bluuebunny/crossref_metadata_2025_split huggingface dataset:
262 The BRAF V600E Mutation and Tumor Cells Are Frequently Seen in Seemingly Normal Brain Parenchyma Beyond Ganglioglioma Tumor Borders: Implications for Seizure and Tumor Control
Authors: Bokhari Rakan Farouk Y. , Karamchandani Jason , Jabado Nada , Guiot Marie-Christine , Dudley Roy W. R. 
Published: March 2024

INTRODUCTION:
Gangliogliomas are WHO grade I glioneural tumors that are frequently encountered in the work up of medically refractory focal epilepsy. Their management typically involves gross total resection of the MRI-visible tumor. However, seizures may continue to be experienced by the patient post-operatively with no clear explanation.
Recent evidence suggested both the unexpected invasive nature of these tumors, as well as an inherent epileptogenic nature of the BRAF-V600 mutation independent of tumor presence.

METHODS:
We analyzed the peri-lesional tissue resected in epilepsy surgical cases secondary to gangliogliomas in seven patients.

RESULTS:
Unexpectedly, we identified either satellite tumors within the tissue, or evidence of extension of the BRAF mutation into morphologically normal tissue in four of the five patients with BRAF-V600 positive tumors. No such findings were encountered in the two BRAF-V600 negative cases.

CONCLUSIONS:
This work highlights the need of extending research efforts into the parenchyma beyond structural lesions in these cases, as our preliminary results suggest a role for field cancerization in these tumors. In addition, these findings have significant implications on the understanding and management of these tumors, which appear to have a poorly described invasive nature. It also provides a potential explanation and treatment target for seizures persisting in patients despite a gross total resection of MRI-visible tumor.
266 Combination Drug Therapy in H3 K27-Altered Diffuse Midline Glioma Enhances Tumor Retention and Treatment Efficacy
Authors: Rechberger Julian , Anderson Jacob , Ge Jizhi , Zhang Liang , Daniels David J. 
Published: March 2024

INTRODUCTION:
Diffuse midline gliomas (DMG) with H3 K27 alterations are uniformly lethal tumors for which no therapy has been found to be effective. One reason for our therapy failure is the blood-brain barrier (BBB), which severely restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) has emerged as a technique that circumvents the BBB by directly infusing therapeutics into the tumor parenchyma through generation of a mechanical pressure gradient, allowing for homogenous drug distribution at high local concentrations with minimal systemic toxicity. However, efflux transport proteins expressed by the BBB and the tumor, including P-gp and BCRP, rapidly clear the majority of drugs given by CED, severely limiting its therapeutic potential.

METHODS:
A panel of FDA-approved drugs (ponatinib, topotecan, tretinoin) were evaluated alone and in combination with the known efflux transporter inhibitor everolimus.

RESULTS:
A high degree of formal synergy was observed in multiple DMG cell lines in vitro, which was attributed to everolimus’ ability to inhibit mTOR signaling and P-gp/BCRP. In vivo, drugs that were expected to penetrate the BBB and be less likely to undergo active efflux persisted at the site of infusion the longest following CED. Concurrent dosing with everolimus further enhanced this effect, which was particularly apparent with the dual P-gp/BCRP substrate ponatinib.

CONCLUSIONS:
The proclivity of many drugs to be rapidly cleared from the brain by efflux transporters generates a vulnerability that can be exploited for the development of novel therapeutic regimens in DMG, such as with concomitant dosing of P-gp/BCRP-inhibiting drugs when using CED.
268 Integrative Genomics Identifies Evolutionary, Temporal, and Cell-lineage Origin of Hydrocephalus Risk Gene
Authors: Hale Andrew T. , Song Yuwei , Chong Zechen 
Published: March 2024

INTRODUCTION:
Our previous work identified MAEL, a gene involved in regulation of DNA transposon activity and histone methylation, as a transcriptome-wide predictor of pediatric hydrocephalus (Hale et al., Cell Reports, 2021). Here we aim to characterize the function of MAEL across timescales and cell-lineages in the developing human brain to understand the pathophysiological basis of hydrocephalus.

