bluuebunny/crossref_metadata_2025_split huggingface dataset:
519 Single Nucleus ATAC Sequencing Reveals Increased PPP1R17 Chromatin Accessibility Driving Cushing’s Disease
Authors: Asuzu David , Stoica Stefan , Elkahloun Abdel , Johnson Kory , Chittiboina Prashant 
Published: March 2023

INTRODUCTION:
Epigenetic drivers of pituitary adenomas causing Cushing’s disease (CD) are virtually unknown. Here, we investigate the epigenetic mechanisms underlying gene dysregulation in CD.

METHODS:
We isolated single nuclei from 3 CD adenoma – normal gland pairs and performed single nucleus RNA sequencing (snRNAseq) and assays for transposase-accessible chromatin (snATACseq, 10x Genomics). We integrated these data with prior paired single cell data (scRNAseq, n = 3) and bulk RNAseq (CD = 3, non-CD = 3). We performed bulk DNA methylation assays on independent adenomas (CD = 3, non-CD = 3; Illumina Infinium MethylationEPIC). CD adenomas were examined by multiplexed immunohistochemistry (mIHC). We generated murine corticotroph (mCort) cell lines stably transfected with lentiviral expression vectors (Origene) and assessed for cell-cycle changes (Click-IT EdU) and cell proliferation (OneGlo).

RESULTS:
snATACseq and snRNAseq data identified increased chromatin accessibility with upregulated PPP1R17 expression in single nuclei from CD adenomas, in agreement with our prior scRNAseq and bulk RNAseq data (16-fold in paired analysis, FDR < 0.01). DNA methylation failed to identify global or local differential methylation at the PPP1R17 locus. mIHC confirmed PPP1R17 protein overexpression in human CD tumors. PPP1R17 overexpression in mCort cells accelerated the cell cycle with fewer cells accumulating in S-phase (16.4% vs 24.1%, P < 0.01), and increased cell proliferation (two-way ANOVA P < 0.01).

CONCLUSIONS:
We identified coordinated chromatin accessibility, transcriptional activation and protein expression of PPP1R17 in human CD adenomas compared to surrounding normal tissues, and recapitulated hyperproliferation in-vitro by stable PPP1R17 overexpression. Our findings uncover targetable epigenetic mechanisms in CD pathogenesis.
520 Glioblastoma Susceptibility to SARS-CoV-2: Analysis of Cancer Stem Cells and Immune Tumor Microenvironment on Human Brain, Patient-Derived Tumors, and Organoid Models
Authors: Ruiz Garcia Henry Jeison , Watanabe Fumihiro , Suarez-Meade Paola , Rafferty Seamus , Garcia Diogo P. , Jentoft Mark E. , Schiapparelli Paula , Imitola Jaime , Quinones-Hinojosa Alfredo 
Published: March 2023

INTRODUCTION:
Glioblastoma (GBM) is the most common and deadliest primary brain tumor, characterized by chemoradiation resistance and an immunosuppressive tumor microenvironment (TME). SARS-CoV-2, the COVID-19 virus, produces a significant pro-inflammatory response and a spectrum of clinical presentations after central nervous system infection.

METHODS:
Patient-derived GBM tissue, primary cell lines, and organoids were analyzed with immunohistochemistry and pixel-line intensity quantification. Data from tumor-bulk and single-cell transcriptomics served to describe the cell-specific expression of SARS-CoV-2 receptors in GBM and its association with the immune TME phenotype. Normal brain and iPSC-derived organoids served as controls.

