Heterogeneous growth of the insula shapes the human brain.

The human cerebrum consists of a precise and stereotyped arrangement of lobes, primary gyri, and connectivity that underlies human cognition [P. Rakic, Nat. Rev. Neurosci. 10, 724-735 (2009)]. The development of this arrangement is less clear. Current models explain individual primary gyrification but largely do not account for the global configuration of the cerebral lobes [T. Tallinen, J. Y. Chung, J. S. Biggins, L. Mahadevan, Proc. Natl. Acad. Sci. U.S.A. 111, 12667-12672 (2014) and D. C. Van Essen, Nature 385, 313-318 (1997)]. The insula, buried in the depths of the Sylvian fissure, is unique in terms of gyral anatomy and size. Here, we quantitatively show that the insula has unique morphology and location in the cerebrum and that these key differences emerge during fetal development. Finally, we identify quantitative differences in developmental migration patterns to the insula that may underlie these differences. We calculated morphologic data in the insula and other lobes in adults (N = 107) and in an in utero fetal brain atlas (N = 81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Spherical projection analysis demonstrates that the lenticular nuclei obstruct 60 to 70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify radial glial fascicles that originate from the VZ and curve around the lenticular nuclei to form the insula. These results confirm existing models of radial migration to the cortex and illustrate findings that suggest differential insular and cerebral development, laying the groundwork to understand cerebral malformations and insular function and pathologies.

Assessing chiasm perfusion and postoperative visual function with superior hypophyseal artery indocyanine green angiograms during endoscopic endonasal surgery.

BACKGROUND: To date, there are no validated intraoperative tools to predict postoperative visual function following endoscopic endonasal surgery (EES). Assessment of post-surgical vision during surgery can help in postoperative planning and disposition and inform surgical decisions in real-time. The objective of this study was to evaluate the capability of intraoperative endoscopic indocyanine green (ICG) angiography to measure optic chiasm perfusion and determine its relationship with postoperative visual function. METHODS: A retrospective review was performed on patients undergoing EES for sellar and suprasellar lesions. ICG was injected prior to surgical closure at a time when the optic chiasm and anterior circulation were visible. Luminescence of the superior hypophyseal artery (SHA) branches enveloping the optic chiasm was registered 10 seconds after ICG penetration into the anterior cerebral arteries (ACAs). Pre and post-operative visual acuity and field exams were used to assess visual function. Patients with and without new deficits were compared to examine statistical association with intraoperative ICG findings. RESULTS: Twenty patients were included (mean age 49 years, 55% female). Eighteen patients displayed stable or improved vision after resection and demonstrated luminescence of all chiasmatic branches within 10 s of ACA fluorescence. Two patients experienced new postoperative visual deficits. Upon review, their ICG administrations showed no fluorescence of the SHA branches enveloping the chiasm. A lack of chiasm fluorescence within ten seconds of ACA fluorescence was associated with new postoperative vision deficits (p = 0.005). CONCLUSIONS: This study shows that the lack of ICG fluorescence of SHA branches at the chiasm correlates with ischemic changes and new post-operative bitemporal hemianopsia. Lack of chiasm fluorescence after 10 seconds of observation reflects compromised chiasm perfusion and likely new post-surgical visual deficits.

A new perspective on an old method: gated SPECT imaging for left ventricular contractile function assessment.

The ejection fraction (LVEF) is a commonly used marker of left ventricular function. However, because it is strongly influenced by loading conditions, it can be inaccurate in representing cardiac contractility. We therefore evaluated a gated SPECT based tool to simultaneously assess preload, afterload, and contractility. Using gated SPECT-determined ventricular volumes and arterial tension measurements, we calculated ventricular and arterial elastance (Ev and Ea), as well as end-diastolic volumes, which are surrogates for contractility, afterload, and preload, respectively. We applied this protocol to 1462 consecutive patients and assessed the ventricular function in patients with and without myocardial infarction. The median LVEF was 68% (IQR 62-74%). Patients with infarction exhibited decreased contractility (ventricular elastance of 3 mmHg/ml vs. 6 mmHg/ml), compensated by an increase of preload (end-diastolic volume of 100 ml vs. 78 ml) and a decrease in afterload (arterial elastance of 1.8 mmHg/ml vs. 2.2 ml/mmHg). These interactions yielded a preserved ejection fraction in both groups. Gated SPECT-measured volumes were consistent with values reported in the literature. In addition, the combination of nuclear imaging and arterial tension measurement accounted for not only the ejection fraction but also the loading context, providing a more accurate representation of cardiac contractility.

Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases.

OBJECTIVE: Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS: All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS: There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.

Genomic alterations associated with rapid progression of brain metastases.

OBJECTIVE: The aim of this study was to investigate associations between genomic alterations in resected brain metastases and rapid local and distant CNS recurrence identified at the time of postoperative adjuvant radiosurgery. METHODS: This was a retrospective study on patients who underwent resection of intracranial brain metastases. Next-generation sequencing of more than 500 coding genes was performed on brain metastasis specimens. Postoperative and preradiosurgery MR images were compared to identify rapid recurrence. Genomic data were associated with rapid local and distant CNS recurrence of brain metastases using nominal regression analyses. RESULTS: The cohort contained 92 patients with 92 brain metastases. Thirteen (14.1%) patients had a rapid local recurrence, and 64 (69.6%) patients had rapid distant CNS progression by the time of postoperative adjuvant radiosurgery, which occurred in a median time of 25 days (range 3-85 days) from surgery. RB1 and CTNNB1 mutations were seen in 8.7% and 9.8% of the cohort, respectively, and were associated with a significantly higher risk of rapid local recurrence (RB1: OR 13.6, 95% CI 2.0-92.39, p = 0.008; and CTNNB1: OR 11.97, 95% CI 2.25-63.78, p = 0.004) on multivariate analysis. No genes were found to be associated with rapid distant CNS progression. However, the presence of extracranial disease was significantly associated with a higher risk of rapid distant recurrence on multivariate analysis (OR 4.06, 95% CI 1.08-15.34, p = 0.039). CONCLUSIONS: Genomic alterations in RB1 or CTNNB1 were associated with a significantly higher risk of rapid recurrence at the resection site. Although no genomic alterations were associated with rapid distant recurrence, having active extracranial disease was a risk factor for new lesions by the time of adjuvant radiotherapy after resection.

Different Principles Govern Different Scales of Brain Folding.

The signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal magnetic resonance imaging with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms; therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

Blood supply to the corticospinal tract: A pictorial review with application to cranial surgery and stroke.

The corticospinal tract (CST) is the main neural pathway responsible for conducting voluntary motor function in the central nervous system. The CST condenses into fiber bundles as it descends from the frontoparietal cortex, traveling down to terminate at the anterior horn of the spinal cord. The CST is at risk of injury from vascular insult from strokes and during neurosurgical procedures. The aim of this article is to identify and describe the vasculature associated with the CST from the cortex to the medulla. Dissection of cadaveric specimens was carried out in a manner, which exposed and preserved the fiber tracts of the CST, as well as the arterial systems that supply them. At the level of the motor cortex, the CST is supplied by terminal branches of the anterior cerebral artery and middle cerebral artery. The white matter tracts of the corona radiata and internal capsule are supplied by small perforators including the lenticulostriate arteries and branches of the anterior choroidal artery. In the brainstem, the CST is supplied by anterior perforating branches from the basilar and vertebral arteries. The caudal portions of the CST in the medulla are supplied by the anterior spinal artery, which branches from the vertebral arteries. The non-anastomotic nature of the vessel systems of the CST highlights the importance of their preservation during neurosurgical procedures. Anatomical knowledge of the CST is paramount to clinical diagnosis and treatment of heterogeneity of neurodegenerative, neuroinflammatory, cerebrovascular, and skull base tumors.

Extensive tumor calcification in response to pre-operative reductive chemotherapy in pediatric esthesioneuroblastoma: a case report.

Esthesioneuroblastomas are uncommon tumors in pediatric patients and are typically treated with multimodal therapy. Changes in gross tumor quality and character in response to adjuvant treatment have not been clearly reported. We report the case of a 15-year-old female with a diagnosis of Kadish stage C esthesioneuroblastoma who was treated with neoadjuvant chemotherapy and surgical resection. The patient's tumor demonstrated cytoreduction after chemotherapy but also was found to have calcified. A combined trans-frontal sinus craniotomy with endoscopic endonasal resection was performed and resulted in negative margins and good clinical outcome.

15-Lipoxygenase 1 in nasal polyps promotes CCL26/eotaxin 3 expression through extracellular signal-regulated kinase activation.