METHODS:
We performed taxonomic analysis of MAEL across species using Ensemble. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across the prenatal period from the Developing Human Brain Atlas (Allen Institute) and an atlas of late-prenatal cortical tissue identified temporospatial MAEL expression patterns. Finally, to estimate the degree to which in vitro models recapitulate expression patterns of MAEL in the developing brain, we analyzed scRNA-seq from human neural and choroid-plexus organoids.

RESULTS:
We performed taxonomic evolutionary gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in model systems. MAEL is among the top 0.01% human-specific genes and shares < 50% sequence homology with mammalian model organisms. scRNA-seq identified MAEL first detected in the telencephalon at 9 weeks post-conception, highest expressed in the sub-ventricular zone at 16 weeks, and lowest expressed in the hippocampus at 21 weeks post conception. Temporospatial expression of MAEL in the late-prenatal cortex identifies MAEL expression largely restricted to the neural progenitor cells before reaching steady-state expression throughout the cortical layers at 39 weeks gestation. Finally, spatial MAEL expression is largely preserved in brain organoids and robustly expressed in choroid plexus organoids highlighting the utility of these models in future mechanistic studies.

CONCLUSIONS:
We delineate the evolutionary origin and temporospatial patterns of MAEL expression in the developing human brain and organoid models. These data provide the premise for understanding the detailed molecular-genetic underpinnings of hydrocephalus.
274 Predicting Reoperation in Surgically Managed Pediatric Chiari I Malformation
Authors: Johnstone Thomas , Barros Guinle Maria Isabel , Grant Gerald 
Published: March 2024

INTRODUCTION:
Chiari I malformation (CMI) involves the herniation of cerebellar tonsils into the spinal canal, without brainstem involvement. When patients are symptomatic, surgical decompression is recommended, but reoperation rates can be as high as 30%.

METHODS:
Patients were queried from the 2007-2016 MarketScan Databases with the CPT code (61343) for CM decompression. To be included, a patient had to have been diagnosed with CMI, received decompressive surgery, and be eighteen or younger at the time of first operation. Patients were excluded if they had a diagnosis of any other class of Chiari malformation at any point. Next, the Elixhauser Comorbidity Index was constructed for each patient. These variables were then used as covariates in a multivariate regression model to predict reoperation following surgical decompression. Odds ratios, their corresponding confidence intervals, and metrics of significance were determined.

RESULTS:
2,823 patients were included, with an average age of 10.4 (SD = 5.4). 169 (6.0%) patients underwent reoperations. As patient age at first operation increased, their reoperation rate decreased steadily (OR = 0.95, 95% CI = 0.93-0.98, p = 0.002). This association was primarily driven by a sharp decline in reoperation rate after the first three years of life. Patients in their first year had a mean reoperation rate of 17.6%; by age three, the reoperation rate declined to 5.2%, remaining fairly stable from age four (5.1%) to eighteen (4.9%). Use of duraplasty (OR = 0.75, 95% CI = 0.52-1.06, p = 0.112) did not alter the likelihood of reoperation.

CONCLUSIONS:
In a national pediatric cohort of patients with surgically managed Chiari I malformations, there was a significantly increased likelihood of reoperation in younger children. Our findings suggest that, when medically feasible, initial CMI surgery should be delayed until the age of three to minimize the chance of reoperation.
277 Clinical Outcome With and Without Adherence to Evidence-based Medicine Guidelines for Lumbar Degenerative Spondylolisthesis Fusion Patients
Authors: Gonzalez Ozuna Glenn Arturo , Porto Guilherme Bastos , Jingya Miao , Hines Kevin , Franco Daniel , O'Leary Matthew , Thalheimer Sara , Harrop James S. 
Published: March 2024

INTRODUCTION:
Degenerative lumbar spondylolisthesis (DS) patients are treated with instrumented fusion, following EBM guidelines, and typically have excellent clinical outcomes. However, not all lumbar fusion procedures adhere to EBM guidelines, typically due to a lack of prospective data.

