bluuebunny/crossref_metadata_2025_split huggingface dataset:
328 Incidence and Number of Missed Chemical Venous Thromboembolic Event Prophylactic Doses Predict the Development of Venous Thromboembolic Events in Traumatic Brain Injury Patients
Authors: Cole Kyril , Nguyen Sarah Elizabeth , Gelhard Savannah , Menacho Sarah Tamara , Grandhi Ramesh 
Published: March 2023

INTRODUCTION:
Venous thromboembolic events (VTE) are a major concern in trauma and intensive care, with traumatic brain injury (TBI) patients at an elevated risk. Chemical VTE prophylaxis is used to prevent VTE development. Concerning TBI patients, achieving a fine balance between the risk of worsening hemorrhage and clot development is important. To date, there has been no correlation between the number of missed doses and VTE development in this population.

METHODS:
Data were retrospectively collected among 818 TBI patients admitted to a level I trauma center between 2015-2020.

RESULTS:
Overall VTE incidence was 9% (7.6% DVT; 3.2% PE; 1.7% both). Median time to DVT and PE was 7 (IQR: 4-11) and 5 days (IQR: 3-12), respectively. VTE occurred in 37.8% of patients who missed prophylactic doses and 28.4% who did not (p = 0.089). In patients who experienced a VTE, compared to non-VTE patients, missed chemical prophylaxis dosing was primarily due to a pending invasive procedure (44.8% vs. 25.2%, p = 0.02) and the presence of additional bleeding (13.8% vs. 2.8%, p = 0.005). Non-VTE patients missed prophylactic dosing primarily from patient or family refusal (42.1% vs. 3.4%, p < 0.001). VTE incidence was higher in patients receiving invasive neurosurgery (45.9% vs. 30.5%, p = 0.007). Univariate analysis demonstrated 4-6 total missed doses as predicting the highest VTE risk (OR 4.08, 95% CI: 1.53-10.86, p = 0.005). No VTE were seen in >7 missed doses, presumably due to an overall high mortality rate of 13.5%.

CONCLUSIONS:
This study is novel in showing the incidence and number of missed chemical VTE prophylaxis to predict an increased VTE risk in TBI patients. Our study suggests a threshold of 4 missed doses to be particularly important in this critical patient population.
336 Prognostic Significance of Plasma Insulin Level for Deep Venous Thrombosis in Patients with Severe Traumatic Brain Injury in Critical Care
Authors: Du Min , Tang Rui , Zhang Qing-Hong , Liu Haiyan , Ji Zongsu , Zhou Min 
Published: March 2023

INTRODUCTION:
Whether insulin resistance is underlying the deep venous thrombosis (DVT) development in patients with traumatic brain injury (TBI) is elusive.

METHODS:
A prospective observational study of 73 severe TBI patients who had measurements of plasma insulin, glucose, glucagon-like peptide 1 (GLP-1), inflammatory factors, and hematological profile within 4 preset time periods during 2 weeks after TBI. Ultrasonic surveillance of DVT was tracked weekly. Two-way ANOVA analysis was applied to determine whether the factors could discriminate between patients with and without DVT. Partial correlations of insulin level with other variables were carried out in patients with or without DVT. Factors associated with DVT were analyzed by multivariable logistic regression. Neurological outcome 6 months after TBI was assessed for Glasgow Outcome Scale (GOS).

RESULTS:
Among patients with an average (SD) age of 53 ± 16 years, DVT developed in 20 patients (27%). The 14-day plasma insulin levels were higher in patients with DVT (P = 0.01). Platelet profile discriminated significantly between patients with and without DVT. None of other factors differed between the two groups. Patients with insulin therapy had significant higher insulin (P = 0.006), glucose (P < 0.001) and GLP-1 (P = 0.01) levels, and were more likely to develop DVT (60% vs. 15%, P < 0.001) with concomitant platelet depletion. Insulin levels correlated with glucose, GLP-1 levels, and platelet exclusively in patients without DVT. Conversely, in patients with DVT, insulin correlated negatively with GLP-1 level (r = -0.297, P = 0.016). Age (P = 0.01) and elevated insulin level at day 4-7 (P = 0.04) were independently associated with DVT. Patients with insulin therapy also showed worse GOS (P = 0.001).

