bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-14. REAL-WORLD RETROSPECTIVE ANALYSIS OF TUMOR TREATING FIELDS IN THE TREATMENT OF HIGH-GRADE GLIOMA BASED ON CHINESE POPULATION
Authors: Chen Lingchao , Chen Junrui , Song Kun , Nie Jingtao , Zhuang Dongxiao , Wang Yang , Yao Yu , Wu Jinsong , Qin Zhiyong
Published: November 2021

OBJECTIVES

Tumor Treating Fields (TTFields) has been approved for the treatment of newly diagnosed and relapsed glioblastoma（GBM）in China in 2020. Only few TTFields data in Asia patients were reported. This retrospective analysis is aimed at investigating the efficacy, safety and the potential relationship with biomarkers of TTFields treatment in the real-world clinical practice of the Chinese glioma population.

METHODS

High-grade glioma patients who were under TTFields treatment from May 2019 to May 2021 in Shanghai Huashan Hospital were analyzed, including baseline data, efficacy data and incidence of adverse events.

RESULTS

Eighty-two patients (median age 51.0 [26.0 - 47.0] years) with high-grade glioma were enrolled, including 60 newly diagnosed GBM, 16 recurrent GBM, and 6 WHO grade III gliomas. The median time was 9.9 (4.6-15.7) months for follow-ups, median time for TTFields treatment was 4.3(1.1-20.35) months. The median compliance rate was 90% (40%-97%). For newly diagnosed GBM (n=60) and recurrent GBM (n=16), the 6-month PFS rate were 78.4% (95%CI: 63.9-87.6) and 46.7% (95%CI: 21.2- 67.8) respectively. The 10-month OS rate were 86.3% (95%CI: 69.6- 94.2) and 60.0% (95%CI: 12.6- 88.2) respectively. The 6-month PFS rate in the IDHw/TERTm population was 69.9% (95%CI: 45.9-84.9) and 78.3% (95%CI: 46.5-92.5) in the IDHw/TERTw patients with newly diagnosed GBM. 59(72%) patients had skin-related adverse reactions, and majority are grade 1-2 (grade 1-2, 69.5%; grade 3, 2.5%).

CONCLUSIONS

This is the 1st retrospective analysis done using TTFields in the treatment of high-grade gliomas in the Chinese population with the largest sample size. From our short follow up, TTFields appears good efficacy among GBM patients. The incidence of skin adverse reactions is higher comparable to published data, but mainly consisted of grade1-2. Long-term efficacy data need to be further followed-up.
NCOG-17. FACTORS INFLUENCING POOR INDEPENDENCE LEVEL FOLLOWING RESECTION OF THE RIGHT TEMPORO-PARIETAL GLIOBLASTOMAS
Authors: Nakada Mitsutoshi , Nakajima Riho , Okita Hirokazu , Kinoshita Masashi
Published: November 2021

In glioma surgeries, cognitive outcomes for the dominant hemisphere have gained much attention compared to the non-dominant hemisphere. For non-dominant hemispheric glioblastomas, we previously observed decreased independence level following glioblastoma resection of the posterior temporal to the parietal lobes. Here, we investigated the reason for the poor Karnofsky Performance Status (KPS) in such glioblastomas. A total of 41 patients with resection of the right cerebral hemispheric primary glioblastoma were enrolled for the study. Several kinds of neuropsychological functions and KPS of the brain regions were evaluated at pre- and postoperative 3 months by performing the Spearman’s correlation analysis and voxel-based lesion symptom mapping (VLSM). Additionally, the correlation between the resected volume of each gyrus or white matter tract and neuropsychological function score was analyzed. KPS at chronic phase (73.6) declined significantly compared with preoperation (81.0, p = 0.020). Functional factors influencing the KPS were general cognitive function, visuospatial cognition, emotion recognition, executive function, and apathy. The VLSM analysis revealed that the resection of the ventral parietal lobe and supramarginal gyrus (VPL-SMG) resulted in significantly poor KPS. Among the functional factors affecting KPS, VPL-SMG resection contributed to significantly lower scores in visuospatial cognition, emotion recognition, and apathy than those without resection (p = 0.0045, 0.047, and 0.0002, respectively). Further, we investigated whether the damage of the VPL-SMG could result in KPS related functional deficit. We found visuospatial cognition related to the posterior occipital lobe, SMG, arcuate fasciculus (AF), and dorsal superior longitudinal fasciculus, emotion recognition to the middle to inferior occipital gyrus and AF, and apathy to the inferior parietal lobe and middle temporal gyrus. We concluded that deficits of visuospatial cognition, emotion recognition, and apathy due to the damage of the cortical and white matter areas, including the VPL-SMG, were responsible for KPS of the non-dominant hemispheric glioblastomas.
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