METHODS:
This study compared outcomes of lumbar fusion procedures for degenerative spondylolisthesis in two groups: 125 patients treated according to EBM guidelines and 21 patients without EBM literature support. ODI scores were collected pre- and post-surgery and categorized into SCB, MCID, no MCID, or no change/worsening. Statistical analysis included χ2, Fisher exact, and t-student tests. Multivariate logistic regression analyzed the odds of achieving MCID after six months of follow-up.

RESULTS:
The study included a total of 146 lumbar fusion patients, with the majority (125/146) adhering to EBM guidelines (EBM concordant) while a smaller proportion (21/146) did not (EBM discordant). The EBM concordant group demonstrated a statistically significant improvement in ODI scores compared to the EBM discordant group (p = 0.02). Compliance with EBM guidelines was associated with higher odds of achieving MCID, with an odds ratio of 2.93 and a confidence interval of 1.128-7.58 (p = 0.027). In the EBM concordant group, 42% of patients achieved SCB, and 64.8% showed MCID, whereas in the EBM discordant group, only 14% achieved SCB, and 38.1% showed MCID. These findings suggest that adherence to EBM guidelines in lumbar fusion procedures may lead to better clinical outcomes for patients.

CONCLUSIONS:
Patients whose lumbar fusions met the EBM criteria exhibited better self-reported outcomes at six months compared to those who did not meet the requirements. In order to strengthen EBM-guided patient care, an expanded knowledge base is needed.
278 Lateral Anterior Column Release in Short Construct... Is It Worth It?
Authors: Flores-Milan Gabriel , Carballo Cesar 
Published: March 2024

INTRODUCTION:
Adjacent Segment Disease (ASD) is a common complication after lumbar spinal fusions. Ways to reduce the rates for ASD are highly sought after mainly to avoid re-operation.

METHODS:
We conducted a retrospective cohort study that consisted of patients that underwent 1-2 level LLIF for degenerative spine disease from 2014-2020. Patients needed to have at least one year of follow-up and have postoperative standing x-rays. Preoperative demographics, perioperative surgical characteristics, and postoperative outcomes were recorded.

RESULTS:
92 patients were included for analysis after inclusion criteria. Median follow-up period of 25 months. 54% F, 64 years of age, BMI 31. 11 patients (12%) developed ASD at a median follow up of 29 months. In the patients with ASD, 9 (82%) underwent anterior column release (ACR) with the placement of hyper-lordotic cages > 20 degrees. In our cohort of short construct LLIF ACR was done 9 patients (L3/4 (7 patients) and L4/5 (2 patients). In the univariate analysis we found that age-adjusted PI-LL mismatch (p < 0.003), the use of a hyperlordotic cage (p = 0.003), and ACR release (p < 0.001) were significantly associated with ASD. A multivariate logistic regression model was created and showed only that ACR was predictive for ASD (Odds Ratio: 69.1, 95% confidence interval: 10.71-446.3, p < 0.001).

CONCLUSIONS:
ACR was predictive for developing ASD in lumbar degenerative disease patients that undergo short-segment LLIF. While other factors may play a role, this was the predominant factor identified in our cohort with at least 10-fold increase risk. ACR is a powerful tool to be use in only spinal deformity. We recommend against ACR in short construct LLIF.
283 Decoding Mechanotransduction in Spinal Pseudoarthrosis: A Mouse Model of Spinal Fusion for Developing Mechanosensitive Osteobiologics
Authors: Connolly Ian David , Burns Ryan P. , Kiapour Ali , Phan Duy , Esposito Eric , Kahle Kristopher Thomas , Shin John H. , Hadzipasic Muhamed , Shankar Ganesh 
Published: March 2024

INTRODUCTION:
Pseudoarthrosis (PA), represents a significant complication after spinal fusion. Efforts to reduce its occurrence predominantly involve the use of osteobiologics, the majority of which, are linked to various complications. It is well known that bone formation relies heavily on mechanical signaling cues. Recently, Piezo 1 has emerged as an important mechanosensitive calcium channel with a role in bone formation during development.

METHODS:
Normal human spine bone samples and PA tissue samples were collected intraoperatively. Samples underwent biomechanical and histologic characterization. Mice underwent spinal fusion surgery using iliac crest allograft. Weekly micro CT scans were performed over 4 weeks. Explanted mouse fusion bed (week 4) and normal spine underwent three-point bending testing.

