bluuebunny/crossref_metadata_2025 huggingface dataset:
869 Early Signs of Elevated Intracranial Pressure (ICP) on Computed Tomography Correlate With Measured ICP in the Intensive Care Unit and Six-month Outcome Following Moderate to Severe TBI
Authors: Lucke-Wold Brandon
Published: March 2024

INTRODUCTION:

Identifying patients at risk for increased intracranial pressure (ICP) followingTBI via baseline computed tomography (CT) has not previously been validated in a prospective dataset.

METHODS:

Data were obtained from the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECTIII) multicenter clinical trial. Baseline CT scans for 881 participants were individually reviewed by a blinded central neuroradiologist. Five signs of elevated ICP were measured (sulcal obliteration, lateral ventricle compression, 3rd ventricle compression, midline shift, and herniation). Associations between signs of increased ICP and outcomes (6-month functional outcome and mortality) were assessed.

RESULTS:

Sulcal obliteration (p = 0.029) and third ventricular compression (p = 0.039) were associated with elevated ICP. Univariate regression analyses indicated that increasing combinations of the five defined signs of elevated ICP were associated with mortality, poor functional outcome, and time to death. There was also an increased likelihood of mortality if patients required craniotomy (OR = 4.318, 95% Confidence Interval [1.330-16.030]) or hemicraniectomy (OR = 2.993 [1.109-8.482]). On multivariate regression analyses, hemorrhage location was associated with mortality (posterior fossa, OR = 3.208 [1.120-9.188] and basal ganglia, OR = 3.079 [1.178-8.077]). Volume of hemorrhage >30cc was also associated with increased mortality, OR = 3.702 [1.575-8.956]). The proportion of patient hours with sustained ICP = 20 mmHg, and maximum ICP = 20 mmHg, were also directly correlated with increased mortality (OR = 64.99 [7.731-635.51]; and OR = 1.025 [1.004-1.047]). Poor functional outcome was predicted by concurrent presence of all five radiographic signs of elevated ICP (OR = 4.44 [1.514-14.183]) and presence of frontal lobe (OR = 2.951 [1.265-7.067]), subarachnoid (OR = 2.231 [1.067-4.717]), or intraventricular (OR = 2.249 [1.159-4.508]) hemorrhage. Time to death was modulated by total patient days of elevated ICP = 20 mmHg (Effect Size = 3.424 [1.500, 5.439]) in the first two weeks of hospitalization.

CONCLUSIONS:

ICP-related imaging variables can be prognosticate for moderate-severe TBI.
872 Natural History of Conservatively Managed Patients With Chiari Malformation Type I and Syringomyelia
Authors: Patel Jay , Huang Jesse , Agwu Chibueze , Das Paramita
Published: March 2024

INTRODUCTION:

Chiari malformation type 1 (CM1) describes caudal ectopia of the cerebellar tonsils. Though often asymptomatic earlier in life and found incidentally on imaging, CM1 can disturb cerebrospinal fluid (CSF) flow and generate an array of symptoms. Surgical treatment for CM1 centers around procedures to increase the posterior fossa volume and improve CSF circulation. Many surgeons elect to operate on CM1 patients in the setting of a syrinx, making it difficult to understand the natural history of these patients.

METHODS:

Retrospective study of 37 CM1 patients with syrinx who were managed conservatively at our institution. All patients had initial and follow-up clinic visits with a neurologist or neurosurgeon. Of the 37 patients, 27 had initial and follow-up MRI images at least six months apart. Student t-tests were used to compare radiological parameters.

RESULTS:

A total of three patients saw complete resolution of their syrinxes. Regarding clinical symptomatology, 19 out of 32 patients who were initially symptomatic saw clinical improvement by follow up, while 13 remained stable, and five declined. Of the five patients that declined, three had worsening neurological conditions not attributed to the syrinx or CM1 while the remaining two patients were the only patients that declined surgery despite recommendation. A total of 16 patients saw decreases in both syrinx size and tonsillar descent. There were no statistically significant differences between tonsillar descent, syrinx size, and number of vertebral bodies spanned by syrinx between the initial and latest follow up. The presence of tonsillar pegging was predictive of decrease in syrinx size. Tonsillar descent and syrinx size were not predictive of clinical outcomes.

CONCLUSIONS:

Although the surgical treatment of the CM1 patient successfully resolves the syrinx, the natural history of the syrinx can be benign.
893 Psychophysical Pain Encoding in the Cingulate Cortex Predicts Responsiveness of Electrical Stimulation
Authors: Caston Rose , Smith Elliot , Davis Tyler , Singh Hargunbir , Rahimpour Shervin , Rolston John David
Published: March 2024

INTRODUCTION:

The anterior cingulate cortex (ACC) plays an important role in pain's cognitive and emotional processing. Prior studies have used deep brain stimulation (DBS) to treat chronic pain, but results have been inconsistent. This may be due to network adaptation over time and variable causes of chronic pain. Identifying patient-specific pain network features may be necessary to determine patients' candidacy for DBS.

