Spatially Resolved Microglia/Macrophages in Recurrent Glioblastomas Overexpress Fatty Acid Metabolism and Phagocytic Genes.

BACKGROUND: Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs. METHODS: NanoString GeoMx® Digital Spatial Transcriptomic Profiling of microglia/macrophages (Iba1+) and glial cells (Gfap+) cells identified on tumor sections was performed on paired de novo and recurrent samples obtained from three IDH-wildtype GBM patients. The impact of differentially expressed genes on patient survival was evaluated using publicly available data. RESULTS: Unsupervised analyses of the NanoString GeoMx® Digital Spatial Profiling data revealed clustering based on the transcriptomic data from Iba1+ and Gfap+ cells. As expected, conventional differential gene expression and enrichment analyses revealed upregulation of immune-function-related genes in Iba1+ cells compared to Gfap+ cells. A focused differential gene expression analysis revealed upregulation of phagocytosis and fatty acid/lipid metabolism genes in Iba1+ cells in recurrent GBM samples compared to de novo GBM samples. Importantly, of these genes, the lipid metabolism gene PLD3 consistently correlated with survival in multiple different publicly available datasets. CONCLUSION: Tumor-associated microglia/macrophages in recurrent GBM overexpress genes involved in fatty acid/lipid metabolism. Further investigation is needed to fully delineate the role of PLD phospholipases in GBM progression.

Untangling the web of glioblastoma treatment resistance using a multi-omic and multidisciplinary approach.

Glioblastoma (GBM), the most common human brain tumor, has been notoriously resistant to treatment. As a result, the dismal overall survival of GBM patients has not changed over the past three decades. GBM has been stubbornly resistant to checkpoint inhibitor immunotherapies, which have been remarkably effective in the treatment of other tumors. It is clear that GBM resistance to therapy is multifactorial. Although therapeutic transport into brain tumors is inhibited by the blood brain barrier, there is evolving evidence that overcoming this barrier is not the predominant factor. GBMs generally have a low mutation burden, exist in an immunosuppressed environment and they are inherently resistant to immune stimulation, all of which contribute to treatment resistance. In this review, we evaluate the contribution of multi-omic approaches (genomic and metabolomic) along with analyzing immune cell populations and tumor biophysical characteristics to better understand and overcome GBM multifactorial resistance to treatment.

Metabolomic differentiation of tumor core versus edge in glioma.

OBJECTIVE: Gliomas exhibit high intratumor and interpatient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between the glioma core (inner) and edge (infiltrating) regions. This proof-of-concept study differentiates metabolic signatures associated with these regions, with the potential for prognosis and targeted therapy that could improve surgical outcomes. METHODS: Paired glioma core and infiltrating edge samples were obtained from 27 patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples and metabolomic data were obtained via 2D liquid chromatography-mass spectrometry/mass spectrometry. To gauge the potential of metabolomics to identify clinically relevant predictors of survival from tumor core versus edge tissues, a boosted generalized linear machine learning model was used to predict metabolomic profiles associated with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. RESULTS: A panel of 66 (of 168) metabolites was found to significantly differ between glioma core and edge regions (p ≤ 0.05). Top metabolites with significantly different relative abundances included DL-alanine, creatine, cystathionine, nicotinamide, and D-pantothenic acid. Significant metabolic pathways identified by quantitative enrichment analysis included glycerophospholipid metabolism; butanoate metabolism; cysteine and methionine metabolism; glycine, serine, alanine, and threonine metabolism; purine metabolism; nicotinate and nicotinamide metabolism; and pantothenate and coenzyme A biosynthesis. The machine learning model using 4 key metabolites each within core and edge tissue specimens predicted MGMT promoter methylation status, with AUROCEdge = 0.960 and AUROCCore = 0.941. Top metabolites associated with MGMT status in the core samples included hydroxyhexanoycarnitine, spermine, succinic anhydride, and pantothenic acid, and in the edge samples metabolites included 5-cytidine monophosphate, pantothenic acid, itaconic acid, and uridine. CONCLUSIONS: Key metabolic differences are identified between core and edge tissue in glioma and, furthermore, demonstrate the potential for machine learning to provide insight into potential prognostic and therapeutic targets.

