bluuebunny/crossref_metadata_2025_split huggingface dataset:
151 Exceptional Responders to Base Excision Repair (BER) Inhibition for Recurrent Glioblastoma Display Enrichment for DNA Damage Response Pathways: RNA Sequencing Analysis From a Multicenter Trial
Authors: Ozair Ahmad , Drappatz Jan , Ye Xiaobu , Berens Michael , Peng Sen , Rath Sanhita , Dhruv Harshil , Walbert Tobias , Holdhoff Matthias , Lesse Glenn , Cloughesy Timothy F. , Sloan Andrew E. , Couce Marta , Peereboom David M. , Nabors Burt , Wen Patrick , Rogers Lisa R. , Grossman Stuart , Ahluwalia Manmeet 
Published: March 2024

INTRODUCTION:
Therapies for glioblastoma recurrence after surgery and chemoradiation are warranted. TRC102 (methoxyamine), a small molecule DNA base-excision repair (BER) inhibitor, reverses temozolomide (TMZ) resistance in preclinical glioma models. We had investigated efficacy of TRC102+TMZ for recurrent glioblastoma (rGBM) through multicenter trial.

METHODS:
A two-arm, two-stage, non-randomized, Phase II trial of TRC102+TMZ for adults with rGBM was conducted. Arm 1 included bevacizumab-naive patients at first recurrence, with primary aim of estimating response rates using RANO criteria. If sufficient activity was identified, arm 2 was planned in bevacizumab-refractory patients. Secondary aims were to determine overall survival (OS), progression-free survival (PFS), PFS at six months, and toxicity using CTCAE v4.0. Exploratory aims were correlating clinical outcomes with MPG expression and MGMT methylation. Differential gene expression profiling was analyzed using DESeq2 GSVA (RRID:SCR_015687) and transformed into enrichment scores for 'hallmark of DNA repair' pathways from Molecular Signatures Database (MSigDB, RRID:SCR_016863) to assign mechanistic signatures of therapeutic vulnerability.

RESULTS:
Arm 1 enrolled 19 patients with median of two treatment cycles, but objective responses were not observed. Hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). MGMT promoter was unmethylated in 14/19 patients, and MPG expression was present in 8/14 cases with available tumor tissue. MGMT methylation and MPG non-expression were associated with better OS and PFS. However, two ‘exceptional responders’ had PFS = 11 months, with MGMT methylated and MPG expressed. RNA sequencing of their tumor tissue demonstrated significant enrichment for DNA damage response (DDR) pathways (MSigDB), chromosomal instability gene signatures (CIN70,CIN25), and proliferative gene signatures (PCNA25).

CONCLUSIONS:
rGBM patients with elevated levels of MPG and DDR molecular signature may have impaired BER and respond better to TRC102+TMZ.
159 PD-1 Agonism as a Strategy to Prevent Neuroinflammation After Acute Large Vessel Occlusion
Authors: Kim Jennifer E. , Lee Ryan P. , Yazigi Eli , Feghali James , Atta Lyla , Pant Ayush , Levitan Idan , Xu Risheng , Patel Kisha K. , Kannapadi Nivedha , Shah Pavan P. , Kim Eileen , Caplan Justin M. , Fernando Gonzalez , Huang Judy , Lim Michael , Tamargo Rafael Jesus , Koehler Raymond , Janzie Lauren , Robinson Shenandoah , Jackson Christopher Mitchell 
Published: March 2024

INTRODUCTION:
Stroke is a leading cause of death and long-term disability worldwide. Acute ischemia results in a profound inflammatory response that is counterproductive to short- and long-term recovery. Programmed Death Protein 1 (PD-1) is an immune checkpoint that has been shown to be upregulated after acute cerebral injury, and—upon binding its ligand PD-L1—negatively regulates immune cells to limit the inflammatory response.

METHODS:
C57BL/6J mice underwent middle cerebral artery occlusion (MCAO) and were randomized into three arms: (1)sham surgery, (2)MCAO control, and (3)MCAO+PD-L1. Survival, brain water content, and volumetric MRI analysis of cerebral edema were measured. Brains were analyzed by flow cytometry to quantify PD-1 expression on infiltrating immune cells. Peripheral blood was harvested for single-cell RNA-sequencing. Blood from stroke patients was collected, and the frequency of PD-1+ monocytes was correlated to clinical outcomes.