BACKGROUND: 15-Lipoxygenase 1 (15LO1) is expressed in airway epithelial cells in patients with type 2-high asthma in association with eosinophilia. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also associated with type 2 inflammation and eosinophilia. CCL26/eotaxin 3 has been reported to be regulated by 15LO1 in lower airway epithelial cells. However, its relation to 15LO1 in patients with CRSwNP or mechanisms for its activation are unclear. OBJECTIVE: We sought to evaluate 15LO1 and CCL26 expression in nasal epithelial cells (NECs) from patients with CRSwNP and healthy control subjects (HCs) and determine whether 15LO1 regulates CCL26 in NECs through extracellular signal-regulated kinase (ERK) activation. METHODS: 15LO1, CCL26, and phosphorylated ERK were evaluated in NECs from patients with CRSwNP and HCs. 15LO1/CCL26 and CCL26/cytokeratin 5 were colocalized by means of immunofluorescence. IL-13-stimulated NECs were cultured at an air-liquid interface with or without 15-lipoxygenase 1 gene (ALOX15) Dicer-substrate short interfering RNAs (DsiRNA) transfection, a specific 15LO1 enzymatic inhibitor, and 2 ERK inhibitors. Expression of 15LO1 and CCL26 mRNA and protein was analyzed by using quantitative RT-PCR, Western blotting, and ELISA. RESULTS: 15LO1 expression was increased in nasal polyp (NP) epithelial cells compared with middle turbinate epithelial cells from patients with CRSwNP and HCs. 15LO1 expression correlated with CCL26 expression and colocalized with CCL26 expression in basal cells of the middle turbinate and NPs from patients with CRSwNP. In primary NECs in vitro, IL-13 induced 15LO1 and CCL26 expression. 15LO1 knockdown and inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression. ERK inhibition (alone) similarly decreased IL-13-induced CCL26. Phosphorylated ERK expression was increased in NECs from CRSwNP subjects and positively correlated with both 15LO1 and CCL26 expression. CONCLUSIONS: 15LO1 expression is increased in NP epithelial cells and contributes to CCL26 expression through ERK activation. 15LO1 could be considered a novel therapeutic target for CRSwNP.

[Endoscopic treatment of 140 pituitary tumors, results and complications]. / Tratamiento endoscópico de 140 tumores de hipófisis, resultados y complicaciones.

OBJECTIVE: To present the clinical and radiographic outcomes of 140 patients with pituitary adenomas treated by an endoscopic endonasal approach (EEA) over a period of 4 years. MATERIAL AND METHODS: A retrospective analysis was performed between 2011 and 2014. Pre and post operative MRI, ophtalmological assessment, endocrinological laboratory evaluation and surgical morbidity and mortality were assessed. RESULTS: 57,9% of the patients had functional tumors (n=81), acromegaly being the most frequent sub-type (29.3%). 78.6% of the lesions were macroadenomas (n=110) of which 56.4% (n=62) involved the cavernous sinus, 61 patients presented with visual field defects (44%) of which 50.8% of patients showed improvement after surgery. Gross total removal was achieved in 60% of the cases. Hormonal remission was achieved in the 75% of the patients with functional tumors. The morbidity rate was 15% and one patient died after surgery (mortality 0.7%). CONCLUSION: EEA is a safe and effective tool to treat pituitary adenomas. The main limitation for complete surgical resection is the cavernous sinus invasion.

Posterior lumbar dynamic stabilization instead of arthrodesis for symptomatic adjacent-segment degenerative stenosis: description of a novel technique.

