Image-based assessment of natural killer cell activity against glioblastoma stem cells.

Glioblastoma (GBM) poses a significant challenge in oncology and stands as the most aggressive form of brain cancer. A primary contributor to its relentless nature is the stem-like cancer cells, called glioblastoma stem cells (GSCs). GSCs have the capacity for self-renewal and tumorigenesis, leading to frequent GBM recurrences and complicating treatment modalities. While natural killer (NK) cells exhibit potential in targeting and eliminating stem-like cancer cells, their efficacy within the GBM microenvironment is limited due to constrained infiltration and function. To address this limitation, novel investigations focusing on boosting NK cell activity against GSCs are imperative. This study presents two streamlined image-based assays assessing NK cell migration and cytotoxicity towards GSCs. It details protocols and explores the strengths and limitations of these methods. These assays could aid in identifying novel targets to enhance NK cell activity towards GSCs, facilitating the development of NK cell-based immunotherapy for improved GBM treatment.

Developmentally Unique Cerebellar Processing Prioritizes Self- over Other-Generated Movements.

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self-generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) 8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses with twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.

Blood-Brain Barrier Disruption for the Treatment of Primary Brain Tumors: Advances in the Past Half-Decade.

PURPOSE OF REVIEW: To review relevant advances in the past half-decade in the treatment of primary brain tumors via modification of blood-brain barrier (BBB) permeability. RECENT FINDINGS: BBB disruption is becoming increasingly common in the treatment of primary brain tumors. Use of mannitol in BBB disruption for targeted delivery of chemotherapeutics via superselective intra-arterial cerebral infusion (SIACI) is the most utilized strategy to modify the BBB. Mannitol is used in conjunction with chemotherapeutics, oligonucleotides, and other active agents. Convection-enhanced delivery has become an attractive option for therapeutic delivery while bypassing the BBB. Other technologic innovations include laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) which have emerged as prime modalities to directly target tumors and cause significant local BBB disruption. In the past 5 years, interest has significantly increased in studying modalities to disrupt the BBB in primary brain tumors to enhance treatment responses and improve clinical outcomes.

Developmentally unique cerebellar processing prioritizes self-over other-generated movements.

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self-generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) P8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses to twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.

A Decade of Global Skull Base Researchers: Gender Data from over 2,700 Abstract Authors in the Journal of Neurological Surgery Part B: Skull Base.

Objective The North American Skull Base Society (NASBS) annual conference brings together skull base researchers from surgical and nonsurgical fields. Our objective was to quantify the contributions of the authors by gender, who presented their work at NASBS and were subsequently published in the Journal of Neurological Surgery Part B: Skull Base . Methods Oral and poster abstracts presented at the NASBS annual meeting from January 1, 2011 to December 31, 2020 were extracted from the Journal of Neurological Surgery Part B: Skull Base. The genderize.io Web application programming interface was utilized to determine authorship gender. A minority of first and last authors had departmental affiliations listed; a subgroup analysis was performed of these authors. Results Female gender was assigned to 498 (17.8%) of the 2,798 first authors and 269 (9.7%) of the 2,762 last authors. Female authorship has consistently increased over the last decade. Representation was higher in otolaryngology (23.3% of first authors, 12.1% of last authors; p = 0.018) than neurosurgery (13.5% of first authors, 4.3% of last authors; p = 0.004). Female researchers were not less likely than their male counterparts to receive prestigious oral presentations. Of the 52 total countries represented, 20 (38.5%) had at least one female first author. Representation varied dramatically between countries. Conclusion The NASBS' efforts have undoubtedly contributed to these impressive strides toward gender parity. More work is needed to ensure that the best and the brightest, regardless of background, continue to contribute to skull base surgery research.

A Decade of Global Skull Base Researchers: Authorship Trends from 3,295 Abstracts in the Journal of Neurological Surgery Part B: Skull Base.