RESULTS:
PD-L1 significantly decreased brain edema as measured by brain water content (p = 0.0277) and high-resolution MRI (p < 0.0001), and improved overall survival (p = 0.0022). PD-1+ monocytes are upregulated in the ischemic hemisphere, and appear to be critical mediators of edema. PD-L1 treatment decreased PD-1+ monocyte infiltration , while global PD-1 (PD-1-/-) and myeloid-specific knockout of PD-1 (PD-1f/fLysMcre) abrogated the treatment effect on edema. Single-cell RNA sequencing and differential expression analysis of peripheral monocytes revealed downregulation of multiple pro-inflammatory pathways in the treated mice versus the controls. Human correlative studies confirmed that PD-1+ monocytes were present in the peripheral blood of MCA stroke patients, and the frequency of this cell population correlated with post-stroke cerebral edema.

CONCLUSIONS:
Our results support PD-L1 as a novel therapeutic strategy for neuroinflammation and cerebral edema after acute ischemic stroke.
160 Gamme Knife Radio Surgery for Cerebral Arteriovenous Malformation (AVM) in Children: A Systematic Review and Meta-analysis of Clinical Outcomes
Authors: Florez-Perdomo William , Moscote-Salazar Luis Rafael , Agrawal Amit , Janjua Tariq , Chavda Vishal , García-Ballestas Ezequiel , Abdulla Ebtesam 
Published: March 2024

INTRODUCTION:
As radiosurgical devices are becoming more commonly used and applied to treat cerebral arteriovenous malformations (cAVMs), there is a growing concern about whether the outcomes of radiosurgery might differ between children, adolescents, and adults due to the distinct characteristics of cAVMs in these age groups.

METHODS:
Search: A search for RCT, not RCT, prospective and retrospective cohort studies in PUBMED; SCOPUS; Central Cochrane Registry ofControlled Trials (The Cochrane Library); MEDLINE; EMBASE (Ovid); CINAHL. The search strategy include subject headings (MeSH) and text words connected with Booleans term. Population: Children (younger than 18 years old) with Cerebral Arterio-venous Malformation (AVMs). Intervention: Gamma Knife radiosurgery (GKS). Outcomes: Primary Outcome: Mortality to end of Follow-up and Surgery successfull determined by the percentage of obliterated AVMs. Secondary Outcome: New Neurological deterioration and Post-Radiosurgery intracranial hemorrhage.

RESULTS:
21 studies with 2142 children who had Gamma knife surgery for cerebral arteriovenous malformations were found for this systematic review. For children with cerebral AVMs treat with GKS, the death rate was 0.725% (95% CI 0.411%-1.126%; I2 = 0%) while the success rate of gamma knife radiosurgery was 71.74% (95% CI 65.716%-77.211%; I2 = 88.13). The rate of complications, such as the rate of new neurological deficits, was 2.57% (1.43% to 3.89%; I2 = 66.78%), and the postoperative intracranial bleeding rate was 2.463% (1.348% to 3.9%; I2 = 70.14%).

CONCLUSIONS:
Gamma Knife radiosurgery is a safe and effective treatment option for cerebral arteriovenous malformations, with high surgical success rates, low mortality, and low complication rates. However, further high-quality case-control studies are needed to evaluate its long-term efficacy and safety.
175 A Patient Prioritization Tool for Non-elective Spine Surgeries: Improving Patient Outcomes and Reducing Adverse Events in a Level-1 Trauma Center
Authors: Rodriguez Beato Freddie Y. , Soufi Khadija , Ebinu Julius O. 
Published: March 2024

INTRODUCTION:
The ability to provide comprehensive care at a level 1 trauma center has become challenging, especially considering the impact of COVID on healthcare. These resource-intensive challenges have been exacerbated by provider burnout and a shortage of healthcare providers. In a high-volume tertiary care center, these factors have led to delayed access to care, and potentially an increased incidence of adverse outcomes for non-elective surgical patients. As health systems learn to adapt to these challenges, developing protocols or tools to prioritize patients is paramount for sustainable healthcare systems.

METHODS:
A database review of all non-elective surgeries at a single level 1 trauma center.