METHODS:

Four patients who underwent intracranial monitoring for epilepsy (stereo-electroencephalography) participated in a pain task. Subjects placed their hand on a device capable of eliciting thermal pain for five seconds and rated their pain. Current-controlled biphasic trains of electrical stimulation were applied to a random subset of trials for each subject. Thermal pain thresholds with and without electrical stimulation were determined. To evaluate whether patients had neural activity susceptible to modulation, generalized linear mixed-effects models assessed the relationship between broadband high-frequency local field potential amplitude within the cingulate cortex (HFA; 70-150 Hz) and the resulting psychophysical pain evaluations.

RESULTS:

The pain threshold for each patient was determined from the psychometric probability density function. Two patients had a higher pain threshold with stimulation than without, while the others had no difference. We also evaluated the relationship between neural activity and pain responses. We found that patients who responded to stimulation had specific time windows where high-frequency activity was associated with increased pain ratings.

CONCLUSIONS:

Stimulation of cingulate regions with increased pain-related neural activity was more effective at modulating pain perception than stimulating non-encoding regions. Personalized evaluation of neural activity biomarkers could help identify the best target for stimulation and predict its effectiveness in future studies evaluating DBS.
907 Do Grades Suffer After Sport-Related Concussion? A Study of 94 Adolescent Athletes
Authors: Jo Jacob , Rigney Grant Harding , Williams Kristen , Burns Carter , Terry Douglas , Zuckerman Scott L. , Chanbour Hani
Published: March 2024

INTRODUCTION:

Academic performance upon return-to-learn (RTL) following sport-related concussion (SRC) in adolescent athletes is an understudied yet important topic in the concussion literature.

METHODS:

A retrospective, cohort study was conducted of athletes 12-24-years-old who were treated for a SRC at a regional sports concussion center between 11/2017-04/2022. Athletes/parents were interviewed via phone regarding grades following concussion. Outcome variables included worsening of grades (yes/no) upon RTL to school and delayed time-to-normalization-of-grades (dichotomized: 0-90 days vs. >90 days). Independent variables include demographics, personal/family medical history, injury characteristics, school factors (type [private/public], accommodations received [yes/no], presence of concussion specialist/athletic trainer at school [yes/no], participant rating of teacher/school’s concussion knowledge [1-10]), and recovery (return-to-learn [RTL], symptom resolution, return-to-play). Univariate logistic regressions were performed.

RESULTS:

A total of 94 participants (60.4% male, 16.6 ± 2.6 years-old) were interviewed at a median time of 286 days (IQR: 247-420) post-concussion. The mean RTL of the cohort was 9.0 ± 13.2 days. Of all participants, 30/94 (31.9%) endorsed having worsening of grades upon RTL, and of those, 17/30 (43.6%) reported delayed time-to-normalization-of-grades (>90 days). Univariate analysis revealed no statistically significant predictors for worsening of grades; however, marginal significance was obtained as such that those with worse initial concussion symptoms were more likely to endorse feeling their grades worsened (OR = 1.02, p = .08, 95% CI 0.99, 1.04). No statistically significant predictors of delayed time-to-normalization-of-grades were found.

CONCLUSIONS:

In a cohort of adolescents with SRC, approximately 1 in 3 athletes reported worsening of grades, and 18% reported their grades did not normalize for >3 months. Marginal significance was obtained supporting the notion that those with worse initial symptoms were more likely to report worsened grades.
926 End of Life Decision-Making Inequities for Pediatric Patients With Severe Traumatic Brain Injury
Authors: Malhotra Armaan K. , Shakil Husain , Smith Christopher , Sader Nicholas , Ladha Karim , Wijeysundera Duminda , Singhal Ashutosh , Kulkarni Abhaya Vivek , Wilson Jefferson , Witiw Christopher , Nathens Avery
Published: March 2024

INTRODUCTION:

The decision to withdraw life sustaining treatment (WLST) for pediatric patients with severe traumatic brain injury (TBI) is challenging for clinicians and families with limited evidence quantifying existing practices.

METHODS:

This retrospective study utilized data collected from trauma centers through the American College of Surgeons Trauma Quality Improvement Program between 2017-2020. We included pediatric patients (<19 years) with severe TBI and a documented decision for WLST. We utilized a random intercept multilevel logistic regression model to quantify patient, injury and hospital characteristics influencing WLST. In order to quantify the impact of disparate WLST practices on mortality, we ranked centers by their conditional random intercept computed quartile-specific adjusted mortality.

RESULTS:

We identified a total of 9803 children with severe TBI treated across 515 trauma centers, of which 1003 (10.2%) had WLST. Patient-level factors associated with increased likelihood of WLST were young age (<3 years), higher severity intracranial and extracranial injuries and mechanism of injury related to firearms. Following adjustment for patient and hospital attributes, the median odds ratio was 1.54 (95% CI: 1.50-1.57), reflecting residual variation in WLST between centers. When centers were grouped into quartiles by their propensity for WLST, adjusted mortality was higher for fourth compared to first quartile centers (OR 1.67, 95% CI: 1.47-1.90).