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

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 < 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

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

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

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

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 < 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

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

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

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

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 > 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 >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.
QOLP-03. OBSERVATIONS OF COMPLEMENTARY CANNABIS THERAPY IN MALIGNANT GLIOMA PATIENTS
Authors: Blondin Nicholas
Published: November 2021

INTRODUCTION

As of 5/15/2021, medical marijuana programs exist in 37 states, and marijuana is legal for recreational use in 17 states. In Connecticut, the CT Medical Marijuana Program (MMP) was created in 2012 and I began certifying my patients with malignant glioma (brain cancer) for the program in 2014. I now provide data on my experience with complementary cannabis therapy.

PART 1

Between 9/1/2014 and 6/1/2018, 23 patients with malignant glioma were registered in the CT MMP and received a card. Of these 23 patients, 15 patients took a daily cannabis oil supplement for at least 6 months during their treatment, and 7 patients used cannabis products only as needed. 3 patients are still alive, all in the daily cannabis oil group (41, 54 and 77 months). The median overall survival in the daily group was 22.0 months, versus 16.9 months in the as needed group.

PART 2

Since 9/1/2014, 71 patients with malignant glioma were certified for the CT MMP. Of these 71 patients, 15 did not complete the patient registration process and did not receive a card for the MMP. As of 5/15/2021, of the 56 registered patients, there are 20 Active patients and 36 Inactive patients. Regarding the Inactive patients, 29 have died and 7 are alive but did not renew their card. Amongst Active patients, 4 are currently taking a daily cannabis oil supplement as a complementary therapy, and 16 are currently using cannabis products only as needed for symptoms. The 4 patients employing complementary therapy currently have a survival of 8, 31, 33, and 35 months.

CONCLUSION

In my experience, complementary cannabis treatment is well tolerated in malignant glioma patients, and can provide significant palliative benefit to treat insomnia and nausea. Serious adverse events attributed to cannabis products, or decreased survival, have not been observed.
QOLP-04. THE KETOGENIC DIET PLUS STANDARD CARE FOR RECENTLY DIAGNOSED GLIOBLASTOMA: A PHASE 1 SAFETY AND FEASIBILITY TRIAL
Authors: Hu Jethro , Amaral L J , Gresham Gillian , Nelson Thomas , Welborn Amelia , Lockshon Laura , Tighiouart Mourad , Kim Sungjin , Noorvash Brandon , Mack Alexandra , Rudnick Jeremy , Phuphanich Surasak , Irwin Scott , Freedland Stephen
Published: November 2021

INTRODUCTION

There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) for glioblastoma patients. We conducted a single-arm phase 1 trial to assess the safety and feasibility of KD plus standard-of-care (SOC) in glioblastoma patients (NCT03451799).

METHODS

Adults within 3 months of diagnosis participated in a 16-week intervention of a classic 3:1 KD (grams fat : grams carbohydrate + protein) with dietitian support. Blood glucose and ketone levels were assessed twice daily (Keto-Mojo), with remote monitoring of daily weight and activity (Fitbit). The primary objective was to assess safety (weight stability, CTCAE) and feasibility (maintaining ketosis > 0.3mM for > 50% of study period). Secondary objectives included assessments of progression-free survival (PFS), overall survival (OS), health-related quality of life (HRQOL), and cognition (MoCA).