Objective The North American Skull Base Society (NASBS) multidisciplinary annual conference hosts skull base researchers from across the globe. We hypothesized that the work presented at the NASBS annual conference would reveal diverse authorship teams in terms of specialty and geography. Methods In this retrospective review, abstracts presented at the NASBS annual meeting and subsequently published in the Journal of Neurological Surgery Part B: Skull Base between 01/01/2011 and 12/31/2020 were collected. Variables extracted included year, type of presentation, and author names and affiliations. Statistical analyses were performed with SPSS V23.0 with p -values less than 0.05 considered significant. Geographic heat maps were created to assess author distribution, and a network analysis was performed to display authorship collaboration between geographic regions. Results Of 3,312 published abstracts, 731 (22.1%) had an author with an affiliation outside of the United States. Fifty-seven distinct countries were represented. Three-hundred twenty-four abstracts (9.8%) had authorship teams representing at least 2 different countries. The top five US states by abstract representation were Pennsylvania, California, New York, Ohio, and Minnesota. A majority of authors reported neurosurgery affiliations (56.7% first authors, 53.2% last authors), closely followed by otolaryngology (39.1% first authors, 41.5% last authors). No solo authors and very few (3.3%) of the first authors reported a departmental affiliation outside of otolaryngology or neurosurgery. Conclusions Authors from many countries disseminate their work through poster and oral presentations at the NASBS annual meeting. Ten percent of abstracts were the product of international collaboration. Most authors were affiliated with a neurosurgery or otolaryngology department.

Predictors of Surgical Outcomes in Patients with Abducens Nerve Schwannoma: A Comprehensive Systematic Review and a Case Report.

BACKGROUND: Abducens nerve (AN) schwannomas are extremely rare tumors. Clinical characteristics and factors that influence postoperative outcomes are not well defined. OBJECTIVE: To characterize clinical features of AN schwannomas and predictors of surgical outcomes. METHODS: PRISMA-guided systematic review of the literature on AN schwannomas was performed. Subsequently, univariate and multivariate regression analyses were performed to identify the predictive value of variables that influence postoperative outcomes. RESULTS: A total of 42 studies with 55 patients were evaluated. The mean age at presentation was 43.9 ± 14.6 years. The most common presenting symptom was cranial nerve VI palsy (69.1%). Cavernous sinus (49.1%) and prepontine cistern (36.3%) were the most commonly involved locations. Complete recovery after surgery was seen in 36.3% at a median follow-up of 28.4 ± 25.8 months. Preoperative AN palsy (P < 0.001), suboccipital approach (P = 0.007), and subtotal resection of tumor (P = 0.044) were significant protective factors for postoperative complications. Prepontine location and postoperative complications were poor prognostic indicators of AN recovery (odds ratio [OR], 0.10, P = 0.030 and OR, 0.10, P = 0.028, respectively). Subtotal resection was significantly correlated with higher odds of AN recovery (OR, 6.06; P = 0.040). CONCLUSIONS: AN schwannomas are rare but serious tumors that can cause significant morbidity, with only approximately one third of patients showing complete recovery after surgery. The suboccipital approach was a protective factor for postoperative complications, especially when combined with subtotal resection. Knowledge of these factors along with tumor characteristics helps optimize surgical planning and preoperative counseling.

Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Neuro-oncology authorship trends in gender since 1944: a systematic review of 14,020 articles from five top-tier academic journals.

