bluuebunny/crossref_metadata_2025 huggingface dataset:
370 Single-Cell Analysis of Human Glioma and Immune Cells Identifies S100A4 as an Immunotherapy Target
Authors: Huntoon Kristin , Abdelfattah Nourhan , Wang Caiyi , Kumar Parveen , Jiang Wen , Kim Betty Y. S. , George Joshy , Yun Kyuson
Published: March 2023

INTRODUCTION:

Tumor-associated myeloid cells are critical regulators of tumor progression, metastasis, and immune evasion and are promising therapeutic targets. However, elucidating their functional and molecular heterogeneity in human cancers has been challenging given a lack of lineage-specific markers and their highly plastic nature, which precludes faithful modeling and analysis in vitro. Therefore a major rate-limiting step in developing more effective immunotherapies for glioblastoma (GBM) is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas.

METHODS:

Via RNAseq we integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level generating multi-regional and -dimensional analyses of human gliomas and in doing so map GBM cellular heterotypia and spatial, molecular, and functional heterogeneity of glioma and associated stromal cells, including immune cells.

RESULTS:

We discovered extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100A4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival.

CONCLUSIONS:

This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.
373 Exploring Principles of the Interplay Between Cancer Stem Cells and Cancer Activated Fibroblasts Towards Advanced Therapies Against Glioblastoma
Authors: Lubanska Dorota , Soliman Mohamed AR , Alrashed Sami , Shamisa Abdalla , DeCarvalho Ana , Cieslukowski Alan , Nadeem Fatima , Kulkarni Swati , Porter Lisa
Published: March 2023

INTRODUCTION:

The extremely poor response to therapy, resulting in relapse of patients with GBM, is attributed to the existence of Cancer Stem Cells (CSCs). Lately we have come to understanding that regulation of CSCs comes also from the tumour microenvironment (TME), making the attempts to therapeutically target CSCs solely, largely ineffective.

METHODS:

Using Fluorescent Activated Cell Sorting (FACS) of six individual patient-derived GBM samples, we obtained fraction of CAFs based on their FAP+/COL1A1+/CD90+/CD31-/EPCAM- marker signature and the remaining fraction of the sample was cultured to enrich for CSCs. The functional tumour aggressiveness assays as well as gene expression analysis were performed using the optimized GBM organoid system with integrated fluorescent, CAF and/or normal fibroblast (nF) component to mimic the in vivo setting.

RESULTS:

3D live-cell analysis of the organoid growth time-course demonstrated nF recruitment and their activation into CAFs by glioma cells in the co-culture setting which was confirmed by increased CAF-specific gene and protein expression levels compared to control with p < 0.001 and p < 0.0001 at 25% and 50% of co-cultured nFs, respectively. The recruited nFs enhanced proliferation (p < 0.05) at day 9 and CSC marker expression (p < 0.01) in GBM cells when compared to appropriate controls. We found that CAFs control changes of the chemical composition of TME of glioblastoma with upregulation of hyaluronan and Vinculin (p < 0.05; both) and post-treatment changes in invasion, in comparison to CAF-depleted culture controls.

CONCLUSIONS:

Our data demonstrates that TME is an essential player in the GBM resistance to therapy and tumour recurrence and that normal fibroblast component is a potential source of CAFs in brain tumours warranting further investigation.
375 Vorinostat for Missense Mutated Von Hippel Lindau Disease Associated Hemangioblastomas: A Pilot Study
Authors: Chittiboina Prashant , Mandal Debjani , Bugarini Alejandro , Mastorakos Panagiotis , Stoica Stefan , Boyle Jacqueline , Alvarez Reinier , Edwards Nancy A. , Scott Gretchen , Smith Carolyn , Maric Dragan , Zhuang Zhengping , Chew Emily , Yang Chunzhang , Linehan Marston , Lonser Russell R.
Published: March 2023

INTRODUCTION:

Missense mutated VHL protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation, loss of function and tumor initiation/progression of VHL-associated tumors. Histone deacetylase inhibitors (HDACi) can rescue missense mutated pVHL and arrest tumor growth in pre-clinical models.

METHODS:

Seven subjects with missense VHL received 400mg/day of vorinostat (7-days) and surgical resection of hemangioblastomas. We analyzed vorinostat-treated HBs (and paired untreated HBs from the same patients) for gene and protein expression in the pVHL-HIF-VEGF pathway, and protein-protein interactions. We explored the transcriptional landscape of these tumors with single nucleus gene expression analysis. We recapitulated patient specific missense mutations and validated the clinical findings using lentiviral expression recombinant constructs in VHL-/- 786-O cells.

RESULTS:

Short-term oral vorinostat was well tolerated by all patients (age 46.0 ± 14.5 years; 25-61 years). In the 6 evaluable tumors, pVHL expression in neoplastic stromal cells of vorinostat treated tumors was significantly elevated compared to untreated tumors (p = 0.01). We found transcriptional suppression of downstream effectors including VEGF-A and GLUT1 in human tumor samples and validated the effects in patient-specific missense mutations expressed in VHL 786-O cells. Mechanistically, we found that vorinostat prevented Hsp90 recruitment to missense mutated pVHL. The vorinostat effects on pVHL rescue, transcriptional repression and Hsp90-pVHL interaction was independent of the location of the mutation on VHL. Lastly, we found a HB stromal cell specific effect in suppression of pro-tumorigenic pathways with single nucleus gene expression analysis.

