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Methods for quantifying gene expression 1 and chromatin accessibility 2 in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been technically challenging. In this study, we adapted the CUT&Tag method 3 to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment. An improved method for single-cell analysis of histone modifications is applied to stem cell differentiation and cancer.

IntroductionEndovascular embolization of intracranial meningiomas is commonly used as an adjunct to surgical resection. We sought to describe the anatomic locations and vascular supplies of meningiomas to identify characteristics predictive of successful preoperative endovascular embolization.MethodsWe conducted a retrospective review of 139 meningioma cases receiving cerebral angiograms for possible preoperative endovascular embolization at our institution between December 2000 and March 2017. The extent of embolization, arterial supply, anatomic location, and procedural complications were recorded for each case. Univariate and multivariate analyses were performed to identify tumor characteristics that predicted successful embolization.ResultsOf the total meningioma patients undergoing preoperative angiography, 78% (108/139) were successfully embolized, with a 2.8% periprocedural complication rate (3/108). Within the subset of patients with successful embolization, 31% (33/108) achieved complete angiographic embolization. Significant multivariate predictors of embolization (either partial or complete) were convexity/parasagittal locations (OR 5.15, 95% CI 0.93 to 28.54, p=0.060), meningohypophyseal trunk (MHT, OR 4.65, 95% CI 1.63 to 13.23, p=0.004), middle meningeal artery (MMA, OR 10.89, 95% CI 3.43 to 34.64, p<0.001), and ascending pharyngeal artery supply (APA, OR 9.96, 95% CI 1.88 to 52.73, p=0.007). Significant predictors for complete embolization were convexity/parasagittal locations (OR 4.79, 95% CI 1.66 to 13.84, p=0.004) and embolized APA supply (OR 6.94, 95% CI 1.90 to 25.39, p=0.003). Multiple arterial supply was a negative predictor of complete embolization (OR 0.38, 95% CI 0.15 to 0.98, p=0.05).ConclusionsTumor characteristics can be used to predict the likelihood of preoperative meningioma embolization. Parasagittal and convexity meningiomas, and those with APA supply, are most likely to achieve complete angiographic embolization.

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multi-omic single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multi-omic data with single-cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that modulate cell state transitions across subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches to an individual patient in a concurrent, adjuvant, or recurrent setting.

Advancements in immunotherapeutics promise new possibilities for the creation of glioblastoma (GBM) treatment options. Ongoing work in cancer stem cell biology has progressively elucidated the role of this tumor sub-population in oncogenesis and has distinguished them as prime therapeutic targets. Current clinical trials take a multifaceted approach with the intention of harnessing the intrinsic cytotoxic capabilities of the immune system to directly target glioblastoma cancer stem cells (gCSC) or indirectly disrupt their stromal microenvironment. Monoclonal antibodies (mAbs), dendritic cell (DC) vaccines, and chimeric antigen receptor (CAR) T cell therapies have emerged as the most common approaches, with particular iterations incorporating cancer stem cell antigenic markers in their treatment designs. Ongoing work to determine the comprehensive antigenic profile of the gCSC in conjunction with efforts to counter the immunosuppressive tumor microenvironment holds much promise in future immunotherapeutic strategies against GBM. Given recent advancements in these fields, we believe there is tremendous potential to improve outcomes of GBM patients in the continuing evolution of immunotherapies targeted to cancer stem cell populations in GBM.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood–brain barrier (BBB) penetration, hemodynamic complexities, and drug–tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