CONCLUSIONS:
Elevated insulin level in the first 14 days after TBI may present insulin resistance in TBI, which was associated with consistent platelet activation, thus increasing risk of DVT.
343 Influence of Duraplasty on Clinical, Radiological, and Surgical Factors Associated with Syrinx Location in Children Treated for Chiari Malformation Type I and Syringomyelia: A Park-Reeves Syringomyelia Research Consortium Study
Authors: Emmert A. Scott , Yahanda Alexander T. , Limbrick David Delmar , Mangano Francesco T. 
Published: March 2023

INTRODUCTION:
Analyses of factors associated with syrinx location in Chiari malformation type I (CM-I) and syringomyelia (SM) are limited by the low individual incidences of syringes in certain spinal cord segments but could have important clinical implications on surgical planning, interpretation of postoperative imaging, and outcomes.

METHODS:
The Park-Reeves Syringomyelia Research Consortium database of pediatric patients with CM-I with SM was queried for patients who underwent first-time operation for posterior fossa decompression with (PFDD) or without (PFD) duraplasty. Clinical, radiological, and surgical data were compared among patients with cervical, thoracic, cervicothoracic, and holocord syringes.

RESULTS:
390 patients (90 cervical, 41 thoracic, 149 cervicothoracic, and 110 holocord) were analyzed. PFDD enhanced the magnitude of change on postoperative imaging in patients with cervical syringes. Patients with cervical or cervicothoracic syringes who underwent PFDD were less likely to develop postsurgical headaches, nausea and vomiting, or infections. However, PFDD was associated with more complications less than 6 months after surgery in patients with thoracic syringes and more complications overall in patients with cervicothoracic and holocord syringes.

CONCLUSIONS:
In the largest multi-institutional analysis of the effects of syrinx location in CM-I with SM, patients with cervicothoracic and holocord syringes experienced the greatest magnitude of change on postoperative imaging parameters while those with thoracic syringes experienced the fewest and smallest magnitude of postoperative radiological changes. PFDD-associated enhancement of postoperative radiological changes in cervical, thoracic, and holocord syringes did not necessarily translate into improvements in clinical symptoms or complication rates following surgery. PFDD is associated with greater clinical benefit for patients with cervical or cervicothoracic syringes but is less appropriate for patients with thoracic syringes based on outcomes and complication profiles.
357 Image-Guided Farlateral Lumbar Foraminotomy and Microdiscectomy: Operative Technique and Outcomes
Authors: De Biase Gaetano , Garcia Diogo P. , Pirris Stephen M. , Nottmeier Eric W. 
Published: March 2023

INTRODUCTION:
Three dimensional image-guidance is frequently used to improve the safety of complex spine surgeries. Its adoption remains mostly limited as and aid with instrumentation placement.

METHODS:
We performed a retrospective chart review of image-guided farlateral foraminotomies and microdiscectomies performed by a single surgeon from January 2018 to July 2021. Demographics, operative times and outcomes were collected. The stealth reference arc is fixated on the patient's skin using the Ioband. The O-arm is used to perform an intraoperative CT-scan automatically registered to the image-guided system. The location of the paraspinal incision is ascertained using the image-guided dilator to allow adequate trajectory to the neural foramen that minimizes the amount of facet joint that needs to be removed. The foraminotomy and/or discectomy is accomplished using microsurgical technique. Image guidance can be used to help guide the foraminotomy.

RESULTS:
20 patients were included in our study; 14 (70%) underwent image-guided farlateral microdiscectomy and 6 (30%) foraminotomy. The most common microdiscectomy level was L5-S1 (50%). Mean age was 66 ± 10.2 (SD) years; 16(80%) were male; BMI 27.5 ± 3 kg/m2;. Total procedure time was 117.4 ± 24.6 minutes; OR time 172.5 ± 22.5 minutes; EBL 21.5 ± 16.6 ml. Average length of stay 0.85 ± 0.6 days, with 5 (25%) discharge on the same day; all patients were discharged home. We did not observe intraoperative complications; all patients reported significant improvement of their presenting symptoms. Mean follow-up was 19.4 ± 28.7 months.

