Faculty Bibliography

Sinonasal glomangiopericytoma is a rare vascular tumor of the respiratory epithelium. Treatment consists mainly of surgical resection, though there is no consensus regarding the use of adjuvant therapies or preoperative endovascular embolization. The postsurgical prognosis is favorable, though there is a high risk of delayed recurrence. Here, we present the case of a patient who underwent endoscopic resection of a sinonasal glomangiopericytoma and a review of the literature.

PURPOSE/OBJECTIVE:Orientation Distribution Function (ODF) peak finding methods typically fail to reconstruct fibers crossing at shallow angles below 40°, leading to errors in tractography. ODF-Fingerprinting (ODF-FP) with the biophysical multicompartment diffusion model allows for breaking this barrier. METHODS:A randomized mechanism to generate a multidimensional ODF-dictionary that covers biologically plausible ranges of intra- and extra-axonal diffusivities and fraction volumes is introduced. This enables ODF-FP to address the high variability of brain tissue. The performance of the proposed approach is evaluated on both numerical simulations and a reconstruction of major fascicles from high- and low-resolution in vivo diffusion images. RESULTS:ODF-FP with the suggested modifications correctly identifies fibers crossing at angles as shallow as 10 degrees in the simulated data. In vivo, our approach reaches 56% of true positives in determining fiber directions, resulting in visibly more accurate reconstruction of pyramidal tracts, arcuate fasciculus, and optic radiations than the state-of-the-art techniques. Moreover, the estimated diffusivity values and fraction volumes in corpus callosum conform with the values reported in the literature. CONCLUSION/CONCLUSIONS:The modified ODF-FP outperforms commonly used fiber reconstruction methods at shallow angles, which improves deterministic tractography outcomes of major fascicles. In addition, the proposed approach allows for linearization of the microstructure parameters fitting problem.

We recently demonstrated that GPR133 (ADGRD1), an adhesion G protein-coupled receptor (aGPCR) involved in raising cytosolic cAMP levels, is necessary for growth of glioblastoma (GBM) and is de novo expressed in GBM relative to normal brain tissue. Our previous work suggested that dissociation of autoproteolytically generated N-terminal and C-terminal fragments (NTF and CTF) of GPR133 at the plasma membrane correlates with receptor activation and signaling. To promote the goal of developing biologics that modulate GPR133 function, we investigated the effects of antibodies against the N-terminus of GPR133 on receptor signaling. Here we show that treatment of HEK293T cells overexpressing GPR133 with these antibodies increased cAMP levels in a concentration-dependent manner. Analysis of culture medium following antibody treatment further indicated the presence of complexes of these antibodies with the autoproteolytically cleaved NTF of GPR133. In addition, cells expressing a cleavage-deficient mutant of GPR133 (H543R) did not respond to antibody stimulation, suggesting that the effect is cleavage-dependent. Finally, we demonstrate the antibody-mediated stimulation of wild-type GPR133, but not the cleavage-deficient H543R mutant, was reproducible in patient-derived GBM cells. These findings provide a paradigm for modulation of GPR133 function with biologics and support the hypothesis that the intramolecular cleavage in the N-terminus modulates receptor activation and signaling.

Background/UNASSIGNED:wild-type glioblastoma. Methods/UNASSIGNED:wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results/UNASSIGNED:promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions/UNASSIGNED:wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

BACKGROUND/UNASSIGNED:Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses. METHODS/UNASSIGNED:Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were sub-classified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole-genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up. RESULTS/UNASSIGNED:= .02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses. CONCLUSION/UNASSIGNED:Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes.

Background Gliomas account for roughly 27% of all brain tumors and there is an urgent need to develop new therapeutic modalities. A glioblastoma multiforme (GBM) prognosis signifies a survival time of 14-16 months with only 5% of patients surviving more than 5 years. (1) A significant challenge for traditional GBM drug delivery is the inability to: a) treat tumor cells with cytotoxic drugs due to their poor solubility and lack of blood brain barrier (BBB) permeation; b) specifically target tumor cells while avoiding normal tissue with such cytotoxic agents c) stimulate drug release; and d) monitor GBM status and therapy non-invasively. (2) Theranostic agents are being developed for their ability to diagnose disease and improve therapeutic delivery and can address these requirements because treatments specific to GBM do not currently exist. (3) While considerable efforts have been made in developing protein-based systems as drug-delivery carriers or as diagnostic agents (4), we are investigating a fundamental new insight that is helping us develop a single protein-based system combining drug delivery capabilities with the ability to cross the BBB and remain at cancer site due to the enhanced permeation and retention (EPR) effect. This biomaterial also incorporates functional groups detectable via magnetic resonance (MR) spectroscopy and imaging as well as near-infrared fluorescence (NIR) to enable visualization during chemotherapy. The protein-based theranostic agent we have engineered is called fluorinated thermo-responsive assembled protein (F-TRAP) that bears a non-canonical fluorinated amino acid (trifluoroleucine or TFL), can self-assemble into micellar structures, and encapsulate hydrophobic drugs. Methods and Materials Circular dichroism and dynamic light scattering have been performed to observe F-TRAP's secondary structure and micelle formation respectively (2). Additionally, 19F magnetic resonance imaging (MRI) has been carried out to visualize F-TRAP (5) and near infra-red fluorescence imaging (NIRF) has been utilized to determine its pharmacokinetic properties in a glioblastoma (GBM) mouse model. Results Results indicate that F-TRAP has an ?-helical secondary structure and forms micelles 30 nm in size. F-TRAP shows favorable pharmacokinetic data with a half-life of 123 minutes and high plasma retention. Importantly, animal data also reveals the ability of F-TRAP to cross the BBB and to be imaged inside the brain. Conclusions F-TRAP is capable of encapsulating small hydrophobic molecules, such as dox. It crosses the BBB and undergoes EPR effect allowing it to accumulate therein and be visualized NIRF imaging and is capable of undergoing MR imaging due to an appropriate half-life of about 123 min

The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.

BACKGROUND AND PURPOSE/OBJECTIVE:We reviewed the literature to evaluate cerebrospinal fluid (CSF) results from patients with coronavirus disease 2019 (COVID-19) who had neurological symptoms and had an MRI that showed (1) central nervous system (CNS) hyperintense lesions not attributed to ischemia and/or (2) leptomeningeal enhancement. We sought to determine if these findings were associated with a positive CSF severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR). METHODS:We performed a systematic review of Medline and Embase from December 1, 2019 to November 18, 2020. CSF results were evaluated based on the presence/absence of (1) ≥ 1 CNS hyperintense lesion and (2) leptomeningeal enhancement. RESULTS:In 117 publications, we identified 193 patients with COVID-19 who had an MRI of the CNS and CSF testing. There were 125 (65%) patients with CNS hyperintense lesions. Patients with CNS hyperintense lesions were significantly more likely to have a positive CSF SARS-CoV-2 PCR (10% [9/87] vs. 0% [0/43], p = 0.029). Of 75 patients who had a contrast MRI, there were 20 (27%) patients who had leptomeningeal enhancement. Patients with leptomeningeal enhancement were significantly more likely to have a positive CSF SARS-CoV-2 PCR (25% [4/16] vs. 5% [2/42], p = 0.024). CONCLUSION/CONCLUSIONS:The presence of CNS hyperintense lesions or leptomeningeal enhancement on neuroimaging from patients with COVID-19 is associated with increased likelihood of a positive CSF SARS-CoV-2 PCR. However, a positive CSF SARS-CoV-2 PCR is uncommon in patients with these neuroimaging findings, suggesting they are often related to other etiologies, such as inflammation, hypoxia, or ischemia.

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.