CONCLUSIONS:

Several patient and injury factors were associated with WLST decision-making for pediatric patients with severe TBI. We also showed variation in WLST practices between trauma centers after adjustment for case mix; these differences were associated with differing quartile-specific adjusted mortality rates. Taken together, these findings highlight the presence of care provision inequities among North American trauma centers regarding WLST practice patterns for pediatric patients with severe TBI.
Comparative Analysis of Single Versus Dual Anti-Epileptic Drugs for Controlling Intra-Operative and Early Postoperative Seizure in Glioma Patients Undergoing an Awake Craniotomy; A Retrospective Study
Authors: Zandpazandi Sara , Pour-Rashidi Ahmad
Published: March 2024

INTRODUCTION:

Awake craniotomy (AC) is the standard approach for tumors of eloquent areas. However, concerns remain regarding the perioperative seizure risks and complications requiring general anesthesia (GA) or termination.

METHODS:

This retrospective cohort study included patients who underwent awake craniotomy for Glioma resection. Patients were divided into two groups based on their seizure control medication: Group S (N = 29) received one AED, while Group D (N = 26) received dual AEDs. We compared intraoperative seizures (IOS) and post-operative seizures (POS) rates between Groups S and D. Additionally, we evaluated the risk factors associated with POS and the 1-month post-operative Karnofsky Performance Scale (1M-KPS).

RESULTS:

This study considered a power of 0.9 so the effect size obtained was 0.866. 55 patients (41.8% female) with a median age of 39.0 (IQR 33.0-51.0) entered. The rate of IOS was 8 (27.6%) in Group S and 3 (11.5%) in Group D, with no statistically significant difference. (p = 0.137) POS occurred in 7 (24.1%) patients in group S and 2 (7.7%) patients in group D, (p = 0.100) pointing out no significant difference. The length of hospital stay (p = 0.606) and the length of ICU stay (p = 0.141), Post-op KPS, and 1M-KPS were not significantly different between the two cohorts (p = 0.131 and p = 0.217, respectively). The occurrence of POS was influenced neither by adjuvant therapy nor IDH1 mutation. The univariate and multivariate regression models showed pre-op KPS and the extent of resection had a significant effect on 1M-KPS.

CONCLUSIONS:

The addition of a second AED did not significantly affect POS prevention, IOS rate, or 1M-KPS improvement. Further research is needed for optimized strategies and improved patient outcomes.
Determining the Underlying Mechanisms of Glioma Progression and Recurrence
Authors: Voisin Mathew , Patil Vikas , Liu Jeffrey , Sosa Julio , Khan Shahbaz , Nassiri Farshad , Kislinger Thomas , Zadeh Gelareh
Published: March 2024

INTRODUCTION:

Gliomas are the most common malignant brain tumour. Despite standard-of-care therapy, these tumours inevitably recur. Recurrent tumours are often treatment-resistant and associated with a poor prognosis, and there is an urgent need for novel treatments.

METHODS:

The epigenome-wide methylome, transcriptome, and proteome was analyzed in a total of 271 samples from 176 patients with gliomas, including 166 primary (pre-treatment) and 105 recurrent (post-treatment) tumours. Included is a unique cohort of 81 patients with paired tumour samples collected at both pre- and post- treatment.

RESULTS:

Epigenomics accounted for the majority of observed variance between samples and was driven by IDH status. Paired analyses identified epigenetic stability in IDH wildtype tumours at recurrence, compared to a loss of methylation at recurrence in IDH mutant tumours. Loss of methylation in IDH mutant gliomas at recurrence was driven by astrocytomas undergoing malignant transformation. Integrated, multi-platform analyses of paired samples undergoing malignant transformation identified novel genetic markers and pathways of transformation. Finally, a novel subgroup of IDH wildtype GBM with improved survival and a distinct proteomics signature was discovered. Multi-platform analyses characterized this novel subgroup as exhibiting hypermethylation, increased DNA mismatch repair and cell cycle regulation, and an altered tumour microenvironment.

CONCLUSIONS:

In conclusion, this study identifies targetable molecular factors that promote malignant transformation in IDH mutant gliomas and classifies a novel subgroup of IDH wildtype GBM with improved prognosis.
Human Plasma-Like Medium Activates Immune Elements in Glioma
Authors: El Shami Mohamad , Savani Milan , Hicks William Harrison , Gattie Lauren , McBrayer Samuel , Abdullah Kalil G.
Published: March 2024

INTRODUCTION:

Glioma Surgically eXplanted Organoids (SXOs) are ex vivo three-dimensional models demonstrated to recapitulate the parental tumor microenvironment (TME). Human plasma-like medium (HPLM), a culture medium that mirrors physiologic nutrient conditions, has been found in other cancer subtypes to induce transcriptional differences in T-lymphocyte activation. We hypothesized that SXO culture in HPLM would maintain immune cell populations and induce physiologically relevant immune-modulatory pathways.

METHODS:

SXOs were established and cultured in conventional Glioma Organoid Complete medium (GOC) and transitioned to HPLM for 24 or 120 hours. Formalin-fixed paraffin-embedded samples were stained for tumor cells (GFAP), immune cells (CD45), and nucleic acid (SYTO-13) and analyzed using the Nanostring GeoMx™ Digital Spatial Profiler for spatial transcriptomics. Gene expression clustering profiles were conducted using GSEA and CIBERSORT. The gene expression differences of SXOs cultured in HPLM for 24 and 120 hours compared to those in GOC were analyzed by unpaired t-tests.

