Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Tuberculum sellae meningiomas (TSMs) can be resected through transcranial (TCA) or expanded endonasal approach (EEA). The objective of this study was to report TSM management trends and outcomes in a large multicenter cohort. METHODS:This is a 40-site retrospective study using standard statistical methods. RESULTS:In 947 cases, TCA was used 66.4% and EEA 33.6%. The median maximum diameter was 2.5 cm for TCA and 2.1 cm for EEA ( P < .0001). The median follow-up was 26 months. Gross total resection (GTR) was achieved in 70.2% and did not differ between EEA and TCA ( P = .5395). Vision was the same or better in 87.5%. Vision improved in 73.0% of EEA patients with preoperative visual deficits compared with 57.1% of TCA patients ( P < .0001). On multivariate analysis, a TCA (odds ratio [OR] 1.78, P = .0258) was associated with vision worsening, while GTR was protective (OR 0.37, P < .0001). GTR decreased with increased diameter (OR: 0.80 per cm, P = .0036) and preoperative visual deficits (OR 0.56, P = .0075). Mortality was 0.5%. Complications occurred in 23.9%. New unilateral or bilateral blindness occurred in 3.3% and 0.4%, respectively. The cerebrospinal fluid leak rate was 17.3% for EEA and 2.2% for TCA (OR 9.1, P < .0001). The recurrence rate was 10.9% (n = 103). Longer follow-up (OR 1.01 per month, P < .0001), World Health Organization II/III (OR 2.20, P = .0262), and GTR (OR: 0.33, P < .0001) were associated with recurrence. The recurrence rate after GTR was lower after EEA compared with TCA (OR 0.33, P = .0027). CONCLUSION/CONCLUSIONS:EEA for appropriately selected TSM may lead to better visual outcomes and decreased recurrence rates after GTR, but cerebrospinal fluid leak rates are high, and longer follow-up is needed. Tumors were smaller in the EEA group, and follow-up was shorter, reflecting selection, and observation bias. Nevertheless, EEA may be superior to TCA for appropriately selected TSM.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Tuberculum sellae meningiomas are resected via an expanded endonasal (EEA) or transcranial approach (TCA). Which approach provides superior outcomes is debated. The Magill-McDermott (M-M) grading scale evaluating tumor size, optic canal invasion, and arterial involvement remains to be validated for outcome prediction. The objective of this study was to validate the M-M scale for predicting visual outcome, extent of resection (EOR), and recurrence, and to use propensity matching by M-M scale to determine whether visual outcome, EOR, or recurrence differ between EEA and TCA. METHODS:Forty-site retrospective study of 947 patients undergoing tuberculum sellae meningiomas resection. Standard statistical methods and propensity matching were used. RESULTS:The M-M scale predicted visual worsening (odds ratio [OR]/point: 1.22, 95% CI: 1.02-1.46, P = .0271) and gross total resection (GTR) (OR/point: 0.71, 95% CI: 0.62-0.81, P < .0001), but not recurrence ( P = .4695). The scale was simplified and validated in an independent cohort for predicting visual worsening (OR/point: 2.34, 95% CI: 1.33-4.14, P = .0032) and GTR (OR/point: 0.73, 95% CI: 0.57-0.93, P = .0127), but not recurrence ( P = .2572). In propensity-matched samples, there was no difference in visual worsening ( P = .8757) or recurrence ( P = .5678) between TCA and EEA, but GTR was more likely with TCA (OR: 1.49, 95% CI: 1.02-2.18, P = .0409). Matched patients with preoperative visual deficits who had an EEA were more likely to have visual improvement than those undergoing TCA (72.9% vs 58.4%, P = .0010) with equal rates of visual worsening (EEA 8.0% vs TCA 8.6%, P = .8018). CONCLUSION/CONCLUSIONS:The refined M-M scale predicts visual worsening and EOR preoperatively. Preoperative visual deficits are more likely to improve after EEA; however, individual tumor features must be considered during nuanced approach selection by experienced neurosurgeons.

Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.

Mild traumatic brain injury (TBI) and concussion can have serious consequences that develop over time with unpredictable levels of recovery. Millions of concussions occur yearly, and a substantial number result in lingering symptoms, loss of productivity, and lower quality of life. The diagnosis may not be made for multiple reasons, including due to patient hesitancy to undergo neuroimaging and inability of imaging to detect minimal damage. Biomarkers could fill this gap, but the time needed to send blood to a laboratory for analysis made this impractical until point-of-care measurement became available. A handheld blood test is now on the market for diagnosis of concussion based on the specific blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1). This paper discusses rapid blood biomarker assessment for mild TBI and its implications in improving prediction of TBI course, avoiding repeated head trauma, and its potential role in assessing new therapeutic options. Although we focus on the Abbott i-STAT TBI plasma test because it is the first to be FDA-cleared, our discussion applies to any comparable test systems that may become available in the future. The difficulties in changing emergency department protocols to include new technology are addressed.

Estimating structural connectivity from diffusion-weighted magnetic resonance imaging is a challenging task, partly due to the presence of false-positive connections and the misestimation of connection weights. Building on previous efforts, the MICCAI-CDMRI Diffusion-Simulated Connectivity (DiSCo) challenge was carried out to evaluate state-of-the-art connectivity methods using novel large-scale numerical phantoms. The diffusion signal for the phantoms was obtained from Monte Carlo simulations. The results of the challenge suggest that methods selected by the 14 teams participating in the challenge can provide high correlations between estimated and ground-truth connectivity weights, in complex numerical environments. Additionally, the methods used by the participating teams were able to accurately identify the binary connectivity of the numerical dataset. However, specific false positive and false negative connections were consistently estimated across all methods. Although the challenge dataset doesn't capture the complexity of a real brain, it provided unique data with known macrostructure and microstructure ground-truth properties to facilitate the development of connectivity estimation methods.

#brain #injury in the #football #player - we need better #diagnosis and #prevention. #view our #latest #publication in the #journal Concussion @futuresciencegp on @thegame #Blood test #biomarker #innovation #safety @NFL.

The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity proteomics to identify the transmembrane protein PTK7 as an extracellular binding partner of GPR133 in glioblastoma. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7's anchoring in the plasma membrane. PTK7's allosteric action on GPR133 signaling is additive with but topographically distinct from orthosteric activation by soluble peptide mimicking the endogenous tethered Stachel agonist. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this ligand-receptor interaction is relevant to the pathogenesis of glioblastoma and possibly other physiological processes in healthy tissues.

GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gαs and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca²⁺-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca²⁺-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca²⁺ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM impairs tumor growth in vitro, suggesting functions of ESYT1 beyond the interaction with GPR133. Our findings suggest a novel mechanism for modulation of GPR133 signaling by increased cytosolic Ca²⁺, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.

Traumatic brain injury (TBI) results when external physical forces impact the head with sufficient intensity to cause damage to the brain. TBI can be mild, moderate, or severe and may have long-term consequences including visual difficulties, cognitive deficits, headache, pain, sleep disturbances, and post-traumatic epilepsy. Disruption of the normal functioning of the brain leads to a cascade of effects with molecular and anatomical changes, persistent neuronal hyperexcitation, neuroinflammation, and neuronal loss. Destructive processes that occur at the cellular and molecular level lead to inflammation, oxidative stress, calcium dysregulation, and apoptosis. Vascular damage, ischemia and loss of blood brain barrier integrity contribute to destruction of brain tissue. This review focuses on the cellular damage incited during TBI and the frequently life-altering lasting effects of this destruction on vision, cognition, balance, and sleep. The wide range of visual complaints associated with TBI are addressed and repair processes where there is potential for intervention and neuronal preservation are highlighted.