RESULTS

From 04/2018-02/2021, 14 patients were evaluable: female:male, 8:6, median age 55 years, KPS 80, BMI 24.5. MGMT promoter methylation: 6 present, 7 absent, 1 indeterminate. Adherence to KD was high, with all patients maintaining ketosis ( > 0.3mM) > 50% and 11 patients maintaining ketosis > 85% of study days. Adverse events (> Grade 2) potentially attributable to KD: appetite loss (Grade 2: 2); fatigue (Grade 2: 5); flu-like symptoms (Grade 2: 1); constipation (Grade 2: 5, Grade 3: 1). No patients were removed from study for safety reasons. HRQOL was stable, with improvements in role function (not statistically significant). MoCA score improved in 10/14 patients. Median PFS and OS from KD initiation were 11.7 and 29.1 months, respectively.

CONCLUSION

Our findings suggest that a supervised KD plus SOC is safe and feasible in glioblastoma patients. KD was well-tolerated with encouraging trends in HRQOL and cognition. PFS and OS in this small trial compare favorably to historical control. A multicenter phase 2 trial powered to assess efficacy is planned.
QOLP-05. HEALTH-RELATED QUALITY OF LIFE IN LOW-GRADE GLIOMA SURVIVORS 26 YEARS AFTER DIAGNOSIS
Authors: Boele Florien , Reijneveld Jaap , Hamer Philip de Witt , van Thuijl Hinke , Wesseling Pieter , Lagerwaard Frank , Taphoorn Martin , Kouwenhoven Mathilde , Snijders Tom , Douw Linda , Klein Martin
Published: November 2021

BACKGROUND

Patients with low-grade gliomas (LGGs) often survive for many years, yet little is known about patients’ health-related quality of life (HRQOL) in long-term survivorship. We previously investigated HRQOL in LGG patients diagnosed on average 6 years prior to assessment (T1, N=195) with a follow-up in stable patients on average 12 years after diagnosis (T2, N=65). We present a final follow-up of LGG survivors (T3), now decades after diagnosis.

METHODS

Patients completed questionnaires to assess HRQOL (Short Form-36 Health Survey; EORTC-BN20), fatigue (Checklist Individual Strength (CIS)), and depressive symptoms (Center for Epidemiological Studies-Depression Scale (CES-D)). Changes over time (T1-T2-T3) on group level and participant level were assessed.

RESULTS

Of the 65 patients approached, 18 (27.7%) were deceased, 3 (4.6%) experienced tumour progression to WHO III, 7 (10.8%) declined, and 3 (4.6%) could not be contacted. Thirty-four patients (52.3%) participated (missing HRQOL data N=2; N=32 included in analysis). Survivors were M=52.0 (sd=11.3) years old and diagnosed M=26.2 (sd=3.7, range:19-35) years prior. On group level, a statistically significant (but not clinically relevant) improvement in mental health (p=0.049), and a clinically relevant (but not statistically significant) decline in emotional role functioning was found. Minimal detectable change in HRQOL scale scores over time was observed in individual participants (28.1% only improvement; 25.0% only decline; 21.9% both improvement and decline) with 25.0% remaining completely stable. At T3, 25.0% and 53.1% of survivors scored above the cut-off for high risk of depression (≥16 CES-D) and severe fatigue (≥35 CIS), respectively.

CONCLUSION

In LGG survivors, assessed decades after diagnosis and treatment, HRQOL does not appear to be greatly impacted during survivorship. However, depressive symptoms and fatigue remain relatively common. Findings can help inform patients, their families, and clinicians and can serve as a benchmark for treatment trials evaluating interventions that can have very long-term effects.
QOLP-07. EXPLORING CALM IN PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Loughan Ashlee , Willis Kelcie , Lanoye Autumn , Braun Sarah , Rodin Gary , Davies Alexandria , Svikis Dace , Mazzeo Suzanne , Thacker Leroy , Malkin Mark
Published: November 2021

BACKGROUND

Patients with high-grade glioma report substantial psychological distress, yet are frequently excluded from psycho-oncology research. Managing Cancer and Living Meaningfully (CALM) is an expressive-supportive psychotherapy designed to address the inevitable challenges that patients with advanced cancer face. CALM was shown in a large randomized controlled trial to reduce depression and death-related distress, but brain cancer was an exclusion criterion.