RESULTS:
Human PA tissue was an elastic tissue that did not contain any mineralized bone with a mechanical stiffness of 12±4.1 N/mm. Bone had a measured stiffness of 341 ± 70 N/mm. Immunostaining showed that bone contained Piezo 1 expressing cells. PA demonstrated loss of osteocytes and loss of Piezo 1 expression. Mouse micro CT imaging of fusion bed at week 4 showed contiguous areas of fused bone. Fused mouse spine had a stiffness of 5.87 ± 2 N/mm. Normal mouse spine had a stiffness of 1.17 ± 0.47 N/mm.

CONCLUSIONS:
Human PA tissue is biomechanically and histologically distinct from normal bone with loss of Piezo 1 and osteocytes. Mice that underwent fusion surgery displayed radiographic and biomechanical evidence of bone fusion in a Piezo1-dependent manner, revealing a role for targeting mechanosensitive channels as a local biologic to promote arthrodesis.
289 Mental Health Comorbidities in Workers Compensation Patients and the Effect on Pain, Disability, Quality of Life, and Return to Work After Lumbar Spine Surgery
Authors: Monk Steve Hubert , Hani Ummey , Pfortmiller Deborah , Stanley Gerry , Bohl Michael , Kim Paul Keetae , Holland Christopher Michael , McGirt Matthew J. 
Published: March 2024

INTRODUCTION:
Outcomes after lumbar spine surgery in workers’ compensation (WC) patients have been reported to be worse than the general population. Anxiety and depression are modifiable risk factors that also adversely affect outcomes after lumbar spine surgery.

METHODS:
We queried a nationwide, prospective surgical outcomes registry (AANS-QOD) for all patients undergoing lumbar spine surgery at over 200 hospital systems from 2012 to 2021. Perioperative safety, facility utilization, one-year patient-reported outcomes (pain, disability, and quality-of-life), and return to work (RTW) were measured as a function of WC and mental health comorbidity status.

RESULTS:
A total of 27,525 patients (1018 WC, 26,507 non-WC) undergoing 1-4 level lumbar spine surgery (14,914 laminectomy, 12,611 fusion) were reviewed. WC patients were younger, healthier (lower ASA grade), more likely to be minorities, less educated, more likely to smoke, and had greater baseline back pain, disability, and quality of life compared to non-WC patients. The prevalence of anxiety and depression was similar between groups. WC patients had worse outcomes for all measures and lower rates of RTW compared to non-WC patients. WC patients with anxiety and depression demonstrated even greater disparities in all outcomes. After propensity matching, WC patients with anxiety or depression (n = 107) continued to demonstrate significantly worse outcomes in comparison to WC patients without anxiety or depression (n = 107).

CONCLUSIONS:
Disparities in outcomes after lumbar spine surgery in WC patients are exacerbated in patients with anxiety and depression. WC patients with mental health comorbidities receive the least benefit from lumbar spine surgery and may represent the most vulnerable subset of patients with spinal pathology. Addressing mental health comorbidities preoperatively may represent an opportunity for valuable resource allocation and surgical optimization in the WC population.
291 Supra-maximal Extent of Resection is Associated With Improved Progression-Free Survival in Patients With IDH Wild-Type Glioblastoma Once Negative TERT Promoter Molecular Margins are Achieved
Authors: Smith William , Massaad Elie , Bradley Joseph , Esposito Eric , Curry William T. , Barker Frederick George , Carter Bob S. , Nahed Brian V. , Cahill Daniel P. , Shankar Ganesh 
Published: March 2024

INTRODUCTION:
The standard of care for isocitrate dehydrogenase (IDH) wild-type GBM involves safe maximal resection with subsequent chemoradiation. TERT promoter (TERTp) mutations are clonal in >85% of IDH wild-type GBMs, detectable in all tumor cells. Advances in surgical management have focused on optimizing maximal resection given the positive correlation between extent of resection (EOR) and post-operative outcomes.

