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.

The influence of facility type on intracranial meningioma treatment and outcomes: predicting overall survival using the National Cancer Database.

OBJECTIVE: There is a growing body of evidence demonstrating improved outcomes for patients with CNS neoplasms treated at academic centers (ACs) versus nonacademic centers (non-ACs), which represents a potential healthcare disparity within neurosurgery. In this paper, the authors sought to investigate the relationship between facility type and surgical outcomes in meningioma patients. METHODS: The National Cancer Database was queried for adult patients diagnosed with intracranial meningioma between 2004 and 2019. Patients were stratified by facility type, and the Mann-Whitney U-test and Fisher exact test were used for bivariate comparisons of continuous and categorical variables, respectively. Multivariate logistic regression was used to assess whether demographic variables were associated with treatment at ACs. Furthermore, multivariate Cox proportional hazards models were used to determine whether facility type was associated with overall survival (OS) outcomes. RESULTS: Data on 139,304 patients (74% male, 84% White) were retrieved. Patients were stratified by facility type, with 50,349 patients (36%) treated at ACs and 88,955 patients (64%) treated at non-ACs. Patients treated at ACs were more likely to have private insurance (41% vs 34%, p < 0.001) and less likely to have Medicare (46% vs 57%, p < 0.001). Patients treated at ACs were more likely to have larger tumors (36.91 mm vs 33.57 mm, p < 0.001) and more likely to undergo surgery (47% vs 34%, p < 0.001). Interestingly, patients treated at ACs had decreased comorbidities (Charlson Comorbidity Index rating 0: 74% vs 69%) and similar income levels (income ≥ $46,000: 44% vs 43%). With respect to survival outcomes, patients treated at ACs demonstrated a higher median OS at 10 years than patients treated at non-ACs (65.2% vs 54.1%). The association of improved OS in patients treated at ACs continued to be true when adjusting for all other clinical and demographic variables (HR 0.900, 95% CI 0.882-0.918; p < 0.001). CONCLUSIONS: The results of this study indicate that facility type is associated with disparate survival outcomes in the treatment of intracranial meningiomas. Namely, patients treated at non-ACs appear to have a survival disadvantage even when controlling for additional comorbidities.

Comparative Assessment of Biomechanical Parameters in Subjects With Multiple Cerebral Aneurysms Using Fluid-Structure Interaction Simulations.

Cerebral aneurysm progression is a result of a complex interplay of the biomechanical and clinical risk factors that drive aneurysmal growth and rupture. Subjects with multiple aneurysms are unique cases wherein clinical risk factors are expected to affect each aneurysm equally, thus allowing for disentangling the effect of biomechanical factors on aneurysmal growth. Toward this end, we performed a comparative computational fluid-structure interaction analysis of aneurysmal biomechanics in image-based models of stable and growing aneurysms in the same subjects, using the cardiovascular simulation platform simvascular. We observed that areas exposed to low shear and the median peak systolic arterial wall displacement were higher by factors of 2 or more and 1.5, respectively, in growing aneurysms as compared to stable aneurysms. Furthermore, we defined a novel metric, the oscillatory stress index (OStI), which indicates locations of oscillating arterial wall stresses. We observed that growing aneurysms were characterized by regions of combined low wall shear and high OStI, which we hypothesize to be associated with regions of collagen degradation and remodeling. Such regions were either absent or below 5% of the surface area in stable aneurysms. Our results lay the groundwork for future studies in larger cohorts of subjects, to evaluate the statistical significance of these biomechanical parameters in cerebral aneurysm growth.

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.

Assessment of Factors Associated With Internal Carotid Injury in Expanded Endoscopic Endonasal Skull Base Surgery.

Importance: Injury to the internal carotid artery (ICA) during endoscopic endonasal skull base surgery does not typically occur as an isolated circumstance but often is the result of multiple factors. Objective: To assess the factors associated with ICA injury in an effort to reduce its occurrence. Design, Setting, and Participants: This quality improvement study used a multicenter root cause analysis of ICA injuries sustained during endoscopic endonasal skull base surgery performed at 11 tertiary care centers across 4 continents (North America, South America, Europe, and Asia) from January 1, 1993, to December 31, 2018. A fishbone model was built to facilitate the root cause analysis. Patients who underwent an expanded endoscopic endonasal approach that carried a substantial potential risk of an ICA injury were included in the analysis. A questionnaire was completed by surgeons at the centers to assess relevant human, patient, process, technique, instrument, and environmental factors associated with the injury. Main Outcomes and Measures: Root cause analysis of demographic, human, patient, process, technique, instrument, and environmental factors as well as mortality and morbidity data. Results: Twenty-eight cases of ICA injury occurred during 7160 expanded endoscopic endonasal approach procedures (incidence of 0.4%). The mean age of the patients was 49 years, with a female to male predominance ratio of 1.8:1 (18 women to 10 men). Anatomical (23 [82%]), pathological (15 [54%]), and surgical resection (26 [93%]) factors were most frequently reported. The surgeon's mental or physical well-being was reported as inadequate in 4 cases (14%). Suboptimal imaging was reported in 6 cases (21%). The surgeon's experience level was not associated with ICA injury. The ICA injury was associated with use of powered or sharp instruments in 20 cases (71%), and use of new instruments or technology in 7 cases (25%). Two patients (7%) died in the operating room, and 3 (11%) were alive with neurological deficits. Overall, patient-related factors were the most frequently reported risk factors (in 27 of 28 cases [96%]). Factors associated with ICA injury catalyzed a list of preventive recommendations. Conclusions and Relevance: This study found that human factors were associated with intraoperative ICA injuries; however, they were usually accompanied by other deficiencies. These findings suggest that identifying risk factors is crucial for preventing such injuries. Preoperative planning and minimizing the potential for ICA injury also appear to be essential.

Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry.

OBJECTIVE: The authors describe a rapid intraoperative ambient ionization mass spectrometry (MS) method for determining isocitrate dehydrogenase (IDH) mutation status from glioma tissue biopsies. This method offers new glioma management options and may impact extent of resection goals. Assessment of the IDH mutation is key for accurate glioma diagnosis, particularly for differentiating diffuse glioma from other neoplastic and reactive inflammatory conditions, a challenge for the standard intraoperative diagnostic consultation that relies solely on morphology. METHODS: Banked glioma specimens (n = 37) were analyzed by desorption electrospray ionization-MS (DESI-MS) to develop a diagnostic method to detect the known altered oncometabolite in IDH-mutant gliomas, 2-hydroxyglutarate (2HG). The method was used intraoperatively to analyze tissue smears obtained from glioma patients undergoing resection and to rapidly diagnose IDH mutation status (< 5 minutes). Fifty-one tumor core biopsies from 25 patients (14 wild type [WT] and 11 mutant) were examined and data were analyzed using analysis of variance and receiver operating characteristic curve analysis. RESULTS: The optimized DESI-MS method discriminated between IDH-WT and IDH-mutant gliomas, with an average sensitivity and specificity of 100%. The average normalized DESI-MS 2HG signal was an order of magnitude higher in IDH-mutant glioma than in IDH-WT glioma. The DESI 2HG signal intensities correlated with independently measured 2HG concentrations (R2 = 0.98). In 1 case, an IDH1 R132H-mutant glioma was misdiagnosed as a demyelinating condition by frozen section histology during the intraoperative consultation, and no resection was performed pending the final pathology report. A second craniotomy and tumor resection was performed after the final pathology provided a diagnosis most consistent with an IDH-mutant glioblastoma. During the second craniotomy, high levels of 2HG in the tumor core biopsies were detected. CONCLUSIONS: This study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDH-WT conditions by DESI-MS during tumor resection. DESI-MS analysis of tissue smears is simple and can be easily integrated into the standard intraoperative pathology consultation. This approach may aid in solving differential diagnosis problems associated with low-grade gliomas and could influence intraoperative decisions regarding extent of resection, ultimately improving patient outcome. Research is ongoing to expand the patient cohort, systematically validate the DESI-MS method, and investigate the relationships between 2HG and tumor heterogeneity.

Analysis of human gliomas by swab touch spray-mass spectrometry: applications to intraoperative assessment of surgical margins and presence of oncometabolites.

Touch spray mass spectrometry using medical swabs is an ambient ionization technique (ionization of unprocessed sample in the open air) that has potential intraoperative application in quickly identifying the disease state of tissue and in better characterizing the resection margin. To explore this potential, we studied 29 human brain tumor specimens and obtained evidence that this technique can provide diagnostic molecular information that is relevant to brain cancer. Touch spray using medical swabs involves the physical sampling of tissue using a medical swab on a spatial scale of a few mm2 with subsequent ionization occurring directly from the swab tip upon addition of solvent and application of a high voltage. Using a tertiary mixture of acetonitrile, N,N-dimethylformamide, and ethanol, membrane-derived phospholipids and oncometabolites are extracted from the tissue, incorporated into the sprayed microdroplets, vacuumed into the mass spectrometer, and characterized in the resulting mass spectra. The tumor cell load was assessed from the complex phospholipid pattern in the mass spectra and also separately by measurement of N-acetylaspartate. Mutation status of the isocitrate dehydrogenase gene was determined via detection of the oncometabolite 2-hydroxyglutarate. The lack of sample pretreatment makes touch spray mass spectrometry using medical swabs a feasible intraoperative strategy for rapid surgical assessment.

Intraoperative assessment of tumor margins during glioma resection by desorption electrospray ionization-mass spectrometry.

Intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS) is used to characterize tissue smears by comparison with a library of DESI mass spectra of pathologically determined tissue types. Measurements are performed in the operating room within 3 min. These mass spectra provide direct information on tumor infiltration into white or gray brain matter based on N-acetylaspartate (NAA) and on membrane-derived complex lipids. The mass spectra also indicate the isocitrate dehydrogenase mutation status of the tumor via detection of 2-hydroxyglutarate, currently assessed postoperatively on biopsied tissue using immunohistochemistry. Intraoperative DESI-MS measurements made at surgeon-defined positions enable assessment of relevant disease state of tissue within the tumor mass and examination of the resection cavity walls for residual tumor. Results for 73 biopsies from 10 surgical resection cases show that DESI-MS allows detection of glioma and estimation of high tumor cell percentage (TCP) at surgical margins with 93% sensitivity and 83% specificity. TCP measurements from NAA are corroborated by indirect measurements based on lipid profiles. Notably, high percentages (>50%) of unresected tumor were found in one-half of the margin biopsy smears, even in cases where postoperative MRI suggested gross total tumor resection. Unresected tumor causes recurrence and malignant progression, as observed within a year in one case examined in this study. These results corroborate the utility of DESI-MS in assessing surgical margins for maximal safe tumor resection. Intraoperative DESI-MS analysis of tissue smears, ex vivo, can be inserted into the current surgical workflow with no alterations. The data underscore the complexity of glioma infiltration.

Disparities and guideline adherence in drugs of abuse screening in intracerebral hemorrhage.

OBJECTIVE: To characterize the pattern of urine drug screening in a cohort of intracerebral hemorrhage (ICH) patients at our academic centers. METHODS: We identified cases of primary ICH occurring from 2009 to 2011 in our academic centers. Demographic data, imaging characteristics, processes of care, and short-term outcomes were ascertained. We performed logistic regression to identify predictors for screening and evaluated preguideline and postguideline reiteration screening patterns. RESULTS: We identified 610 patients with primary ICH in 2009-2011; 379 (62.1%) were initially evaluated at an outside hospital. Overall, 142/610 (23.3%) patients were screened, with 21 positive for cocaine and 3 for amphetamine. Of patients <55 years of age, only 65/140 (46.4%) were screened. Black patients <55 years of age were screened more than nonblack patients <55 years of age (38/61 [62.3%] vs 27/79 [34.2%]; p = 0.0009). In the best multivariable model, age group (p = 0.0001), black race (p = 0.4529), first Glasgow Coma Scale score (p = 0.0492), current smoking (p < 0.0001), and age group × black race (p = 0.0097) were associated with screening. Guideline reiteration in 2010 did not improve the proportion <55 years of age who were screened: 42/74 (56.8%) were screened before and 23/66 (34.9%) after (p = 0.01). CONCLUSIONS: We found disparities in drugs of abuse (DOA) screening and suboptimal guideline adherence. Systematic efforts to improve screening for DOA are warranted. Improved identification of sympathomimetic exposure may improve etiologic classification and influence decision-making and prognosis counseling.

Is there a shortage of neurosurgeons in the United States?

BACKGROUND: Neurosurgical workforce decision-making is typically driven by the 1 neurosurgeon per 100,000 population ratio proposed in 1977 in the Study on Surgical Services for the United States report. The actual ratio has always been higher than suggested. OBJECTIVE: We evaluated whether the 1:100,000 ratio from the Study on Surgical Services for the United States report is still valid, whether there are enough neurosurgeons in the United States to meet patient needs, and whether demand is driven by patient need. METHODS: For our analysis, the distribution of practicing US neurosurgeons was merged with census data to yield density indices of neurosurgeons by state; a survey assessing practice characteristics was e-mailed to practicing neurosurgeons; and a compilation of job advertisements for US neurosurgeons was evaluated. RESULTS: Multivariant statistical analyses yielded inconclusive results regarding patient demand because existing data sets are not designed to establish patient demand and many neurosurgeons are subspecialized. The data indicated that the ratio of neurosurgeons to total US population is 1:65,580. In the survey responses, neurosurgeon-to-patient ratios varied dramatically by state and were inconsistently correlated with whether neurosurgeons indicated they were overworked or underworked. The 305 job advertisements may indicate a shortage. Twenty-four percent of advertising practices indicated that they are recruiting only for emergency department coverage, and an additional 26% indicated that they might not be recruiting if not for the need for emergency coverage. CONCLUSION: Demand ratios should be reevaluated by region and subspecialty to consider changes in neurosurgery practice. A "shortage" in the employment market may reflect factors other than patient need.

Minitubular transcortical microsurgical approach for gross total resection of third ventricular colloid cysts: technique and assessment.

OBJECTIVE: "Open" transcortical and transcallosal approaches allow gross total colloid cyst resection but require a wider surgical corridor through normal brain tissue compared with endoscopic techniques. Although the use of tubular retractor systems has been previously reported, the minimum required diameter size for the retractor tube has been approximately 16 to 22 mm. Our objective was to explore the use of smaller retractor tubes for total resection of colloid cysts. METHODS: A minitubular retractor with a 12-mm diameter was used to access and resect colloid cysts using microsurgical techniques while preserving stereoscopic vision as an alternative to open and endoscopic surgical routes. RESULTS: This technique was adopted in five patients with larger than 10-mm colloid cysts to allow for gross total resection of the cysts in every case without any complication. CONCLUSIONS: Smaller retractor tubes may be used for resection of colloid cysts while minimizing brain retraction injury and potentially improving outcomes.