RESULTS:

Glioma SXOs retain diverse cell populations, with 20-30% of cells belonging to the TME. CD4+ T-cells were the most common (9.7 ± 1.0), followed by CD8+ T-cells (4.4 ± 0.6) and macrophages (3.1 ± 1.2). Following the transition to HPLM for 24 or 120 hours, there were no significant differences in tumor, immune, and stromal cell fractions. HPLM culture upregulated the immune response in SXOs, encompassing enhanced cytokine secretion, as well as improved adaptive and innate immune pathways. We particularly highlighted CD4+ T-cell activation (CD69+), Treg, and TGF-β signaling pathways as significantly increased.

CONCLUSIONS:

Here, we present that the culture of SXOs in physiologically similar media retains the heterogeneous TME and activates innate and adaptive immune signaling pathways. Culture in HPLM enables investigation of the glioma immune microenvironment, expanding the biological relevance of experimental results from in vitro SXO models.
Stereotactic Radiosurgery for WHO Grade 2 and 3 Oligodendroglioma: An International Multicenter Study
Authors: Langlois Anne-Marie , Iorio-Morin Christian , Kallos Justiss , Niranjan Ajay , Lunsford L. Dade , Peker Selcuk , Samanci Yavuz , Park David J. , Barnett Gene H. , Liscak Roman , Simonova Gabriela , Sheehan Jason P. , Pikis Stylianos , Mantziaris Georgios , Lee Cheng-Chia , Yang Huai-Che , Bowden Gregory N. , Mathieu David
Published: March 2024

INTRODUCTION:

Oligodendrogliomas are primary brain tumors classified as IDH-mutant and 1p19q co-deleted in the 2021 WHO Classification. Surgery, fractionated radiotherapy and chemotherapy are well established treatments for these tumors, but there are few studies evaluating the efficacy of stereotactic radiosurgery (SRS). As these tumors are less infiltrative than astrocytomas and typically recur locally, they could be appropriate for local therapy such as SRS.

METHODS:

This was a retrospective multicenter study performed through the International Radiosurgery Research Foundation (IRRF). Adult patients were included if they underwent single-fraction SRS for a grade 2 or 3 oligodendroglioma. The primary endpoints were overall survival and progression-free survival. Secondary endpoints included clinical evolution and occurrence of adverse radiation events or other complications.

RESULTS:

Eight institutions submitted data for a total of 55 patients with a median clinical follow-up of 24 months. Median age at treatment was 46 years old and median pre-treatment KPS was 90. Median treatment volume was 4cc and median marginal dose delivered was 15Gy. The KPS remained stable post-SRS in 51% and worsened in 46.7% of patients, most often due to tumor progression (73.1%). Radiation-induced changes occurred in 29.6% of which 4 patients were symptomatic. Median progression-free survival was 17 months, with actuarial rates of 60.1% at 1 year, 31% at 2 years and 24.4% at 5 years after SRS. Median overall survival post-SRS was 58 months, with actuarial rates of 91.5% at 1 year, 83.4% at 2 years and 49.3% at 5 years post-SRS. Factors significantly associated with worsened survival were WHO grade 3 and prior radiotherapy and chemotherapy. Factors significantly associated with worsened PFS were WHO grade 3, prior radiotherapy and chemotherapy and higher treatment marginal dose.

CONCLUSIONS:

SRS appears to be a valuable management option for oligodendrogliomas.
Skull-Derived Myeloid Cells Augment T Cell Responses and Suppress Glioblastoma Growth
Authors: Lad Meeki , Young Jacob , Salha Diana , Lui Austin , Aghi Manish Kumar
Published: March 2024

INTRODUCTION:

Recent studies have implicated skull marrow as a functional myeloid reservoir in CNS pathology. However, its contribution to malignancy remains unexplored.

METHODS:

Fluorescently labeled calvarial flaps were transplanted onto syngeneic glioblastoma-bearing mice, followed by flow cytometric profiling of tumor-infiltrative leukocytes. To assay the functional relevance of SDMCs, tumor-bearing C57BL/6 mice were treated with preemptive calvarial ablation (13 Gy irradiation), or conversely intracalvarial AMD3100 to augment myeloid egress from marrow niches. Tumor burden was monitored via survival and bioluminescent imaging.

RESULTS:

72 h following CMFDA-stained calvarial transplantation into tumor-bearing Balb/C mice, 40.3% of tumor-infiltrative myeloid cells were fluorescent and thus skull-derived; transplantation in an alternative longitudinal model (GFP+ flaps, C57BL/6) validated that SDMCs were robust and viable at 3 weeks post-operatively. As MHCII+ cells were disproportionately enriched among SDMCs (87.9% vs 67.3%, p = 0.012), we interrogated the immunogenicity of these cells through targeted ablation. Skull-ablated mice had reduced infiltration by antigen-presenting cells than controls (cDCs: 1.1% vs 4.5%, p = 0.002; macrophages: 14.4% vs 36.6%, p < 0.001) and 6-fold greater necrosis (67.7% vs 13.5% apoptotic, p < 0.001), suggesting an impaired ability to mount a controlled, adaptive immune response. The stimulatory role of SDMCs was further demonstrated via intracalvarial AMD3100 administration, which through its promotion of myeloid precursor egress (0.26% vs 0.02%, p < 0.001) and cDC2 infiltration (10.4% vs 3.0%, p = 0.003) yielded robust CD4+ T cell activation and effector memory differentiation. These differences were clinically meaningful, as skull irradiation accelerated tumor growth and attenuated survival compared to controls, while AMD3100 treatment accomplished the opposite (median OS: 17d vs 22d, p < 0.001; 26.5d vs 22d, p = 0.006).

