bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-07. BARRIER TO PROGRESS: DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) INDUCES A TIGHTENED BLOOD-BRAIN BARRIER PHENOTYPE
Authors: Ung Caitlin , Upton Dannielle , Venkat Pooja , Pandher Ruby , Mayoh Chelsea , Tsoli Maria , Ziegler David 
Published: November 2023

Abstract
DIPG is an incurable paediatric brainstem tumour. Treatments have been significantly hindered by the necessity for drugs to penetrate the blood-brain barrier (BBB). We, and others, have shown that the BBB remains intact in DIPG, and it is thought that the BBB in the brainstem may be even less permeable in the presence of DIPG tumor cells. We performed in vivo studies in orthotopic DIPG mouse models that showed higher efficacy of mTOR inhibitor, temsirolimus, in cortex-injected DIPG compared to brainstem-injected DIPG. Analysis showed significantly increased survival, higher temsirolimus levels and decreased proliferating tumour cells in the cortex. Subsequently, the effect of DIPG on brain vasculature was interrogated by single-cell RNA sequencing. Microvascular endothelial cells were isolated from the brainstem and cortex, where DIPG cells or Matrigel were implanted. Transcriptomic analysis of DIPG-injected brainstem uncovered significant downregulation of inflammatory pathways, especially P38MAPK, downregulation of antigen presentation, and increased transporter Mfsd2a, suggesting a tightened BBB. Apoptotic signalling pathways were significantly upregulated, particularly MCL-1. Further analysis into cortex-injected DIPG revealed downregulation of interferon β pathways, suggesting a leakier phenotype. To overcome the tightened barrier in the brainstem, MCL-1 inhibitor S63845, was investigated as a BBB modulator. S63845 significantly reduced transendothelial electrical resistance, increased tracer dye leakage in an in vitro BBB transwell model with DIPG and decreased protein expression of claudin-5. In vivo, S63845 increased permeability to 3kDa Texas-red dextran after a single dose in DIPG mouse models. Overall, this study revealed that DIPG directly affects endothelial cell pathways associated with BBB permeability, resulting in a tightened BBB and reduced therapeutic efficacy. S63845 represents a promising BBB modulator that can be easily administered and may facilitate the delivery of therapeutics through the constricted BBB. This discovery has the potential to enhance the activity of anti-DIPG therapeutics that were previously considered impenetrable.
DDEL-10. RETROSPECTIVE REVIEW OF INTRA-CSF DRUG DELIVERY: SAFETY AND DRUG DISTRIBUTION PROFILES OF INTRACEREBROVENTRICULAR (ICV), LUMBAR INTRATHECAL (LIT), AND INTRA-CISTERNA MAGNA (ICM) INJECTIONS
Authors: Lee Grace , Glicksman Marcie , Patel Rajan , Vanjani Nisheka , Kumthekar Priya 
Published: November 2023

Abstract

INTRODUCTION
The blood-brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics. Given this limitation, intra-cerebrospinal fluid (CSF) drug delivery can be utilized. Here we review and compare thesafety and drug distribution of the different intra-CSF drug delivery methods.

METHODS
A retrospective literature review of the three most common CSF access methods (intracerebroventricular (ICV), lumbar intrathecal (LIT), and intra-cisterna magna (ICM)) was performed. The search consisted of human clinical trials published on PubMed from 2000 to present, with the following terms: intracerebroventricular/intraventricular/ICV, intrathecal/IT, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF.

RESULTS
The search yielded 34 ICV, 72 LIT, and 6 ICM studies. To investigate the safety and drug concentration profiles of each delivery method, we excluded studies reporting drug adverse events (AEs) rather than AEs related to the specific drug delivery method, leaving 21 ICV, 30 LIT, and 1 ICM studies, all of which spanned oncology and non-oncology treatment studies. ICV-specific safety was addressed in 10 ICV studies, with infection (N=6) and device malfunction (N=2) being among the most frequently mentioned device/procedure-associated AEs. LIT-specific safety was provided in 17 studies, with post-procedural headache (N=9), infection (N=5), and pain (N=5) being among the most mentioned AEs. For drug distribution, 42.9% (N=9) of ICV studies concluded that ICV delivery achieved sufficient drug exposure in the CNS for a meaningful therapeutic benefit, with drug concentrations reaching minimum effective doses and/or achieving high therapeutic indices. The single ICM study with infusion of bupivacaine for pain management did not analyze safety or drug distribution. Meanwhile, 30.0% (N=9) of LIT studies reached the same conclusion or achieved concentrations consistent with predicted values.

CONCLUSION
The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild-to-moderate device/procedure-associated AEs. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods.
DDEL-14. EXPLORING THE ROLE OF WNT PATHWAY INHIBITION ON GLIOMA STEM CELLS PROGRESSION AND BRAIN ENDOTHELIAL INTEGRITY
Authors: Tang Kayen , Kang Jeonghan , Conrad Christina , Lim Sanghee , Kwak Minhye , Cesaire Melissa , Jackson Sadhana 
Published: November 2023

Abstract
The blood–brain barrier (BBB) is a specialized neurovascular unit evolved to maintain brain homeostasis and prevent effective agents from reaching malignant brain tumors such as glioblastoma. The Wnt/β-catenin signaling pathway helps to ensure BBB integrity and previous studies demonstrate Wnt pathway inhibition increases BBB permeability. High grade gliomas express increased Wnt expression compared with normal tissue. We hypothesize that Wnt pathway inhibition in glioma stem cells (GSCs) will hinder progression, increase BBB permeability, and enhance overall treatment response. In this study, we transduced primary pediatric-derived glioma stem cells with lentiviral vectors overexpressing Wnt inhibitors (DKK1 or WIF1) and then characterized migration, proliferation, and cell cycle progression. WNT inhibition on brain endothelial cell integrity was evaluated with GSC conditioned media (GSC-CM) +/- CHIR99021 (Wnt pathway activator) for function via electrical cell-cell impedance and junctional expression. Wnt inhibitor overexpression was verified using RNAseq, proteomic analysis, and immunoblotting. We found that GSC-DKK1 demonstrated significantly decreased cell migration (p&lt; 0.005) and proliferation (p&lt; 0.0001). We also found that CHIR99021 treated GSC-CM endothelial cells displayed decreased tight junctional proteins and increased fenestration protein expression (p&lt; 0.0005), correlating with a more porous endothelium. Overall, our studies showed Wnt inhibitor overexpressing GSCs impaired glioma progression in vitro and indirectly disrupted endothelial cell integrity. Future studies will evaluate orthotopic Wnt inhibitor overexpressing transplant rodent models to assess changes in BBB integrity, drug permeability, model survival, and treatment response. Further understanding of the Wnt pathway in both GSCs and the BBB has the potential for improved central nervous system treatment penetration and prolonged disease response.
DDEL-15. EXPLORING THE USE OF MACHINE LEARNING TO PREDICT BLOOD BRAIN BARRIER PERMEABILITY OF DRUG MOLECULES
Authors: Lim Megan Amber , Mostafa Wael Hassaneen 
Published: November 2023

Abstract
The blood-brain barrier (BBB) is a selective boundary of the central nervous system (CNS) that plays a critical role in protecting the brain microenvironment by allowing passage of certain molecules. Clinical experiments accurately determine which chemotherapy drugs effectively cross the BBB to reach the tumor site but are also time consuming and labor intensive. Machine learning offers the ability to rapidly screen large datasets of drug molecules and assess their potential for CNS therapeutic effect. The goal of this study is to compare the performance across machine learning, deep learning, and transfer learning methods in predicting BBB permeability on public drug datasets. The dataset used for training and validation was composed of 7,807 compounds compiled from 50 published resources. The machine and deep learning methods used in this study included support vector machines (SVMs), deep neural networks (DNNs), and graph convolutional neural networks (GCNNs). For transfer learning, we first trained DNN models to a single quantum chemical property before appending neural network layers and retraining to the new task of BBB permeability. The prediction accuracies on the validation set for SVM, DNN, GCNN, transfer learning of polarizability, and transfer learning of dipole moment were 82.33%, 83.09%, 87.14%, 76.89%, and 70.23%, respectively. Overall, the results indicate that GCNN was the best performing model. This highlights GCNNs ability to learn the molecular features most relevant to the predictive task in the first stage of the algorithm. Future work entails expanding the set of input features to include key chemical and structural information such as the presence or absence of certain functional groups as well as training more transfer learning models to other quantum chemical properties. This study further motivates the predictive capability of machine learning methods in identifying drug compounds with potential CNS-activity.
DDDR-28. DNA DAMAGE SENSING KINASES ATR AND ATM-DEPENDENT PHOSPHORYLATION OF RRM2 PROMOTES PROTEIN STABILIZATION AND CHEMO-ADAPTATION
Authors: McManus Graysen , Perrault Ella , Park Cheol , Ventrapragada Divya , Budhiraja Shreya , Buechler Killian , Stepniak Amelia , Mishra Snehasis , Miska Jason , Ahmed Atique 
Published: November 2023

Abstract
Glioblastoma (GBM) is a highly heterogeneous, primary malignant brain tumor in adults that shows limited response to standard-of-care therapies, such as chemotherapy and radiation. This is due, in part, to the development of therapeutic resistance. To characterize the adaptive mechanisms GBM cells use to evade the standard chemotherapy, temozolomide (TMZ), single-cell RNA sequencing analysis was conducted on an in vivo patient-derived xenograft (PDX) model of GBM, before, during, and following TMZ-based therapy. Our data revealed 149 genes to be uniquely expressed in the during-TMZ condition (p&lt; 0.0001), including the rate-limiting regulatory enzyme of dNTP metabolism, ribonucleotide reductase (RNR) enzyme. Network analysis of pathways enriched during therapy revealed an interaction between the (RNR) enzyme, RRM2, and DNA damage response genes in the ATM and ATR kinase-signaling pathways. RRM2-dependent deoxynucleotide (dNTP) production is required for DNA repair and cell survival following TMZ treatment. Therefore, we investigated whether ATR and ATM kinases directly interact with RRM2 to promote its stability. TMZ treatment triggered the activation of DNA damage response machinery and protein kinases, ATM, ATR, CHK1, and CHK2, which physically interacted with RRM2 across multiple GBM PDX cell lines. Co-IP and immunoblot analyses along with cycloheximide chase analysis showed increased phosphorylation of the threonine residue on RRM2 during therapy, preventing its degradation. As such, we hypothesize that early DNA damage sensing by ATM and ATR kinases, and their subsequent phosphorylation of RRM2, promotes the maintenance of purine nucleotide pools needed for DNA repair and development of chemo-resistance. This novel and targetable TMZ response axis presents a promising clinical opportunity for GBM therapy, using FDA-approved inhibitors of these targets to block the purine metabolic adaptations that drive resistance and sensitize GBM cells to TMZ therapy.
DDDR-29. TARGETING FGFR FUSIONS: A CASE OF CATEQUENTINIB (AL3818) AND TEMOZOLOMIDE COMBINATION THERAPY FOR RECURRENT MGMT METHYLATED TACC-FGFR FUSION POSITIVE GLIOBLASTOMA
Authors: Seas Andreas , Patel Mallika , Kowalsky Martin , Rudd Daniel S , Jacobs Susanne D , Miller Elizabeth S , Volas-Redd Gena H , Johnson Margaret O 
Published: November 2023

Abstract

BACKGROUND
There is no gold-standard for the management of recurrent glioblastoma (GBM). However, advances at the interface of molecular testing and rational drug design have opened avenues for personalized medicine. Here we describe the case of a 52-year-old patient with recurrent GBM (WHO grade 4) with known FGFR3-TACC3 fusion and MGMT promoter methylation by Caris molecular profiling. Initial treatment included radiotherapy with concomitant and adjuvant temozolomide. However, after 18 months off therapy, the patient became clinically and radiographically progressive with multifocal disease. Herein, we describe our experience with temozolomide and catequentinib (AL3818) in a single patient.

METHODS
We reviewed the available literature on targeting FGFR3-TACC3 fusion positive glioblastoma with catequentinib (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-Yl] oxy] methyl] cyclopropanamine dihydrochloride). Catequentinib is an oral small-molecule pan-kinase inhibitor with selective VEGFR2 inhibition, it is under investigation in multiple phase 2 and 3 clinical trials and can safely be administered concomitantly with temozolomide. We obtained single-patient Investigational New Drug (IND) approval and free drug was shipped directly from the manufacturer (Advenchen Laboratories; Jiangsu Chia-Tai Tianqing Pharmaceutical) to our institution’s investigational chemotherapy pharmacy. We administered catequentinib 12 mg by mouth for 14 days on and 7 days off of a 21-day cycle along with temozolomide 50mg/m2/day of a 28-day cycle with routine monitoring of laboratory parameters.

RESULTS
The combination of temozolomide and catequentinib was well-tolerated, resulted in clinical stability, and partial radiographic response at 3-month follow-up.

CONCLUSION
Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.
EOLP-05. SUPPLEMENTAL ENTERAL NUTRITION DOES NOT IMPROVE SURVIVAL IN OLDER PATIENTS WITH PRIMARY MALIGNANT BRAIN TUMORS
Authors: Johnson Margaret O , Parish Alice , Cohen Seth M , Niedzwiecki Donna , Peters Katherine , Leiman David A 
Published: November 2023

Abstract

BACKGROUND
The risk of dysphagia increases with age and is prevalent among older adults with primary malignant brain tumors (PMBTs). As a result, patients with PMBTs may receive supplemental enteral nutrition (EN) but its impact on outcomes is uncertain. Therefore, we compared survival among Medicare beneficiaries with PMBTs and dysphagia by use of EN.

METHODS
We analyzed a Medicare 5% limited data set from 2013-2018. We included beneficiaries ≥65 years with PMBTs and solid tumors (lung, breast, melanoma, renal, and colorectal) identified by ICD9/10 codes. Predisposing conditions for dysphagia were excluded. To assess differences in survival of dysphagic patients by EN access (i.e., gastrostomy tube), hazard ratios and 95% confidence intervals (CI) from a Cox proportional-hazards model were calculated after adjusting for age, sex, race, and Elixhauser Comorbidity Index (ECI).

RESULTS
The rate of dysphagia among 79,926 beneficiaries was 4.7% (n=3,777), and significantly higher among those with PMBTs (11%, p&lt; 0.01) compared to solid organ tumors with (8.0%) and without brain metastases (4.4%). Among patients with PBMTs, the presence of dysphagia was associated with lower survival compared to those without dysphagia (p&lt; 0.001). For patients with PMBT and dysphagia, adjusted models showed no significant difference (p=0.08) in survival among those who received EN (N=78) compared to those that did not (N=271); however, those with EN had a 33% higher hazard of death compared to those without EN [HR= 1.34, 95% CI: (0.99, 1.81)].

CONCLUSION
Dysphagia is common among older patients with brain cancer and disproportionally affects those with PMBTs. The use of EN in this population-based study of Medicare beneficiaries did not significantly improve survival and there was a trend toward harm. Given the frequency of EN use and observed worse outcomes, further validation in a larger clinical dataset is warranted.
EPID-01. ANTINEOPLASTIC, RADIATION, AND SYNCHRONICITY EFFECTS ON BRAIN METASTASIS SURVIVAL: A RETROSPECTIVE POPULATION-BASED STUDY
Authors: Rincon-Torroella Jordina , Jiang Kelly , Parker Megan , Materi Joshua , Azad Tej , Kamson David , Kleinberg Lawrence , Ye Xiaobu , Bettegowda Chetan 
Published: November 2023

Abstract

INTRODUCTION
Brain metastases (BM) are the most common central nervous system tumors. The impact of oncological treatment on the prevention of BM is not well-defined. We report the effects of chemotherapy and radiotherapy directed at primary cancer on synchronous and metachronous BM survival.

METHODS
A large nationwide multi-institutional claims-based platform (TriNetX Diamond Network) was queried. Patients diagnosed during 2013-2023 with the 15 most common primary cancers that metastasize to the brain were included. Metachronous was defined as BM diagnosed &gt; 2 months after primary cancer. Cohorts were propensity score matched for age, extracranial metastasis, and adjuvant therapy. Kaplan-Meier plots were used to compare survival.

RESULTS
113,827 (38%) patients with synchronous and 187,036 (62%) with metachronous BM were identified. Patients with synchronous BM had 26 months shorter median survival compared to metachronous BM (11 vs. 37 months, HR 2.17, 95%CI 2.14-2.19, P&lt; 0.0001). However, no survival advantage was observed from the time of BM diagnosis (11 vs. 12 months, HR 1.06, 95%CI 1.05-1.08, P=0.411). Antineoplastic treatment prior to BM improved median BM-free survival by 13 months (4 vs. 18 months, HR 1.66, 95%CI 1.77-1.82, P &lt; 0.0001) and median OS by 17 months (25.15 vs. 42.26 months, HR 1.48, 95%CI 1.46-1.51, P&lt; 0.0001). Radiation therapy prior to BM incurred a significant but smaller increase in median BM-free survival by 6 months (5 vs. 11 months, HR 1.27, 95%CI 1.26-1.29, P&lt; 0.0001) and median OS by about 3 months (30.13 vs. 32.82 months, HR 1.06, 95%CI 1.04-1.08, P &lt; 0.0001).

