Current status of artificial intelligence technologies in pituitary adenoma surgery: a scoping review.

PURPOSE: Pituitary adenoma surgery is a complex procedure due to critical adjacent neurovascular structures, variations in size and extensions of the lesions, and potential hormonal imbalances. The integration of artificial intelligence (AI) and machine learning (ML) has demonstrated considerable potential in assisting neurosurgeons in decision-making, optimizing surgical outcomes, and providing real-time feedback. This scoping review comprehensively summarizes the current status of AI/ML technologies in pituitary adenoma surgery, highlighting their strengths and limitations. METHODS: PubMed, Embase, Web of Science, and Scopus were searched following the PRISMA-ScR guidelines. Studies discussing the use of AI/ML in pituitary adenoma surgery were included. Eligible studies were grouped to analyze the different outcomes of interest of current AI/ML technologies. RESULTS: Among the 2438 identified articles, 44 studies met the inclusion criteria, with a total of seventeen different algorithms utilized across all studies. Studies were divided into two groups based on their input type: clinicopathological and imaging input. The four main outcome variables evaluated in the studies included: outcome (remission, recurrence or progression, gross-total resection, vision improvement, and hormonal recovery), complications (CSF leak, readmission, hyponatremia, and hypopituitarism), cost, and adenoma-related factors (aggressiveness, consistency, and Ki-67 labeling) prediction. Three studies focusing on workflow analysis and real-time navigation were discussed separately. CONCLUSION: AI/ML modeling holds promise for improving pituitary adenoma surgery by enhancing preoperative planning and optimizing surgical strategies. However, addressing challenges such as algorithm selection, performance evaluation, data heterogeneity, and ethics is essential to establish robust and reliable ML models that can revolutionize neurosurgical practice and benefit patients.

Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.

Volumetric measurement of intracranial meningiomas: a comparison between linear, planimetric, and machine learning with multiparametric voxel-based morphometry methods.

PURPOSE: To compare the accuracy of three volumetric methods in the radiological assessment of meningiomas: linear (ABC/2), planimetric, and multiparametric machine learning-based semiautomated voxel-based morphometry (VBM), and to investigate the relevance of tumor shape in volumetric error. METHODS: Retrospective imaging database analysis at the authors' institutions. We included patients with a confirmed diagnosis of meningioma and preoperative cranial magnetic resonance imaging eligible for volumetric analyses. After tumor segmentation, images underwent automated computation of shape properties such as sphericity, roundness, flatness, and elongation. RESULTS: Sixty-nine patients (85 tumors) were included. Tumor volumes were significantly different using linear (13.82 cm3 [range 0.13-163.74 cm3]), planimetric (11.66 cm3 [range 0.17-196.2 cm3]) and VBM methods (10.24 cm3 [range 0.17-190.32 cm3]) (p < 0.001). Median volume and percentage errors between the planimetric and linear methods and the VBM method were 1.08 cm3 and 11.61%, and 0.23 cm3 and 5.5%, respectively. Planimetry and linear methods overestimated the actual volume in 79% and 63% of the patients, respectively. Correlation studies showed excellent reliability and volumetric agreement between manual- and computer-based methods. Larger and flatter tumors had greater accuracy on planimetry, whereas less rounded tumors contributed negatively to the accuracy of the linear method. CONCLUSION: Semiautomated VBM volumetry for meningiomas is not influenced by tumor shape properties, whereas planimetry and linear methods tend to overestimate tumor volume. Furthermore, it is necessary to consider tumor roundness prior to linear measurement so as to choose the most appropriate method for each patient on an individual basis.

Awake craniotomy during pregnancy: A systematic review of the published literature.

Neurosurgical pathologies in pregnancy pose significant complications for the patient and fetus, and physiological stressors during anesthesia and surgery may lead to maternal and fetal complications. Awake craniotomy (AC) can preserve neurological functions while reducing exposure to anesthetic medications. We reviewed the literature investigating AC during pregnancy. PubMed, Scopus, and Web of Science databases were searched from the inception to February 7th, 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Studies in English investigating AC in pregnant patients were included in the final analysis. Nine studies composed of nine pregnant patients and ten fetuses (one twin-gestating patient) were included. Glioma was the most common pathology reported in six (66.7%) patients. The frontal lobe was the most involved region (4 cases, 44.4%), followed by the frontoparietal region (2 cases, 22.2%). The awake-awake-awake approach was the most common protocol in seven (77.8%) studies. The shortest operation time was two hours, whereas the longest one was eight hours and 29 min. The mean gestational age at diagnosis was 13.6 ± 6.5 (2-22) and 19.6 ± 6.9 (9-30) weeks at craniotomy. Seven (77.8%) studies employed intraoperative fetal heart rate monitoring. None of the AC procedures was converted to general anesthesia. Ten healthy babies were delivered from patients who underwent AC. In experienced hands, AC for resection of cranial lesions of eloquent areas in pregnant patients is safe and feasible and does not alter the pregnancy outcome.