CONCLUSIONS:

Short-term treatment with vorinostat increased pVHL levels and suppressed tumor progression signaling in VHL-associated hemangioblastomas. These results indicate that proteostasis modulation can rescue tumor pVHL in germline missense mutated VHL patients and such treatment could arrest tumor growth.
380 A Rapid CSF Assay Accelerates Diagnosis and Treatment Initiation for CNS Neoplasms
Authors: Gupta Mihir , Bradley Joseph , Massaad Elie , Burns Evan , Forst Deborah , Cahill Daniel P. , Barker Frederick George , Jordan Justin , Dietrich Jorg , Lennerz Jochen K. , Nahed Brian V. , Carter Bob S. , Shankar Ganesh
Published: March 2023

INTRODUCTION:

The low yields of CSF studies and serologies in current diagnostic workflows for suspected CNS neoplasms often lead to neurosurgical biopsies of high-risk lesions. To address this need, we developed an assay to rapidly identify hallmark mutations of CNS neoplasms in CSF.

METHODS:

Targeted Rapid Sequencing (TetRS) was developed as a qPCR-based method to detect IDH1/2, TERT promoter, BRAF, H3F3A, and MYD88 mutations in CSF-derived DNA within 80 minutes of collection. CSF was prospectively collected over 18 months from 98 patients with suspected new CNS neoplasms. Results were utilized in clinical decision-making.

RESULTS:

40 of 98 patients were ultimately diagnosed with a neoplasm. TetRS detected a mutation in 15 out of 40 patients with a neoplasm (37.5%), including cases of CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Detection of a mutation accelerated diagnosis in comparison to cases where a mutation was not detected (median 0.5 vs 10.5 days, p < 0.00001). In multiple cases, a positive TetRS result obviated the need for biopsy and enabled initiation of disease-directed therapy. In one such case, detection of the MYD88 L265P variant was diagnostic of CNS lymphoma, enabling methotrexate and rituximab initiation within 3 days of admission. Results of repeated CSF samplings correlated with treatment response and recurrence. In another case, detection of the IDH1 R132G variant was diagnostic of IDH-mutant brainstem glioma, enabling IDH inhibitor and radiation therapy, with clinical and radiographic response.

CONCLUSIONS:

The targeted cell-free DNA panel for CSF presented here is a novel tool to rapidly, cost-effectively and broadly diagnose CNS neoplasia, initiate therapies and follow disease progression in the absence of neurosurgical tissue sampling.
382 Human Cancer Cells Migrating in Human Brain: Directly from the Operating Room
Authors: Suarez-Meade Paola , Ravin Rea , Guerrero-Cazares Hugo , Busse Brad , Blank Paul S. , Vivas-Buitrago Tito , Norton Emily , Bezrukov Ludmila , Chaichana Kaisorn L. , Zimmerberg Joshua , Quinones-Hinojosa Alfredo
Published: March 2023

INTRODUCTION:

Glioblastoma (GBM) is a highly invasive tumor for which there is no effective treatment. Migratory cells invade the healthy parenchyma, evading treatment and promoting recurrence. The role microenvironment plays in the invasion of GBM has been commonly studied with reductionist systems that do not recapitulate the cytoarchitecture of the human brain.

METHODS:

Healthy brain samples were obtained from patients undergoing non-cancer related surgery. Organotypic explants from human brain were prepared and maintained for two weeks. GFP-labeled GBM cells were injected into the organotypic under microscopic visualization. Migration was evaluated via microscopy and immunohistochemistry techniques. Motility was analyzed by a computational method designed for this project.

RESULTS:

After inoculation, cells migrated successfully into the tissue. After 7 days, immuno-staining demonstrated that GBM cells were located near blood vessels. Approximately 50 ± 20% of cells had migrated to within 10 μm of the vessel (n = 28 regions, 10 tissues). Cells initially migrated with limited directionality sending processes in different directions and upon contact, cells moved faster towards the vessel. After merging, migration speed decreased and continued to decrease with time (p < 0.001). Directionality increased after a process contact with the vessel (p < 0.001) and then returned to the pre-contact directionality once merged (p < 0.001). After perivascular localization, migration was limited along the blood vessels in both directions. The percentage of cells that contact and then continue to migrate along the vessel was 96.8 ± 3.1% while the percentage of cells that migrate to the vessel and leave was 3.2 ± 3.1%.

CONCLUSIONS:

Our human-tumor-on-human-brain organotypic model serves as a favorable system to study GBM invasion. We confirm that GBM utilizes blood vessels to migrate and found that there is a change in migratory dynamics upon blood vessel contact.
383 Artificial Neural Network Modeling of Outcomes in Subarachnoid Hemorrhage
Authors: Steed Tyler , Hsu Alice , Akbik Feras , Luu Kevin , Samuels Owen B. , Sadan Ofer , Grossberg Jonathan Andrew
Published: March 2023

INTRODUCTION:

Aneurysmal subarachnoid hemorrhage is a devastating neurological condition which requires complex neurocritical care and neurosurgical decision-making yet results in remarkably variable outcomes. Robust methods of identifying patients who may need operative and critical care interventions, such as those who develop hydrocephalus requiring long-term shunting or cerebral vasospasm, or predicting patients who may go on to have long-term disability or worsened neurological outcomes are lacking.

METHODS:

Data used to train our models included demographic data (gender, age and race), history of medical conditions (hypertension, diabetes, coronary artery disease, hyperlipidemia, tobacco use), Hunt and Hess scale, ventriculostomy data (external ventricular drain (EVD) output, EVD level, EVD age), and cerebrospinal fluid (CSF) lab values (CSF protein and glucose levels). The models were trained on a subpopulation of 85% of subjects and then individually validated in a training-naive subset of 15% of subjects with high accuracy.