Trends and Impact of Treatment Modalities (Surgery and Radiation Therapy) on Health Care Utilization in Patients With Glomus Jugulare Tumors (GJTs): An Inverse Probability of Treatment Weight Analysis.

OBJECTIVES: The trend of practice pattern and impact on health care utilization for surgery and radiation therapy (RT) in patients with glomus jugulare tumors (GJTs) is not well defined. METHODS: The IBM (Armonk, NY) MarketScan database was queried using the ICD-9/10 and CPT 4th edition, 2000-2020. We included patients ≥18 years of age who underwent either surgery or RT with at-least 1-year follow-up. We compared the health care utilization at 3-month, 6-month, and 1-year follow up using the inverse probability of treatment weight technique. RESULTS: A cohort of 333 patients was identified. Of these, 72.7% (n = 242) underwent RT and 27.3% (n = 91) underwent surgery. RT use increased from 2002-2004 (50%) to 2017-2019 (91%). Patients in the surgery cohort were younger (median age 49 vs. 56 years, P < 0.0001) and had a higher 3+ comorbidity index (34% vs. 30%, P = 0.43) compared with patients in the RT cohort. Patients who underwent surgery had higher complications at index hospitalization (22% vs. 6%, P < 0.0001) and at 30 days (14% vs. 5%, P = 0.0042). No difference in combined index and 6- or 12-month payments were noted (6-months: surgery, $66m108, RT: $43m509, P = 0.1034; 12-months: surgery, $73,259, RT: $51,576, P = 0.1817). Only 4% of patients who had initial RT underwent RT and none underwent surgery at 12 months, whereas 6% of patients who had initial surgery underwent RT and 2% underwent surgery at 12 months. CONCLUSIONS: RT plays an increasingly important role in the treatment for patients with GJTs, with fewer complications and a comparable health care utilization at 1 year.

Intraoperative MRI use in transsphenoidal surgery for pituitary tumors: Trends and healthcare utilization.

BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) use in transsphenoidal approach (TSA) for pituitary tumors (PTs) has been reported to improve the extent of resection (EOR). The aim of this study is to report the trends and the impact of iMRI on healthcare utilization in patients who underwent TSA for PTs. MATERIALS AND METHODS: MarketScan database were queried using the ICD-9/10 and CPT-4, from 2004 to 2020. We included patients ≥ 18 years of age PTs with > 1 year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments. RESULTS: A cohort of 10,192 patients were identified from the database, of these 141 patients (1.4%) had iMRI used during the procedure. Use of iMRI for PTs remained stable (2004-2007: 0.85%; 2008-2011: 1.6%; 2012-2015:1.4% and 2016-2019: 1.46%). No differences in LOS (median 3 days each), discharge to home (93% vs. 94%), complication rates (7% vs. 13%) and payments ($34604 vs. $33050) at index hospitalization were noted. Post-discharge payments were not significantly different without and with iMRI use at 6-months ($8315 vs. $ 7577, p = 0.7) and 1-year ($13,654 vs. $ 14,054, p = 0.70), following the index procedure. CONCLUSION: iMRI use during TSA for PTs remained stable with no impact on LOS, complications, discharge disposition and index payments. Also, there was no difference in combined index payments at 6-months, and 1-year after the index procedure in patients with and without iMRI use for PTs.

Demographic variations and time to initiation of adjunct treatment following surgical resection of anaplastic astrocytoma in the United States: a National Cancer Database analysis.

