bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-38. PREDICTORS OF COGNITIVE PERFORMANCE IN PATIENTS WITH PRIMARY BRAIN TUMORS: AN ANALYSIS OF BRAIN FITNESS CENTER (BFC) AT WALTER REED NATIONAL MILITARY MEDICAL CENTER
Authors: Robertson Ian , Theeler Brett , Law Wendy , Sullivan Katherine , Hartman Maddie 
Published: November 2021

Abstract

INTRODUCTION
Although developed initially for patients with traumatic brain injury (TBI), cognitive rehabilitation training (CRT) has expanded its use to include patients suffering from a variety of neurocognitive disorders including neurologic malignancies. The Brain Fitness Center (BFC) at Walter Reed National Military Medical Center (WRNMMC) is a cognitive rehabilitation clinic that offers computer-based cognitive training programs as an adjunctive rehabilitation resource for a diverse patient population with cognitive complaints.

METHODS
Using a retrospective analysis of data from the BFC at WRNMMC, our study analyzed forty patients with primary brain tumors who had completed both symptom self-report questionnaires and cognitive assessments at the BFC. Self-report questionnaires included the neurobehavioral symptom inventory (NSI) and headache symptom inventory (HIT-6) while cognitive assessments were done using the Automated Neuropsychological Assessment Metrics (ANAM). Our study examined the relationship between subjective cognitive complaints, headache severity, neuropsychiatric symptoms and objective cognitive performance before and after initial CRT. The influence of high vs low grade tumors was also evaluated.

RESULTS
Our analysis demonstrated that increased number of affective symptoms, particularly self-reported irritability, were the strongest predictors of baseline, objective cognitive performance (r= -.377, p=0.008). Patient self-reported forgetfulness, but not overall subjective cognitive complaints, was also negatively correlated with objective cognitive performance (r= - 0.353, p= 0.020). A mean difference in objective cognitive performance between high grade and low grade tumors was also found (p=0.003).

CONCLUSIONS
Our results point to potential patient-level factors which could predict benefit from CRT including self-reported irritability, self-reported forgetfulness, and tumor grade. Further prospective studies will help to examine the true benefit of sustained CRT, and the subset of patients with CNS neoplasms most likely to benefit from this training.
NCOG-47. CONGRUENCE BETWEEN PROVIDER REPORTED PERFORMANCE STATUS AND BOTH OBJECTIVE AND PERCEIVED COGNITION IN A GLIOMA POPULATION
Authors: Panzer Marissa , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri 
Published: November 2021

Abstract
Karnofsky performance status (KPS) scale, a clinician-reported measure, is used to assess patients’ functional ability and as a metric for trial eligibility. Glioma patients often have a degree of neurologic deficit which can invariably affect performance status. There is little research comparing KPS, patient-reported cognitive outcomes, and objective cognitive outcomes. 273 primary brain tumor patients enrolled in the NOB Natural History Study were included in this report. We evaluated Pearson correlations between KPS (range 40-100), dichotomized as Good KPS (KPS ≥ 90) and Poor KPS (KPS ≤ 80), and MDASI-BT cognitive symptom factor, NeuroQoL Cognitive Function t-score, EQ-5D-3L index score, and objective MoCA test. The majority of patients were white (81%), male (58%) with a median 50 years of age (range 24-79). Most had high grade gliomas (74%), 22% were on active treatment, and 55% had prior tumor recurrences. Providers reported a poor KPS in 37% of patients. KPS correlated with the MDASI-BT cognitive symptoms (r = -0.32), NeuroQoL (r = 0.39), and EQ-5D-3L index score (r = 0.55) (all p &lt; 0.01). Patients with poor KPS reported moderate-severe cognitive symptoms on the Neuro-QoL Cognitive Function (40%), moderate-severe difficulty remembering on the MDASI-BT (37%), and difficulty with usual activities on the EQ-5D-3L (83%). In a subset of 27 patients, MoCA scores were assessed but no significant correlation was found with KPS (r = 0.19, p = 0.352). Patient-reported and objective cognitive dysfunction was seen in up to 36% of those with good KPS. These data demonstrate that perceived cognitive testing is associated with poor KPS but may also occur in those with good performance status. The results underscore the need for alternative measures of cognitive functioning to further explore the impact in those with good KPS and the use of the MoCA in a larger sample.
NCOG-50. CHARACTERIZING MENINGIOMA IN YOUNG PATIENTS UNDER 40
Authors: Attia Moshe , Mirkin Yehoshua , Hershcovitch Rotem , Cohen Zvi , Zibly Zion , Zauberman Jacob , Wohl Anton , Harnof Sagi , Spiegelmann Roberto , Hadani Moshe , Furman Orit , Zach Leor 
Published: November 2021