RESULTS:

Using this data, we have generated artificial neural network classifiers with hyperparameter tuning which predict the need for long-term cerebrospinal fluid (CSF) diversion via placement of a shunt (receiver operating characteristic area under the curve) (ROC AUC) = 0.8312), vasospasm (ROC AUC = 0.8058), and the categorical outcome of patient disposition (model accuracy = 0.7786).

CONCLUSIONS:

We hope the use of artificial intelligence and machine learning techniques will continue to demonstrate power in predicting complex medical outcomes and ultimately help neurosurgeons and neuro-critical care personnel prognosticate and provide appropriate and timely treatment.
386 Stereotactic Implantation of Autologous Mesenchymal Stem Cells Improves Neurological Outcomes in a Rat Model of Chronic Middle Cerebral Artery Stroke
Authors: Hines Kevin , Myers Max , Spagnuolo Gabrielle , Gray Andrew , Galvez Yolanda Gomez , Cai Jingli , Tjoumakaris Stavropoula I. , Rosenwasser Robert H. , Iacovitti Lorraine
Published: March 2023

INTRODUCTION:

Limited treatment options exist for patients with chronic infarcts. Multipotent adult mesenchymal stem cells (MSC) show promise as a treatment for chronic stroke. Allogeneic MSCs have been implanted successfully in chronic stroke1,2. However, no literature evaluates the use of autologous MSCs delivered via stereotactic implantation. Autologous MSCs provide safety and accessibility benefits.

METHODS:

Male Sprague-Dawley rats underwent transient right MCAO for 120 minutes. Brain MRI and sensorimotor behavior were used to evaluate stroke. Sixteen days post stroke, tibial bone marrow was aspirated and MSCs were grown in a closed bioreactor. At 28 days post stroke, 3 trajectories of MSCs were implanted in the peri-infarct zone using a stereotactic robot. The treatments consisted of group 1 (5 x 106 cell dose, N = 6), group 2 (1 x 106 cell dose, N = 6) and a control group (saline injection, N = 9). In a second cohort of animals, Q-dot labeled autologous MSCs were tracked in the brain for 7 or 30 days.

RESULTS:

Behavior as determined by the modified neurological severity score (0-16) significantly improved in both groups. Stroke volume did not decrease. Histological analysis confirmed increased astrocyte and microglia presence in the affected hemisphere. Quantum dot analysis of injections showed presence of MSCs along trajectory as well as targeting perilesional brain tissue at 7 and 30 days post-implantation.

CONCLUSIONS:

Stereotactic injection of autologous MSCs represent an effective treatment for chronic stroke. Cells were effective at the lowest dose studied, with no added benefit at higher cell dosages. Unlike allogeneic MSCs which disappear over days to weeks3, autologous MSCs persist long term in the brain, potentially providing continued benefit. This treatment warrants human trials to study its effectiveness.
394 R2* and QSM Reliability for Measuring Brain Tissue Iron Concentrations
Authors: Fliegner Max , Lin Leanne , Chaudhary Neeraj , Pandey Aditya S. , Keep Richard , Xi Guohua , Troost Jonathan , Chenevert Tom
Published: March 2023

INTRODUCTION:

Pathologic levels of iron have been implicated in various neurological disease states, such as Parkinson’s, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Stroke (hemorrhagic & ischemic). Using brain tissue iron concentration as a biomarker for disease progression has great potential for clinical translation; however, measuring iron concentrations non-invasively remains challenging. MRI based R2* and quantitative susceptibility mapping (QSM) values have been shown to correlate with iron levels in previous cadaveric studies.

METHODS:

Ten normal human subjects (ages 35-73) underwent test and retest MRI scans approximately 10 minutes apart. T1 and gradient-echo images were used to segment 7 regions of the brain bilaterally. The gradient-echo sequences were used to calculate the R2* and QSM for each region of interest. Iron concentrations were calculated from the R2* values based on R2* calibrated with a phantom.

RESULTS:

R2* values ranged from 19.45 Hz in the hand homunculus to 38.81 Hz in the substantia nigra and were consistent across 8-echo and 6-echo sequences. Mean QSM values ranged from -0.041 in the internal capsule to 0.046 in the globus pallidus. Calculated iron concentrations ranged from 52.1 mg/kg in the centrum semiovale to 104.6 mg/kg in the substantia nigra. Test and retest values showed consistency across brain regions for R2* with weighted coefficient variation percent of 3.9-9.6%. White matter iron concentrations ranged from 52.1-59.5 mg/kg, while deep grey nuclei iron concentrations ranged from 72.5-104.6 mg/kg.

CONCLUSIONS:

Our study demonstrates the ability of gradient-echo MRI to reliably measure tissue iron levels in non-disease states in healthy human subjects. Further research is needed to validate the ability of specific MRI sequences to be a surrogate biomarker in disease states.
399 Role of Plaque Inflammation in Symptomatic Carotid Stenosis
Authors: Zheng Yilong , Rui Jun Rui Lim Mervyn Jun , Tan Benjamin , Chan Bernard , Paliwal Prakash , Ong Jonathan , Bharatendu Chandra , Chan Amanda , Yeo Leonard , Vijayan Joy , Chee Young Heng , Wong Lily , Chen Jintao , Chong Yao Feng , Dong Yanhong , Tan Chi Hsien , Sunny Sibi , Teoh Hock Luen , Sinha Arvind Kumar , Sharma Vijay
Published: March 2023

INTRODUCTION:

Prior studies have shown that plaque inflammation on FDG-PET and the SCAIL score were associated with recurrent ischemic events. However, the findings have thus far not been widely validated.