OBJECTIVE The development of symptomatic adjacent-segment disease (ASD) is a well-recognized consequence of lumbar fusion surgery. Extension of a fusion to a diseased segment may only lead to subsequent adjacent-segment degeneration. The authors report the use of a novel technique that uses dynamic stabilization instead of arthrodesis for the surgical treatment of symptomatic ASD following a prior lumbar instrumented fusion. METHODS A cohort of 28 consecutive patients was evaluated who developed symptomatic stenosis immediately adjacent to a previous lumbar instrumented fusion. All patients had symptoms of neurogenic claudication refractory to nonsurgical treatment and were surgically treated with decompression and dynamic stabilization instead of extending the fusion construct using a posterior lumbar dynamic stabilization system. Preoperative symptoms, visual analog scale (VAS) pain scores, and perioperative complications were recorded. Clinical outcome was gauged by comparing VAS scores prior to surgery and at the time of last follow-up. RESULTS The mean follow-up duration was 52 months (range 17-94 months). The mean interval from the time of primary fusion surgery to the dynamic stabilization surgery was 40 months (range 10-96 months). The mean patient age was 51 years (range 29-76 years). There were 19 (68%) men and 9 (32%) women. Twenty-three patients (82%) presented with low-back pain at time of surgery, whereas 24 patients (86%) presented with lower-extremity symptoms only. Twenty-four patients (86%) underwent operations that were performed using single-level dynamic stabilization, 3 patients (11%) were treated at 2 levels, and 1 patient underwent 3-level decompression and dynamic stabilization. The most commonly affected and treated level (46%) was L3-4. The mean preoperative VAS pain score was 8, whereas the mean postoperative score was 3. No patient required surgery for symptomatic degeneration rostral to the level of dynamic stabilization during the follow-up period. CONCLUSIONS The use of posterior lumbar dynamic stabilization may offer a valid and safe option for the management of patients who develop ASD rostral to a previously instrumented arthrodesis. The technique may serve as an alternative to multilevel arthrodesis in this patient population. By implanting a dynamic stabilization device instead of an extension of a rigid construct, this might translate into a reduction in the development of yet another level of ASD.

Pathological changes of the hippocampus and cognitive dysfunction following frontal lobe surgery in a rat model.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a known complication after intracranial surgery. Impaired hippocampal neurogenesis has been associated with cognitive dysfunction in animal models. METHODS: In order to assess hippocampal changes after brain surgery, a frontal lobe corticectomy was performed in ten adult Wistar rats (group 4). Three different control groups (n = 10 each) included no treatment (G1), general anesthesia alone (G2), and craniectomy without dural opening (G3). Twenty-four hours after surgery, half of the animals were killed, and the mRNA levels for IL-6, TNF-α, and brain-derived growth factor (BDNF) in the contralateral hippocampus were assessed by qPCR. Seven days later, the remaining animals underwent anxiety and memory testing. Afterwards, the number of immature neurons in the hippocampal cortex was measured by doublecortin (DCX) staining. RESULTS: Twenty-four hours after surgery, mRNA levels of IL-6 and TNF-α increased and BDNF decreased in both surgical groups G3 and G4 (p = 0.012). Cognitive tests demonstrated an increase in anxiety levels and memory impairment in surgical groups compared with non-surgical animals. These changes correlated with an inhibition of hippocampal neurogenesis evidenced by a decreased number of new neurons (mean ± SD for G1-4: 66.4 ± 24; 57.6 ± 22.2; 21.3 ± 3.78; 5.7 ± 1.05, p < 0.001, non-parametric ANOVA). CONCLUSIONS: Intracranial surgery was demonstrated to induce an inflammatory reaction within the hippocampus that compromised neurogenesis and impaired normal cognitive processing. Corticectomy had a greater effect than craniotomy alone, indicating a central trigger for hippocampal inflammatory changes. POCD after craniotomy may originate from a central inflammatory response resulting from surgical trauma to the brain parenchyma.

Use of a Monopolar Stimulator to Preserve the Frontotemporal Branches of the Facial Nerve During a Pterional Approach: 2-Dimensional Operative Video.

Preservation of the frontotemporal branches of the facial nerve is essential to obtain good cosmetic outcomes after anterolateral cranial base approaches.1,2 Since the description of the interfacial dissection, most nerve injuries are due to retraction of the nerve fibers and not direct transection.3-5 In this video, we showcase the use of a monopolar stimulator to guide the placement of hook retractors and assess no undue retraction is applied to the nerve fibers during a pterional craniotomy. This simple tool can help in preserving frontalis function after anterolateral skull base craniotomies. Institutional review board approval was not required; the patient consented to the procedure and to the publication of his/her image.

Use of Real-Time Superior Hypophyseal Artery Indocyanine Green Angiogram During Endoscopic Resection of a Third Ventricular Craniopharyngioma: 2-Dimensional Operative Video.