BACKGROUND AND IMPORTANCE:Moyamoya disease is a rare cerebrovascular disorder often treated by direct and indirect revascularization bypass techniques as a result of a typically devastating disease course and poor response to medical therapy. In this report, we describe the formation and subsequent management of a de novo arteriovenous fistula identified in the setting of a patient treated with direct bypass surgery, a previously unreported phenomenon. CLINICAL PRESENTATION:A 51-year-old woman presenting with Suzuki stage IV bilateral moyamoya disease underwent bilateral extracranial-to-intracranial superficial temporal artery--to--middle cerebral artery bypass without complication at our institution. At the 6-month follow-up, she demonstrated no evidence of residual neurological deficits or continued symptoms despite documentation of an arteriovenous fistula arising at the site of the right extracranial-to-intracranial bypass on routine follow-up cerebral angiography. CONCLUSION:We present the first reported case of de novo arteriovenous fistula formation after superficial temporal artery-to-middle cerebral artery bypass for the treatment of moyamoya disease. Treatment of such iatrogenic arteriovenous fistulae fed by a patent bypass vessel may prove challenging without associated compromise of the bypass, meriting careful evaluation of all potential therapeutic options. The fistula described herein most likely occurred secondary to recanalization of a previously thrombosed vein of Trolard. This case demonstrates the possibility of arteriovenous fistula formation as a potential sequela of revascularization bypass surgery and lends support to the previously described traumatic origin of fistula formation. ABBREVIATIONS:AVF, arteriovenous fistulaEC-IC, extracranial-to-intracranialMCA, middle cerebral arterySTA, superficial temporal artery

Basilar tip aneurysm clipping is technically challenging because of the depth of operative corridor, rarity in presentation, and important perforators supplying deep, critical structures. Two major approaches to basilar tip aneurysms include (1) a frontotemporal (transorbital) trans-sylvian approach for most aneurysms and (2) a modified subtemporal approach for aneurysms with low-lying necks. A 53-yr-old woman presented to our institution with a large unruptured basilar tip aneurysm notable for a low, broad neck (6.4 mm). After discussion of risks and benefits of endovascular vs surgical options, the patient consented to operative intervention. She underwent a right frontotemporal craniotomy with zygomatic osteotomy, intradural petrous apicectomy, elective sectioning of the fourth cranial nerve (CN IV), and intracavernous removal of the dorsum sellae and posterior clinoid process to provide more space for aneurysm dissection. After temporary clipping of the basilar artery, the perforating arteries were dissected free from the aneurysm and the aneurysm occluded with 2 fenestrated clips. Important technical nuances of the approach include (1) achieving ample working room for temporary occlusion aneurysm dissection, (2) careful dissection of the perforators and contralateral P1, and (3) utilization of 2 fenestrated clips to accommodate and preserve the ipsilateral P1 segment. Postoperative angiogram showed complete aneur-ysmal occlusion. Postoperatively, the patient demonstrated mild cognitive impairment and a right CN IV palsy. At 6-wk follow-up, cognition recovered to normalcy. More recently, at 12-mo follow-up, the patient noted intermittent diplopia. Formal neuro-ophthalmologic assessment confirmed persistence of a CN IV palsy treated with prism lenses but no other neurological deficits.

Abstract BACKGROUND: The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis. OBJECTIVE: Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells. METHODS: Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated. RESULTS: PDGFRαhiCD15hi cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree. CONCLUSION: Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.

The use of CyberKnife (CK) stereotactic radiosurgery (SRS) for the management of central nervous system chondrosarcomas has not been previously reported. To evaluate outcomes of primary, recurrent, and metastatic chondrosarcomas of the skull base and spine treated with CK SRS, a retrospective observational study of 16 patients treated between 1996 and 2011 with CK SRS was performed using an IRB-approved database at Stanford University Medical Center. Twenty lesions (12 cranial, 8 spinal) across six males and ten females were analyzed. The median age at SRS was 51 years and median follow-up was 33 months. Median tumor volume was 11.0 cm 3 and median marginal dosages were 22, 24, 26, 27, and 30 Gy for one to five fractionations, respectively. Overall Kaplan–Meier survival rates were 88, 88, 80, and 66 % at 1, 3, 5, and 10 years after initial presentation. Survival rates at 1, 3, and 5 years after CK were 81, 67, and 55 %, respectively. Actuarial tumor control was 41 ± 13 % at 60 months. At 36 months follow-up, tumor control was 80 % in primary lesions, 50 % in recurrent lesions, and 0.0 % in metastatic disease ( p  = 0.07). Tumor control was 58 % in cranial lesions and 38 % in spinal lesions. Radiation injury was reported in one patient. CK SRS appears to be a safe adjuvant therapy and offers moderate control for primary cranial chondrosarcoma lesions. There appears to be a clinically, albeit not statistically, significant trend towards poorer outcomes in similarly treated metastatic, recurrent, and spinal chondrosarcomas ( p  = 0.07). Lesions not candidates for single fraction SRS may be treated with hypofractionated SRS without increased risk for radiation necrosis.