METHODS:

This was a single-center prospective cohort study that included patients with (1) recent TIA or ischemic stroke within the past 30 days, (2) ipsilateral carotid artery stenosis of ≥50%, and (3) not considered for early carotid revascularization. The (1) maximum standardized uptake value (SUVmax) of the symptomatic carotid plaque, (2) stenosis severity of the symptomatic carotid artery, and (3) the SCAIL score (a composite score consisting of the degree of plaque inflammation and stenosis severity) were measured for all patients. The outcomes were (1) a 90-day ipsilateral ischemic stroke and (2) a 90-day ipsilateral symptomatic TIA or major adverse cardiovascular event (MACE).

RESULTS:

Of 131 included patients, 21 (16.0%) patients had a 90-day ischemic stroke, and 41 (31.3%) patients had a 90-day TIA or MACE. Symptomatic plaque SUVmax (AUC = 0.92; 95% CI = 0.82–1.00) was superior to the SCAIL score (AUC = 0.79; 95% CI = 0.65, 0.92) in predicting 90-day ischemic stroke. Symptomatic plaque SUVmax (AUC = 0.84; 95% CI = 0.76, 0.92) was also superior to the SCAIL score (AUC = 0.76; 95% CI = 0.66, 0.85) in predicting 90-day TIA or MACE.

CONCLUSIONS:

Plaque inflammation may serve as a reliable biomarker for risk stratification and selection of patients for carotid revascularization and/or anti-inflammatory therapy.
404 Identification of Persistent Racial Inequities in Recommendations for Resection of Primary Brain Tumors Using a Harmonized Dual Registry Analysis
Authors: Butterfield Jack , Golzarian Sina , Johnson Reid Alexander , Fellows Emily , Dhawan Sanjay , Chen Clark C C. , Marcotte Erin , Venteicher Andrew Sean
Published: March 2023

INTRODUCTION:

Disparities in outcomes disproportionately affect minority populations in many surgical fields. In contrast, racial disparities in surgical decision-making remains an enigma due to the difficulty in capturing surgeon recommendations during initial patient workup.

METHODS:

The odds of recommendation against surgical resection at initial diagnosis of primary brain neoplasms was determined using multivariable logistic regression with clinical, demographic, and socioeconomic factors. A dual registry analysis was designed using two national databases (NCDB and SEER), with independent analyses that were harmonized to ensure robustness of conclusions. Adults with the six most common intracranial neoplasms were included in the analysis.

RESULTS:

Two registries were queried to identify adults with meningioma (n = 63674, n = 222673), glioblastoma (n = 35258, n = 104047), pituitary adenoma (n = 27506, n = 87772), vestibular schwannoma (n = 11525, n = 30745), astrocytoma (n = 5402, n = 10631), and oligodendroglioma (n = 3977, n = 9187) in SEER and NCDB databases, respectively. Multivariable analysis in SEER demonstrated that, independent of clinical, demographic, and socioeconomic factors, Black patients had significantly higher odds of recommendation against surgical resection of meningioma (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.06-1.21, p < 0.001), glioblastoma (OR 1.14, 95% CI 1.01-1.28, p = 0.038), pituitary adenoma (OR 1.13, 95% CI 1.05-1.22, p < 0.001), and vestibular schwannoma (OR 1.48, 95% CI 1.19-1.84, p < 0.001) when compared to White patients in the SEER dataset. Performing a parallel analysis in NCDB confirmed these results in meningioma (OR 1.26, 95% CI 1.22-1.30, p < 0.001), glioblastoma (OR 1.20, 95% CI 1.13-1.29, p < 0.001), pituitary adenoma (OR 1.26, 95% CI 1.22-1.31), p < 0.001), and vestibular schwannoma (OR 1.30, 95% CI 1.15-1.48, p < 0.001). These findings persisted independent of both patient comorbidities and potential overlap between the databases.

CONCLUSIONS:

Racial disparities in surgery recommendations for patients with primary brain tumors independent of multiple potential confounders including clinical, demographic, and socioeconomic factors.
405 Cost and Cost-Effectiveness in the Development of Brain Tumor Clinical Trials
Authors: Koester Stefan Wolfgang , Chinard Stephen , Ani Chinonso , Liles David Campbell , Dambrino Robert J. , Feldman Michael , Chambless Lola Blackwell
Published: March 2023

INTRODUCTION:

New approaches to brain tumor treatment are constantly evolving, as evidenced by the high number of completed and ongoing clinical trials. While treatment outcomes are the primary focus of such work, allocation of resources is also an important consideration in a constrained healthcare environment.

METHODS:

The Clinical.Trials.gov website was queried for all studies involving brain tumors that mention cost. Data on trial characteristics were analyzed to generate an overview of how cost was discussed in these studies. Data collected pertained to start date, enrollment size, study funding/sponsors, country of origin, and cost as a primary, secondary, or tertiary outcome.

RESULTS:

2,572 studies were identified. Our search yielded 42 (1.63%) results that discussed cost. 27 of 42 (64.3%) studies discussed cost as being a part of the study. Of those, 2 (7.4%) has cost as a primary outcome, 19 (70.4%) has cost as a secondary outcome, and 6 (22.2%) has cost as an additional outcome. Of the 27 studies, 11 (40.7%) studies utilized a cost-effectiveness analysis as part of their design study. 11 (40.7%) studies came from drug or device trials and 7 (26.0%) studies came from procedural intervention trials. Considering evolution of cost consideration over time, 10 (37.0%) of the studies were within the last 5-year time period from 2017 - 2022, and 10 (37%) from the prior 5-year period from 2012-2017.