The endoscopic endonasal approach for resection of craniopharyngiomas has gained popularity because of its minimal need for retraction and superior visualization of and access to the optic chiasm.1-4 Despite these advantages, the proximity of craniopharyngiomas to the optic apparatus still challenges the preservation of visual function.5-10 Indocyanine green (ICG) angiography can evaluate the perfusion of the chiasm and can predict visual outcomes after endonasal approaches, in addition to known uses of the dye.3 ICG angiography may therefore hold promise in the real-time assessment of optic chiasm perfusion during resection of craniopharyngiomas by delineating details of the superior hypophyseal artery (SHA) system. Here, we present a case in which ICG angiogram was used to assess the perfusion of the chiasm before, during, and after tumor resection. This technique signaled thrombosis of the left principal SHA during tumor resection that was compensated by the anastomotic SHA system from the right. The case shows an endoscopic endonasal approach for the resection of a third ventricular craniopharyngioma in a 21-year-old woman presenting with unremitting headaches, endocrine dysfunction, and vision loss. Postoperatively, the patient's neurological examination remained unchanged and visual function improved within 2 weeks. This case underscores the potential for real-time intraoperative ICG angiography to assist in the careful resection of craniopharyngiomas while improving visual outcomes. Institutional review board approval was not required; the patient consented to the procedure and to publishing of the operative video.

Use of a Suction-Monopolar Stimulator for Continuous Neurophysiology Monitoring During Endonasal Resection of a Cavernous Sinus Schwannoma: 2-Dimensional Operative Video.

Cavernous sinus schwannomas are exceptionally rare tumors.1,2 Although these tumors commonly originate from the trigeminal nerve, instances involving the oculomotor, abducens, trochlear nerves, and the carotid plexus have also been documented.2-7 In this operative video, we showcase a 44-year-old man with a medical history of acromegaly and schwannomatosis who presented with retro orbital pain and a growing cystic lesion in the left cavernous sinus. Genetic testing ruled out neurofibromatosis types 1 and 2. An endonasal resection was recommended considering the left side and extradural location of the lesion.8 The tumor was excised through an endonasal transpterygoid approach using 2 suctions, one of which was equipped with an electrode tip for continuous monitoring of extraocular nerves during the resection process. Imaging postoperatively demonstrated near-total resection. Institutional review board approval was not required; the patient agreed to undergo the procedure and to have his operative video published.

Interhemispheric axonal sprouting occurs after pial removal in mice.

White matter lacks the kind of plasticity that is present in the cortex, and subcortical injuries often result in permanent neurological deficits. Because cortical regions share common subcortical nuclei, creating new intergyral connections may allow for the bypass of subcortical damage. In this manuscript, a surgical interhemispheric bridge is created in mice, providing a model for an intercortical transpial bypass. To model this bypass, a midline craniotomy followed by interhemispheric (IH) pial removal was performed in C57BL/6 mice, allowing for the juxtaposition of the right and left prefrontal cortices. Adeno-associated virus (AAV) expressing tdTomato under a neuronal-specific promoter were injected into the right hemisphere. Animals were sacrificed two and four weeks after surgery, and axonal sprouting and glial changes were assessed in the "bypass" (BP) operation and sham surgery. Surgery did not result in any clear functional impairments. Removing the pia resulted in the formation of a physical connection between the hemispheres and the loss of the normal pial IH barrier. Cortical layer I became thinner with neuronal bodies in closer proximity than in the sham group. New interhemispheric axonal crossings were visible at two and four weeks in the BP group but not in the sham mice. These findings constitute the first step in the development of a cortico-cortico transpial bypass, allowing us to test a new way to surgically restore neurological function.

Calcified Meningiomas Demonstrate Equivocal Grade, Proliferation, and Immediate Surgical Outcomes.

BACKGROUND/OBJECTIVE: Meningioma calcification is thought to predict reduced growth potential and aggression. However, historical studies have primarily focused on correlating calcification in small meningiomas (diameter less than 2.5 cm) rather than analyzing characteristics of calcified meningiomas across all sizes. In this study, we investigate the pathologic and clinical implications of meningioma calcification. METHODS: We utilized a historical database of 342 consecutive newly diagnosed intracranial meningiomas with preoperative computed tomography and magnetic resonance imaging scans treated at a single institution from 2005 to 2019. We correlated the presence of calcification with patient demographics, grade, Mindbomb Homolog-1 index, location, volume, Simpson grade, and recurrence using both univariate and multivariate generalized linear models. RESULTS: On univariate analysis, no single variable correlated with tumor calcification. Notably, neither tumor 2021 World Health Organization grade (P = 0.91) nor Mindbomb Homolog-1 index (P = 0.62) predicted calcification. After accounting for demographic characteristics and tumor volume and location, there was no significant association between 2021 World Health Organization grade (P = 0.52) and Mindbomb Homolog-1 index (P = 0.54) and calcification. Calcification had no influence on resection grade (P = 0.59) or recurrence (P = 0.80). CONCLUSIONS: In this series, calcified meningiomas exhibited similar 2021 World Health Organization tumor grading distribution, proliferation indexes, and immediate surgical outcomes compared to their noncalcified counterparts. These findings question the historical role of using meningioma calcification as an independent guide to their management.