METHODS:
TERTp mutation detection in margin specimens was performed via a novel 30min qPCR-based method. A machine learning algorithm incorporating preoperative anatomic and intraoperative characteristics was developed using 148 patients to predict EOR. This model was prospectively applied to 44 patients to assess the correlation between a TERTp mutation negative margin and survival in cases when GTR was predicted.

RESULTS:
Retrospective analysis of 148 patients who underwent resection of GBM revealed significant improvement in 36-month survival with residual volume (RV) <4.9 cc). The primary predictive characteristics for achieving this RV were tumor volume, ventricular contact, multifocality, and Sawaya grade. Prospective analysis of 44 patients showed that, in cases where GTR was predicted and achieved, 26% obtained a TERTp negative margin. Although small, this group's PFS was significantly prolonged (0% vs 75% event-free at 30 months, p = 0.02), and a numerically superior prolonged OS was observed, while survival in GTR with positive molecular margin was indistinguishable from STR.

CONCLUSIONS:
These findings provide novel evidence supporting the utility of supramaximal resection targeting a “molecular margin” to maximize postoperative survival for a subset of patients with “localized” GBM. Further study is warranted to assess intraoperative, quantitative testing of TERTp mutation in GBM specimens to guide marginal resection in these patients.
293 The Impact of Tumor Mutational Status on Protoporphyrin IX Accumulation in Tumor-Associated Macrophages in Glioblastoma Patients
Authors: Lock Emily Katherine , Alber Daniel Alexander , Smith Andrew , Lee Sangwon Karl , Movah-Ezazi Misha , Hollon Todd Charles , Oermann Eric Karl , Orringer Daniel A. 
Published: March 2024

INTRODUCTION:
Immunotherapies provide promising new treatment options for lung cancer and melanoma, however success in glioblastoma (GBM) patients has been much rarer and uneven. Identifying candidates with GBM that are most likely to benefit from immunotherapy remains a challenge. The abundance of tumor-associated macrophages (TAMs) correlates response to immunotherapy in GBM patients. Here we leverage a new imaging technique for quantifying TAMs via tandem stimulated Raman histology (SRH) and two-photon excitation fluorescence microscopy (TPEF) to assess the impact of genetic classification on the abundance of TAMs.

METHODS:
We conducted tandem SRH and TPEF on specimens from 79 patients undergoing high-grade glioma resection with 5-ALA. We trained a MaskR-CNN deep neural network to identify TAMs and compute their density in each specimen. Corresponding clinical, demographic, genomic and methylomic data were collected for each patient. Independent sample t-tests were used to identify significant correlations between genetic markers, treatment, and TAM density.

RESULTS:
We analyzed 3,121,524 300 x 300 micron fields of view, from 151 fresh specimens, enabling segmentation of 611,789 TAMs. IDH-mutant tumors had significantly lower TAM density than IDH-wildtype tumors (p < 0.01). The absence of MGMT promoter hypermethylation was associated with significantly higher TAM density (p = 0.03). Tumors with EGFR amplification averaged significantly lower TAM density than EGFR wildtype specimens (p < 0.01). Recurrent tumors possessed 31.5% lower TAM density than primary resections.

CONCLUSIONS:
Tandem SRH and TPEF can estimate variations in TAM density in human GBMs. We found TAM density to be associated with IDH status, MGMT promoter methylation, and EGFR amplification. This imaging technique creates a new avenue for forecasting response to immunotherapy in GBM patients.
302 Targeted Inhibition of the Epigenetically Activated miR-483-5p IGF-2 Pathway as a Novel Therapeutic Strategy for Meningioma
Authors: Uhlmann Erik , Mackel Charles E. , Deforzh Evgeny , Rabinovsky Rosalia , Brastianos Priscilla , Varma Hemant , Krichevsky Anna , Vega Rafael A. 
Published: March 2024

INTRODUCTION:
Meningioma is the most common primary central nervous system tumor. These are usually treated by surgical resection with curative intent, however gross total resection is not always feasible and there are many cases of recurrent and refractory disease despite adjuvant radiotherapy. Presently, there is no effective pharmacotherapeutic options for these tumors.

METHODS:
Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells.

RESULTS:
Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and Ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma.

CONCLUSIONS:
Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a new feasible meningioma treatment target.