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.

Functional expression of CD73 on human natural killer cells.

The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73- NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.

Hemodynamics of Cerebral Aneurysms: Connecting Medical Imaging and Biomechanical Analysis.

In the last two decades, numerous studies have conducted patient-specific computations of blood flow dynamics in cerebral aneurysms and reported correlations between various hemodynamic metrics and aneurysmal disease progression or treatment outcomes. Nevertheless, intra-aneurysmal flow analysis has not been adopted in current clinical practice, and hemodynamic factors usually are not considered in clinical decision making. This review presents the state of the art in cerebral aneurysm imaging and image-based modeling, discussing the advantages and limitations of each approach and focusing on the translational value of hemodynamic analysis. Combining imaging and modeling data obtained from different flow modalities can improve the accuracy and fidelity of resulting velocity fields and flow-derived factors that are thought to affect aneurysmal disease progression. It is expected that predictive models utilizing hemodynamic factors in combination with patient medical history and morphological data will outperform current risk scores and treatment guidelines. Possible future directions include novel approaches enabling data assimilation and multimodality analysis of cerebral aneurysm hemodynamics.

Primary and radiation induced skull base osteosarcoma: a systematic review of clinical features and treatment outcomes.

PURPOSE: We aim to systematically review and summarize the demographics, clinical features, management strategies, and clinical outcomes of primary and radiation-induced skull-base osteosarcoma (SBO). METHODS: PubMed, Scopus, and Cochrane databases were used to identify relevant articles. Papers including SBO cases and sufficient clinical outcome data were included. A comprehensive clinical characteristic review and survival analysis were also conducted. RESULTS: Forty-one studies describing 67 patients were included. The median age was 31 years (male = 59.7%). The middle skull-base was most commonly involved (52.7%), followed by anterior (34.5%) and posterior (12.7%) skull-base. Headache (27%), exophthalmos (18%), and diplopia (10%) were common presenting symptoms. Sixty-eight percent of patients had primary SBO, while 25% had radiation-induced SBO. Surgery was the main treatment modality in 89% of cases. Chemotherapy was administered in 65.7% and radiotherapy in 50%. Median progression-free survival (PFS) was 12 months, and the overall 5-year survival was 22%. The five-year survival rates of radiation-induced SBO and primary SBO were 39% and 16%, respectively (P < 0.05). CONCLUSION: SBO is a malignant disease with poor survival outcomes. Surgical resection is the primary management modality, in conjunction with chemotherapy and radiotherapy. Radiation-induced SBO has a superior survival outcome as compared to its primary counterpart. Complete surgical resection showed a statistically insignificant survival benefit as compared to partial resection.

Thalamic gliomas in adults: a systematic review of clinical characteristics, treatment strategies, and survival outcomes.

PURPOSE: Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas. METHODS: Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted. RESULTS: We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017). CONCLUSION: Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms.

Developmental innervation of cranial dura mater and migraine headache: A narrative literature review.

INTRODUCTION: Migraine headache prevalence, etiology, and clinical presentations change from childhood to adulthood. Dural innervation plays a role in headache symptomatology, but the changes in innervation during development have not been fully explored in the literature. METHODS: A narrative literature review on developmental innervation of cranial dura mater in the context of migraine headache. RESULTS: Dural structures, nerve distributions, and pain attributed to migraine headache at varying stages of development are discussed herein with a focus on clinical findings and presentations. CONCLUSIONS: There are many differences in migraine presentation throughout development. Notably, the nervus spinosus and nervus tentorii may play a role in developmental differences in migraine headache presentations between children and adults.

Higher Monocyte Count is Associated with 30-Day Case Fatality in Intracerebral Hemorrhage.