CONCLUSIONS:
FDA-approved use of spinal image-guidance requires a reference arc to be attached to the bony spine. Our technique of attaching the reference arc to the skin is an off-label use, we do not recommend it for instrumentation placement as there is mild navigation inaccuracy (2-3 mm). This technique allows for general accuracy to ascertain the location of the incision and trajectory and can help guide the foraminotomy.
363 Treatment of Spinal Metastasis in the 21th Century
Authors: Bonk Maximilian-Niklas , Wolfert Christina , Shiban Ehab 
Published: March 2023

INTRODUCTION:
Spinal metastases may present with different degrees of mechanical instability. The Spinal Instability Neoplastic Score (SINS) was developed to assess spinal neoplastic-related instability. Few have validated it clinically

METHODS:
A retrospective analysis of patients with a pathologic fracture due to a spinal metastasis between 01/2018-12/2020 was performed. We selected patients with a minimum follow-up of 12 months and analyzed them according to the SINS criteria. In the conservative-group group no spinal surgery was perfomed, in contrast the patients in the surgical-group underwent one or more surgeries, respectively. For both groups were the primary endpoint the progression of vertebral-body fracture following radiotherapy.

RESULTS:
In the conservative-group 332 Patients were identified. 30/283/19 Patients presented with low/moderate/high SINS, respectively. Fracture progression following radiotherapy was seen in 30%/30%/42% in cases with low/moderate/high SINS (P = 0.522), respectively. 17% of the progression cases in the moderate-group developed neurological deficits. In the interventional-group 35 patient were identified. 6/48/16 Patient presented with low/moderate/high SINS, respectively. Fracture-progression following radiotherapy was not seen in any case. In all cases we did not see any secondary alignment disorder or hints for an instability like loosening-hem. The overall survival was 59% in the conservative-group and 75% in the interventional-group. Analyzing the quality of life, we choose the walking-ability as a main-feature. 92% in the interventional-group are still able to walk, in contrast 86% in the conservative-group.

CONCLUSIONS:
SINS is an especially useful tool for assess stability of a pathologic fractures. Moderate or high SINS are associated with a remarkably high risk of fracture progression as well as risk for neurological deterioration. Furthermore, there are hints, that a corpectomy is not always necessary due to the secondary strengthening of the vertebral body by radio oncology.
369 Successful Image-Guided Stereotactic Radiosurgery for Treatment of Spasticity
Authors: Romanelli Pantaleo , Thomas Evan M. 
Published: March 2023

INTRODUCTION:
Close to 100 million people worldwide suffer the sequelae of severe trauma to the brain or spinal cord. Spasticity and related pain are a common and debilitating long-term complication in survivors. Conventional surgical treatments such as baclofen pumps & cordotomy are effective but offered to a very limited number of patients.

METHODS:
Four patients with refractory spasticity and related pain due to traumatic brain and/or spinal cord injury, brain and/or spinal cord surgery, and stroke underwent stereotactic irradiation of selected cervical or lumbar roots. The treatment was delivered to the post-ganglionic sensory segment of cervical roots or to the dorsolateral sensory region of lumbar roots. Selection of the irradiated roots was based on somatotopic distribution of spasticity and related pain as well as EMG findings. Modified Ashworth Scale (MAS) and Visual Analogue Score (VAS) have been used to assess spasticity and related pain levels before and after the procedure.

RESULTS:
The treatment was well tolerated. Marked symptomatic relief on spasticity and pain was found in all the patients. After 2 years, the median reduction of MAS score was 50%. The mean reduction of MAS and VAS was, respectively, 43,7% and 64.3%.

CONCLUSIONS:
SRS of spinal nerve roots appears to be a safe and effective noninvasive treatment for patients with spasticity and pain caused by brain or spinal cord injury. This technique provides a useful option for the treatment of a wide variety of patients suffering from the long-term sequelae of neurological injury and can broadly expand the ability to treat patients currently orphan of treatment. A randomized, sham-controlled prospective study is underway to provide further insight.
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.