BACKGROUND AND AIMS: The aim of this study was to analyze the trends, demographic differences in the type and time to initiation (TTI) of adjunct treatment AT following surgery for anaplastic astrocytoma (AA). MATERIAL AND METHODS: The National Cancer Database (NCDB) was queried for patients diagnosed with AA from 2004 to 2016. Cox proportional hazards and modeling was used to determine factors influencing survival, including the impact of time to initiation (TTI) of adjuvant therapy. RESULTS: Overall, 5890 patients were identified from the database. The use of combined RT + CT temporally increased from 66.3% (2004-2007) to 79% (2014-2016), p < 0001. Patients more likely to receive no treatment following surgical resection included elderly (> 60 years old), hispanic patients, those with either no or government insurance, those living > 20 miles from the cancer facility, those treated at low volume centers (< 2 cases/year). AT was received following surgical resection within 0-4 weeks, 4.1-8 weeks, and > 8 weeks in 41%, 48%, and 3%, respectively. Compared to patients who received RT + CT, patients were likely to receive RT only as AT either at 4-8 weeks or > 8 weeks after the surgical procedure. Patients who received AT within 0-4 weeks had the 3-year OS of 46% compared to 56.7% for patients who received treatment at 4.1-8 weeks. CONCLUSION: We found significant variation in the type and timing of adjunct treatment following surgical resection of AA in the United States. A considerable number of patients (15%) received no AT following surgery.

Impact of Management Strategies on New-Onset Mental Health Disorders and Associated Health Care Utilization in Patients with Vestibular Schwannoma.

OBJECTIVE: To compare the impact of different management strategies on diagnosis of new-onset mental health disorders (MHDs) in patients with vestibular schwannoma (VS) and health care utilization at 1-year follow-up. METHODS: MarketScan databases were queried using the International Classification of Diseases, Ninth Revision and Tenth Revision and Current Procedural Terminology, Fourth Edition, 2000-2020. We included patients ≥18 years old with a diagnosis of VS who underwent clinical observation, surgery, or stereotactic radiosurgery (SRS) with at least 1 year of follow-up. We looked at health care outcomes and MHDs at 3-month, 6-month, and 1-year follow-up. RESULTS: The database search identified 23,376 patients. Of these, 94.2% (n = 22,041) were managed conservatively with clinical observation at the initial diagnosis, and 2% (n = 466) underwent surgery. The surgery cohort had the highest incidence of new-onset MHDs followed by SRS and clinical observation cohorts at 3 months (surgery: 17%; SRS: 12%; clinical observation: 7%), 6 months (surgery: 20%; SRS: 16%; clinical observation: 10%), and 12 months (surgery: 27%; SRS: 23%; clinical observation: 16%) (P < 0.0001). The median difference in combined payments between patients with and without MHDs was highest in the surgery cohort followed by SRS and clinical observation cohorts at all time points (12 months: surgery: $14,469; SRS: $10,557; clinical observation: $6439; P = 0.0002). CONCLUSIONS: Compared with clinical observation only, patients who underwent surgery for VS were 2 times more likely and patients who underwent SRS were 1.5 times more likely to develop MHDs with corresponding increase in health care utilization at 1-year follow-up.

Feasibility of Transcranial Motor Evoked Potentials and Electromyography during MRI-Guided Laser Interstitial Thermal Therapy for Glioblastoma.

BACKGROUND: Intraoperative neuromonitoring (IONM) is routinely used during neurosurgical procedures. Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (LITT) is increasingly being used in patients with various brain lesions. Use of IONM (transcranial motor evoked potential [TcMEP] and electromyography [EMG]) during LITT of a brain lesion has not been described previously. METHODS: In this report, we describe a 70-year-old man who presented with motor weakness in whom imaging revealed a left thalamic lesion. Due to the difficulty in accessing the lesion and proximity to the motor tracts, patient was offered MRI-guided LITT using TcMEP and EMG. RESULTS: The patient underwent satisfactory ablation of the lesion with successful recording of the TcMEP and EMG. Technical nuances related to the set-up and procedure is discussed in this report. No procedure-related complications were encountered. CONCLUSIONS: We describe the first report of safety and feasibility of TcMEP and EMG during MRI-guided LITT for left thalamic glioblasatoma. This report paves the way for further prospective investigations regarding the utility of this technique for eloquent brain tumors.

The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo.

INTRODUCTION: Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro. METHODS: We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions. RESULTS: Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone. CONCLUSIONS: Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.

Primary Spinal Glioblastoma Mimicking Neuroschistosomiasis: A Case Report.