RESULTS:
A total of 2,088 surgeries were analyzed and 764 (36%) of surgeries were delayed. There was an increase in the prevalence of delays following the start of COVID-19 (33% to 37%), especially amongst the patients who did not require emergent surgery (<12 hours) (51% vs 38%, p < 0.0001). The average time delay to surgery increased from 54.5 hours to 168 hours peaking at 312 hours mid-pandemic. The prevalence of any complication for all patients was 13.3%, including 1.2% mortality rate, 8.1% readmission rate within 90 days, 0.6% infection rate and prolonged LOS (10.2 vs 9.2 days). Amongst the patients with surgical delays, there was a statistically higher mortality rate (3% vs 1%, p-value < 0.05), complication rate (34.7% vs 13.1%, p < 0.0001) and readmission rate (23% vs 8%, p < 0.0001).

CONCLUSIONS:
An increase in delay for non-elective spine surgery led to increased hospital resource utilization, higher complication and readmission rates, and higher mortality rates in a level-1 trauma center.
181 Initial Experience With Sonodynamic Therapy Using Low-Intensity Focused Ultrasound and ALA for Pediatric Patients With Diffuse Intrinsic Pontine Glioma
Authors: Patel Nirali , Chesney Kelsi M. , Bryant Jean-Paul , Stabingas Kristen , Packer Roger , Kilburn Lindsay , Sheridan Adriana Fonseca , Keating Robert F. , Syed Hasan R. 
Published: March 2024

INTRODUCTION:
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with poor prognosis. Aminolevulinic acid (ALA) sonodynamic therapy (SDT) is a non-invasive strategy where tissues sensitized with ALA are exposed to MR-guided focused ultrasound (MRgFUS). Preclinical studies have demonstrated significant slowing in growth of gliomas and increased survival in animal models.

METHODS:
A Phase1/2 study (NCT05123534, clinicaltrials.gov) in patients with newly diagnosed DIPG is ongoing. MRIs at 24hrs and 1- and 3-months post procedure are obtained to evaluate safety and efficacy. A total of 18-45 patients will be enrolled in 9 different dose-escalation cohorts. The three patients from the first cohort are described below.

RESULTS:
Three patients with DIPGs were treated with 5 mg/kg of ALA and 200 J of MRgFUS in the first cohort. They were aged 5-7 years and 2 were females. They had received radiotherapy 8-10 weeks prior and interval imaging showed no disease progression. The first patient received two treatments with one half of the pons treated during each visit. The other two received one treatment targeting the entire pons. They all tolerated the procedure well. One of the patients noted a transient worsening of his diplopia after the treatment. No significant edema or hemorrhage were noted on postoperative scans obtained within 24 hrs of treatment. MRIs obtained 1- and 3-months after treatment have shown significant decrease in tumor burden in 2 of the patients.

CONCLUSIONS:
The first-in-human experience with a new therapeutic modality for DIPG patients demonstrates safety and efficacy. Future procedures will involve ascending drug and MRgFUS energy dose combinations. The use of focused ultrasound signals an innovative approach for challenging to treat pediatric brain tumors.
192 Feasibility of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor Patients With Low Skull Density Ratio
Authors: Ng Patrick , Blitz Sarah , Jie Chua Melissa Ming , Segar David J. , Cosgrove G. Rees 
Published: March 2024

INTRODUCTION:
Magnetic resonance-guided focused ultrasound (MRgFUS) is a safe, effective treatment for essential tremor (ET). Skull density ratio (SDR), the ratio between the densities of cancellous bone and cortical bone, affects energy penetration of the skull. Major clinical trials and guidelines have excluded patients with low skull density ratio due to concerns of disrupted treatment, though these patients represent nearly 40% of ET patients.

METHODS:
In this single-surgeon cohort study of prospectively collected and retrospectively analyzed data, we report the characteristics and clinical outcomes of all ET patients with low SDR (<0.40) vs. high SDR (=0.40) treated at Brigham and Women’s Hospital between June 2019 and February 2023. Clinical outcomes were determined by Fahn-Tolosa-Marin (FTM) scores in the affected limb and percentage of patients with clinical improvements.

RESULTS:
Thirty-one patients had low SDR. 239 patients had high SDR. Mean (±SD) SDRs in the low SDR and high SDR groups were 0.36 (±0.02) and 0.51 (±0.08), respectively. There were no significant differences between the two groups in the following characteristics: sex, handedness, duration of tremor, total preoperative Fahn-Tolosa-Marin (FTM) score, intention + posture preoperative FTM score, age at treatment, treatment laterality, and rate of intraoperative complications. While there were significant differences in the clinical outcomes of low SDR vs. high SDR patients on postoperative day 1 (POD1), the clinical outcomes between the two groups were not significantly different at every follow-up time point, including up to three years post-treatment.