BACKGROUND: Previous studies have suggested that elevated neutrophils, monocytes, and neutrophil-to-lymphocyte ratio (NLR) may be associated with poor outcomes in intracerebral hemorrhage (ICH). We sought to determine whether white blood cell (WBC) types were independently associated with poor outcome in ICH in a large cohort. METHODS: We performed a retrospective study of primary ICH at two academic centers. Cases were identified via ICD-9 code and verified via physician review. We included only those patients with WBC types obtained within 24 h of ICH onset. RESULTS: We identified 593 patients with primary ICH and WBC differentials in the first 24 h. Independent factors (OR, 95% CI) associated with 30-day case fatality were age > 80 (2.4 (1.4, 4.2)), p = 0.0023; NIHSS greater than median (3.9 (2.4, 6.3)), p < 0.0001; ICH volume quartiles (Q1: ref, Q2: 1.5 (0.7, 3.0), Q3: 3.2 (1.6, 6.6), Q4: 11.9 (5.3, 26.4)), p < 0.0001; non-lobar location (3.3 (1.9, 5.9)), p ≤ 0.0001; IVH (2.3 (1.4, 3.6)), p = 0.0005, monocytes greater than median (1.6 (1.0, 2.4)), p = 0.0457, and anticoagulant use (3.2 (1.8, 5.6)), p < 0.0001. Elevated NLR was not associated with higher case fatality. CONCLUSIONS: We found that elevated monocytes were independently associated with 30-day case fatality. Future studies will investigate whether there are subgroups of ICH patients, including those with particular blood or imaging biomarkers, in which WBC types might help predict poor outcome and provide targets for intervention.

Endovascular Intervention Versus Surgery in Ruptured Intracranial Aneurysms in Equipoise: A Systematic Review.

Background and Purpose- The benefits of endovascular intervention over surgery in the treatment of ruptured aneurysms of anterior circulation remains uncertain. Recently, published studies did not find superiority of endovascular intervention, challenging earlier evidence from a clinical trial. The earlier evidence also had a higher than average proportion of patients in good clinical status, leading to uncertainty about external validity of earlier trials. Methods- We performed a systematic review of studies after 2005 under a protocol published in the International Prospective Register of Systematic Reviews. Primary outcomes were posttreatment rebleeding and adverse events (procedural complications). Secondary outcomes were dependency at 3 to 6 and 12 months, delayed cerebral ischemia, and seizures. Results- Rebleeding was more frequent after endovascular intervention (Peto OR, 2.18 [95% CI, 1.29-3.70]; 3104 participants; 15 studies; I2=0%, Grading of Recommendations, Assessment, Development and Evaluation: very low certainty of evidence). Fewer adverse events were reported with the endovascular intervention (RR, 0.71 [95% CI, 0.53-0.95]; 1661 participants; 11 studies; I2=14%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence). Three to six months dependency (RR, 0.82 [95% CI, 0.73-0.93]; 4081 participants; 18 studies; I2=15%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence) and 12-month dependency (RR, 0.76 [95% CI, 0.66-0.86]; 1981 participants; 10 studies; I2=0%, Grading of Recommendations, Assessment, Development and Evaluation: low certainty of evidence) were lower after endovascular intervention. Conclusions- This study found consistent results between recent studies and the earlier evidence, in that endovascular intervention results in lower chance of dependency compared with surgery for repair of ruptured anterior circulation aneurysms. A lower proportion of patients in good clinical status in this review supports the application of the earlier evidence. Registration- URL: https://www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42018090396.

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.

The Neurosurgical Atlas: advancing neurosurgical education in the digital age.