OBJECTIVE: This study was performed to compare authorship trends, by gender, in the neurosurgical oncology literature. METHODS: Complete author listings for neurosurgical oncology articles published between 1944 and 2021 in five top neuro-oncology journals were extracted from the PubMed database and journal websites on December 2, 2021. Author gender was characterized with the web application programming interface (API) genderize.io. The statistical significance (p < 0.05) of time-, journal-, and gender-based differences was determined by independent-samples t-test, chi-square test, and/or Fisher's exact test. RESULTS: A total of 14,020 articles were written by 67,115 unique authors occupying 97,418 authorship spots. The gender for 80,030 authorship positions (82.2%) was successfully characterized. Male authors were significantly more likely than the female authors to have a first-author publication, have a last-author publication, and have authored multiple articles within the data set. Among authors who published in multiple different years (n = 11,532), women had a shorter time window of publishing (5.46 vs 6.75 years between first and last publication: mean difference [MD] 1.28 [95% CI 1.06-1.50] years, p < 0.001). During this window, however, they were slightly more productive than the men, based on the mean number of publications per year (1.06 vs 1.01 articles: MD 0.05 [95% CI 0.02-0.09] articles, p = 0.002). The percentage of female authors on each neuro-oncology research team has increased by 3.3% (95% CI 2.6%-3.9%) per decade to a mean of 26.5% in the 2020s. Having a female last author was positively associated with having a female first author (OR 2.57 [95% CI 2.29-2.89]) and a higher proportion of women on the research team overall. The percentages of female first and last authors increased at significantly higher rates in medically oriented journals than in surgically oriented journals (first authors: 0.72% [95% CI 0.58%-0.87%] vs 0.36% [95% CI 0.30%-0.42%] per year, p < 0.001; and last authors: 0.50% [95% CI 0.38%-0.62%] vs -0.03% [95% CI -0.10% to 0.05%] per year, p < 0.001). CONCLUSIONS: Female authorship in top neuro-oncology journals has increased since the 1940s, with female-led teams showing greater gender diversity. However, female researchers lag behind their male counterparts in quantity of published research and are less likely to hold first or last authorship positions. This difference is more pronounced in the three neurosurgical oncology journals than in the two medical neuro-oncology journals, which may reflect the relatively low female representation in neurosurgery relative to medical oncology. Collectively, these trends have meaningful implications for career advancement, which is often dependent on academic productivity.

Image-Based Assessment of Natural Killer Cell Activity against Glioblastoma Stem Cells.

Glioblastoma (GBM) poses a significant challenge in oncology and stands as the most aggressive form of brain cancer. A primary contributor to its relentless nature is the stem-like cancer cells, called glioblastoma stem cells (GSCs). GSCs have the capacity for self-renewal and tumorigenesis, leading to frequent GBM recurrences and complicating treatment modalities. While natural killer (NK) cells exhibit potential in targeting and eliminating stem-like cancer cells, their efficacy within the GBM microenvironment is limited due to constrained infiltration and function. To address this limitation, novel investigations focusing on boosting NK cell activity against GSCs are imperative. This study presents two streamlined image-based assays assessing NK cell migration and cytotoxicity towards GSCs. It details protocols and explores the strengths and limitations of these methods. These assays could aid in identifying novel targets to enhance NK cell activity towards GSCs, facilitating the development of NK cell-based immunotherapy for improved GBM treatment.

Hemoglobin Concentration May Influence the Incidence of Postoperative Transient Neurological Events in Patients With Moyamoya After Extracranial-intracranial Arterial Bypass: A Retrospective Single Center Experience.

BACKGROUND: Moyamoya is a rare condition characterized by cerebral angiographic findings of intracranial carotid artery stenosis with abnormal net-like vessels in the brain, and often presents as transient ischemic attacks or intracranial hemorrhage. Revascularization in the form of extracranial-intracranial (EC-IC) artery bypass has demonstrated efficacy in preventing ischemic attacks and intracranial hemorrhage, although it is associated with a relatively high rate of perioperative ischemic and hemorrhagic stroke. This retrospective analysis aims to evaluate the possible association between postoperative hemoglobin (Hgb) concentration and early postoperative transient neurological events (TNEs) experienced at our center. METHODS: Consecutive patients undergoing EC-IC bypass between January 1, 2017 and August 31, 2019 were identified, resulting in a study population of 24 patients with 34 individual cases for different cerebral hemispheres. Postoperative Hgb level was evaluated upon arrival to the intensive care unit (ICU) and the primary outcome was the occurrence of TNEs within 24-hours after surgery. RESULTS: The incidence of TNEs within 24 hours postoperatively was 12% (n=4). Statistically significant differences were demonstrated between patients who did and did not experience TNEs in the postoperative period: total Hgb value (mean 9.4 vs. 11.3 g/dL, respectively; P=0.012) and percentage of patients with Hgb <10 g/dL (75% vs. 20%, respectively; P=0.048). Patients with a postoperative Hgb value <10 g/dL upon arrival to the ICU were significantly more likely to experience TNEs (odds ratio, 12; 95% confidence interval, 1.053-136.794; P=0.045). CONCLUSIONS: This study reports a possible association between postoperative Hgb level and the occurrence of TNEs within the first 24 hours after surgery in patients undergoing EC-IC for moyamoya.