Primary glioblastoma of the spinal cord (sGB) is a rare and challenging diagnosis. In the diagnostic algorithm, reversible causes should be considered while the diagnosis of sGB is under evaluation. We present a case of cervical sGB mimicking neuroschistosomiasis. A 21-year-old Somali man presented with neck pain, sensory disturbances, and spastic tetraplegia. Cervical spine magnetic resonance imaging with contrast showed a heterogeneously enhancing intramedullary mass spanning from the level of the C1 to T3 vertebrae. Cerebrospinal fluid analysis showed a lymphocytic predominance and elevated protein. Due to the patient's history of poorly treated schistosomiasis, praziquantel and dexamethasone were initiated while the diagnostic work-up was completed. Three days after the patient was discharged to a rehabilitation facility where he experienced worsened motor function with radiographic progression of the lesion and increased cord edema. The patient underwent a surgical biopsy which confirmed a diagnosis of primary sGB. sGB is an unusual diagnosis that can masquerade as a non-neoplastic lesion. However, the diagnosis of sGB should be considered in patients with an intramedullary spinal cord lesion who exhibit rapid radiographic and clinical progression.

Is intraoperative MRI use in malignant brain tumor surgery a health care burden? A matched analysis of MarketScan Database.

BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) is a useful adjunct for resection of primary malignant brain tumors (MBTs). The aim of our study is to investigate the impact of iMRI on health care utilization in patients who underwent craniotomy for resection of MBTs. MATERIALS AND METHODS: MarketScan database were queried using the ICD-9/10 and CPT 4th edition, from 2008 to 2020. We included patients ≥ 18 years of age who underwent a craniotomy with at-least one year follow-up. Outcomes were length of stay (LOS), discharge disposition, hospital/emergency room (ER) re-admissions, outpatient services, medication refills and corresponding payments. RESULTS: Of 6,640 patients who underwent craniotomy for MBTs, 465 patients (7%) had iMRI used during the procedure with 0.7% per year increase in iMRI use during the study period. Patients without iMRI use had higher complications at index hospitalization compared to those with iMRI use (19% vs. 14%, p = 0.04). There was no difference in the ER admission rates among the patients who underwent surgery with and without iMRI use at 6-months and 1-year after the index procedure. In terms of post-discharge payments, no significant differences were noted among the patients without and with iMRI use at 6-months ($81,107 vs. $ 81,458, p = 0.26) and 1-year ($132,657 vs. $ 118,113, p = 0.12). CONCLUSION: iMRI use during craniotomy for MBT gradually increased during the study period. iMRI did not result in higher payments at index hospitalization, 6-months, and 1-year after the index procedure.

90-Day Bundled Payment Simulation, Health Care Utilization, and Complications following Craniopharyngioma Resection in Adult Patients.

Context Bundled payment and health care utilization models inform cost optimization and surgical outcomes. Economic analysis of payment plans for craniopharyngioma resection is unknown. Objective This study aimed to identify impact of endocrine and nonendocrine complications (EC and NEC, respectively) on health care utilization and bundled payments following craniopharyngioma resection. Design This study is presented as a retrospective cohort analysis (2000-2016) with 2 years of follow-up. Setting The study included national inpatient hospitalization and outpatient visits. Patients Patients undergoing craniopharyngioma resection were divided into the following four groups: group 1, no complications (NC); group 2, only EC; group 3, NEC; and group 4, both endocrine and nonendocrine complications (ENEC). Interventions This study investigated transphenoidal or subfrontal approach for tumor resection. Main Outcome Hospital readmission, health care utilization up to 24 months following discharge, and 90-day bundled payment performances are primary outcomes of this study. Results Median index hospitalization payments were significantly lower for patients in NC cohort ($28,672) compared with those in EC ($32,847), NEC ($36,259), and ENEC ($32,596; p < 0.0001). Patients in ENEC incurred higher outpatient services and overall median payments at 6 months (NC: 38,268; EC: 49,844; NEC: 68,237; and ENEC: 81,053), 1 year (NC: 46,878; EC: 58,210; NEC: 81,043; and ENEC: 94,768), and 2 years (NC: 58,391; EC: 70,418; NEC: 98,838; and ENEC: 1,11,841; p < 0.0001). The 90-day median bundled payment was significantly different among the cohorts with the highest in ENEC ($60,728) and lowest in the NC ($33,089; p < 0.0001). Conclusion ENEC following surgery incurred almost two times the overall median payments at 90 days, 6 months, 1 year. and 2 years compared with those without complications. Bundled payment model may not be a feasible option in this patient population. Type of complications and readmission rates should be considered to optimize payment model prediction following craniopharyngioma resection.