CONCLUSIONS:

The preferential polarization of SDMCs into immunostimulatory APCs warrants the continued exploration of local marrow-targeting agents (e.g., AMD3100) as therapeutic modalities.
Increased Survival and Symptom Relief Following Palliative Cerebrospinal Fluid Diversion for Neoplastic Leptomeningeal Disease: A Case Series and Systematic Review
Authors: Wu Adela , Zhou James , Skirboll Stephen
Published: March 2024

INTRODUCTION:

Leptomeningeal disease (LMD) indicates widespread or advanced cancer and can lead to symptomatic hydrocephalus, for which palliative cerebrospinal fluid (CSF) diversion may be indicated.

METHODS:

We analyzed survival and symptom relief outcomes from a 10-year period at a single institution of patients with LMD secondary to cancer, symptoms of obstructive hydrocephalus, and documented date of death. We also searched PubMed, Embase, and Web of Science from database inception until 8/20/2022, using search terms including ‘cancer’, ‘hydrocephalus’, and ‘shunt’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed.

RESULTS:

In our series of 50 patients, 30 (60%) underwent CSF diversion surgery after LMD diagnosis with comparable median age in both surgery (58.4 ± 14.4 years) and non-surgery (57.8 ± 14.5 years) groups. Twenty-three patients (76.7%) achieved symptom relief. The surgery group lived longer after LMD diagnosis than patients in the non-surgery group (6.6 ± 6.0 vs. 1.3 ± 4.3 months, p < 0.001) and had higher likelihood of survival (hazard ratio 2.49, 95% confidence interval 1.37-4.52, p = 0.002). Median survival after surgery was 2.8 ± 3.8 months. Out of 23 articles reporting outcomes for 2895 patients, 995 (34.3%) presented with LMD. Postoperative complication rates were 0-37.7% with no cases of extraneural metastases. Symptom relief rates were 50-100%. Three studies reported median survival after surgery for LMD (2-3.3 months).

CONCLUSIONS:

A rare entity with dismal prognosis, LMD can present as symptomatic hydrocephalus in patients with cancer. Symptom relief can be achieved with palliative surgery for permanent CSF diversion with relatively low complication rates. Prospective studies are needed to further assess outcomes and needs of this patient population.
Characterization of Immune Cell Heterogeneity, Key B Cell Subtypes, and Macrophages Functions Using Multiplex Immunofluorescence and Single-cell RNA Sequencing in Chordomas
Authors: Arrieta Victor Andrés , Benotmane Jasim K. , Zhao Junfei , Dhiantravan Silpol , Hou David , Katz Joshua L. , Pandey Surya , Cholak Meghan E. , Han Yu , Bettegowda Chetan , Horbinski Craig , Miska Jason , Stupp Roger , Lesniak Maciej S. , Sonabend Adam M. , Wolinsky Jean-Paul , Heiland Henrik , Chang Catalina Lee
Published: March 2024

INTRODUCTION:

Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of chordomas to establish a rationale for immunotherapeutic intervention.

METHODS:

We analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival, 3 cervical, 2 lumbar, and 14 sacral tumors) through multiplex immunofluorescence. In addition, we investigated the phenotype of tumor-infiltrating and peripheral B cells and myeloid cells from five chordoma patients employing single-cell RNA sequencing.

RESULTS:

Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of B cells, T cells, and macrophages. Cluster 1 was characterized by moderate immune cell infiltration, cluster 2 was immune-desertic, and cluster 3 was highly infiltrated by B and T cells. Findings from single-cell transcriptomics revealed that regulatory B cells and plasma cells were the most abundant B cell populations infiltrating tumors. In addition, we found the presence of tumor-infiltrating macrophages with angiogenic and complement-related functions.

CONCLUSIONS:

Our study provides crucial insights into the immune landscape of chordomas. The identification of distinct clusters based on immune cell infiltration emphasized the heterogeneity of chordomas. The findings from this study may serve as a foundation for future research and the development of targeted immunotherapies for chordomas.
Molecular Mechanism of Targeting Epithelial Membrane Protein-2 in Malignant Meningiomas
Authors: Yang Isaac , Mekonnen Mahlet , Chandla Anubhav , Aguirre Brian , Wadehra Madhuri
Published: March 2024

INTRODUCTION:

Meningiomas compose approximately one third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%.

METHODS:

In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and have analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay.

RESULTS:

Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p < 0.001). Moreover, cellular migration and invasion regulated by EMP2 was tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti- EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2 mediated signal transduction (p = 0.0031).

