducted a systematic review of the effects of extended reality (XR) in neurosurgery with an emphasis on the perioperative period, to provide a guide for future clinical optimization. Seven primary electronic databases were screened following guidelines outlined by PRISMA and the Institute of Medicine. Reported data related to outcomes in the perioperative period and resident training were all examined, and a focused analysis of studies reporting controlled, clinical outcomes was completed. After removal of duplicates, 2548 studies were screened with 116 studies reporting measurable effects of XR in neurosurgery. The majority (82%) included cranial based applications related to tumor surgery with 34% showing improved resection rates and functional outcomes. A rise in high-quality studies was identified from 2017 to 2020 compared to all previous years (p = 0.004). Primary users of the technology were: 56% neurosurgeon (n = 65), 28% residents (n = 33) and 5% patients (n = 6). A final synthesis was conducted on 10 controlled studies reporting patient outcomes. XR technologies have demonstrated benefits in preoperative planning and multimodal neuronavigation especially for tumor surgery. However, few studies have reported patient outcomes in a controlled design demonstrating a need for higher quality data. XR platforms offer several advantages to improve patient outcomes and specifically, the patient experience for neurosurgery.

BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary brain tumor with median overall survival of 15 months and 5-7 months for patients with newly diagnosed or recurrent disease (nGBM or rGBM), respectively. Selinexor is a first-in-class, oral, selective inhibitor of nuclear export which blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing cancer cell death. Increased XPO1 expression in gliomas is associated with higher pathological grade and poorer prognosis. Consistent with these data, selinexor inhibited tumor growth and prolonged survival in an animal model of GBM. Importantly, selinexor showed encouraging intra-tumoral penetration and single-agent efficacy in rGBM (KING study). The current trial tests the hypothesis that adding selinexor to standard therapy will improve clinical outcomes for patients with nGBM or rGBM. METHODS To facilitate the successful development of new therapies, consensus recommendations are to use biomarker enrichment and flexible design that allows expansion of promising cohorts. Accordingly, this phase 1a dose finding study is followed by a phase 1b dose expansion (and ultimately by a 1:1 randomized phase 2 efficacy exploration trial) to independently evaluate: radiation + selinexor in nGBM with unmethylated MGMT promoter (Arm A), radiation + temozolomide + selinexor for nGBM with methylated MGMT promoter (Arm B), and lomustine + selinexor in rGBM (Arm C). Bevacizumab or TTField + selinexor in rGBM (Arms D & E, respectively) are being considered. The Phase 1a primary endpoint is maximum tolerated dose/recommended phase 2 dose. The phase 1b primary endpoint is PFS at 3 months against historic controls. The phase 1b dose expansion is included to evaluate preliminary efficacy before launching into a randomized phase 2 trial. Patient quality of life during the trial will be objectively measured using digital devices (e.g. smartwatch/customized smartphone app). We are currently enrolling patients nationwide. Clinical Trial Registration number: NCT04421378.

Background Glioblastoma is the most common primary brain tumor and remains uniformly fatal, highlighting the dire need for developing effective therapeutics. Significant intra- and inter-tumor heterogeneity and inadequate delivery of therapeutics across blood–brain barrier continue to be significant impediments towards developing therapies which can significantly enhance survival. We hypothesize that microRNAs have the potential to serve as effective therapeutics for glioblastoma as they modulate the activity of multiple signaling pathways, and hence can counteract heterogeneity if successfully delivered. Methods Using a computational approach, we identified microRNA-34a as a microRNA that maximally reduces the activation status of the three core signaling networks (the receptor tyrosine kinase, p53 and Rb networks) that have been found to be deregulated in most glioblastoma tumors. Glioblastoma cultures were transfected with microRNA-34a or control microRNA to assess biological function and therapeutic potential in vitro. Nanocells were derived from genetically modified bacteria and loaded with microRNA-34a for intravenous administration to orthotopic patient-derived glioblastoma xenografts in mice. Results Overexpression of microRNA-34a strongly reduced the activation status of the three core signaling networks. microRNA-34a transfection also inhibited the survival of multiple established glioblastoma cell lines, as well as primary patient-derived xenograft cultures representing the proneural, mesenchymal and classical subtypes. Transfection of microRNA-34a enhanced temozolomide (TMZ) response in in vitro cultures of glioblastoma cells with primary TMZ sensitivity, primary TMZ resistance and acquired TMZ resistance. Mechanistically, microRNA-34a downregulated multiple therapeutic resistance genes which are associated with worse survival in glioblastoma patients and are enriched in specific tumor spatial compartments. Importantly, intravenous administration of nanocells carrying miR-34a and targeted to epidermal growth factor receptor (EGFR) strongly enhanced TMZ sensitivity in an orthotopic patient-derived xenograft mouse model of glioblastoma. Conclusions Targeted bacterially-derived nanocells are an effective vehicle for the delivery of microRNA-34a to glioblastoma tumors. microRNA-34a inhibits survival and strongly sensitizes a wide range of glioblastoma cell cultures to TMZ, suggesting that combination therapy of TMZ with microRNA-34a loaded nanocells may serve as a novel therapeutic approach for the treatment of glioblastoma tumors.