CONCLUSIONS:

Less than 1% of clinical trials pertaining to brain tumors report cost as any endpoint, despite cost being a major future consideration to implementation and use within the healthcare system. This metric has not changed within recent years, and we implore more investigators to consider and discuss cost openly to gain a more insightful economic perspective to juxtapose their proposed shift in brain tumor technologies.
421 Quantifying the Opportunity Cost of Neurosurgical Resident Education
Authors: Venkatraman Vishal , Suarez Alexander , Kirsch Elayna , Heo Helen , Wu Kevin , McDaniel Kate , Yang Zidanyue , Dharmapurikar Rajeev , Lad Nandan P. , Haglund Michael M.
Published: March 2023

INTRODUCTION:

Education is at the core of neurosurgical residency, but little research has been done on the opportunity cost of surgical education.

METHODS:

SAP structures cases into zones of proximal development (opening, exposure, key section, and closing) and is used to evaluate resident mastery. All 1-4 level ACDF non-reoperative cases between March 2014 and March 2022 from one attending surgeon at Duke University were divided into three groups: cases without residents, cases with residents prior to implementation of SAP (before June 2018) and cases with residents after implementation with SAP (after June 2018). Surgical times for all cases were collected via electronic record review. Times were compared within levels of surgery between groups.

RESULTS:

There were 2140 ACDF cases identified, of which 1758 were done independently, 223 with residents prior to SAP, and 159 with residents and SAP. Across 1, 2, 3, and 4 level ACDF surgeries, cases with residents took longer to complete than when done independently, with SAP adding additional time. For 2-level ACDF cases, the average surgical time was 72.0 ± 18.2 min independently, 121.7 ± 33.7 min pre-SAP, and 143.4 ± 34.9 min post-SAP, with t-tests showing significant differences between all three groups.

CONCLUSIONS:

There is a significant time cost for neurosurgeons to educate residents, but with some additional time, more structured education can be implemented. There is also a significant monetary cost to educating residents compared to operating independently, since it is expensive to run an operating room. Since attending neurosurgeons lose opportunities to perform more surgeries when working with residents, there is a need to incentivize and compensate surgeons who dedicate time to education.
429 Intramedullary Spinal Arteriovenous Malformations—Definition of Two Distinct Subtypes
Authors: Srinivasan Visish M. , Scherschinski Lea , Rhodenhiser Emmajane , Karahalios Katherine , Garcia Joseph , Catapano Joshua , Labib Mohamed , Graffeo Christopher Salvatore , Spetzler Robert F. , Lawton Michael T.
Published: March 2023

INTRODUCTION:

Intramedullary spinal arteriovenous malformations (SpiAVM) are complex lesions. Due to their rarity, reports of their management and outcomes are limited.

METHODS:

Our neurovascular database was reviewed SpiAVMs between January 1986 and December 2021. Demographic, clinical, radiographic, and outcome data were obtained. Eccentric SpiAVMs were defined as those with a significant portion presenting through the pia mater into the subarachnoid space, with large vessels coursing outside the parenchyma. Concentric SpiAVMs were defined as those embedded within the spinal cord parenchyma, not presenting to pia mater, and well circumscribed.

RESULTS:

Fifty-nine patients (mean [SD] age, 34 [15] years; female sex, 34) were identified. Patients exhibited myelopathy (88%), including pain (51%), paresis (88%), sensory deficits (46%), and bowel and bladder dysfunction (46%). Twenty-seven patients (46%) presented with hemorrhage. Forty-nine percent of lesions were located in the cervical spine and 51% in the thoracic spine. Thirty-five lesions (59%) were previously embolized. Twenty-eight patients (51%) were classified as eccentric and 27 (49%) as concentric SpiAVMs. Postoperative outcomes were similar with no significant differences (improved, 8/18 [44%] vs. 9/17 [53%]; unchanged, 8/18 [44%] vs. 7/17 [41%]; worse, 2/18 [11%] vs. 1/17 [6%]). Retreatment rates were not significantly different between both subtypes (eccentric, 9/28 [32%]; concentric, 6/27 [22%]). Eccentric and concentric SpiAVMs were associated with similar rates of complete resection (eccentric, 14/26 [54%], concentric, 18/26 [69%]). Of 55 classifiable lesions, 4 (7%) were determined to have a mixed phenotype, harboring characteristics of eccentric and concentric SpiAVMs.

CONCLUSIONS:

Intramedullary AVMs may cause significant symptoms. The eccentric and concentric subtypes have different angioarchitecture and outcomes. While complete resection is usually the preferred surgical objective, eccentric SpiAVMs are amenable to the pial resection that may achieve angiographic obliteration without complete resection.
430 Cranially Directed Upper Instrumented Vertebrae Screw Angles are Associated with Proximal Junctional Kyphosis in Adult Spinal Deformity Surgery
Authors: Chen Jeffrey , Longo Michael , Chanbour Hani , LaBarge Matthew , Abtahi Amir , Stephens Byron , Zuckerman Scott L.
Published: March 2023

INTRODUCTION:

The effect of the upper instrumented vertebral (UIV) screw angle in adult spinal deformity (ASD) surgery on surgical complications and patient outcomes remains understudied.

METHODS:

A single-institution, retrospective cohort study was undertaken from 2011-17. UIV screw angle was trichotomized into: 1) Positive: cranially-directed screws relative to the UIV superior endplate (2° ≤ Θ); 2) Neutral: screws parallel to the UIV superior endplate (-2° <Θ <2°); and 3) Negative: caudally-directed screws relative to the UIV superior endplate (-2° ≥ Θ). The primary outcome was PJK/F. Secondary outcomes included remaining mechanical complications, reoperation, and PROMs: Oswestry Disability Index (ODI), Numeric Rating Scale (NRS) back/leg, and EuroQol (EQ-5D). Regression controlled for age, BMI, postoperative sagittal vertical axis, and pelvic-incidence to lumbar-lordosis mismatch.