METHODS

In this ongoing ORBIT Model Phase Ib Refine trial, 10 adults with high-grade glioma and heightened distress (PHQ/DADDS) participated in CALM. Feasibility and acceptability were assessed based on established metrics, satisfaction was explored by surveys and exit-interviews, and preliminary efficacy of reducing distress was analyzed by pre to post-CALM paired t-tests; effect sizes estimated using Cohen’s d.

RESULTS

Of 11 patients referred and screened, 10 enrolled in the study (91% enrollment rate; 70% GBM; 70% female; M age =55yrs). Reasons for withdrawal was disinterest in intervention topics (n=2). Eight patients completed baseline assessments and at least one CALM session. To date, seven have completed treatment. Retention is 63%, with one participant still in active treatment. No adverse events were determined to be study-related. Perceived benefit was high (4.8/5), and all participants reported they would recommend program to others. Pre- to post-CALM analyses show medium-to-large effects on reducing depression (d=1.2), anxiety (d=.74), and death-related distress (d=.54). Small effects were seen for quality-of-life improvement (d=.26). Fear of cancer recurrence worsened (d=.75).

CONCLUSIONS

Preliminary data suggests that CALM is both feasible and acceptable in adult patients with high-grade glioma. Enrollment and retention rates were adequate. Patients reported high benefit and recommendation to others. Depression, generalized anxiety, and death-related distress all improved with medium-to-large effects, suggesting CALM may be a promising intervention for high-grade glioma patients as they navigate the challenges of brain cancer. Adjunctive treatment may be necessary to address fear of cancer recurrence.
QOLP-08. THE LANDSCAPE OF EPILEPSY ASSOCIATED WITH DIFFUSELY INFILTRATIVE GLIOMAS
Authors: Drumm Michael , Templer Jessica , Bushara Omar , Unruh Dusten , Walshon Jordain , Javier Rodrigo , McCortney Kathleen , Burdett Kirsten , Kurz Jonathan , Swanson Geoff , Horbinski Craig
Published: November 2021

Seizures are among the most prevalent co-morbidities associated with glioma, and pose a serious threat to patients. Our prior work showed that IDH mutation (IDHmut) was associated with much greater seizure frequency at the time of initial glioma diagnosis. However, less is known about the variables that contribute to seizure risk throughout the course of disease. We therefore collected data from 247 patients with grade 2–4 glioma, and determined seizure risk using Kaplan-Meier survival probabilities and multivariable cox regression analyses. Median follow-up of IDH wildtype (IDHwt) and IDHmut glioma patients was 15 months and 36 months, respectively. Incidence of pre-operative seizures for IDHwt and IDHmut patients was 75/168 (45%) and 60/79 (76%), and incidence of post-operative seizures was 70/168 (42%) and 43/79 (54%), respectively. Patients who had a pre-operative seizure had a shorter time to their first post-operative seizure than patients who never had a pre-operative seizure in both IDHwt (P< 0.0001) and IDHmut (P= 0.039) cohorts. Among IDHmut glioma patients, those with subtotal resections developed post-operative seizures faster (median time to first seizure= 9.9 months) than those with gross-total resections (median not reached) (P= 0.0005), but a similar pattern was not observed in IDHwt glioma patients (P= 0.20). Those with IDHmut astrocytomas more quickly developed post-operative seizures (median= 11.1 months), compared to those with IDHwt astrocytomas (24.9 months) or IDHmut oligodendrogliomas (median not reached) (P= 0.033). Tumor progression closely followed post-operative seizures in patients with IDHwt gliomas when either their first post-operative seizure occurred longer than 6 months following resection, or when their post-operative seizures worsened in quality. These data suggest the best predictors of post-operative seizures are as follows: the presence of pre-operative seizures; extent of surgical resection; IDHmut status. These data will help clinicians better manage glioma patients by identifying those at greatest risk of seizures.
QOLP-12. ILLNESS UNDERSTANDING AND PERCEPTIONS ABOUT PROGNOSIS IN PATIENTS WITH MALIGNANT GLIOMAS AND THEIR CAREGIVERS
Authors: Rhee John , Mesa Michelle , Kaslow-Zieve Emilia , Traeger Lara , El-Jawahri Areej , Temel Jennifer , Forst Deborah
Published: November 2021

BACKGROUND

Malignant gliomas (MG) are incurable tumors with limited survival. Prognostic awareness is essential for informed decision making, but patients’ and caregivers’ perceptions about their illness and prognosis are not well understood.