CONCLUSIONS:
While clinical outcomes were significantly different on POD1, low SDR and high SDR patients had similar long-term clinical outcomes, suggesting that MRgFUS of ET patients with SDR < 0.40 is feasible and effective.
195 Targeting Thalamocortical Circuits For Closed-Loop Stimulation in Lennox-Gastaut Syndrome
Authors: Warren Aaron , Butson Chris , Hook Matthew , Dalic Linda , Archer John , Macdonald-Laurs Emma , Schaper Frederic , Singh Hargunbir , Johnson Lise , Bullinger Katie , Gross Robert E. , Morrell Martha J. , Rolston John 
Published: March 2024

INTRODUCTION:
Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy associated with frequent seizures, cognitive impairment, and high burden of care. Electrical stimulation of the thalamus can be an effective treatment for LGS, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown.

METHODS:
Brain network maps from 3 group-level studies of LGS were averaged to define the area of peak overlap: combined electroencephalography-functional MRI (EEG-fMRI) of paroxysmal fast activity, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) of hypometabolism, and structural connectivity associated with efficacy in a previous trial of deep brain stimulation. The resulting “hotspot” was used as a seed in a normative fMRI connectivity analysis to identify connected networks. Two patients underwent bilateral thalamocortical implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analyzed for presence and synchrony of epileptiform activity.

RESULTS:
Peak overlap was in bilateral premotor cortex. Functional connectivity of this hotspot revealed a network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-fMRI and FDG-PET. Intracranial electrophysiology showed characteristic epileptiform activity of LGS in the cortical hotspot that preceded or co-occurred with similar thalamic activity.

CONCLUSIONS:
Premotor cortex shows peak involvement in LGS, and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for neuromodulation therapies, including thalamocortical stimulation. Compared to thalamus-only stimulation, addition of this cortical target may allow more rapid detections and responsive stimulations of seizures, and broader modulation of the brain network underlying LGS to achieve greater seizure control.
249 Interprofessional Consultation to Reduce Unnecessary Transfers of Complicated Mild TBI to Tertiary Referral Centers
Authors: Blitz Sarah , Rosen Carlo , Anderson Jonathan , Stenson Bryan , Stippler Martina 
Published: March 2024

INTRODUCTION:
The neurosurgical intervention rate for complicated mild traumatic brain injury (cmTBI) is less than 1%. However, the absence of transfer guidelines and fear of malpractice results in unnecessary transfers of cmTBI patients to tertiary referral centers.

METHODS:
Between April 2021 and March 2023, we implemented a Tele-TBI at three community hospitals for cmTBI patients seen in the emergency department (ED). An interprofessional telehealth-based consultation between emergency medicine and neurosurgery determined if a patient needed to be transferred to the Level-1Trauma Center or could be cared for at the community hospital. A retrospectively chart review was used to determine if transfers were unnecessary. Transfer rates were compared for patients from hospitals with and without the Tele-TBI protocol.

RESULTS:
Out of 822 cmTBI patients seen in our ED, 73% (n = 602) were transferred from other hospitals. The mean age of transferred patients was 67.5 (±19.9) and median GCS was 15. During this time, 128 Tele-TBI consultations were performed. The mean age was 75.7 (±16.2), and median GCS was 15. The overall transfer rate was decreased by 89% (n = 15/128) when Tele-TBI consultations were initiated. Tele-TBI-enabled hospitals had significantly fewer (p < 0.001) unindicated transfers (28.7%, n = 66 versus 71.3% n = 164) and led to fewer (p = 0.003) transferred patients discharged directly from the Level-1Trauma Center ED (28.6%, n = 66 versus 72.3%, n = 173). ICU admissions and frequency of neurosurgical intervention did not differ between hospitals with or without tele-TBI implementation.

CONCLUSIONS:
Interprofessional telehealth-based consultation can effectively triage patients with cmTBI presenting to community hospitals, leading to fewer unnecessary transfers with similar rates of ICU admissions and neurosurgical interventions.
261 Perioperative Complications and Secondary Retethering After Pediatric Tethered Cord Release Surgery
Authors: Pan James , Boop Scott , Barber Jason , Susarla Srinivas , Durfy Sharon , Ojemann Jeffrey G. , Goldstein Hannah Emily , Lee Amy , Browd Samuel R. , Ellenbogen Richard G. , Hauptman Jason Scott 
Published: March 2024

INTRODUCTION:
Tethered cord syndrome refers to a constellation of symptoms characterized by neurological, musculoskeletal, and urinary symptoms, caused by traction on the spinal cord. Various surgical techniques have been developed to address tethered cord syndrome depending on a diverse set of etiologies. Understanding perioperative complications and secondary retethering is crucial for optimizing patient outcomes and refining surgical techniques.

