Telescoping flow diverters for a pediatric fusiform distal anterior cerebral artery aneurysm: technical case report.

BACKGROUND AND IMPORTANCE: Pediatric intracranial aneurysms are rare, with fusiform aneurysms of the distal anterior circulation even more so. A limited number of prior reports detail the management of this pathology. CLINICAL PRESENTATION: We report a case of a 15-year-old boy presenting with new-onset headache found to have a 3.1 cm × 1.4 cm × 1.4 cm fusiform partially thrombosed aneurysm of the A2 segment of the left anterior cerebral artery. Subsequent treatment with flow diversion resulted in the placement of five telescoping PEDs (2.5 mm × 20 mm, 2.75 mm × 20 mm, 2.75 mm × 20 mm, 3 mm × 25 mm, and 3 mm × 20 mm) from the left pericallosal artery to the left A1 segment. Catheter-based angiography at 6 months post-placement indicated normal vessel caliber, no residual aneurysm, and no in-stent stenosis. The patient's headache resolved after treatment. CONCLUSION: Telescoping PEDs are a feasible low-risk treatment option for long-segment fusiform distal ACA aneurysms in children that can have optimal clinical and radiographic outcomes.

Does stroke etiology influence outcome in the posterior circulation? An analysis of 107 consecutive acute basilar occlusion thrombectomies.

OBJECTIVE: Acute basilar artery occlusion (BAO) harbors a more guarded prognosis after thrombectomy compared with anterior circulation large-vessel occlusion. Whether this is a function of a greater proportion of atherosclerotic/intrinsic lesions is not well studied. The authors aimed to elucidate the prevalence and predictors of intracranial intrinsic atherosclerotic disease in patients with acute BAO and to compare angiographic and clinical outcomes between patients with BAO secondary to embolic versus intrinsic disease. METHODS: A prospectively maintained stroke database was reviewed for all patients presenting between January 2013 and December 2019 to a tertiary care academic comprehensive stroke center with acute, nontandem BAO. Patient data were extracted, subdivided by stroke mechanism and treatment modality (embolic [thrombectomy only] and intrinsic [thrombectomy + stenting]), and angiographic and clinical results were compared. RESULTS: Of 107 patients, 83 (78%) had embolic occlusions (thrombectomy only) and 24 (22%) had intrinsic disease (thrombectomy + stenting). There was no significant difference in patient age, presenting National Institutes of Health Stroke Scale score, time to presentation, selected medical comorbidities (hypertension, hyperlipidemia, diabetes, and atrial fibrillation), prior stroke, and posterior circulation Alberta Stroke Program Early CT Score. Patients with intrinsic disease were more likely to be active smokers (50% vs 26%, p = 0.04) and more likely to be male (88% vs 48%, p = 0.001). Successful recanalization, defined as a modified Thrombolysis in Cerebral Infarction (mTICI) grade of 2b or 3, was achieved in 90% of patients and did not differ significantly between the embolic versus intrinsic groups (89% vs 92%, p > 0.99). A 90-day good outcome (modified Rankin Scale [mRS] score 0-2) was found in 37% of patients overall and did not differ significantly between the two groups (36% vs 41%, p = 0.41). Mortality was 40% overall and did not significantly differ between groups (41% vs 36%, p = 0.45). CONCLUSIONS: In the current study, demographic and clinical results for acute BAO showed that compared with intrinsic disease, thromboembolic disease is a more common mechanism of acute BAO, with 78% of patients undergoing thrombectomy alone. However, there was no significant difference in revascularization and outcome results between patients with embolic disease and those with intrinsic disease.

Biographies of international women leaders in neurosurgery.

We received so many biographies of women neurosurgery leaders for this issue that only a selection could be condensed here. In all of them, the essence of a leader shines through. Many are included as "first" of their country or color or other achievement. All of them are included as outstanding-in clinical, academic, and organized neurosurgery. Two defining features are tenacity and service. When faced with shocking discrimination, or numbing indifference, they ignored it or fought valiantly. When choosing their life's work, they chose service, often of the most neglected-those with pain, trauma, and disability. These women inspire and point the way to a time when the term "women leaders" as an exception is unnecessary.-Katharine J. Drummond, MD, on behalf of this month's topic editors.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Disrupted Surfaces of Porous Membranes Reduce Nuclear YAP Localization and Enhance Adipogenesis through Morphological Changes.