OBJECTIVE: The advent of the internet and the popularity of e-learning resources has promoted a shift in medical and surgical education today. The Neurosurgical Atlas has sought to capitalize on this shift by providing easily accessible video and online education to its users on an international scale. The rising popularity of social media has provided new avenues for expanding that global reach, and the Atlas has sought to do just that. In this study, the authors analyzed user demographics and web traffic patterns to quantify the international reach of the Atlas and examined the potential impact of social media platforms on the expansion of that reach. METHODS: Twitter, Facebook, and Instagram metrics were extracted using each respective service's analytics tool from the date of their creation through October 2019. Google Analytics was used to extract website traffic data from September 2018 to September 2019 and app data from January 2019 to October 2019. The metrics extracted included the number of platform users/followers, user demographic information, percentage of new versus returning visitors, and a number of platform-specific values. RESULTS: Since the authors' previous publication in 2017, annual website viewership has more than doubled to greater than 500,000 viewing sessions in the past year alone; international users accounted for more than 60% of the visits. The Atlas Twitter account, established in August 2012, has more than 12,000 followers, primarily hailing from the United States, the United Kingdom, Canada, and Saudi Arabia. The Atlas Facebook account, established in 2013, has just over 13,000 followers, primarily from India, Egypt, and Mexico. The Atlas Instagram account (established most recently, in December 2018) has more than 16,000 followers and the highest percentage (31%) of younger users (aged 18-24 years). The Atlas app was officially launched in May 2019, largely via promotion on the Atlas social media platforms, and has since recorded more than 60,000 viewing sessions, 80% of which were from users outside the United States. CONCLUSIONS: The Neurosurgical Atlas has attempted to leverage the many e-learning resources at its disposal to assist in spreading neurosurgical best practice on an international scale in a novel and comprehensive way. By incorporating multiple social media platforms into its repertoire, the Atlas is able to ensure awareness of and access to these resources regardless of the user's location or platform of preference. In so doing, the Atlas represents a novel way of advancing access to neurosurgical educational resources in the digital age.

Online Impact and Presence of a Specialized Social Media Team for the Journal of Neurosurgery: Descriptive Analysis.

BACKGROUND: Social media use continues to gain momentum in academic neurosurgery. To increase journal impact and broaden engagement, many scholarly publications have turned to social media to disseminate research. The Journal of Neurosurgery Publishing Group (JNSPG) established a dedicated, specialized social media team (SMT) in November 2016 to provide targeted improvement in digital outreach. OBJECTIVE: The goal of this study was to examine the impact of the JNSPG SMT as measured by increased engagement. METHODS: We analyzed various metrics, including impressions, engagements, retweets, likes, profile clicks, and URL clicks, from consecutive social media posts from the JNSPG's Twitter and Facebook platforms between February 1, 2015 and February 28, 2019. Standard descriptive statistics were utilized. RESULTS: Between February 2015 and October 2016, when a specialized SMT was created, 170 tweets (8.1 tweets/month) were posted compared to 3220 tweets (115.0 tweets/month) between November 2016 and February 2019. All metrics significantly increased, including the impressions per tweet (mean 1646.3, SD 934.9 vs mean 4605.6, SD 65,546.5; P=.01), engagements per tweet (mean 35.2, SD 40.6 vs mean 198.2, SD 1037.2; P<.001), retweets (mean 2.5, SD 2.8 vs mean 10.5, SD 15.3; P<.001), likes (mean 2.5, SD 4.0 vs mean 18.0, SD 37.9; P<.001), profile clicks (mean 1.5, SD 2.0 vs mean 5.2, SD 43.3; P<.001), and URL clicks (mean 13.1, SD 14.9 vs mean 38.3, SD 67.9; P<.001). Tweets that were posted on the weekend compared to weekdays had significantly more retweets (mean 9.2, SD 9.8 vs mean 13.4, SD 25.6; P<.001), likes (mean 15.3, SD 17.9 vs mean 23.7, SD 70.4; P=.001), and URL clicks (mean 33.4, SD 40.5 vs mean 49.5, SD 117.3; P<.001). Between November 2015 and October 2016, 49 Facebook posts (2.3 posts/month) were sent compared to 2282 posts (81.5 posts/month) sent between November 2016 and February 2019. All Facebook metrics significantly increased, including impressions (mean 5475.9, SD 5483.0 vs mean 8506.1, SD 13,113.9; P<.001), engagements (mean 119.3, SD 194.8 vs mean 283.8, SD 733.8; P<.001), and reach (mean 2266.6, SD 2388.3 vs mean 5344.1, SD 8399.2; P<.001). Weekend Facebook posts had significantly more impressions per post (mean 7967.9, SD 9901.0 vs mean 9737.8, SD 19,013.4; P=.03) and a higher total reach (mean 4975.8, SD 6309.8 vs mean 6108.2, SD 12,219.7; P=.03) than weekday posts. CONCLUSIONS: Social media has been established as a crucial tool for the propagation of neurosurgical research and education. Implementation of the JNSPG specialized SMT had a demonstrable impact on increasing the online visibility of social media content.

Cerebral circulation time derived from fMRI signals in large blood vessels.