CONCLUSIONS:

Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefit in malignant meningiomas.
A Population-Based Analysis of Brain Metastasis Burden and Management in 8705 Small Cell Lung Cancer Patients
Authors: Gaebe Karolina , Erickson Anders , Leighl Natasha , Chan Kelvin , Lok Benjamin , Das Sunit
Published: March 2024

INTRODUCTION:

Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for intracranial metastatic disease (IMD), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. These patients traditionally receive whole brain radiation therapy (WBRT) for IMD, however, a recent systematic review has indicated that OS following stereotactic radiosurgery (SRS) may be non-inferior compared with WBRT.

METHODS:

We included all patients diagnosed with SCLC between April 2007 and March 2018 identified through a provincial health administrative database. Information on patient and treatment characteristics, incidence and time to IMD, and OS from time of SCLC diagnosis were collected and analyzed using R.

RESULTS:

A total of 8705 patients were included. Median age was 68 years (range 18-103). Most patients presented with extensive disease (n = 5625) and were diagnosed after 2011 (n = 5768). Patients who received chemotherapy (n = 5563) had significantly longer OS than those who did not (median 10.64 vs 1.58 mo, HR 0.36, 95% CI 0.34-0.37). 6662 patients received brain imaging at the time of primary diagnosis (CT: 5126, MRI: 1536), and 88% of patients surviving longer than 6 mo received more than one follow-up brain scan. 31% developed IMD (synchronous: 1175, asynchronous: 1511) with median intracranial progression-free survival of 5.65 mo. Median OS of patients with IMD was 9.76 mo, 29 and 1300 received SRS and WBRT as first treatment for their IMD, respectively. OS was in favour of SRS over WBRT (median 20.47 vs 8.74 mo, HR 0.57, 95% CI 0.39-0.84), which remained significant in multivariate analysis (p < 0.001).

CONCLUSIONS:

OS for patients with SCLC remains poor and many patients present with IMD. Some patients with SCLC may benefit from SRS treatment.
Treatment Plan Optimization Following Laser Interstitial Thermal Therapy (LITT) for Recurrent Metastasis Using Cleveland Clinic Scaling System (CCSS)
Authors: Sabahi Mohammadmahdi , Santiago Raphael Bastianon , Naik Mihir , Adada Badih , Ranjan Surabhi , Borghei-Razavi Hamid
Published: March 2024

INTRODUCTION:

Laser interstitial thermal therapy (LITT) is an effective treatment option for recurrent metastasis (RM). However, determining the best treatment approach for each patient following LITT remains challenging due to mixed pathology and lack of consensus. The Cleveland Clinic Scaling System (CCSS) has been proposed to facilitate decision-making in patients with radiation necrosis (RN) and/or RM following LITT.

METHODS:

We conducted a retrospective analysis of data from 20 patients who underwent LITT for RN and/or RM between 2019 and 2022 at Cleveland Clinic. Based on the symptomatic RN and/or RM which was confirmed by MRI, LITT, and biopsy were carried out. Three samples were acquired from the superficial, middle, and deep parts of each patient’s lesion. The samples were then classified into three main categories: RN, RM, or a mixture of the two, based on pathological results. Patient management was guided by our novel CCSS. According to CCSS, patients with 100% RN underwent continued observation with a 3-month MRI, individuals with >20% tumor component received a low-dose or standard-dose radiation therapy ± CNS-penetrating targeted therapy, while those with <20% tumor underwent short-term observation with 6-week MRIs ± CNS-penetrating targeted therapy.

RESULTS:

Among the patients, 57% were females, lung cancer was the most prevalent malignancy (61.4%), and the median age was 52 years (ranging from 25 to 83 years). Our analysis demonstrated that the application of the CCSS protocol significantly improved treatment outcomes after LITT, resulting in 93% lesion control at the 10-month follow-up.

CONCLUSIONS:

The use of the CCSS protocol can refine the treatment plan for patients with RN and/or RM following LITT. This approach has the potential to enhance patient safety by improving tumor control and minimizing unnecessary radiation.
Combinatorial Checkpoint Blockade and Laser Interstitial Thermal Therapy: A Single Center Study
Authors: Haskell-Mendoza Aden Pepe , Wachsmuth Lucas , Srinivasan Ethan , Jackson Joshua , Zaidi Saif , Reason Elle , Gonzalez Ariel Tomas , Schwalb Allison , Lerner Emily , Fecci Peter Edward
Published: March 2024

INTRODUCTION:

Immune checkpoint blockade (ICB) has gained acceptance as a life-extending therapy in a variety of solid tumor types. For patients with brain metastases, combination stereotactic radiosurgery (SRS) and ICB remains an area of clinical equipoise. Similarly, for recurrent or difficult-to-access intracranial lesions, safety and synergy of laser interstitial thermal therapy (LITT) and ICB has yet to be explored.

METHODS:

In accordance with an IRB-approved protocol, all patients undergoing LITT at a tertiary center from 2015-2022 were retrospectively reviewed. Patients who received ICB within 6 weeks of LITT were included in the LITT + ICB cohort. Demographic, clinical, and survival data were collected.