Deep learning represents end-to-end machine learning in which feature selection from images and classification happen concurrently. This articles provides updates on how deep learning is being applied to the study of glioma and its genetic heterogeneity. Deep learning algorithms can detect patterns in routine and advanced MR imaging that elude the eyes of neuroradiologists and make predictions about glioma genetics, which impact diagnosis, treatment response, patient management, and long-term survival. The success of these deep learning initiatives may enhance the performance of neuroradiologists and add greater value to patient care by expediting treatment.

Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1–12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Background The Coronavirus disease 2019 (COVID-19) outbreak has left a lasting mark on medicine globally. Methods Here we outline the steps that the Lenox Hill Hospital/Northwell Health Neurosurgery Department—located within the epicenter of the pandemic in New York City—is currently taking to recover our neurosurgical efforts in the age of COVID-19. Results We outline measurable milestones to identify the transition to the recovery period and hope these recommendations may serve as a framework for an effective path forward. Conclusions We believe that recovery following the COVID-19 pandemic offers unique opportunities to disrupt and rebuild the historical patient and office experience as we evolve with modern medicine in a post–COVID-19 world.

This manuscript will review emerging applications of artificial intelligence, specifically deep learning, and its application to glioblastoma multiforme (GBM), the most common primary malignant brain tumor. Current deep learning approaches, commonly convolutional neural networks (CNNs), that take input data from MR images to grade gliomas (high grade from low grade) and predict overall survival will be shown. There will be more in-depth review of recent articles that have applied different CNNs to predict the genetics of glioma on pre-operative MR images, specifically 1p19q codeletion, MGMT promoter, and IDH mutations, which are important criteria for the diagnosis, treatment management, and prognostication of patients with GBM. Finally, there will be a brief mention of current challenges with DL techniques and their application to image analysis in GBM.

ObjectiveWe report a series of 2 brothers who each developed tumefactive brain lesions, initially thought to have brain tumors or tumefactive multiple sclerosis (MS), but who were ultimately diagnosed with a rare autosomal dominant condition known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL).MethodsCase series and literature review.ResultsWe present 2 brothers who developed tumefactive right frontal brain lesions leading to gait disturbances and cognitive changes. Both brothers also had nonspecific brain calcifications and T2-hyperintense lesions, and both had ophthalmic and liver disease of unclear etiology. The first brother had been extensively evaluated by various specialists, underwent inconclusive brain and liver biopsies, and was ultimately unsuccessfully treated for a diagnosis of tumefactive MS. The second brother also underwent unrevealing evaluation with CSF analysis and brain biopsy. Further family history revealed that the patients' father developed a tumefactive brain lesion in the 1980s and had been diagnosed with CNS vasculitis. Given the familial link, RVCL was suspected, and genetic analysis confirmed the diagnosis with a 3-prime repair exonuclease 1 (TREX1) C-terminal mutation.ConclusionThe presence of tumefactive brain lesions, nonspecific brain calcifications, liver disease, and retinal vasculopathy, coupled with suggestive family history, led to the RVCL diagnosis. This report contributes to the limited understanding of RVCL, which can cause brain lesions that mimic gliomas or tumefactive MS. Recognition of this entity may prevent unnecessary invasive procedures and inappropriate therapeutic interventions, and would allow for proper counseling of family members.