The disrupted surface of porous membranes, commonly used in tissue-chip and cellular coculture systems, is known to weaken cell-substrate interactions. Here, we investigated whether disrupted surfaces of membranes with micron and submicron scale pores affect yes-associated protein (YAP) localization and differentiation of adipose-derived stem cells. We found that these substrates reduce YAP nuclear localization through decreased cell spreading, consistent with reduced cell-substrate interactions, and in turn enhance adipogenesis while decreasing osteogenesis.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

First Female Neurosurgeon in the United States: Dorothy Klenke Nash, MD.

Dr Dorothy Klenke Nash (1898-1976) became the first female neurosurgeon in the United States in 1928 and maintained her status as the country's only female neurosurgeon until 1960. She graduated with her medical degree from the Columbia College of Physicians and Surgeons in 1927 and then trained at the Neurologic Institute of New York under Dr Byron Stookey. During her training, she contributed to the advancement of neurosurgical practice through academic research. In 1931, she married Charles B. Nash, and together they had 2 children, George (1932) and Dorothy Patricia (1937). Dr Nash became a senior surgeon at St. Margaret's Hospital in Pittsburgh in 1942. Shortly thereafter, she joined the inaugural University of Pittsburgh Department of Neurosurgery led by Dr Stuart N. Rowe and became an instructor of neurosurgery at the University of Pittsburgh School of Medicine. In acknowledgment of her advocacy for public access to services for mental health and cerebral palsy, Dr Nash was recognized as a Distinguished Daughter of Pennsylvania (1953) and honored by Mercy Hospital (1957), Bryn Mawr College (1960), and Columbia University (1968). She retired from neurosurgical practice in 1965, at which time she devoted herself to her grandchildren and her Catholic faith. She died on March 5, 1976 at the age of 77. With unwavering tenacity, Dr Nash paved the way for all women in neurosurgery.

Evaluation of free-hand screw placement in cervical, thoracic, and lumbar spine by neurosurgical residents.

BACKGROUND: Knowledge of free-hand screw technique remains critical to adequately train neurosurgical residents. The purpose of this study was to evaluate the accuracy of screw placement via the free-hand technique in lumbar, thoracic, and cervical spine by neurosurgical residents completing an enfolded spine fellowship. METHODS: Medical records of all patients who underwent free-hand screw placement at all spinal levels over a 6-month period by senior neurosurgical residents enrolled in an in-folded spine fellowship were retrospectively reviewed. Postoperative CT images were assessed for presence and direction of cortical breach. RESULTS: Twenty-six patients underwent 162 free-hand screw placements. The most commonly placed screws were cervical lateral mass screws (n = 69), thoracic (n = 41), and lumbar pedicle screws (n = 41). The most common indication for surgery was deformity (n = 22), followed by infection (n = 2) and trauma (n = 2). Fifty-five breaches were identified in 44 (27 %) screws placed in 21 patients (81 %). Anterior breach was identified in 22 cases (40.0 %), lateral in 12 (23.6 %), superior in 7 (12.7 %), and inferior in 7 (12.7 %), and medial in 6 (10.9 %). The most common level of breach was observed in cervical lateral mass screws (n = 19, 43 %) and least common in C2 pars screws (n = 1, 2%). With an average length of follow up of 12.1 ± 7.7 months of follow-up, no clinical sequalae of screw breach was observed. CONCLUSIONS: Despite the high prevalence of screw breach using the free-hand technique by neurosurgical residents, the absence of clinical sequelae implies safety and emphasizes the importance of early exposure to this technique during neurosurgical residency training.

Socioeconomic Implications of Professional Relationships within Modern Care Delivery Systems.

No physician can successfully deliver high-value patient care in the modern-day health care system in isolation. Delivery of effective patient care requires integrated and collaborative systems that depend on dynamic professional relationships among members of the health care team. An overview of the socioeconomic implications of professional relationships within modern care delivery systems and potential employment models is presented.

A History of the Lobes of the Brain.

The division of the cerebrum into 5 lobes is widely accepted in the scientific community. Despite this, a history of the lobes of the brain has not been discussed in the literature. Therefore, this article recounts this history with emphasis on the contributions of Thomas Willis (1664), Felix Vicq d'Azyr (1796), Johann-Christian Reil (1796), François Chaussier (1807), and Louis Pierre Gratiolet and François Leuret (1857) into one of the most widely accepted concepts in neuroanatomy.