RESULTS:

Combination LITT and ICB occurred in 25 patients with clinically recurrent tumors. The median cohort age was 62 (40-78) and 12 (48%) were female. The median KPS was 80 (50-100). The most common primary pathology was non-small cell lung cancer (NSCLC) in 15 patients (60%), followed by melanoma in 3 (12%); two high-grade gliomas were additionally treated. The majority of the cohort (24 patients, 96%) recieved single agent ICB in combination with LITT, with pembrolizumab (12, 48%) and nivolumab (6, 24%) most common. Median duration between ICB dosing and LITT was 2.85 (0.85-5.84) weeks. Ten patients (40%) had evidence of immune-related adverse events attributable to ICB, with only 1 event > grade 3 according to Common Terminology Criteria; 17 (68%) had a pre-LITT steroid requirement. Intracranial adverse events related to LITT were rare, with median overall survival for the cohort of 8.6 months (1.4-26.4 months).

CONCLUSIONS:

Combination LITT and ICB appears safe and feasible. No prospective studies have compared cytoreduction with LITT to LITT + ICB; construction of a matched NSCLC cohort is ongoing. Exploration of the immune consequences of LITT + ICB is needed.
PCV Adjuvant Therapy as a Preferred Treatment Option for Oligodendroglioma Patients: A Comparative Study With Temozolomide and Concurrent Radiotherapy
Authors: Chen Adrian , Begley Sabrina , Schulder Michael , Goenka Anuj
Published: March 2024

INTRODUCTION:

When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life.

METHODS:

87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis.

RESULTS:

The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in terms of age, tumor genetic profiling, extent of resection, or KPS score, however, the TMZ-based group had more patients receiving concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer for those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for factors mentioned above, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99).

CONCLUSIONS:

PCV confers improved progression-free survival than TMZ-based treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as a preferred therapeutic option for oligodendroglioma patients.
Next Generation Sequencing Mutational Profiles of Gliomas Reveal Clinical and Genetic Factors Predicting Refractory Postoperative Seizures
Authors: Shukla Poojan , Nguyen Minh P. , Young Jacob , Lee Anthony T. , Chang Edward
Published: March 2024

INTRODUCTION:

Postoperative seizures are a common complication of gliomas following resection, but little is known about their course and the role of tumor biology in their development.

METHODS:

Single-center retrospective review of adults who underwent surgical management of glioma with targeted next generation sequencing of tumor samples obtained 2017-2020. Univariate analysis for relevant cohort characteristics and adjustment with multivariate regression was performed.

RESULTS:

Among 341 patients with at least 3 months of follow-up, 174 (51.0%) experienced postoperative seizures and 89 (26.1%) had refractory seizures, defined as seizures occurring monthly or more frequently. Patients with refractory seizures were younger, presented with seizure, had IDH-mutated tumors, and had recurrent tumors. Postoperative refractory seizures had a median length of 9.4 months. In a multivariate analysis adjusting for age, seizures at presentation, newly diagnosed or recurrent status, WHO grade, and IDH status, PIK3R1 mutation emerged as an independent predictor of increased odds of developing refractory seizures (log(OR) 0.89 [0, 1.8], p = 0.044) with PIK3CA mutations trending towards significance (log(OR) 0.66 [-0.12, 1.4], p = 0.09). In another stratified multivariate analysis, CKD4 (log(OR) 1.9 [0.42, 3.4], p = 0.014), PIK3CA (log(OR) 1.3 [0.15, 2.4], p = 0.026) emerged as predictors of refractory seizure among recurrent tumors while presenting with seizure (log(OR) 0.81, [0.08, 1.5], p = 0.03) was the only significant predictor among newly diagnosed tumors.

CONCLUSIONS:

PIK3R1 and PIK3CA mutations were independent predictors of increased odds of postoperative refractory seizures, with CDK4 mutations as an additional predictor among recurrent tumors. Seizures at presentation predicted refractory postoperative seizures in newly diagnosed tumors, suggesting the need for close clinical follow-up in these patients. Future analysis of this cohort will enable better characterization of the influence of tumor mutational profile on postoperative seizure activity.
Metabolomic Differentiation of Tumor Core vs. Edge in Glioma Via Machine Learning
Authors: Williams Brian Jeremy , Frieboes Hermann , Baxter Mary , Miller Hunter , Chen Joseph
Published: March 2024

INTRODUCTION:

Gliomas exhibit high intra-tumor and inter-patient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between glioma core (inner) and edge (invasive) regions.

METHODS:

Paired glioma core and infiltrating edge samples were obtained from 27 human patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples, and metabolomic data was obtained via 2DLC-MS/MS. A boosted generalized linear model was employed to predict metabolomic profiles associated with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation.

RESULTS:

A panel of 52 of 160 metabolites were found to significantly differ between the glioma core and edge regions (p = 0.05). Top metabolites with significantly different relative abundances included nicotinamide, creatine, cystathione, D-pantothenic acid, and maleic acid. The machine learning model predicted MGMT promotor methylation status using 5 key metabolic features within the core and edge tissue specimens with AUROCEdge = 0.935 and AUROCCore = 0.959. Top metabolites associated with MGMT status in core included Y-L-glutamyl-L-glutamic acid, D-pantothenic acid, uric acid, and in edge included itaconic acid, N,N-dimethylarginine, cytosine.