Background and importance Olfactory neuroblastoma, also known as esthesioneuroblastoma (ENB), is a malignant neoplasm with an unpredictable behavior. Currently, the widely accepted treatment is inductive chemotherapy, with or without surgery, followed by radiotherapy. Since data on genetics and molecular alterations of ENB are lacking, there is no standard molecularly targeted therapy. However, ENB commonly expresses the somatostatin receptor (SSTR) that is also expressed by neuroendocrine tumors. Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues, such as 177Lu-octreotate, is an effective treatment for the latter. We present the complex neuroradiological and neuropathological changes associated with 177Lu-octreotate treatment of a patient with a highly treatment-resistant ENB. Clinical presentation A 60-yr-old male presented with an ENB that recurred after chemotherapy, surgery, stereotactic radiosurgery, and immunotherapy. Pathology revealed a Hyams grade 3 ENB and the tumor had metastasized to lymph nodes. Tumor SSTR expression was seen on 68Ga-octreotate positron emission tomography (PET)/computed tomography (CT), suggesting that PRRT may be an option. He received 4 cycles of 177Lu-octreotate over 6 mo, with a partial response of all lesions and symptomatic improvement. Four months after the last PRRT cycle, 2 of the lesions rapidly relapsed and were successfully resected. Three months later, 68Ga-octreotate PET/CT and magnetic resonance imaging indicate no progression of the disease. Conclusion We describe imaging changes associated with 177Lu-octreotate PRRT of relapsing ENB. To our knowledge, this is the first report describing neuropathological changes associated with this treatment. PRRT is a promising therapeutic option to improve the disease control, and potentially, the survival of patients with refractory ENB.

Among spinal tumors that occur intradurally, meningiomas, nerve sheath tumors, ependymomas, and astrocytomas are the most common. While a spinal MRI is the state of the art to diagnose intradural spinal tumors, in some cases CT scans, angiography, CSF analyses, and neurophysiological examination can be valuable. The management of these lesions depends not only on the histopathological diagnosis but also on the clinical presentation and the anatomical location, allowing either radical resection as with most extramedullary lesions or less invasive strategies as with intramedullary lesions. Although intramedullary lesions are rare and sometimes difficult to manage, well-planned treatment can achieve excellent outcome without treatment-related deficits. Technical advances in imaging, neuromonitoring, minimally invasive approaches, and radiotherapy have improved the outcome of intradural spinal tumors. However, the outcome in malignant intramedullary tumors remains poor. While surgery is the mainstay treatment for many of these lesions, radiation and chemotherapy are of growing importance in recurrent and multilocular disease. We reviewed the literature on this topic to provide an overview of spinal cord tumors, treatment strategies, and outcomes. Typical cases of extra- and intramedullary tumors are presented to illustrate management options and outcomes.

Purpose This study evaluates FTY720/Fingolimod, modulator of sphingosine-1-phosphate (S1P) receptor, as a potential mitigator of radiation-induced neurocognitive dysfunction. Methods and materials To study radiation-induced neurocognitive deficits, 6 week-old C57/Bl/6J mice received 0 or 7 Gy cranial irradiation and were treated with FTY720 or vehicle for seven weeks. Fear conditioning and Morris water maze were then employed to test learning and memory. Immunohistochemical staining for neural progenitor cells (NPCs) and mature neurons was used to assess changes in hippocampal neurogenesis. To test effects on tumor growth, mice harboring brain tumor xenografts were treated with FTY720 or vehicle for six weeks. Results In irradiated mice, learning deficits were manifested by significantly longer latency times in the Morris Water Maze compared to non-irradiated controls (p = 0.001). The deficits were fully restored by FTY720. In irradiated brains, FTY720 maintained the cytoarchitecture of the dentate gyrus granular cell layer and partially restored the pool of NPC. In mice harboring brain tumor stem cell (BTSC) xenografts FTY720 delayed tumor growth and improved survival (p = 0.012). Conclusions FTY720 mitigates radiation-induced learning dysfunction. A partial restoration of neurogenesis was observed. Furthermore, FTY720 appears to delay tumor growth and improve survival in a xenograft glioma mouse model.