GammaTile for Gliomas: A Single-Center Case Series.

GammaTile® (GT Medical Technologies, Tempe, Arizona) is a surgically targeted radiation source, approved by FDA for brachytherapy in primary and secondary brain neoplasms. Each GammaTile is composed of a collagen sponge with four seeds of cesium 131 and is particularly useful in recurrent tumors. We report our early experience in seven patients with recurrent gliomas to assess this type of brachytherapy with particular attention to ease of use, complication, and surgical planning. This study represents a retrospective chart review of surgical use and early clinical outcomes of GammaTile in recurrent gliomas. The number of tiles was planned using pre-operative imaging and dosimetry was planned based on post-operative imaging. Patients were followed during their hospital stay and were followed up after discharge. Parameters such as case length, resection extent, complication, ICU length of stay (LOS), hospital LOS, pre-operative Glasgow Coma Scale (GCS), immediate post-operative GCS, post-operative imaging findings, recurrence at follow-up, length of follow-up, and dosimetry were collected in a retrospective manner. Seven patients were identified that met the inclusion criteria. Two patients were diagnosed with recurrent glioblastoma multiforme (GBM), one lower-grade glioma that recurred as a GBM, one GBM that recurred as a gliosarcoma, and two recurrent oligodendrogliomas. We found that operation time, ICU LOS, hospital LOS, pre- and post-operative GCS, and post-operative complications were within the expected ranges for tumor resection patients. Further, dosimetry data suggests that six out of seven patients received adequate radiation coverage, with the seventh having implantation limitations due to nearby organs at risk. We report no postoperative complications that can be attributed to the GammaTiles themselves. In our cohort, we report seven cases where GammaTiles were implanted in recurrent gliomas. No implant-related post-operative complications were identified. This early data suggests that GammaTile can be a safe form of brachytherapy in recurrent gliomas.

Fellowship, gender, and scholarly productivity: trends among academic neurosurgeons in the US.

OBJECTIVE: Current data on fellowship choice and completion by neurosurgical residents are limited, especially in relation to gender, scholarly productivity, and career progression. The objective of this study was to determine gender differences in the selection of fellowship training and subsequent scholarly productivity and career progression. METHODS: The authors conducted a quantitative analysis of the fellowship training information of practicing US academic neurosurgeons. Information was extracted from publicly available websites, the Scopus database, and the Centers for Medicare and Medicaid Services Open Payments website. RESULTS: Of 1641 total academic neurosurgeons, 1403 (85.5%) were fellowship trained. There were disproportionately more men (89.9%) compared to women (10.1%). A higher proportion of women completed fellowships than men (p = 0.004). Proportionally, significantly more women completed fellowships in pediatrics (p < 0.0001), neurooncology (p = 0.012), and critical care/trauma (p = 0.001), while significantly more men completed a spine fellowship (p = 0.012). Within those who were fellowship trained, the academic rank of professor was significantly more commonly held by men (p = 0.001), but assistant professor was held significantly more often by women (p = 0.017). The fellowships with the largest mean h-indices were functional/stereotactic, pediatrics, and critical care/trauma. Despite more women completing neurooncology and pediatric fellowships, men had significantly greater h-indices in these subspecialties compared to women. Women had more industry funding awards than men in pediatrics (p < 0.0001), while men had more in spine (p = 0.023). CONCLUSIONS: Women were found to have higher rates for fellowship completion compared with their male counterparts, yet had lower scholarly productivity in every subspecialty. Fellowship choice remains unequally distributed between genders, and scholarly productivity and career progression varies between fellowship choice.