RESULTS:

Among 145 patients undergoing ASD surgery, UIV screw angles were: 35(24.1%) cranially directed, 24(16.6%) neutral, and 86(59.3%) caudally directed. PJK occurred in 47(32.4%) patients. The incidence of PJK was highest for patients with cranially-directed screws (51.43%, p = 0.022). Cranially-directed screws were independently associated with PJK (OR = 4.88, 95%CI = 1.85-13.5, p = 0.002) and PJF (OR = 3.06, 95%CI = 1.32-12.30, p = 0.015), with a threshold value of -8.9° on ROC analysis (AUC = 0.64, 95%CI = 0.55-0.74, p<0.001). There was no association between UIV screw angle and remaining mechanical complications, reoperations, or PROMs. In addition, cranially directed screw angle was associated with increased risk of PJK (OR = 5.56, 95%CI = 1.86-17.90, p = 0.003) in lower thoracic cohort (T8 or below, N = 37), but not in the upper thoracic group (T7 or above, N = 37).

CONCLUSIONS:

Positive, cranially-directed UIV screw angles significantly increased the odds of PJK/F but not other mechanical complications, reoperation, or PROMs. Meticulous attention should be paid to UIV screw angle to reduce PJK/F.
446 Accurate Localization of Back Pain by Radiomic Assessment of Sigma-1 Receptor Expression
Authors: Haider Ghani , Schonfeld Ethan , Biswal Sandip , Veeravagu Anand
Published: March 2023

INTRODUCTION:

The current diagnostic tools that we have for back pain have low sensitivity and poor accuracy which leads to ineffective and unnecessary treatments, resulting in high health care costs and unwanted outcomes. Sigma-1 receptor (s1R) is broadly implicated in nociceptive signaling and peripheral pain sensation.

METHODS:

Specific patient selection for full body ([18F]FTC-146) PET/MRI scan was done after clinical and radiological review by a neurosurgeon specializing in spinal surgery. Six patients with various etiologies of back pain were included. For all the study participants, we recorded all relevant clinical details and reviewed prior diagnostic tests. All PET/MRI scans were completed at our institution’s facilities and images were reviewed and correlated by a musculoskeletal radiologist to identify lesions that may be causing patient’s symptoms.

RESULTS:

Our study results strongly support the likelihood of achieving enhanced diagnostic sensitivity to sources of back pain with the proposed s1r imaging approach. PET/MRI imaging matched the clinical diagnosis in all cases, including disc herniation, nerve compression, stenosis, and arthropathy. Additionally, it offered benefit over traditional MRI by identifying additional “functional” findings both within and outside the spine. This additional functional detail, was useful for patients with either no or multiple structural abnormalities on MRI to pinpoint the true cause of pain demonstrating the synergistic utility of this imaging modality. Such functional detail guided successful interventions including surgery, therapy, and injections in our patient cohort that successfully addressed the pain.

CONCLUSIONS:

Early results show promise for improved confidence and sensitivity in detecting sources of pain using full body ([18F]FTC-146) PET/MRI scan which can potentially improve patient management and outcomes.
449 Stereoencephalography of Centromedian Thalamus Reveals Distinct Patterns of Thalamocortical Synchrony Across Seizure Onset Zones
Authors: Gadot Ron , Reddy Sandesh , Devara Ethan , Dang Huy , Shofty Ben , Gavvala Jay R. , Sheth Sameer A.
Published: March 2023

INTRODUCTION:

Thalamic nuclei are increasingly used targets for study and therapeutic modulation in drug-resistant epilepsy (DRE). Centromedian nucleus of thalamus (CMN) is relatively understudied despite known widespread connectivity and previous reports suggesting a role in both generalized and multifocal epilepsies.

METHODS:

The clinical and electrographic data of 13 consecutive patients who had at least one sEEG electrode sampling CMN were included. Electrographic seizures were visually analyzed for thalamic activity changes at seizure onset (SO), maintenance (SM), and end (SE) periods. Recordings were quantitatively assessed using a measure of sEEG signal interdependency (non-linear regression coefficient, h2) to compare thalamocortical synchrony at SO and SE periods. All analyses were performed using AnyWave software.

RESULTS:

Eighty focal-onset seizures (median 4, range 1-19 per patient) were captured and included in analysis. SOZs were mesial temporal (33%), neocortical temporal (23%), frontal (29%), and non-frontal extratemporal (15%). Median seizure length was 78 (IQR 25-133) seconds. In 74% of seizures, a change in thalamic activity was visually perceptible during the seizure with a median latency of 5 (IQR 2-9) seconds. A low voltage fast activity pattern predominantly in the alpha band was most commonly seen during SO. When thalamic activity changed during SM, a rhythmic spike-wave pattern was most often seen. Rhythmic waves predominantly in the delta band were the most common pattern of activity at SE. Average thalamocortical h2 values in the SE period were significantly higher than the SO period (Kruskal-Wallis p < 0.0001). Mesial temporal, temporal, and frontal seizures demonstrated significant increases in thalamocortical synchronization while non-frontal extratemporal seizures did not.