Abstract

BACKGROUND
Meningiomas are the most common primary CNS tumor in adults, with a median age at diagnosis of 65 years. Younger patients usually have a genetic background or history of prior radiation exposure. Population-level studies suggest 80-85% of meningiomas are WHO grade I (benign), 15-18% grade II (atypical), and 1-3% grade III (anaplastic). This case series describes a single center experience of meningiomas in patients under 40.

METHODS
We reviewed the Sheba Medical Center Neurosurgery and radiotherapy databases containing patients operated on for meningioma between 2011-2020. Digital medical records were retrieved, including pathology reports, surgical reports, clinical and radiological data, and use of radiotherapy or medical treatments.

RESULTS
Of 600 patients in the database, 47 patients under 40 (7.8%) were identified and 54 tumors were reviewed (five patients had multiple operation). 32 patients were female (68%) ; 2 were under 20 years old, 17 were age 20-30 and 28 were age 31-39 at first presentation. Seven patients had received prior radiation therapy for a childhood malignancy. 28 meningiomas were histology confirmed grade I (52%), 22 were grade II (41%), 2 were grade III (4%), and 2 (4%) were grade undetermined. 22 tumors were located in the skull base (41%) and 32 (59%) in the brain convexity. 16 skull base tumors were grade I, five were grade II, and one was grade III. 12 convexity tumors were grade I, 16 were grade II, and two were grade III. Median follow-up was 35 months (range 1 - 98 months).

CONCLUSION
Our experience with meningioma patients under 40 revealed a different grade segregation than the older population, with younger patients showing a higher incidence of grade II tumors. These tumors are generally more aggressive, and require careful resection and consideration for post-surgical radiotherapy. Further validation with population based databases is required.
EXTH-10. EXPLORATION OF A NOVEL TOXIN-INCORPORATING CAR T CELL: HOW DOES CHLOROTOXIN RECOGNIZE GLIOBLASTOMA CELLS?
Authors: Aftabizadeh Maryam , Bawa Lovish , Wang Simiao , Brewster Blake , Wang Dongrui , Wang Xin , Brown Christine , Barish Michael 
Published: November 2021

Abstract
Chlorotoxin, a peptide toxin component of scorpion venom, binds selectively to glioblastoma and other neuroepithelial tumors, with minimal binding to non-malignant cells. We have recently developed a CAR T cell incorporating chlorotoxin (CLTX) as its target recognition domain, and CLTX-CAR T cells are now in clinical trial for recurrent glioblastoma (NCT04214392). We determined in preclinical studies that surface MMP-2 was required for CLTX-CAR T cell killing. However, the precise composition and structure of the cell surface complex recognized by CLTX-CAR T cells remains an unresolved question of increasing importance. Previous investigations have variously proposed matrix metalloprotease-2 (MMP-2), ClC-3 chloride channels, regulators of MMP-2, annexin A2, and neuropilin-1, as receptors, or components of receptors, for CLTX. To approach this question, we have visualized bound Cy5.5-conjugated CLTX peptide (CLTX.Cy5.5) or biotin-conjugated CLTX peptide (CLTX.biotin) on tumor cells in fixed sections of patient resections, on tumor cells in organotypic cultures of patient resections, and on cells of cultured patient-derived glioblastoma tumor lines. At tissue- and cell-level spatial resolution, we saw good correlation of CLTX binding with MMP-2 expression in patient tumor samples and on cultured GBM cells, and between CLTX binding and tumor cell death (cleaved caspase-3) in organotypic GBM cultures. However, at subcellular resolution, surface binding of CLTX was related to, but not precisely overlapping, with MMP-2 or other putative receptors. Rather, on fixed PBT003, PBT030 and PBT106 cells in monolayer cultures, MMP-2 staining was clustered, with diffuse loosely associated CLTX.biotin staining. Diffuse distribution of CLTX.Cy5.5 was also seen in fixed xenograft sections of PBT003-4, PBT1206, PBT030-2, PBT051 and PBT138 tumor cells, and not obviously associated with more discrete staining for IL13Rα2 and EGFR. Ongoing experiments are further examining association of CLTX with other putative components of CLTX receptor complexes, and their redistribution during binding by CLTX and CLTX-CAR T cells.
EXTH-11. COLD ATMOSPHERIC PLASMA SELECTIVELY INDUCES APOPTOSIS AND FERROPTOSIS THROUGH REACTIVE OXYGEN SPECIES IN HIGH-GRADE GLIOMA
Authors: Peeters Sophie , Chen Zhitong , Obenchain Richard , Haist Blake , Prins Robert , Liau Linda , Wirz Richard , Wang Anthony 
Published: November 2021