Hair-sparing technique using absorbable intradermal barbed suture versus traditional closure methods in supratentorial craniotomies for tumor.

BACKGROUND: Hair-sparing techniques in cranial neurosurgery have gained traction in recent years and previous studies have shown no difference in infection rates, yet limited data exists evaluating the specific closure techniques utilized during hair-sparing craniotomies. Therefore, it was the intention of this study to evaluate the rate of surgical site infections (SSIs) and perioperative complications associated with using an absorbable intradermal barbed suture for skin closure in hair-sparing supratentorial craniotomies for tumor in order to prove non-inferiority to traditional methods. METHODS: A retrospective review of supratentorial craniotomies for tumor by a single surgeon from 2011 to 2017 was performed. All perioperative adverse events and wound complications, defined as a postoperative infection, wound dehiscence, or CSF leak, were compared between three different groups: (1) hair shaving craniotomies + transdermal polypropylene suture/staples for scalp closure, (2) hair-sparing craniotomies + transdermal polypropylene suture/staples for scalp closure, and (3) hair-sparing craniotomies + absorbable intradermal barbed suture for scalp closure. RESULTS: Two hundred sixty-three patients underwent hair shaving + transdermal polypropylene suture/staples, 83 underwent hair sparing + transdermal polypropylene suture/staples, and 100 underwent hair sparing + absorbable intradermal barbed suture. Overall, 2.9% of patients experienced a perioperative complication and 4.3% developed a wound complication. In multivariable analysis, the use of a barbed suture for scalp closure and hair-sparing techniques was not predictive of any complication or 30-day readmission. Furthermore, the absorbable intradermal barbed suture cohort had the lowest overall rate of wound complications (4%). CONCLUSIONS: Hair-sparing techniques using absorbable intradermal barbed suture for scalp closure are safe and do not result in higher rates of infection, readmission, or reoperation when compared with traditional methods.

Brain Tumor Surgery is Safe in Octogenarians and Nonagenarians: A Single-Surgeon 741 Patient Series.

OBJECTIVES: Elderly patients with surgically accessible brain tumors are often not offered clinically indicated brain tumor surgery (BTS) because of to assumptions of greater risk for perioperative morbidity and mortality. Because brain tumor incidence is highest in the geriatric population, and because the global population is aging, accurate understanding of BTS risk in elderly patients is critical. We aimed to compare safety of BTS in elderly patients with younger counterparts to better understand the risk-benefit profile of BTS for elderly patients. METHODS: Retrospective cohort study of young (20-29 years), senior (60-79 years), and elderly (80+ years) patients who underwent BTS with a single neurosurgeon. Differences between pre- and postoperative modified Rankin score (ΔmRS), length of hospitalization (LOH), complication rate, and 30-day readmission rates (30DRR) were recorded. RESULTS: A total of 741 patients (83 elderly, 570 senior, and 88 young) were identified. No significant difference in preoperative mRS between different age groups, χ2 = 0.269, P = 0.874. Elderly complication rate was 6.0%, not significantly different from young (4.5%, P = 0.667) or senior (7.2%, P = 0.696) complication rate. Elderly LOH was 1.93 ± SD 0.176 days; not significantly different from young (3.01 ± 0.384 days, P = 0.081) or senior (2.47 ± 0.144 days, P = 0.881). Statistical equivalence testing showed with 95% confidence that there was equivalence in ΔmRS among age groups. CONCLUSIONS: Elderly patients did not have significantly different ΔmRS, LOH, 30DRR, or complication rates after BTS compared with younger counterparts. Therefore, in healthy patients, advanced age alone should not prevent patients from being offered BTS.