METHODS:
Retrospective review of children who underwent TCR surgery from July 2014 to April 2023. Data included demographics, perioperative characteristics, surgical techniques, and follow-up duration. Primary outcomes were 60-day postoperative complications and secondary retethering requiring repeat surgery.

RESULTS:
We identified 363 TCR surgeries (145 simple, 218 complex, 340 subjects). Mean follow-up was 446 days for simple TCRs and 731 days for complex TCRs. The adjusted 60-day complication rate was 3.8% (95%-CI 1.6-9.1) for simple TCRs and 11.9% (95%-CI 9.0-19.4) for complex TCRs. Lower weight, shorter surgical times, and ICU admission were associated with complications for simple TCRs. Soft tissue drains increased complications for complex TCRs. Secondary retethering rates were 1.4% for simple TCRs and 11.9% for complex TCRs. The 1-, 3-, and 5-year progression-free survival in complex cases were 94.7% (95%-CI 89.1-97.4), 77.7% (95%-CI 67.3-85.3), and 62.6% (95%-CI 46.5-75.1). Multivariate analysis revealed that prior detethering (OR 8.15, 95%-CI 2.33-28.50, p = 0.001) and usage of the operative laser (OR 10.43, 95%-CI 1.36-80.26, p = 0.024) were independently associated with secondary retethering in complex cases.

CONCLUSIONS:
This is the largest series examining postoperative complications and long-term secondary retethering in TCR surgery. Simple TCR surgeries demonstrated safety, rare complications, and low secondary retethering rates. Complex TCR surgeries presented higher risks for complications and secondary retethering. Modifiable risk factors, such as operative laser usage, influenced secondary retethering in complex cases.
270 Inducing Neural Maturation and Increasing Survival in SHH Medulloblastoma Using EZH2 Inhibition in a Mouse Model
Authors: Orillac Cordelia Marcela , Snuderl Matija , Galbraith Kristyn , Tylawsky Daniel , Liechty Benjamin , Vaynshteyn Jake , Gerwin Jeffrey , Boue Daniel , Heller Daniel , Raju Praveen 
Published: March 2024

INTRODUCTION:
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Genetically, MB can be divided into four subgroups of which the SHH subtype histologically shows nodular architecture. Within this nodular architecture, there are islands of mature cells, with more abundant neuropil and a low proliferation rate, scattered among sheets of primitive cells.

METHODS:
We performed laser capture microdissection followed by whole transcriptome analysis, spatial transcriptomics using Digital Spatial Profiling, whole genome DNA methylation and ChIP-Seq analysis of mature and primitive areas from 8 medulloblastomas. We developed a genetically-engineered mouse model of SHH MB showing spontaneous maturation and lack of maturation with a conditional EZH2 genetic ablation or EZH2 overactivation respectively. Finally, we developed a fucoidan-based nanoparticle drug delivery across the blood brain barrier (BBB) for targeted molecular inhibition.

RESULTS:
Using whole transcriptome and DNA methylation analysis, we identified ∼120 differentially expressed genes between primitive and mature regions with enrichment for genes regulated by H3K4me3 and H3K27me3. ChIP-Seq analysis showed striking differences in H3K27me3 enrichment between primitive and mature medulloblastoma cells including at the EZH2 locus. Medulloblastoma specific EZH2 genetic ablation resulted in diffuse tumor cell differentiation and prolonged survival in mice (n = 10 per group, log-rank p = 0.01). Conversely, conditional EZH2 (Y641F) activation prevented medulloblastoma differentiation. A fucoidan-based nanoparticle successfully delivered the EZH2 inhibitor (EPZ-6438) across the murine BBB to achieve significant extension of mouse survival (median 70 days compared to 21 days in control mice; *p = 0.01, Mantel-Cox).

CONCLUSIONS:
Spontaneous maturation of medulloblastoma cells can be induced by inhibition of EZH2. Fucoidan-based nanoparticle delivery systems allows tumor specific targeted delivery across the BBB extending survival in mice.