CONCLUSION
Once BM is diagnosed, the synchronicity of diagnosis does not predict survival. Antineoplastic and radiation treatment directed at primary cancer may improve BM-free survival and OS. Studies characterizing the BM-free effects of molecular markers, chemotherapy, and radiotherapy are necessary to improve screening, prevention, and treatment.
EPID-06. TARGETED AGENTS IN PATIENTS WITH RECURRENT GLIOBLASTOMA– A SYSTEMATIC META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS
Authors: Ippen Franziska Maria , Scherm Angelika , Kessler Tobias , Hau Peter , Baurecht Hansjörg , Wick Wolfgang , Knüttel Helge , Leitzmann Michael F , Seliger Corinna 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma (GB) is the most common malignant primary brain tumor in adults and associated with a dismal prognosis. While the standard of care for newly diagnosed GB is defined in current treatment guidelines, recommendations for recurrent GB are less well established. The current systematic meta-analysis of recently published randomized controlled trials (RCTs) represents the strongest available evidence on targeted agents in patients with recurrent GB.

METHODS
Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform and Google Scholar were searched ranging from the year 1954-2022 for RCTs of targeted therapies in patients with recurrent GB. Hazard Ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were extracted to perform a random-effects meta-analysis.

RESULTS
16 RCTs (n=3,025 patients) were included in the meta-analysis. Experimental treatment was either compared to lomustine (CCNU) alone, in combination with CCNU/temozolomide (TMZ) to CCNU alone or to bevacizumab alone. In these three subgroups, targeted agents associated with improved OS compared to the control arm were regorafenib (RR= 0.50; 95% CI 0.33-0.75), Depatux- M+ TMZ (RR= 0.66; 95% CI 0.44-0.93) and rindopepimut + bevacizumab (RR= 0.53; 95% CI 0.32-0.88). Treatment with bevacizumab + CCNU (RR= 0.49; 95% CI 0.35-0.69) and regorafenib (RR= 0.65; 95% CI 0.44-0.95) were associated with improved PFS.

CONCLUSION
In this systematic meta-analysis, we provide the current highest level of evidence for the role of targeted therapies in recurrent GB. Even though some studies revealed a benefit either for OS and/or PFS, results have to be critically reviewed regarding initial distribution of prognostic factors, underlying molecular mechanisms, sample size and trial design. There is a need for more specific and personalized study designs using newly obtained tumor tissue and close monitoring of treatment responses to allow for potential modification of treatment if needed.
EPID-08. CLINICAL AND MOLECULAR DETERMINANTS OF BLEEDING-RELATED ADVERSE OUTCOMES IN HIGH-GRADE GLIOMA
Authors: Dasgupta Pushan , Rousseau Justin 
Published: November 2023

Abstract
Cancer is an independent risk factor for the development of venous thromboembolism (VTE) however patients with high-grade glioma (HGG) including glioblastoma (GBM) are at a particularly high risk of VTE with an incidence up to 20- 30% per year. Patients are often placed on anticoagulation to reduce the risk of VTE. However, patients with primary brain tumors such as HGG are at increased risk for intracerebral hemorrhage (ICH) even without the administration of anticoagulation. The combination of risk factors for ICH with anticoagulation and HGG complicates decision-making. Currently it is not known which of the direct oral anticoagulants (DOACs) are safest for patients with HGG in terms of adverse bleeding-related outcomes such as ICH. Furthermore, a deeper understanding of the clinical and molecular determinants of bleeding-related adverse outcomes in HGG is not fully characterized. In this study, we gathered data on patients with HGG from two Ascension Seton Hospitals in the Austin metro area from July 1, 2017 through June 30, 2022. We identified 76 pathology-confirmed patients with HGG. Patients who were on rivaroxaban (3/7 (43%), p=.022) had a statistically significant association with more bleeding-related adverse events compared to those on apixaban (0/12 (0%)) or enoxaparin (0/5 (0%)) even though the groups were similar in terms of their characteristics including total time on the respective anticoagulation. Patients on anticoagulation vs those never on anticoagulation did not differ in terms of their studied demographic and clinical characteristics. Intriguingly, logistic regression analysis revealed that patients harboring isocitrate dehydrogenase (IDH) mutations had a statistically significant association with more adverse bleeding-related events even when controlling for other relevant factors (Odds Ratio compared to reference GBM: 115.7; p=.014). This study offers insights into our understanding of relevant factors associated with worse bleeding-related adverse outcomes such as ICH in patients with HGG.