BACKGROUND: The systemic low-frequency oscillation (sLFO) functional (f)MRI signals extracted from the internal carotid artery (ICA) and the superior sagittal sinus (SSS) are found to have valuable physiological information. PURPOSE: 1) To further develop and validate a method utilizing these signals to measure the delay times from the ICAs and the SSS. 2) To establish the delay time as an effective perfusion biomarker that associates with cerebral circulation time (CCT). 3) To explore within subject variations, and the effects of gender and age on the delay times. STUDY TYPE: Prospective. SUBJECTS: In all, 100 healthy adults (Human Connectome Project [HCP], age range 22-36 years, 54 females and 46 males), 56 healthy children (Adolescent Brain Cognitive Development project) were included. FIELD STRENGTH/SEQUENCE: Echo planar imaging (EPI) sequence at 3T. ASSESSMENT: The sLFO fMRI signals from the ICAs and the SSSs were extracted from the resting state fMRI data. The maximum cross-correlation coefficients and their corresponding delay times were calculated. The gender and age differences of delay times were assessed statistically. STATISTICAL TESTS: T-tests were conducted to measure the gender differences. The Kruskal-Wallis test was used to detect age differences. RESULTS: Consistent and robust results were found from 80% of the 400 HCP scans included. Negative correlations (-0.67) between the ICA and the SSS signals were found with the ICA signal leading the SSS signal by ∼5 sec. Within subject variation was 2.23 sec at the 5% significance level. The delay times were not significantly different between genders (P = 0.9846, P = 0.2288 for the left and right ICA, respectively). Significantly shorter delay times (4.3 sec) were found in the children than in the adults (P < 0.01). DATA CONCLUSION: We have shown that meaningful perfusion information (ie, CCT) can be derived from the sLFO fMRI signals of the large blood vessels. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1504-1513.

Intraoperative detection of isocitrate dehydrogenase mutations in human gliomas using a miniature mass spectrometer.

Knowledge of the isocitrate dehydrogenase (IDH) mutation status of glioma patients could provide insights for decision-making during brain surgery. However, pathology is not able to provide such information intraoperatively. Here we describe the first application of a miniature mass spectrometer (MS) to the determination of IDH mutation status in gliomas intraoperatively. The instrumentation was modified to be compatible with use in the operating room. Tandem MS was performed on the oncometabolite, 2-hydroxyglutarate, and a reference metabolite, glutamate, which is not involved in the IDH mutation. Ratios of fragment ion intensities were measured to calculate an IDH mutation score, which was used to differentiate IDH mutant and wild-type tissues. The results of analyzing 25 biopsies from 13 patients indicate that reliable determination of IDH mutation status was achieved (p = 0.0001, using the Kruskal-Wallis non-parametric test). With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. Graphical abstract.

Lipid and metabolite profiles of human brain tumors by desorption electrospray ionization-MS.

Examination of tissue sections using desorption electrospray ionization (DESI)-MS revealed phospholipid-derived signals that differ between gray matter, white matter, gliomas, meningiomas, and pituitary tumors, allowing their ready discrimination by multivariate statistics. A set of lower mass signals, some corresponding to oncometabolites, including 2-hydroxyglutaric acid and N-acetyl-aspartic acid, was also observed in the DESI mass spectra, and these data further assisted in discrimination between brain parenchyma and gliomas. The combined information from the lipid and metabolite MS profiles recorded by DESI-MS and explored using multivariate statistics allowed successful differentiation of gray matter (n = 223), white matter (n = 66), gliomas (n = 158), meningiomas (n = 111), and pituitary tumors (n = 154) from 58 patients. A linear discriminant model used to distinguish brain parenchyma and gliomas yielded an overall sensitivity of 97.4% and a specificity of 98.5%. Furthermore, a discriminant model was created for tumor types (i.e., glioma, meningioma, and pituitary), which were discriminated with an overall sensitivity of 99.4% and a specificity of 99.7%. Unsupervised multivariate statistics were used to explore the chemical differences between anatomical regions of brain parenchyma and secondary infiltration. Infiltration of gliomas into normal tissue can be detected by DESI-MS. One hurdle to implementation of DESI-MS intraoperatively is the need for tissue freezing and sectioning, which we address by analyzing smeared biopsy tissue. Tissue smears are shown to give the same chemical information as tissue sections, eliminating the need for sectioning before MS analysis. These results lay the foundation for implementation of intraoperative DESI-MS evaluation of tissue smears for rapid diagnosis.

Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma.

RNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential, and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2 Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma.