bluuebunny/crossref_metadata_2025_split huggingface dataset:
460 MP-Pt(IV): A Platinum (IV)-Based Prodrug for Treating DIPG With Selective Mitochondrial Chemotherapy
Authors: Baskin David S. , Raghavan Sudhir , Sharpe Martyn , Manalo Jeanne , Bailey Callie A. 
Published: March 2023

INTRODUCTION:
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. We previously developed MP-Pt(IV), a platinum (IV) based prodrug that is selectively accumulates in GBM mitochondria upon oxidation by the overexpressed enzyme monoamine oxidase B (MAOB), and is then reduced to the chemotherapeutic cisplatin. Expression levels of MAOB in DIPG is high.

METHODS:
In-vitro cell growth inhibition studies were conducted on DIPG cells using MP-Pt(IV). Labeling studies were carried out with Mitosox, Mitotraker, and H2DCF. Oxygen consumption studies were performed to show mitochondrial targeting. Clonogenic survival assay and scratch assay were performed.

RESULTS:
MP-Pt(IV) shows potent growth inhibition of DIPG in cell culture studies. Mechanistic studies indicate mitochondrial targeting of the prodrug. Significant increases in cellular ROS and hydrogen peroxide levels are observed upon MP-Pt(IV) treatment. Oxygen consumption studies confirm mitochondrial targeting of MP-Pt(IV). MP-Pt(IV) strongly inhibits clonogenic survival and cell migration in treated cells.

CONCLUSIONS:
We demonstrate that MP-Pt(IV) is highly effective in DIPG in vitro, and is a good candidate for testing in an in-vivo mouse intracranial DIPG model, and for further development.
461 Intracranial Tumors Hijack the Meningeal Venolymphatic Network Through VEGFR-2 Signaling
Authors: Ampie Leonel , McGavern Dorian 
Published: March 2023

INTRODUCTION:
Glioblastoma and other intracranial neoplasms have been associated with breakdown of the blood brain barrier. Other protective CNS barriers have sparsely been studied in brain tumors. Here, we identify the ability of intracranial neoplasms to hijack the meningeal venolymphatic network, which is driven through VEGFR-2/VEGF-A signaling.

METHODS:
C57BL/6J mice were stereotactically injected with syngeneic SB28 (glioblastoma) cell lines. Mice were treated with either isotype control or a VEGFR-2 inhibitor. Two-photon microscopy was used to visualize vascular cytoarchitecture and dynamics in vivo. Meningeal whole mounts, brains and spleens were also collected and analyzed by confocal microscopy and high parameter flow cytometry. Similar experiments were conducted with a PECAM-1 inhibitor to assess the role of endothelial cell crosstalk in venolymphatic expansion. Human dura mater from glioblastoma patients underwent multiplex immunohistochemistry to confirm the translatability of our findings.

RESULTS:
Our imaging studies revealed that glioblastomas can generate an extensive de novo network of meningeal blood vessels and lymphatics both in mice and humans. Lymphatic vessels were often observed developing in parallel to the newly formed vasculature. Intravital two-photon microscopy further revealed that the peritumoral vascular bed in the meninges of mice was leaky, dysfunctional, and generated a hypoxic microenvironment. Importantly, inhibition of VEGFR signaling impeded formation of this faulty venolymphatic network, which slowed tumor growth, reduced peritumoral hypoxia, enhanced immune infiltration, and increased survival. PECAM-1 (CD31) inhibition had a similar effect on the tumor microenvironment, suggesting that endothelial cell crosstalk is required for glioblastomas to optimally invade the meninges.

CONCLUSIONS:
Our results demonstrate that glioblastomas can invade the meninges and hijack the venolymphatic network through VEGFR-2 and PECAM-1 signaling. While VEGFR-2 is associated with angiogenesis, our data suggest that it may also have an important role in regulating the simultaneous development of de novo meningeal venous and lymphatic drainage during glioblastoma.
463 Tandem CAR T Cells Targeting EGFRvIII and IL-13R⍺2 are Effective Against Heterogeneous Glioblastoma
Authors: Schmidts Andrea , Srivastava Ambike , Ramapriyan Rishab , Cahill Daniel P. , Carter Bob S. , Curry William T. , Dunn Gavin P. , Ghannam Jack , Nahed Brian V. , Sun Jing , Wakimoto Hiroaki , Maus Marcela V. , Choi Bryan D. 
Published: March 2023

INTRODUCTION:
Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogenous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape.

METHODS:
We generated a TanCART construct with dual specificity consisting of both the humanized anti-EGFRvIII scFv and IL-13 zetakine translated in tandem separated by a flexible glycine-serine linker. We also employed two monospecific CAR T cells, CART-EGFRvIII and CART-IL-13Rɑ2 as controls. We used both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogenous tumors.

RESULTS:
Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < 0.05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < 0.05).

CONCLUSIONS:
We demonstrate that TanCART is effective against heterogenous tumors in the brain. To our knowledge, this is the first report of a tandem CAR T cell targeting EGFRvIII and IL-13Rɑ2 simultaneously. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.
466 Robust Model of Microglia Replacement With Circulation-Derived Microglia-Like Cells (CDMCs) in CNS Malignancies
Authors: Rodrigues Adrian , Mader Marius , Chernikova Sophia , Li Guan , Wang Yuelong , Wong Sam , Petritsch Claudia , Wernig Marius , Gephart Melanie Hayden 
Published: March 2023

INTRODUCTION:
Tumor-associated microglia and macrophages (TAMs) represent a main cell type of brain malignancies and demonstrate complex interactions with cancerous cells and the tumor microenvironment. These interactions have important implications for the progression and treatment of malignant central nervous system (CNS) tumors. TAMs have therefore emerged as therapeutic targets, though their potential to date has been unfulfilled.

METHODS:
C57BL/6 mice were preconditioned for BMT with retroorbital busulfan injections (25 mg/kg), and native microglia were depleted via PLX5622 (1200 mg/kg, chow). Following transplantation, animals underwent intracranial stereotactic injection of syngeneic cell lines of either high-grade glioma (GL261) or breast cancer metastasis (E0771). Following animal sacrifice, we used single cell RNA sequencing of CD45-positive cells to profile the transcriptomic identity of glioma tumor-associated CDMCs (TA-CDMCs).

RESULTS:
Lineage tracing proved high intra- and peri-tumoral chimerism of BMT-graft derived cells among CNS myeloid cells in both models two weeks after tumor cell injection, demonstrating a robust ability to modify the tumor-immune microenvironment in animal models. TA-CDMCs showed a similarly activated morphology as naÏve TAMs under immunohistochemistry. Pathway enrichment analysis revealed an upregulation of immune response pathways in TA-CDMCs compared to regular TAMs, including the overexpression of genes relevant for the regulation of T cell activation, suggesting possible modification of the glioma immune-environment following CDMC repopulation.

CONCLUSIONS:
The present study offered a robust proof-of-concept that highly efficient TAM replacement could be achieved in orthotopic murine brain tumor models. Additionally, it appears that replaced CDMCs retain unique transcriptional patterns in the tumor-immune microenvironment, with the upregulation of several key immune response pathways. These efforts may represent a novel route of tumor-directed immunotherapy and offer exciting opportunities for ex-vivo CDMC manipulation to specifically target neoplastic cells.
467 Stimulator of Interferon Genes Protein (STING) Agonist Incited Sustained Antitumor Immunity in Murine Models of Glioblastoma
Authors: Huntoon Kristin , Lee DaeYong , Lu Yifei , Jiang Wen , Curran Michael , Kim Betty Y.S. 
Published: March 2023

INTRODUCTION:
Introduction: Stimulator of interferon genes (STING) is an innate pattern recognition receptor natively localized to the endoplasmic reticulum that detects both exogenous and endogenous pathogenic or damage-associated cytosolic cyclic dinucleotides (CDNs), activating IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce a potent type I interferon and proinflammatory cytokine responses. Activation of the STING pathway has been recognized as a critical component of the innate immune sensing of tumors that is required for optimal cytotoxic T-cell priming against tumor antigens. Recently a highly potent cyclic dinucleotide STING agonist, IACS-8803, showed robust activation of the STING pathway resulting in systemic anti-tumor response in the B16 murine model of melanoma. Additionally, the STING agonists have been shown to achieve robust tumor regression at both injected and distal lesions and are reported to facilitate generation of long-lived immunologic memory.

METHODS:
Methods: We established murine gliomas with stereotactic implantation of GL261, a murine glioma cell line. Mice were assessed with luciferase imaging to ensure baseline tumor size and then randomized into treatment arms (IgG, IACS-8803, CD47, PD-1 and combinations thereof). Treatment was initiated one week after the tumor implantation.

RESULTS:
Results: All mice that received IACS-8803 had no detectable luciferase activity. Tumor regression was additionally verified via MR Imaging. Utilization of IACS-8803 led to long-term tumor-free survival (p < 0.01). Re-challenge with GL261 tumors ensured long term memory was sustained with a single dose of agonist.

CONCLUSIONS:
Conclusion: Engaging the STING pathway may be an ideal targeting strategy for GBM. Ongoing studies are delineating the mechanisms of activating this pathway with specific attention being paid to reprogramming and education of innate immunity.
471 Automated Detection and Analysis of Cerebral Aneurysms With the Viz.ai ANX Algorithm
Authors: Colasurdo Marco , Shalev Daphna , Robledo Ariadna , Vasandani Viren , Luna Zean Aaron , Rao Abhijit , Garcia Roberto , Edhayan Gautam , Srinivasan Visish M. , Sheth Sunil , Avni Naama , Bibas Orin , Donner Yoni , Limzider Nicole , Shaltoni Hashem , Kan Peter 
Published: March 2023

INTRODUCTION:
Machine learning algorithms have shown groundbreaking results in neuroimaging. We evaluate the performance of a convolutional neural network (CNN) to detect and analyze intracranial aneurysms (IAs) from computed tomography angiography (CTA).

METHODS:
Consecutive patients CTA were identified from a single center between January 2015 and July 2021. The ground truth determination of cerebral aneurysm presence or absence was made by the neuroradiology report. The primary outcome was performance of the CNN at detecting IAs in an external validation set, measured using area-under-the-curve (AUC) receiver-operator curve statistics. Secondary outcomes included accuracy for location and size measurement.

RESULTS:
Among 400 patients with CTA, 150 (37.5%) were male, median age was 39 years (SD 21), and 195 were diagnosed with IAs on neuroradiologist evaluation. Median IAs maximum diameter was 4.6 mm [IQR 2 mm]. In the independent validation imaging dataset, the CNN performed well with 87.6% sensitivity (95%-CI [0.81, 0.92]), 94.0% specificity (95%-CI [0.90, 0.97]) and positive predictive value of 90.9% (95%-CI [0.84, 0.95]) in the subgroup with diameter >=3 mm.

CONCLUSIONS:
The described Viz.ai ANX CNN performed exceptionally well at identifying presence or absence of intracranial aneurysms in an independent validation imaging set.
475 Local Conditional Induction of Brain Arteriovenous Malformations in Alk1-Inducible Knock-Out Mice
Authors: Scherschinski Lea , Han Chul , Winkler Ethan A. , Vajkoczy Peter , Lawton Michael T. , Oh S. Paul 
Published: March 2023

INTRODUCTION:
Current mouse models of familial brain arteriovenous malformations (AVMs) have limitations in long-term survival. These drawbacks are mainly attributed to systemic and ubiquitous genetic recombinations with development of AVMs in peripheral organs that result in hemorrhagic conditions.

METHODS:
Transgenic mice with ubiquitous CreER expression were used (ROSA26CreER;Alk1f/f; Alk1-iKO). 4-hydroxytamoxifen (4-OHTM) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of neonatal mice at postnatal day 1. Mice were evaluated for brain AVMs with systemic latex dye perfusion and 3D time-of-flight magnetic resonance angiography.

RESULTS:
Alk1-iKO mice injected stereotactically with 4-OHTM developed brain AVMs with 68% (21/31) frequency in the striatum, 72% (13/18) in the parietal cortex, and 44% (4/9) in the cerebellum. Brain AVMs formed in or near the injection site with 95% accuracy (36/38). A subset of mice (8%, [3/38]) presented with a communicating hydrocephalus from CSF malabsorption. The formation of AVMs in these Alk1-iKO mice was restricted to the brain, without AVMs developing in peripheral organs (n = 38). The hemoglobin levels were not significantly different between mutant and control Alk1-iKO mice after stereotactic, intracerebral 4-OHTM injection (p = 0.27). The 4-week mortality was 5% (2/38). Longitudinally monitored mice demonstrated good survival at 3 months of age (86%, [6/7]).

CONCLUSIONS:
We present the first experimental mouse model with local, CreER-mediated induction of brain AVMs. The model is advantageous in generating brain AVMs with high efficiency, along with an improved long-term survival and reduced early lethality of mice. Collectively, these features may serve as a framework to accelerate the ongoing investigations of brain AVM pathogenesis, rupture, and preclinical testing of novel therapeutics.
477 Stereotactic Radiosurgery With Versus Without Prior Onyx Embolization for Brain Arteriovenous Malformations
Authors: Chen Ching-Jen , Ding Dale , Lee Cheng-chia , Kearns Kathryn , Pomeraniec Isaac Jonathan , Cifarelli Christopher Paul , Liscak Roman , May Jaromir , Williams Brian Jeremy , Ironside Natasha , Burke Rebecca M. , Warnick Ronald E. , Trifiletti Daniel M. , Mathieu David , Kondziolka Douglas , Feliciano Caleb E. , Rodriguez-Mercado Rafael , Cockroft Kevin M. , Simon Scott Douglas , Lee John Y.K. , Sheehan Jason P. 
Published: March 2023

INTRODUCTION:
Investigations of the combined effects of neoadjuvant Onyx embolization and stereotactic radiosurgery (SRS) on brain arteriovenous malformations (AVM) have not accounted for initial angioarchitectural features prior to neuroendovascular intervention.

METHODS:
The International Radiosurgery Research Foundation AVM databases from 1987–2018 were retrospectively reviewed. Patients were categorized, based on AVM treatment approach, into Onyx embolization and SRS (OE+ SRS) or SRS alone (SRS-only) cohorts and then propensity score-matched in a 1:1 ratio. Primary outcome was AVM obliteration. Secondary outcomes were post-SRS hemorrhage, all-cause mortality, radiologic and symptomatic radiation-induced changes (RIC), and cyst formation. Comparisons were analyzed using crude rates and cumulative probabilities adjusted for competing risk of death.

RESULTS:
The matched OE + SRS and SRS-only cohorts each comprised 53 patients. Crude rates (37.7% vs. 47.2% for OE + SRS vs. SRS-only cohorts, respectively; OR = 0.679, p = 0.327) and cumulative probabilities at 3, 4, 5, and 6 years (33.7%, 44.1%, 57.5%, and 65.7% for OE + SRS cohort vs. 34.8%, 45.5%, 59.0%, and 67.1% for SRS-only cohort, respectively; SHR = 0.961, p = 0.896) of obliteration were similar between the matched cohorts. The secondary outcomes of the matched cohorts were also similar. Asymptomatic and symptomatic embolization-related complication rates in the matched OE + SRS cohort were 18.9% and 9.4%, respectively.

CONCLUSIONS:
Pre-SRS AVM embolization with Onyx does not appear to negatively influence outcomes after SRS. Our analyses, based on de novo nidal characteristics, thereby refute previous studies that found detrimental effects of Onyx embolization on SRS-induced AVM obliteration. However, given the risks incurred by nidal embolization using Onyx, this neoadjuvant intervention should be employed judiciously in multimodal treatment strategies involving SRS for appropriately selected large-volume or angioarchitecturally high-risk AVMs.
478 Microsurgical Outcome of Unruptured Middle Cerebral Artery Aneurysms
Authors: Krisht Ali F. , Pravdenkova Svetlana , Cai Li 
Published: March 2023

INTRODUCTION:
Recently introduced endovascular techniques for treating middle cerebral aneurysms (MCA) has to achieve results superior to surgical outcomes before it becomes the established treatment modality. We present our surgical outcomes in 403 unruptured aneurysms.

METHODS:
Data of 403 MCAs were prospectively collected and retrospectively analyzed. Modified pterional approach with linear dural opening over the Sylvian fissure (Limited brain exposure) was used. Outcome evaluated with Modified Rankin scale (mRS at DC and one year.

RESULTS:
403 unruptured MCA aneurysms were clipped in 354 pts. 48 aneurysms (42 pts) had a ruptured aneurysm of different location and were excluded from analysis leaving 355 aneurysms in 312 patients. M/F ratio-1/2.9 Average age-59.34+ 12.22 and median age-60.109 pts had clipping of single MCA aneurysm during surgery and 203 had multiple aneurysms. Location: MCA bifurcation = 227 (64%), M1 = 101 (28%), M2 = 27 (8%) MCA. Size: Giant = 3 (1%); Large = 32 (9%); Medium = 85 (24%); Small = 235(66%), Outcome- MRs 0-2 at DC = 90%. MRs 0-2 at 3mo-1 year = 98.5%; Mortality = 0.64 % (1- sepsis, comfort care; 1- Massive heart attack); Residual = 0.84% (3/355); Ischemic event - 0.96% (3/312)

CONCLUSIONS:
Recently introduced endovascular techniques for treating middle cerebral aneurysms (MCA) cannot be pushed to become an established modality before at least it matches the present excellent results achieved with microsurgery. Maybe the future should focus on the high level microsurgery.
479 Chronic Subdural Hematomas Treated With Surgical Evacuation Versus Standalone Middle Meningeal Artery Embolization: Volumetric Resolution in Immediate, Early and Late Follow-Up in a Propensity Matched Cohort
Authors: Housley Steven B. , Monteiro Andre , Khawar Wasiq , Donnelly Brianna , Lian Ming , Fritz Alexander , Baig Ammad , Waqas Muhammad , Cappuzzo Justin Mark , Snyder Kenneth Vincent , Siddiqui Adnan Hussain , Levy Elad I. , Davies Jason 
Published: March 2023

INTRODUCTION:
Literature comparing surgery and middle meningeal artery embolization (MMAE) for chronic subdural hematomas (cSDH) is limited by patient selection bias. Furthermore, most studies do not perform volumetric measurements over time when comparing these two modalities.

METHODS:
Retrospective search of our database to include cSDH patients managed with either SEA or standalone MMAE. Propensity-score-matching was performed for axial and coronal lengths, maximum diameter and midline shift. Volumes of cSDH were measured at 24 h post-procedure, 3-12-weeks, 12-24-weeks, 24-36-weeks, 36-48-weeks and 48-60-weeks.

RESULTS:
Forty-eight matched hematoma pairs were obtained. The groups were also similar in demographics, comorbidities, medications and symptoms. Median volume was significantly lower at 24 h in the SEA group (SEA, 12.6 mL vs MMAE, 52.7 mL, P < 0.001). Median volume reduction was significantly greater in the SEA group at 24 h (SEA, 39.1 mL vs MMAE, 8.8 mL, P < 0.001) and in the 3-12 weeks interval (SEA, 50.8 mL vs MMAE, 23.7 mL, P < 0.001). The SEA group had significantly greater median resolution rate at 24 h (39.1 mL/day vs 8.8 mL/day, P < 0.001) and in the 3 to 12 weeks interval (1 mL/day vs 0.4 mL/day, P < 0.001) but not in remaining intervals. Near complete resolution at the 3 to 12 interval (SEA, 26.1% vs MMAE, 28%, P = 1) and 12 to 60 weeks interval (SEA, 78.3% vs MMAE, 80%, P = 1) was not significantly different between the groups. Overall, the recurrence was significantly higher in the SEA group than in the MMAE group (22.9% vs 4.2%, P = 0.01).

CONCLUSIONS:
In comparable cSDH patients, surgical evacuation resulted in better volumetric outcomes in the immediate and early follow-up periods but in extended follow-up intervals. Furthermore, surgical patients experienced a significantly higher rate of recurrence.
490 Beyond Placement of Pedicle Screws - New Applications for Robotics in Spine Surgery: A Multi-Surgeon, Single-Institution Experience
Authors: Tabarestani Troy , Sykes David , Murphy Kelly Ryan , Wang Timothy Y. , Shaffrey Christopher I. , Goodwin C. Rory , Horne Phillip , Than Khoi Duc , Abd-El-Barr Muhammad M. 
Published: March 2023

INTRODUCTION:
Interest in robotic-assisted spine surgery has grown as surgeon comfort and technology have evolved to maximize the benefits of time-saving and precision. However, the Food and Drug Administration (FDA) has currently only approved robotics to assist in determining the ideal trajectory for pedicle screw placement after extensive research supporting its efficacy and efficiency. To be considered a durable and effective option, robotics need to expand beyond the indication of just placing pedicle screws.

METHODS:
We will explore accessing Kambin’s Triangle in percutaneous transforaminal interbody fusion (percLIF), iliac fixation in metastatic cancer, and sacroiliac (SI) fusions. Each of these topics will be covered in-depth with associated background information and subsequent discussion.

RESULTS:
Without the need for laminectomies or facetectomies, minimal tissue disruption was attained by using RA instrumentation finely tuned to each patient’s unique spinal landscape for percLIF. In the cases of iliac fixation, the use of S2AI screws was precluded by the extensive damage to the sacrum. Therefore, a modified iliac screw entry point was utilized with an entry point slightly more medial than the traditional method, with a pre-planned trajectory of the screws using robot assistance. For SI joint fusion, we review our group at Duke University's published case series displaying the “off-label” use of the robot, which is the first reported case series of its kind in the literature.

CONCLUSIONS:
We show that with a proper understanding of its limitations, robots can help surgeons perform difficult surgeries in a safe manner.