RESULTS:
We demonstrate that patient-derived GBM tissue and cell cultures express SARS-CoV2 entry factors such as ACE2, TMPRSS2, and NRP1. NRP1 expression was higher in GBM than in normal brains (p<0.05), where it plays a crucial role in SARS-CoV-2 infection. NRP1 was expressed in a cell-type and phenotype-specific manner and correlated with TME infiltration of immunosuppressive cells: M2 macrophages (r = 0.229), regulatory T cells (r = 0.459), NK cells (r = -0.346), and endothelial cells (r = 0.288) (p < 0.05). Furthermore, gene ontology enrichment analysis showed that leukocyte migration and chemotaxis are among the top 5 biological functions mediated by NRP1 (p < 0.05). We found our GBM organoids recapitulate tumoral expression of SARS-CoV-2 entry factors, which varies based on distance from surface as surrogate of TME oxygenation (p < 0.05).

CONCLUSIONS:
GBM cancer cells and immune TME cells express SARS-CoV-2 entry factors. Glioblastoma organoids recapitulate this expression and allow for currently undergoing studies analyzing the effect of SARS-CoV-2 infection in GBM. Our findings suggest that SARS-CoV-2 could potentially target GBM, opening the door to future studies evaluating SARS-CoV-2-driven immune modulation.
522 Metabolomic Analysis of 54 Meningiomas Reveals Distinct Metabolite Profiles in WHO 1 and WHO 2/3 Tumors
Authors: Dougherty Mark Chrysostom , Taylor Eric , Hansen Marlan 
Published: March 2023

INTRODUCTION:
Meningiomas are the most common primary CNS tumor. Yet when surgical and radiation fail, no further treatments exist. Metabolomics is the study of metabolic networks and has been used to discover new treatments in cancers; however, few attempts have been made to apply metabolomics to meningiomas.

METHODS:
Primary tumors were obtained from surgeries at the University of Iowa. Primary tumor specimens were immediately flash-frozen in liquid nitrogen, while tissue for culture was placed on ice and immediately transferred for cell culturing. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation. Six or 72 hours after radiation the cultures were washed then flash frozen in liquid nitrogen. Metabolomic profiles were obtained with a ThermoISQ gas chromatography-mass spectrometer. Data was analyzed using MetaboAnalyst 5.0.

RESULTS:
Forty WHO grade 1 and fourteen WHO grade 2/3 tumors were included. Eleven tumors were also successfully cultured. Partial least squares-discriminant analysis (PLS-DA) demonstrated expected clustering of primary tumors according to pathologic grade. Among the primary tumors, 12 metabolites were found to be significantly elevated in WHO grade 2/3 tumors.In parallel, primary cell cultures were developed to test the effect of radiation on the tumors, but unsupervised clustering found that inter-tumor heterogeneity was greater than the treatment effect from radiation.

CONCLUSIONS:
High-grade meningiomas display distinct metabolite levels compared to benign meningiomas, suggestive of altered metabolic pathway utilization. Standard cell cultures did not reveal significant metabolic changes following radiation, but it is unclear whether this was due to technique or a true finding. Further experiments are needed to elucidate the functional implications of these findings.
526 Clinical Characteristics and Biomarkers of Aggressive Nonfunctional Pituitary Adenomas and Pituitary Carcinomas
Authors: Aum Diane J. , Hwang Jenie , Rovira Miguel Hernandez , Martirossian Alexandra , Blount Sidney , Silverstein Julie , Kim Albert H. 
Published: March 2023

INTRODUCTION:
Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland. While surgery is the treatment of choice, a subset of aggressive NFPAs is associated with multiple recurrences and treatments. Pituitary carcinomas are a rare group of pituitary tumors, comprised of both functional and non-functional, which metastasize to other locations.

METHODS:
A retrospective review of 601 consecutive patients who underwent endoscopic transsphenoidal surgery between 2010 and 2018 at one institution was conducted. Among 209 NFPA patients, 29 patients had aggressive NFPAs, with ≥2 recurrences and ≥3 treatments. We used Infinium HumanMethylation450 BeadChip arrays along with R (R Core 2014) and Bioconductor for methylation analysis of patients with indolent NFPAs (n = 6), aggressive NFPAs (n = 8), pituitary carcinomas (n = 9), and normal pituitary glands (n=3).

RESULTS:
In multivariate analysis of clinical features, tumor volume and proliferative index were higher in aggressive NFPAs compared to indolent NFPAs. Although significantly different, these features were not specific to aggressive NFPAs. Methylation analysis showed no significant global methylation differences among all samples. However, we identified significant probe-wise differentiation in methylation of over 100 genes between indolent and aggressive NFPA groups. Heat map representation of the most significant differentially methylated genes demonstrated similarity in methylation patterns between the aggressive NFPA and pituitary carcinoma group, which were distinct from the indolent group.

CONCLUSIONS:
Tumor volume and proliferative index were significantly increased in the aggressive compared to the indolent group. In DNA methylation analyses, we identified numerous hypermethylated genes in the aggressive and pituitary carcinoma groups, which were distinct from the indolent group. DNA methylation may provide a useful predictive biomarker to identify aggressive NFPA types and potentially reveal common mechanistic links between aggressive NFPAs and pituitary carcinomas.
528 Robotic Image-Guided LINAC Radiosurgery for Trigeminal Neuralgia: Results After 10 Years
Authors: Romanelli Pantaleo , Thomas Evan M. 
Published: March 2023

INTRODUCTION:
Frameless image-guided robotic radiosurgery delivering 60 Gy to a 6mm mid-cisternal/retrogasserian segment of the affected trigeminal nerve was used to treat 702 patients affected by severe Trigeminal Neuralgia(TN) refractory to medications . Clinical outcomes in 92 patients with minimum follow-up of 10 years are here reported.

METHODS:
702 patients with severe, long-standing TN refractory to medications have been treated at the Cyberknife Center of CDI,Milan,Italy over the last 13 years. A dedicated protocol for imaging ( head CT with and without contrast, slice thickness 0,5 mm; brain MR including MPRAGE and CISS/FIESTA sequences) and treatment( selecting a 6 mm segment of the nerve going from the midcisternal toward the retrogasserian region with a dose prescription of 60Gy @80% isodose) was employed. Regular clinical follow-up was performed one or more times per year according to clinical needs and distance from the treatment. Recurrent pain was treated with the same protocol( a lower dose of 45 Gy was later selected for retreatments).

RESULTS:
Pain control rates of 92%,87%,76%,74% after respectively 1,2, 3 and 5 years have been found. 92 patients with follow-up longer than 10 years show pain control rate of 72% while the rate of persistent bothering parethesias is 5, 4% (5 patients). No other neurological complications have been found.

CONCLUSIONS:
Long-term follow-up shows that frameless Linac radiosurgery provides long-term pain control in over 2/3 of the treated patients, with low rate of sensory complications and no other neurological complications.
529 Neuro-Oncology Practice Patterns and Management Paradigms: A Global Epidemiological Survey
Authors: Haizel-Cobbina Joseline , Chotai Silky , Labuschagne Jason , Belete Addisalem , Sichizya Kachinga , Ahmad Misbahu Haruma , Nketiah Boakye Frank , Shabani Hamisi , Dewan Michael C. 
Published: March 2023

INTRODUCTION:
Understanding of the epidemiology and biology of pediatric central nervous system (CNS) tumors has advanced dramatically over the last decade; however there remains a discrepancy in the understanding of epidemiologic and clinical capacity-oriented data between high income and low middle- or low-income countries.

METHODS:
A cross sectional epidemiological survey was conducted to determine the incidence, diagnosis, management, and follow-up paradigm for pediatric CNS tumors using REDCap. The survey was administered to neurosurgeons at partner hospitals, collecting aggregate data for patients managed over the preceding 3-months. The survey was sent to the sites 3 times at 3-months interval. Descriptive statistics analyses were performed.