CONCLUSIONS:

Key metabolic differences are identified between core and edge tissue in glioma and can predict MGMT status.
Establishing Genetic and Molecular Markers of Sensitivity to a Novel and Potent Tetracyclic Terpenoid Therapy Against High-Grade Gliomas
Authors: Fontaine Dominique , Stathas SpiroAnthony , del Genio Carmen L. , Shentu Yujia , Nguyen Sidney , Zanazzi George , Chan Amy M. , Gaur Arti B.
Published: March 2024

INTRODUCTION:

High-grade gliomas have the worst prognosis of all intracranial tumors, and therapeutic options are very limited. We have previously described a novel, highly selective and potent agonist of ERβ called ent-28 that inhibits the proliferation of patient-derived glioma cells in vitro. In addition, ent-28 significantly decreases the sizes of orthotopically implanted high-grade glioma patient-derived xenografts and induces apoptosis of tumor-derived cells with varying sensitivity.

METHODS:

ent-28 induced cell death of patient-derived tumor adherent- and stem-cells was analyzed in combination with the histopathologic, molecular, and genetic characteristics of each primary resected tumor for respective cell lines. GI50 values and apoptotic death induced by ent-28 were compared to IDH1 and ATRX mutational status as well as MGMT methylation.

RESULTS:

Compared to both untreated and control groups, ent-28-treated tumor-derived MGMT unmethylated cells demonstrated sensitivity. Additionally, tumor adherent cells underwent apoptosis at a higher rate compared to tumor stem cells.

CONCLUSIONS:

We have completed pre-clinical testing, safety, pharmacokinetics, metabolic stability, in vivo efficacy, and species rationalization for developing a novel compound, ent-28, as an anti-glioma therapy. To further enhance the efficacy of ent-28 against high-grade gliomas, we have used histopathologic characteristics of resected primary tumors to identify specific molecular and genetic markers that correlate to drug-sensitivity. Our findings suggest that specific molecular markers of sensitivity to ent-28 can be used to stratify response in patient derived cells, target tumor stem cells specifically, and further support the development of a potent therapy against high-grade gliomas.
Reflet de notre double appartenance et diversité
Authors: Saidali Zohra Saidali
Published: March 2024

Reflet de notre double appartenance et diversité
Le festival «Genéve Méditerranée»
Authors: Al Ashmawi Fawzia
Published: March 2024

Manifestation
A protocol for the development of PhyCaRe: An extension of the CARE guideline for physiotherapy using the Delphi method
Authors: Naqvi Waqar M. , Mishra Gaurav , Pashine Aishwarya A. , Arora Sakshi P. , Gupta Sonia , Goyal Chanan , Varma Ashish R. , Quazi Zahiruddin , Muthukrishnan Ramprasad , Kumar Kandakurti Praveen , Umate Laxmikant
Published: March 2024

Background Case reports are one of the important forms of documentation and publication of clinical physiotherapy presenting the first line of evidence in scientific literature. In order to provide a systematic and precise structure for reporting and presenting cases, the CARE guidelines were established in 2013. However, these guidelines present limitations as while reporting require items of specific specialties following the checklist. Authors from different specialities have developed CARE extensions specifying the characteristic features of corresponding fields, however, an extension dealing with physiotherapy assessment and line of management in the CARE guidelines is proposed as PhyCaRe. Method After consulting with the advisors, a draft will be prepared of the specific elements that should be included in the PhyCaRe using web Delphi methodology considering CARE statement as the source and SurveyMonkey will be used to undertake the web Delphi questionnaire. The web Delphi methodology will be assumed for three rounds and will be open to physiotherapists and others with substantial experience in reviewing case reports. Subsequently, an online consensus meeting, pilot testing, and submission of the CARE extension for physiotherapy will be conducted for publication. Dissemination The 2010 “Guidance for Developers of Health Research Reporting” and instructions from the EQUATOR Network will be followed in the preparation of PhyCaRe guidelines. The guidelines will be propagated at different platforms and journals will be requested to adopt the guidelines. Registration The reporting guideline under development is prospectively registered on the EQUATOR Network website on PhyCaRe – Reporting guideline for physiotherapy case reports.
Clinical rationale for dietary lutein supplementation in post COVID-19 and mRNA vaccine injury syndromes
Authors: Kyriakopoulos Anthony M , Nigh Greg , McCullough Peter A , Seneff Stephanie
Published: March 2024

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in post-COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.
Improving in vivo assays in snake venom and antivenom research: A community discussion
Authors: Marriott Amy E , Casewell Nicholas R , Lilley Elliot , Gutiérrez José-María , Ainsworth Stuart
Published: March 2024

On the 26th January 2023, a free to attend, ‘improving in vivo snake venom research: a community discussion’ meeting was held virtually. This webinar brought together researchers from around the world to discuss current neutralisation of venom lethality mouse assays that are used globally to assess the efficacy of therapies for snakebite envenoming. The assay’s strengths and weaknesses were highlighted, and we discussed what improvements could be made to refine and reduce animal testing, whilst supporting preclinical antivenom and drug discovery for snakebite envenoming. This report summarises the issues highlighted, the discussions held, with additional commentary on key perspectives provided by the authors.