Objective In this series, we present 3 cases that show the use of a skull-mounted tracker for image-guided navigation for anterior skull base surgery and ventricular catheter placement procedures. This system obviates fiducials or face masks during the surgical procedure itself and allows for the performance of facial incisions using the Weber-Ferguson approach. Methods Our series presents the use of a novel intraoperative navigational system that uses a skull-mounted tracker to navigated anterior skull base surgery. Results We present 3 cases using this new system: 1 anterior skull base tumor removal that was operated on without a facemask for navigation and 2 ventricular catheter placement procedures. Conclusions Intraoperative image-guided navigation has revolutionized neurosurgery. It undoubtedly increases the surgeon's confidence and the perception of safety. Although fiducials and facial masks are the most widely used tools for intraoperative navigation, their use is associated with certain complications. This technique permits free movement of the head during surgery, which in turn facilitates the exposure of head and neck lesions and expedites the approach to ventricular catheter placement. Our case series shows the precision and ease of our technique, which is less time consuming and less cumbersome than the traditional frame-based stereotaxy. In addition, the skull-mounted tracker system allows improved anatomic localization and shorter operating time and avoids the complications associated with the use of rigid fixating head frames.

Intra-arterial (IA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated IA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of IA therapy for the treatment of brain tumors and refinement of its potential applications are necessary.We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSIACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of IA therapy for the treatment of brain tumors.Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the IA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy.IA drug delivery may significantly affect the way treatments are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of IA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, IA therapy may offer significant benefits for the treatment of brain tumors.

Awake craniotomy is advocated for the resection of supratentorial low-grade gliomas (LGG). The combination of neurophysiological electrical mapping techniques and performing the craniotomy awake has demonstrated increased total and supratotal resection of LGG, as well as increased overall survival rates. We present an illustrative case where the patient's gross motor function deteriorated during the resection of a LGG and mapping techniques using the phase reversal technique and Taniguchi direct cortical stimulation technique while the patient was awake proved to be valuable in determining continuity of the corticospinal tracts.

TPS2071 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O6-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.

Superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) has emerged as a novel therapy in the treatment of recurrent glioblastoma (GB). This study assessed the use of apparent diffusion coefficient (ADC) in predicting length of survival after SIACI BV and overall survival in patients with recurrent GB. Sixty-five patients from a cohort enrolled in a phase I/II trial of SIACI BV for treatment of recurrent GB were retrospectively included in this analysis. MR imaging with a diffusion-weighted (DWI) sequence was performed before and after treatment. ROIs were manually delineated on ADC maps corresponding to the enhancing and non-enhancing portions of the tumor. Cox and logistic regression analyses were performed to determine which ADC values best predicted survival. The change in minimum ADC in the enhancing portion of the tumor after SIACI BV therapy was associated with an increased risk of death (hazard ratio = 2.0, 95% confidence interval(CI) [1.04–3.79], p = 0.038), adjusting for age, tumor size, BV dose, and prior IV BV treatments. Similarly, the change in ADC after SIACI BV therapy was associated with greater likelihood of surviving less than 1 year after therapy (odds ratio = 7.0, 95% CI [1.08–45.7], p = 0.04). Having previously received IV BV was associated with increased risk of death (OR 18, 95% CI [1.8–180.0], p = 0.014). In patients with recurrent GB treated with SIACI BV, the change in ADC value after treatment is predictive of overall survival.

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the noninvasive strategy of intranasal (IN) delivery of a glioblastoma-directed adduct of curcumin (CC), CC-CD68Ab, into the brain of mouse GBM GL261-implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor-associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261-implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid-encapsulated formulation of CC, Curcumin Phytosome, into the GL261-implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor-associated Iba1+ TAMs, suppressing the tumor-promoting Arginase1high , iNOSlow M2-type TAM population while inducing the Arginase1low , iNOShigh M1-type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF-kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state.

Neuro-oncological research is at the forefront of the rising cancer therapy market, as evidenced by its growing revenue and the multitude of clinical trials investigating innovative treatment approaches. The Feinstein Institute for Medical Research, in conjunction with the Department of Neurosurgery at Lenox Hill Hospital and the Zucker School of Medicine at Hofstra / Northwell, sponsored The Brain Tumor Biotech Summit in New York City in June 2019. The aim of the Summit was to provide a forum that encourages collaboration between cancer specialists, biotechnology and pharmaceutical industry leaders, and the investment community in order to promote innovation and advance emerging therapies for brain tumors. Areas highlighted during the Summit included immunotherapy, precision medicine, and novel applications and experimental treatments such as receptor targeting, methods for improved drug delivery, and innovative intraoperative techniques and technologies. This review synthesizes the recent breakthroughs in brain tumor research as presented at The Brain Tumor Biotech Summit.