RESULTS:
Fourteen percent of outpatient and 13% of operative volume was represented by pediatric neuro-oncology at the partner sites. Only one site had no diagnostic modality available at, others had either CT scan only or both CT scan and MRI. Of 214 patients evaluated, 128 (59.8%) underwent surgery and 16 (7.5%) were referred to other centers. Mean 29.2% patients did not undergo surgery due to inadequate resources. Mean 44.4% received adjuvant chemotherapy and 27.6% received adjuvant radiotherapy when indicated. The most common tumor location was posterior fossa (26.7%). The most common pathology diagnosis was low grade glioma (17.4%). None of the six partner sites had neuropathology expertise.

CONCLUSIONS:
A wide variety of pediatric brain and spine tumor pathology was managed at these six national referral sites in Sub-Saharan African countries. The histopathological profile of the tumors managed at these sites was akin to previously published studies. Further resource allocation focusing on setting up pediatric neuro-neuro-oncology practices might improve care for these patients.
550 Hospital Frailty Risk Score is an Independent Risk Factor for VP Shunt Placement for Ruptured Intracranial Aneurysms
Authors: Koo Andrew B. , Elsamadicy Aladine A. , Sarkozy Margot , Reeves Benjamin , Craft Samuel , Sherman Josiah , Sayeed Sumaiya , Antonios Joseph Paul , Renedo Daniela , Sujijantarat Nanthiya , Hebert Ryan Matthew , Malhotra Ajay , Matouk Charles Christian 
Published: March 2023

INTRODUCTION:
Frailty is an important predictor of poor surgical outcomes. Identifying patients who will require ventriculoperitoneal (VP) shunt placement following endovascular management for ruptured intracranial aneurysms (IA) remains poorly understood.

METHODS:
A retrospective study of the National Inpatient Sample database (2016-2019) was performed. Patients ≥18 years old undergoing endovascular treatment for IA after subarachnoid hemorrhage identified using ICD-10-CM coding were dichotomized by whether they underwent VP shunt placement during the index admission. Only patients with coding for initial external ventricular drain placement were included. Demographics, comorbidities, adverse events (AEs), LOS, discharge disposition and total cost were assessed. A multivariate analysis was used to assess the influence of HFRS on VP shunt placement.

RESULTS:
Of the 12,935 patients identified, 2,805 (21.7%) required VP shunt placement. The shunt population was older (No Shunt: 56.6 ± 13.5 years vs. Shunt: 58.5 ± 12.6 years, p = 0.002). HFRS-defined frailty was greater in the shunted population (No Shunt: 11.1±5.4 vs Shunt: 12.3 ± 5.5, p<0.001). The shunted population experienced more AEs (No Shunt: 83.2% vs. Shunt: 89.5%, p < 0.001). Mean LOS (No Shunt: 23.0 ± 13.6 days vs Shunt: 31.7 ± 18.9 days, p<0.001), mean cost (No Shunt: $115,808 ±64,428 vs Shunt: $160,024 ± 92,014, p < 0.001), and non-routine discharge (No Shunt: 64.5% vs Shunt: 79.9%, p < 0.001) were greater in patients shunted. On multivariate analysis, several risk-factors were associated with VP shunt placement, including frailty, age, female sex, hydrocephalus, dysphagia, pulmonary circulation disorders, other neurological disorders, and aneurysm location. The odds ratio for Frailty was 1.53 (p = 0.025) for intermediate-frailty patients and 1.69 (p=0.011) for high-frailty patients compared to low-frailty patients.

CONCLUSIONS:
Our study demonstrates that HFRS is an independent predictor of VP shunt placement following endovascular treatment of ruptured intracranial aneurysms.
553 Mechanical Thrombectomy for the Treatment of Anterior Cerebral Artery Occlusion
Authors: Dabhi Nisha , Mastorakos Panagiotis , Sokolowski Jennifer D. , Kellogg Ryan Thomson , Park Min S. 
Published: March 2023

INTRODUCTION:
Strokes of the anterior cerebral artery (ACA) and its branches account for up to 4.4% of ischemic strokes and have been associated with disability after discharge. While mechanical thrombectomy (MT) has been established to be safe and highly effective in the treatment of thromboembolic occlusion of the middle cerebral artery, internal carotid artery, and basilar artery, to date, the safety and efficiency of MT for the treatment of acute ACA occlusions have not been clearly delineated.

METHODS:
A systematic literature review was performed for outcomes data in patients with MT-treated ACA occlusions using Pubmed, Ovid Medline, and Web of Science. Recanalization, procedural data, and clinical outcome at last follow-up were collected and summarized.

RESULTS:
In the nine included studies, there were 196 patients with ACA strokes treated with MT, of which 65% (109/168), 34% (57/168), and 33% (56/168) had primary isolated ACA occlusion, primary combined ACA occlusion, and secondary ACA occlusion, respectively. Recanalization mTICI2b/3 was achieved in 80% (134/168), and procedural complications occurred in 23% (39/168) of patients. At the three-month follow-up, mortality rate was 19% (20/106) and rate of good functional outcome was 32% (48/148).

CONCLUSIONS:
MT for the treatment of ACA occlusions is a relatively safe and efficacious option, offering a favorable rate of recanalization and procedural complications. However, MT-treated ACA occlusions are associated with a lower rate of short-term good functional outcome. More single and multicenter studies are needed to further examine the safety and efficacy of MT in ACA occlusions.
555 A Shift from Open to Endovascular Repair in the Treatment of Ruptured Middle Cerebral Artery Aneurysms and its Association With Improved 6-Month Functional Outcomes: A Single Institution Experience
Authors: Diestro Jose Danilo , Li Yangmei , Omar Buddy , Kishore Kislay , Montanera Walter , Sarma Dipanka , Marotta Thomas , Spears Julian , Baratha Aditya 
Published: March 2023

INTRODUCTION:
Middle cerebral aneurysms were underrepresented in the two largest trials (BRAT and ISAT) for the treatment of ruptured intracranial aneurysms. Recent institutional series addressing the choice between endovascular or open repair for this subset of aneurysms are few and have not yielded a definitive conclusion.

METHODS:
We conducted a retrospective review of 138 consecutive patients with ruptured middle cerebral artery aneurysms admitted into our institution from March 2009 to March 2019 to compare endovascular and open surgical outcomes.

RESULTS:
Of the ruptured middle cerebral artery aneurysms, 57 underwent endovascular repair while 81 were treated with open surgery. Over the study period there was a notable shift in practice toward more frequent endovascular treatment of ruptured MCA aneurysms (31% in 2008 vs. 91% in 2018). At discharge (49.1% vs 29.6%; p = .002) and at 6 months (84.3% vs 58.6%; p = 0.003), patients who underwent endovascular repair had a higher proportion of patients with good clinical outcomes (mRS 0-2) compared to those undergoing open surgery. Long term follow-up data (endovascular: 54.9 ± 37.9 months vs clipping: 18.6 ± 13.4 months) showed rebleeding (1.8% vs 3.7%, p = 0.642) and retreatment (5.3% vs 3.7%, p=0.691) in both groups.

CONCLUSIONS:
Our data suggest that endovascular repair was a feasible treatment strategy associated with improved functional outcome at 6 months. Future randomized trials for MCA aneurysms could further clarify the roles of these treatment modalities.
564 The Influence of Presenting Glucose and Glycated Hemoglobin on Outcomes Following Mechanical Thrombectomy for Anterior Circulation Large Vessel Occlusion
Authors: Hoffman Haydn , Wood Jacob , Cote John , Jalal Muhammad Safwan , Otite Fadar , Masoud Hesham , Gould Grahame C.D. 
Published: March 2023

INTRODUCTION:
Elevated presenting glucose and glycated hemoglobin (HbA1C) values may be associated with worse outcomes following mechanical thrombectomy (MT) for anterior circulation large vessel occlusion (ACLVO).