Rare Transsellar Collateral Artery and Secondary Ophthalmic Artery Aneurysm in a Young Adult with Internal Carotid Artery Aplasia.

Internal carotid artery (ICA) aplasia is a rare congenital abnormality in which the third aortic arch fails to develop. Most collateral circulation will originate from the circle of Willis, with other sites being rare. Changes in flow through the collateral vasculature result in aneurysm formation at a young age. A 38-year-old woman had an incidental diagnosis of left ICA aplasia and right ophthalmic artery aneurysm. Arteriography demonstrated that the left supraclinoid ICA originated from the right cavernous ICA and appeared as an anomalous hypertrophied transsellar artery on angiography. Her flow-related aneurysm was treated uneventfully. The present case demonstrates an extremely rare Lie type D collateralization pattern and secondary flow-rated aneurysm in the context of ICA aplasia. Patients identified with this anatomic variant should be monitored for subsequent aneurysm formation. Identification of this variant before endovascular and transsphenoidal procedures is crucial to prevent major intracranial vessel injury.

Porous Substrates Promote Endothelial Migration at the Expense of Fibronectin Fibrillogenesis.

Porous substrates have gained increased usage in cell studies and tissue mimetic applications because they can partition distinct cell types while still allowing important biochemical crosstalk. In the presented work, we investigated how porous substrates with micron and submicron features influence early cell migration and the associated ECM establishment, which can critically affect the rate of cell coverage on the substrate and the ensuing tissue organization. We showed through time-lapse microscopy that cell speed and migratory distance on membranes with 0.5 µm pores were nearly two-fold of those observed on nonporous membranes, while values on membranes with 3.0 µm pores fell in between. Although the cell directionality ratio and the persistence time was unaffected by the presence of pores, the cells did exhibit directionality preferences based on the hexagonal pore patterning. Fibronectin fibrillogenesis exhibited a distinct inverse relationship to cell speed, as the fibrils formed on the nonporous control were significantly longer than those on both types of porous substrates. We further confirmed on a per cell basis that there is a negative correlation between fibronectin fibril length and cell speed. The observed trade-off between early cell coverage and ECM establishment thus warrants consideration in the selection or the engineering of the ideal porous substrate for tissue mimetic applications and may help guide future cell studies.

Membrane Pore Spacing Can Modulate Endothelial Cell-Substrate and Cell-Cell Interactions.

Mechanical cues and substrate interaction affect the manner in which cells adhere, spread, migrate and form tissues. With increased interest in tissue-on-a-chip and co-culture systems utilizing porous membranes, it is important to understand the role of disrupted surfaces on cellular behavior. Using a transparent glass membrane with defined pore geometries, we investigated endothelial fibronectin fibrillogenesis and formation of focal adhesions as well as development of intercellular junctions. Cells formed fewer focal adhesions and had shorter fibronectin fibrils on porous membranes compared to non-porous controls, which was similar to cell behavior on continuous soft substrates with Young's moduli seven orders of magnitude lower than glass. Additionally, porous membranes promoted enhanced cell-cell interactions as evidenced by earlier formation of tight junctions. These findings suggest that porous membranes with discontinuous surfaces promote reduced cell-matrix interactions similarly to soft substrates and may enhance tissue and barrier formation.

Ultrathin transparent membranes for cellular barrier and co-culture models.

Typical in vitro barrier and co-culture models rely upon thick semi-permeable polymeric membranes that physically separate two compartments. Polymeric track-etched membranes, while permeable to small molecules, are far from physiological with respect to physical interactions with co-cultured cells and are not compatible with high-resolution imaging due to light scattering and autofluorescence. Here we report on an optically transparent ultrathin membrane with porosity exceeding 20%. We optimize deposition and annealing conditions to create a tensile and robust porous silicon dioxide membrane that is comparable in thickness to the vascular basement membrane (100-300 nm). We demonstrate that human umbilical vein endothelial cells (HUVECs) spread and proliferate on these membranes similarly to control substrates. Additionally, HUVECs are able to transfer cytoplasmic cargo to adipose-derived stem cells when they are co-cultured on opposite sides of the membrane, demonstrating its thickness supports physiologically relevant cellular interactions. Lastly, we confirm that these porous glass membranes are compatible with lift-off processes yielding membrane sheets with an active area of many square centimeters. We believe that these membranes will enable new in vitro barrier and co-culture models while offering dramatically improved visualization compared to conventional alternatives.