Abstract

INTRODUCTION
Cold atmospheric plasma (CAP) selectively induces reactive oxygen and nitrogen species (ROS/RNS) in many types of cancerous cells. ROS-mediated lipid peroxidation is thought to induce ferroptosis, apoptosis, and autophagy. We hypothesize that ferroptosis and apoptosis are key mechanisms of CAP-mediated cytotoxicity in high-grade glioma (HGG).

METHODS
B16, U87, GL261, EPD-210FHTC and human astrocyte NHA hTERT cells were treated with CAP for 10, 30, 60, 90, and 180 seconds. Proliferation and propidium iodide (PI)/annexin V flow cytometry assays were employed to quantify cytotoxicity, cell cycle phases and apoptosis. Mitochondrial superoxide concentration was measured using MitoSOX Red. Cells were pre-treated with ferroptosis inhibitors Ferrostatin-1 and Deferoxamine (DFO) in rescue assays.

RESULTS
Survival of GL261 and U87 cells after 90 seconds of CAP treatment was 3.7% and 7%, respectively, compared to 62% in NHA cells. A CAP dose-dependent increase in mitochondrial superoxide concentration was observed in GL261 and NHA (R2=0.88 and 0.99, respectively). A shift of EPD and NHA cells into G0 phase was noted after 180 seconds of treatment, compared to baseline (55.4% versus 1.2%, 100% vs. 27.5% respectively). Early apoptosis was more prominent in NHA cells (79% of dead cells), and late apoptosis in EPD cells after 60 seconds of treatment (86% of dead cells). DFO pre-treatment significantly reduced CAP cytotoxicity in GL261 (93% vs. 58% after 10 seconds) and U87 cells (85% vs. 13% after 60 seconds). DFO pre-treatment had no effect on NHA response to CAP.

CONCLUSION
CAP treatment induces dose-dependent increases in ROS and apoptosis in HGG lines tested more significantly than in NHA cells. CAP induces G1-phase cell cycle arrest in treated HGG cells and G0 arrest in non-cancerous cells. CAP-mediated cytotoxicity was significantly mitigated with DFO pre-treatment in HGG cells, suggesting that ferroptosis plays a critical role in the mechanism of CAP treatment in HGG.
EXTH-16. LP-184, A NOVEL ALKYLATING AGENT, IS EFFECTIVE IN GLIOBLASTOMA
Authors: Lal Bachchu , Kulkarni Aditya , McDermott Joseph , Kathad Umesh , Bhatia Kishor , Sharma Panna , Laterra John 
Published: November 2021

Abstract
Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is currently developing LP-184, a hydroxyurea methyl acylfulvene derivative of irofulven guided by its AI platform RADRⓇ analysis showing that tumor cell sensitivity to LP-184 correlates positively with genes commonly upregulated in GBM and either associated with TMZ resistance (e.g. MGMT, UGDH) or tumor promotion (e.g. EGFR, ANXA2). In an in vitro 3D model that mimics the human BBB, the apparent permeability for LP-184 was 1.53E-04 cm/s at 30 minutes, comparable to 1.72E-04 cm/s for TMZ under identical conditions. LP-184 predominantly alkylates DNA at 3’-adenine predicting insensitivity to MGMT expression. In vitro cell toxicity assays in a panel of GBM cell lines and neurospheres reveal an IC50 range of 30 - 400 nM with the MGMT unmethylated cell line LN-18 being among the most sensitive. A single cycle of LP-184 (4 mg/kg, i.v, every other day X 4 doses) induced rapid and near complete regression of subcutaneous U87 xenografts pre-established in immune-deficient mice and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 xenografts (p &lt; 0.0001). LP-184-induced DNA damage is associated with synthetic lethality in tumor cell lines with decreased expression of Nucleotide Excision Repair (NER) genes. Furthermore, interrogation of clinical databases for expression of 112 NER genes revealed that 25 - 37% of clinical GBM clusters in a low NER expression subgroup, predicting high sensitivity of low NER GBM subsets to LP-184. These findings identify LP-184 as a promising new alkylating agent and support its further development for GBM therapy.
EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM
Authors: Power Erica , Oh Juhee , Choi Jonghoon , Elmquist William , Daniels David 
Published: November 2021

Abstract

BACKGROUND
Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials.

OBJECTIVE
The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem.

METHODS
Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis.

RESULTS
No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor.

CONCLUSIONS
These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.
EXTH-50. THE COMPLEXITIES OF FATTY ACID DESATURATION IN GLIOBLASTOMA
Authors: Oatman Nicole , Dasgupta Biplab 
Published: November 2021

Abstract
Fatty acid desaturation is an enzymatic reaction in which a double bond is introduced into an acyl chain. Monounsaturated fatty acids (MUFA) are essential components of membrane. The most abundant MUFA-synthesizing enzyme is the delta 9 desaturate called Stearoyl Co-A Desaturase (SCD and SCD5 in humans, and SCD1-4 in mice). SCD desaturates Stearoyl-CoA (C18) and palmitoyl-CoA (C16) to oleoyl-CoA (C18:1) and palmitoyl-CoA (C16:1), respectively. SCD is often upregulated and a therapeutic target in cancer. We made an unexpected discovery that that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and monoallelic co-deletion with the tumor suppressor PTEN in a subset of patients. Cell lines from this subset, expressed nearly undetectable SCD yet they retained residual SCD enzymatic activity. Surprisingly, these lines evolved to survive independent of SCD through unknown mechanisms. On the other hand, cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Finally, we identify that SCD-dependent lines acquire resistance through a previously unknown mechanism that involved drug-induced target (SCD) upregulation by the transcription factor FOSB. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor bearing mice treated with SCD inhibitor. Our findings reveal an intriguing feature of the cancer genome that may be used to stratify PTEN deleted cancer patients for SCD inhibitor therapy. A recent study showed that some cancer cells can use another MUFA-synthesizing enzyme FADS2 to bypass the SCD reaction. However, our data shows that the SCD inhibitor- resistant GBM lines are also FADS2-independent. Our targeted and untargeted metabolomics studies revealed unexpected findings that cannot be explained by conventional wisdom, and may lead to identification of novel lipogenic targets in GBM.
EXTH-64. COMPARISON OF PANOBINOSTAT CSF PENETRATION WITH CNS PENETRATION FOLLOWING SYSTEMIC ADMINISTRATION IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL
Authors: McCully Cynthia Lester , Warren Katherine , Zimmerman Sara , Peer Cody , Rafael Cruz Garcia , Kramer Joshua , Breed Matthew , Figg William Douglas , Agar Nathalie , Widemann Brigitte 
Published: November 2021

Abstract
Targeted therapies developed for diffuse midline gliomas (DMG) expressing H3K27M have focused on histone deacetylase inhibitors (HDACi). High-throughput drug screening with patient derived DMG cell lines identified the HDACi panobinostat as a prominent clinical agent as well as pre-clinical studies with orthotopic mouse tumors models proving efficacious. Diametrically there is a pronounced lack of measurable panobinostat CSF concentrations in a non-human primate (NHP) non-tumor bearing pre-clinical model and in pediatric brain tumor patients. Notwithstanding, adult and pediatric glioma clinical trials and clinical observation with panobinostat alone or in combination have demonstrated minor responses. Pharmacokinetic models utilize the premise that CSF drug penetration is a surrogate of CNS drug penetration. However, the direct correlation between CSF and CNS drug levels is undefined especially in lieu of geographic CNS extracellular fluid drug variability previously demonstrated in the same NHP pre-clinical model. Utilizing the same NHP model, this study sought to compare panobinostat CSF penetration to CNS penetration via analysis of homogenized normal cerebrum, cerebellum, and brainstem tissue utilizing LC-MS/MS. METHODS: Panobinostat was administered orally as a single dose to three non-human primates. Pre panobinostat plasma and CSF were collected. Following panobinostat administration (1-hr Tmax) CSF, cerebrum, cerebellum, and brain stem tissue were collected as well as plasma to confirm the presence of panobinostat. Tissue slices were individually homogenized and panobinostat extracted via protein precipitation. Plasma, CSF, and tissue panobinostat concentrations were quantified using a LC-MS/MS assay. The lower limit of quantitation (LLOQ) for plasma-0.1 ng/ml, CSF-0.5 ng/ml, and tissue-10.0 pg/mg. RESULTS: Panobinostat was quantifiable in plasma (n=2) at the 1 hour (20.033 ng/mL and 0.153 ng/mL). CSF and CNS tissue samples were below the LLOQ for panobinostat in all samples. CONCLUSIONS: Panobinostat was not measurable from CSF and homogenized brain tissue in a non-tumor bearing NHP model at 1-hour post-administration using LC-MS/MS.
EXTH-78. WP1874, A HIGHLY POTENT UNIQUE DNA BINDING AGENT WITH ENHANCED CNS UPTAKE
Authors: Zielinski Rafal , Cardenas-Zuniga Roberto , Poimenidou Maria , Remiszewski Magdalena , Felix Edd , Fokt Izabela , Skora Stanislaw , Priebe Wademar 
Published: November 2021

Abstract
As part of our drug discovery program, we have developed structure-based modular designs of unique DNA-binding agents. The approach combines DNA intercalating and DNA “minor-groove-binding” modules. We have discovered compound WP1244 that potentially binds up to 10 bp long sequences of DNA. The unique and intriguing feature of WP1244 is its high CNS uptake combined with the picomolar to low nanomolar cytotoxicity against ependymoma and glioblastoma multiforme (GBM) cell lines and demonstrated in vivo activity in the orthotopic model of GBM. To improve water solubility and develop an IV formulation, we have synthesized WP1874, a mesylate salt of WP1244, and initiated its preclinical characterization. WP1874, similarly to its parental compound, shows high cytotoxicity in ependymoma, GBM, and medulloblastoma cell lines with IC50 in low nanomolar range and it was up to 100 to 200 times more potent than doxorubicin. Interestingly, WP1874 does not appear to be cytotoxic against normal kidney cells (VeroC1008) with IC50 &gt; 10 μM. Preliminary pharmacokinetic and biodistribution studies performed in CD-1 mice with intact brains revealed enhanced penetration of WP1874 to the brain with Cmax 1.5-fold greater than in plasma. Respectively, WP1874 Cmax in the brain was 2.3 ug/g (~2.0 μM) vs. 1.5 μg/ml (1.3 μM) in plasma. Acute toxicity in intravenously administered WP1874 was LD50 &gt;15mg/kg. No mortalities or any apparent toxicity symptoms were recorded for six intravenous weekly doses of WP1874 at 2.5 or 5 mg/kg in CD-1, Balb/c, or nude athymic mice. Intraperitoneal administration was well-tolerated up to 5 mg/kg given three times a week for four cycles. High CNS uptake, excellent cytotoxicity against different brain cancer cell lines, and low toxicity in vivo and in vitro against normal cells warrant further investigation of WP1874 as a mechanically unique potential anticancer agent against CNS malignancies.