METHODS:
All patients who underwent MT for ACLVO between 2015 – 2021 at a single institution were reviewed. The outcomes included favorable functional status (modified Rankin Scale [mRS] 0 – 2) at 90 days, any intracranial hemorrhage (ICH), parenchymal hemorrhage, and malignant middle cerebral artery infarction (MMI). Multivariate logistic regression analyses adjusting for age, premorbid mRS, admission NIHSS, ASPECTS, collateral score, tPA administration, onset to reperfusion time, and TICI grade were performed. Youden’s index was used to identify thresholds for glucose and HbA1C that optimized area under the receiving operator characteristic curve for predicting outcomes.

RESULTS:
A total of 332 patients were included. The mean (SD) age was 70.9 years (15.1), 50.3% of patients were female, and 26.9% of patients had a history of diabetes. The median (IQR) presenting glucose, SGR, and HbA1C values were 118 mg/dL (40), 1.0 (0.35), and 5.7% (1.0), respectively. Presenting glucose was associated with any ICH (OR 1.38, 95% 1.08 – 1.80) and MMI (OR 1.48, 95% CI 1.06 – 2.03), but not functional status. SGR was not associated with any outcome. Presenting HbA1C was associated with MMI (OR 1.43, 95% 1.02 – 2.02) but not functional status or ICH. The optimal threshold among glucose values for predicting ICH and MMI were 167 mg/dL and 128 mg/dL, respectively. For HbA1c, the threshold for predicting MMI was 6.0.

CONCLUSIONS:
Presenting glucose and HbA1C were associated with MMI, and glucose was associated with ICH after MT for ACLVO. Improved glucose control prior to admission could decrease the odds of these events.
566 Role of STA-MCA Bypass in Recurrent Ischemic Stroke
Authors: Ferrarez Carlos Eduardo , Bertani Raphael , Batista Sávio , Perret Caio , Koester Stefan Wolfgang , Carvalho Tamires , Landeiro Jose Alberto 
Published: March 2023

INTRODUCTION:
In the recurrent scenario of ischemic strokes, clinicians are faced with the options of switching to a new antiplatelet medication or using a combination of antiplatelet medications in the acute setting and for long-term secondary stroke prevention, balancing future protective benefits and increased hemorrhagic risks.

METHODS:
Patients presenting recurrent ischemic stroke that were surgically treated with STA-MCA bypass at our hospital between 2016 and 2021. Criteria inclusion were patients diagnosed with a minor ischemic stroke or TIA in MCA or ICA territory, submitted or not to thrombolysis, without indication for mechanical thrombectomy, presenting with hypoperfusion > 10% in the affected vascular territory. Were excluded patients presenting malignant ischemic stroke >1/3 of the MCA territory, cardiogenic causes, or atherosclerotic disease in cervical carotid arteries.

RESULTS:
STA-MCA bypass was performed in 10 patients presenting recurrent ischemic stroke. There were 6 males and 4 female patients with an age ranging from 40 to 75 years and a mean age of 59.6 (SD 10.59). Presented initial etiologies were ICA occlusion (40%), MCA occlusion (30%), TIA (10%), Moyamoya disease (10%), and Vertebral Artery occlusion (10%). Middle Cerebral Artery (MCA) was the most common site affected (90%), and the mean initial NIHSS was 11.1 (SD 4.57). 1 Day after surgery, the NIHSS average was 11.1 (SD 4.57), followed by 8.3 (SD 4.98), and 6.7 (SD 5.92) average on days 3 and 14, respectively. When comparing pre-op NIHSS and post-op NIHSS, a significant improvement after STA-MCA Bypass (p = 0.0085) was found.

CONCLUSIONS:
STA-MCA Bypass can be a feasible option in recurrent ischemic strokes and can be indicated in some cases.