CONCLUSIONS:

Consistent dynamic ictal patterns can be visualized within CMN thalamus using sEEG recordings. Bidirectional signal synchronization peaks during the SE period and may be involved in seizure termination.
455 Radiographic Features Predict Genomic Subtype in Meningioma
Authors: Gadot Ron , Khan Basit , Katlowitz Kalman , Gupta Mayuri , Bayley James , Klisch Tiemo , Patel Akash J.
Published: March 2023

INTRODUCTION:

Meningiomas are the most common primary intracranial neoplasms. While most meningiomas demonstrate benign behavior with low rates of recurrence, a large percentage are more aggressive and are currently most widely prognosticated by histological grade. Several groups have published classification systems grouping meningiomas into distinct subtypes based on transcriptomic, cytogenetic, and methylomic signatures that better characterize their activity compared with traditional grading. Methods to preoperatively predict genomic subtype are desired.

METHODS:

Resected tumor samples that were genomically classified through a protocol described in previous publications were included in this analysis. Corresponding preoperative MRIs were gathered. The tumors were characterized using a standardized sheet of semantic variables. Chi-square and Wilcoxon rank-sum tests followed by univariable generalized linear regression were used for feature selection. Random forest algorithms were trained to classify genomic subtype based on radiographic features alone and tested using an 80/20 pseudorandom split.

RESULTS:

One-hundred tumors were included (n = 69 MenG-A/B, 31 MenG-C). Males were significantly more likely to develop MenG-C tumors than females (OR 3.44 [1.43, 8.52] p = 0.006). MenG-C tumors had significantly lower recurrence-free survival than MenG-A/B tumors (log-rank p value <0.01). Supratentorial status, parafalcine location, larger volume, moderate-severe edema, irregular enhancement, hypointensity on T1 non-contrast sequence, and indistinct tumor margins were significant predictors of more aggressive genomic class. A random forest model based on these features blindly predicted MenG-A/B class with 85% accuracy (sensitivity 83%, specificity 100%). Tumor volume, location grouping, and T1 hypointensity were the most important features in accurate classification.

CONCLUSIONS:

Aggressive genomic status in meningioma can be predicted on routine preoperative imaging. These results may aid in preoperative counseling and treatment planning and should be validated across multi-institutional datasets.
459 Neuro-Oncology Spectral Fingerprint Biorepository: A Novel Approach Leveraging a Surgical and Clinical Detailed Repository in a Diverse Patient Population
Authors: Quinones-Hinojosa Alfredo , Basil Aleeshba , Garcia Diogo P. , Meade Paola Suarez , Szymkiewicz Ewa , Jentoft Mark E. , Guerrero-Cazares Hugo , Chaichana Kaisorn L. , Meyer Fredric B.
Published: March 2023

INTRODUCTION:

Despite advances in the understanding of brain cancer, surgery and extent of resection (EOR) continue to be the main predictors of patient outcome. However, currently available public biorepositories do not include extent of resection for individual patients raising important questions regarding confounding effects for some molecular markers. Further, emerging data has supported important novel biomarkers in tumor’s lipidome and optical attenuation properties which could serve as new therapeutic opportunities.

METHODS:

All neuro-oncology surgical cases at our institution were eligible for collection since 2016. Blood was collected from every patient pre-operatively. Cerebrospinal fluid was collected whenever surgically safe. Genomic and transcriptomic analysis was performed. Intra-operative spectral and optical attenuation data was obtained through desorption electrospray ionization mass spectrometry (DESI-MS) over 0 to 1000 m/z and optical coherence tomography, respectively, for biomarker discovery.

RESULTS:

A total of 912 unique patient collections have been performed including 286 gliomas and 205 other rare brain tumors. Demographic, clinical, imaging, surgical and survival data was curated for each individual patient. Extent of resection (EOR) was determined for each patient, with an average of 78.6% for chordomas, 85.9% in glioblastoma, 88.3% in other high-grade gliomas and 72% in low-grade gliomas with predictive of progression-free survival (p < 0.01) and overall survival (p < 0.01). Comprehensive sequencing has been completed for 131 gliomas. Of those, lipid and optical profiling has been completed for multiple tumor samples (330) from a total of 79 patients.

CONCLUSIONS:

We have curated a large biorepository of neuro-oncology tumors with detailed patient information including for the first time to our knowledge detailed surgical, imaging, spectral and optical information. Efforts are ongoing at large-scale biomarker discovery leveraging the unique spectral and optical fingerprint of each tumor to their genomic/transcriptomic profile.
465 Defining the Immune Profile of Radiation Necrosis Through Single-cell Analysis of Intracranial Lesions
Authors: Robert Stephanie , Lu Benjamin , Arnal-Estape Anna , Nguyen Don , Chiang Veronica
Published: March 2023

INTRODUCTION:

The incidence of radiation necrosis (RN), a common and morbid side effect of radiosurgical management of brain metastases, is growing as patient survival and use of immunotherapy increases. RN is thought to be immunologically driven; however, its pathophysiology remains poorly understood. Further, difficulty distinguishing it radiographically from recurrent metastatic disease often necessitates invasive brain biopsies for diagnosis.

METHODS:

Over 12 months, we collected intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor. We created a bank of these 16 patient samples and processed them for scRNAseq analysis. Using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, we analyzed the cellular immune profile of lesional tissue and time-matched blood from each patient.

RESULTS:

Compared to metastases, RN demonstrates decreased expression of FOXP3, NKG7, and GZMB, markers of regulatory and cytotoxic T cells, and natural killer (NK) cells, and increased expression of interleukin 7 receptor (IL7R), a marker of naÏve and memory T cells – profiles reflective of bystander transcriptional signatures. In contrast, metastases demonstrate an antigen-reactive profile, including commonly observed exhaustion signatures. Importantly, blood samples from patients reflect these differences as well. Interestingly, increased IL7R is implicated in autoimmune disorders, suggesting an iatrogenically-induced autoreactive process underlying RN.