Epidemiology, Genetics, and DNA Methylation Grouping of Hyperostotic Meningiomas.

BACKGROUND AND OBJECTIVES: Meningiomas are the most common primary intracranial tumors and are among the only tumors that can form lamellar, hyperostotic bone in the tumor microenvironment. Little is known about the epidemiology or molecular features of hyperostotic meningiomas. METHODS: Using a retrospective database of 342 meningiomas treated with surgery at a single institution, we correlated clinical, tumor-related, targeted next-generation DNA sequencing (n = 39 total, 16 meningioma-induced hyperostosis [MIH]), and surgical variables with the presence of MIH using generalized linear models. Meningioma DNA methylation grouping was analyzed on a separate population of patients from the same institution with preoperative imaging studies sufficient for identification of MIH (n = 200). RESULTS: MIH was significantly correlated with anterior fossa (44.3% of MIH vs 17.5% of non-MIH were in the anterior fossa P < .001, c2) or skull base location (62.5% vs 38.3%, P < .001, c2) and lower MIB-1 labeling index. Gross total resection was accomplished in 27.3% of tumors with MIH and 45.5% of nonhyperostotic meningiomas (P < .05, t test). There was no association between MIH and histological World Health Organization grade (P = .32, c2). MIH was significantly more frequent in meningiomas from the Merlin-intact DNA methylation group (P < .05). Somatic missense mutations in the WD-repeat-containing domain of the TRAF7 gene were the most common genetic alteration associated with MIH (n = 12 of 15, 80%, P < .01, c2). CONCLUSION: In this article, we show that MIH has a predilection for the anterior skull base and affected tumors are less amenable to gross total resection. We find no association between MIH and histological World Health Organization grade, but show that MIH is more common in the Merlin-intact DNA methylation group and is significantly associated with TRAF7 somatic missense mutations. These data provide a framework for future investigation of biological mechanisms underlying MIH.

RNA splicing as a biomarker and phenotypic driver of meningioma DNA methylation groups.

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. CONCLUSIONS: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.

Genomic alterations associated with postoperative nodular leptomeningeal disease after resection of brain metastases.

OBJECTIVE: The relationship between brain metastasis resection and risk of nodular leptomeningeal disease (nLMD) is unclear. This study examined genomic alterations found in brain metastases with the aim of identifying alterations associated with postoperative nLMD in the context of clinical and treatment factors. METHODS: A retrospective, single-center study was conducted on patients who underwent resection of brain metastases between 2014 and 2022 and had clinical and genomic data available. Postoperative nLMD was the primary endpoint of interest. Targeted next-generation sequencing of > 500 oncogenes was performed in brain metastases. Cox proportional hazards analyses were performed to identify clinical features and genomic alterations associated with nLMD. RESULTS: The cohort comprised 101 patients with tumors originating from multiple cancer types. There were 15 patients with nLMD (14.9% of the cohort) with a median time from surgery to nLMD diagnosis of 8.2 months. Two supervised machine learning algorithms consistently identified CDKN2A/B codeletion and ERBB2 amplification as the top predictors associated with postoperative nLMD across all cancer types. In a multivariate Cox proportional hazards analysis including clinical factors and genomic alterations observed in the cohort, tumor volume (× 10 cm3; HR 1.2, 95% CI 1.01-1.5; p = 0.04), CDKN2A/B codeletion (HR 5.3, 95% CI 1.7-16.9; p = 0.004), and ERBB2 amplification (HR 3.9, 95% CI 1.1-14.4; p = 0.04) were associated with a decreased time to postoperative nLMD. CONCLUSIONS: In addition to increased resected tumor volume, ERBB2 amplification and CDKN2A/B deletion were independently associated with an increased risk of postoperative nLMD across multiple cancer types. Additional work is needed to determine if targeted therapy decreases this risk in the postoperative setting.