Hemorrhage and Recurrence of Obliterated Brain Arteriovenous Malformations Treated With Stereotactic Radiosurgery.

BACKGROUND: Although complete nidal obliteration of brain arteriovenous malformations (AVM) is generally presumed to represent durable cure, postobliteration hemorrhage, and AVM recurrence have become increasingly recognized phenomena. The goal of the study was to define hemorrhage and nidal recurrence risks of obliterated AVMs treated with stereotactic radiosurgery (SRS). METHODS: This is a retrospective cohort study from the International Radiosurgery Research Foundation comprising AVM patients treated between 1987 and 2020. Patients with AVM obliteration on digital subtraction angiography (DSA) were included. Outcomes were (1) hemorrhage and (2) AVM recurrence. Follow-up duration began at the time of AVM obliteration and was censored at subsequent hemorrhage, AVM recurrence, additional AVM treatment, or loss to follow-up. Annualized risk and survival analyses were performed. A sensitivity analysis comprising patients with AVM obliteration on magnetic resonance imaging or DSA was also performed for postobliteration hemorrhage. RESULTS: The study cohort comprised 1632 SRS-treated patients with AVM obliteration on DSA. Pediatric patients comprised 15% of the cohort, and 42% of AVMs were previously ruptured. The mean imaging follow-up after AVM obliteration was 22 months. Among 1607 patients with DSA-confirmed AVM obliteration, 16 hemorrhages (1.0%) occurred over 2223 patient-years of follow-up (0.72%/y). Of the 1543 patients with DSA-confirmed AVM obliteration, 5 AVM recurrences (0.32%) occurred over 2071 patient-years of follow-up (0.24%/y). Of the 16 patients with postobliteration hemorrhage, AVM recurrence was identified in 2 (12.5%). In the sensitivity analysis comprising 1939 patients with post-SRS AVM obliteration on magnetic resonance imaging or DSA, 16 hemorrhages (0.83%) occurred over 2560 patient-years of follow-up (0.63%/y). CONCLUSIONS: Intracranial hemorrhage and recurrent arteriovenous shunting after complete nidal obliteration are rare in AVM patients treated with SRS, and each phenomenon harbors an annual risk of <1%. Although routine postobliteration DSA cannot be recommended to SRS-treated AVM patients, long-term neuroimaging may be advisable in these patients.

Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes.

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.

Malignant melanotic nerve sheath tumor with PRKAR1A, KMT2C, and GNAQ mutations.

Malignant melanotic nerve sheath tumor (MMNST) is a rare and potentially aggressive lesion defined in the 2021 WHO Classification of Tumors of the Central Nervous System. MMNST demonstrate overlapping histologic and clinical features of schwannoma and melanoma. MMNST often harbor PRKAR1A mutations, especially within the Carney Complex. We present a case of aggressive MMNST of the sacral region in a 48-year-old woman. The tumor contained PRKAR1A frameshift pR352Hfs*89, KMT2C splice site c.7443-1G>T and GNAQ p.R183L missense mutations, as well as BRAF and MYC gains. Genomic DNA methylation analysis using the Illumina 850K EpicBead chip revealed that the lesion did not match an established methylation class; however, uniform manifold approximation and projection (UMAP) placed the tumor very near schwannomas. The tumor expressed PD-L1, and the patient was treated with radiation and immune checkpoint inhibitors following en bloc resection. Although she had symptomatic improvement, she suffered early disease progression with local recurrence, and distant metastases, and died 18 months after resection. It has been suggested that the presence of GNAQ mutations can differentiate leptomeningeal melanocytic neoplasms and uveal melanoma from MMNST. This case and others demonstrate that GNAQ mutations may exist in malignant nerve sheath tumors; that GNAQ and PRKAR1A mutations are not always mutually exclusive and that neither can be used to differentiate MMNST or MPNST from all melanocytic lesions.