CONCLUSIONS:

These findings demonstrate, firstly, the feasibility of extracting live cells from RN tissue, and, secondly, suggest RN and metastases have unique immune profiles that can be detected in patient blood. Therefore, in addition to beginning to define the immune landscape of this poorly understood pathology, this work has the potential to open new avenues for the development of improved diagnostic and therapeutic approaches to allow for earlier detection and more effective treatment of RN in metastatic brain tumors patients.
469 Palliative Care Effect on Survival in Glioblastoma: Who Receives Palliative Care?
Authors: Pando Alejandro , Patel Aman , Shaari Ariana , Choudhry Hannaan , Eloy Jean Anderson , Goldstein Ira M. , Liu James K.
Published: March 2023

INTRODUCTION:

High grade glioma has a poor overall survival with profoundly negative effects on the patient’s quality of life and their caregivers.

METHODS:

The National Cancer Database was analyzed for patterns of care in patients ≥18-years-old who were diagnosed with histologically confirmed grade IV GBM between 2004 and 2017. All statistical analyses were conducted based on univariate and multivariate regression models.

RESULTS:

A total of 85,380 patients with the diagnosis of GBM were identified. Of the study population, 2,803(3.28%) patients received palliative therapy. On multivariate logistic regression analysis, age ≥70 Years (odds ratio[OR] = 1.28, 95% Confidence Interval [CI] = 1.04-1.58; p < 0.001), Medicare (OR = 1.348, CI = 1.13-1.61; p = 0.001), tumor size ≥5 cm (OR = 1.15, CI = 1.01-1.31; p = 0.036), tumor multifocality (OR = 1.69, CI = 1.47-1.96; p < 0.001), lobe overlapping tumor (OR = 2.09, CI = 1.13-3.86; p = 0.018), Charlson-Deyo score >0, receiving treatment at a non-academic/research program, and medium volume of cancers managed at the treatment facility (OR = 1.19, CI = 1.02-1.38; p = 0.026) were independent risk factors associated with an increased chance of receiving palliative care. In contrast, a household income of ≥$40,227 and high volume of cancer managed at the treatment facility (OR = 0.75, CI = 0.58-0.96; p = 0.02) were independent risk factors associated with decreased palliative care. Patients who received no palliative care had a 2-year overall survival rate longer than those who received palliative care (22% vs. 8.8%; p < 0.001). In patients receiving palliative care, those who received recommended treatment had a 2-year overall survival rate longer than those who declined part or whole recommended treatment (9.1% vs. 3.8%; p = 0.009).

CONCLUSIONS:

In patients with high grade glioma, receiving palliative care is associated with decreased survival. When receiving palliative care, recommended treatment improves survival almost three-fold compared to those declining part or whole treatment.
482 Triple Therapy Versus Dual Antiplatelet Therapy for Dolichoectatic Vertebrobasilar Fusiform Aneurysms Treated With Flow Diverters: The Last Frontier?
Authors: Siddiqui Adnan Hussain , Monteiro Andre , Hanel Ricardo , Kan Peter , Mohanty Alina , Cortez Gustavo , Rabinovich Margarita , Matouk Charles Christian , Sujijantarat Nanthiya , Romero Charles Edward , Stone Jeremy Guy , Ebersole Koji C. , Fry Lane , Natarajan Sabareesh Kumar , Thomson Brittany Owusu-Adjei , Ortega-Gutierrez Santiago , Vivanco-Suarez Juan , Wakhloo Ajay K. , Levy Elad I.
Published: March 2023

INTRODUCTION:

Dolichoectatic vertebrobasilar fusiform aneurysms (DVBFAs) have poor natural history when left untreated and high morbimortality when treated with microsurgery. Flow diversion (FD) with dual-antiplatelet therapy (DAPT) is feasible but carries a high risk of perforator occlusion and progression of brainstem compression. Seeking better hopes for these patients, experts across the US started using triple-therapy (DAPT plus oral anticoagulation) after FD treatment in attempt to improve their clinical outcomes. The rationale was to preserve perforator patency while vessel remodeling occurs. The current study is the result of this multicenter effort.

METHODS:

Retrospective data collection from 8 US centers. Only DVBFAs treated with flow-diversion and either triple-therapy or DAPT alone were included. Patient and aneurysms' characteristics, and clinical and angiographic outcomes were compared.

RESULTS:

The groups (DAPT, n = 13 vs Triple-therapy, n = 14) were similar in age, sex, clinical presentation, baseline disability, aneurysm characteristics, median number of flow-diverters, and adjunctive coiling. Radial access use was significantly higher in the triple-therapy group (71.4% vs. 15.3%, P = 0.006). Acute ischemic stroke rate was lower in the triple-therapy group (7.1% vs. 30.8%, P = 0.167). Overall rate of modified Rankin Scale score decline due to either ischemic stroke or worsening of brainstem compression was significantly lower in the triple-therapy group (7.1% vs. 69.2%, P = 0.001). Overall rate of hemorrhagic complications was numerically higher in the triple-therapy group (28.6% vs. 7.7%, P = 0.162). The rate of moderate-to-severe disability at last follow-up was significantly lower in the triple-therapy group (21.4% vs. 76.9%, P = 0.007). I.

CONCLUSIONS:

Patients with DVBFAs treated with FD and triple-therapy had less ischemic strokes, less symptom progression, and overall better outcomes at last follow-up than similar patients and aneurysms managed with DAPT alone.