Acute posterior reversible encephalopathy syndrome (PRES) in setting of interferon-beta use: case presentation with reduction of edema in 72 h after cessation of interferon-beta therapy with sub-clinical inflammation.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) represents a transient change in mental status with associated vasogenic edema of cortical and subcortical brain structures. It is often attributed to multifactorial etiology including hypertension and altered hemodynamics and disruption of vessel integrity. Patients with autoimmune disease and certain immune modulator therapies are at greater risk. CASE PRESENTATION: A 54-year-old female with past medical history of well-controlled multiple sclerosis on interferon-beta since 2013, presented with witnessed tonic colonic seizure. She also was noted to demonstrate left gaze deviation and left-sided hemiparesis. MRI fluid-attenuated inversion recovery sequence showed hyperintensity of the subcortical U fibers, concentrated in the occipital, parietal lobes and frontal lobes. Systolic blood pressure was 160 mmHg on arrival. The patient was started on seizure prophylxis and Interferon beta was discontinued. The patient's mentation, seizures and hemiapresis significantly improved in next 72 h with tight blood pressure control, and had notble improvement on MRI imaging and inflammatory markers. Lumbar puncture CSF results were devoid of infectious and autoimmune pathology. CONCLUSIONS: A middle-aged female with multiple sclerosis who was on chronic IFN-beta presented to the emergency room with a witnessed tonic-clonic seizure, with MRI T2 FLAIR imaging consistent with PRES. She had notable clinical improvement with decreased edema on imaging and improved inflammatory markers 72 h after cessation of IFN-beta therapy.

Bioengineered Models to Study Microenvironmental Regulation of Glioblastoma Metabolism.

Despite extensive research and aggressive therapies, glioblastoma (GBM) remains a central nervous system malignancy with poor prognosis. The varied histopathology of GBM suggests a landscape of differing microenvironments and clonal expansions, which may influence metabolism, driving tumor progression. Indeed, GBM metabolic plasticity in response to differing nutrient supply within these microenvironments has emerged as a key driver of aggressiveness. Additionally, emergent biophysical and biochemical interactions in the tumor microenvironment (TME) are offering new perspectives on GBM metabolism. Perivascular and hypoxic niches exert crucial roles in tumor maintenance and progression, facilitating metabolic relationships between stromal and tumor cells. Alterations in extracellular matrix and its biophysical characteristics, such as rigidity and topography, regulate GBM metabolism through mechanotransductive mechanisms. This review highlights insights gained from deployment of bioengineering models, including engineered cell culture and mathematical models, to study the microenvironmental regulation of GBM metabolism. Bioengineered approaches building upon histopathology measurements may uncover potential therapeutic strategies that target both TME-dependent mechanotransductive and biomolecular drivers of metabolism to tackle this challenging disease. Longer term, a concerted effort integrating in vitro and in silico models predictive of patient therapy response may offer a powerful advance toward tailoring of treatment to patient-specific GBM characteristics.

High-entropy ejecta plumes in Cassiopeia A from neutrino-driven convection.

Recent multi-dimensional simulations suggest that high-entropy buoyant plumes help massive stars to explode1,2. Outwardly protruding iron (Fe)-rich fingers of gas in the galactic supernova remnant3,4 Cassiopeia A seem to match this picture. Detecting the signatures of specific elements synthesized in the high-entropy nuclear burning regime (that is, α-rich freeze out) would constitute strong substantiating evidence. Here we report observations of such elements-stable titanium (Ti) and chromium (Cr)-at a confidence level greater than 5 standard deviations in the shocked high-velocity Fe-rich ejecta of Cassiopeia A. We found that the observed Ti/Fe and Cr/Fe mass ratios require α-rich freeze out, providing evidence of the existence of the high-entropy ejecta plumes that boosted the shock wave at explosion. The metal composition of the plumes agrees well with predictions for strongly neutrino-processed proton-rich ejecta2,5,6. These results support the operation of the convective supernova engine via neutrino heating in the supernova that produced Cassiopeia A.