METHODS

We conducted a prospective, single-institution study in patients with newly diagnosed MG and their caregivers, following the outpatient visit in which their neuro-oncologist disclosed pathology results and discussed treatment options. Participants (patients and caregivers) completed the Prognosis and Treatment Perceptions Questionnaire to assess information preferences, treatment goals and prognostic understanding.

RESULTS

Of patients approached, 82% (14/17) were eligible and enrolled in the study. The majority of patients were male (9/14, 64%), median age 60 years (range 26-76) and had a glioblastoma (11/14, 79%). Most caregivers were female (8/11, 73%) and married to the patient (7/11, 64%). The majority of patients said their cancer was curable (10/13, 77%, one patient did not answer), while only 3/11 caregivers (27%) said the patient’s cancer was curable. Furthermore, 7/13 patients (54%) and 8/11 caregivers (73%) reported that their oncologist said their cancer was not curable, and the remainder (6/13 patients, 46% and 3/11 caregivers, 27%) said the oncologist “did not say” whether it was curable. Most patients (10/14, 71%) and caregivers (8/11, 73%) expressed a tendency to focus on the best-case scenario in response to information from their oncology team about their cancer.

CONCLUSION

Although most patients with MG and their caregivers acknowledged being told that their cancer was incurable, the majority of patients reported that their cancer was curable. Patients and caregivers often reported focusing on the best-case scenario regarding their cancer. Further investigation is warranted to explore strategies to support patients and caregivers learning about their incurable cancer.
QOLP-22. THE PSYCHO-ONCOLOGICAL BURDEN OF PATIENTS WITH AGGRESSIVE MENINGIOMA – RESULTS FROM A RETROSPECTIVE CROSS-SECTIONAL STUDY
Authors: Jungk Christine , Raedel Madlen , Mattern-Tremper Julia , Warta Rolf , Herold-Mende Christel , Unterberg Andreas
Published: November 2021

Despite the perception of meningioma as a benign disease, up to 35% of patients experience a clinically aggressive course with debilitating treatment and poor outcome. In contrast to the growing interest in novel therapies, the impact on health-related quality of life (HRQoL) is still understudied. Here, we analysed the psycho-oncological burden of patients with aggressive meningioma. Our institutional cohort was searched for meningioma patients with surgery as first intervention and HRQoL was assessed retrospectively at one time point with standardized self-assessment questionnaires (HADS-D, EORTC-QLQ-C30). Aggressive meningioma was defined as WHO grade 2 or 3 or recurrence of a WHO grade 1 meningioma within 5 years after index surgery. Results were correlated with demographic, tumor- and treatment-related factors by multivariate linear regression and compared to internal control patients (WHO grade 1 meningioma, no recurrence within the first 5 years). 400 out of 653 patients returned the questionnaires (62%). Of those, 95 patients (24%) were classified as aggressive meningioma while 305 patients served as internal control. Patients with and without aggressive meningioma differed with regard to sex (p=0.019), age (p=0.015), extent of resection (p< 0.0001) and adjuvant radiotherapy (p< 0.0001) at index surgery and KPS at 1st follow-up (p=0.037). 34% and 24% of aggressive meningioma patients were screened positive on the anxiety and depression subscales of HADS-D as opposed to 33% and 23% of internal controls (not significant). Aggressive meningioma patients fared significantly worse on most of the function scales of QLQ-C30 (QL: p=0.004; PF: p=0.049; RF: p=0.003; CF: p=0.01; SF: p=0.018) and reported more financial difficulties (FI: p=0.015). In multivariate regression analysis, female sex, KPS at 1st follow-up < 70 and aggressive meningioma were independent factors of impaired HRQoL. This cross-sectional analysis demonstrates that HRQoL is impaired in aggressive meningioma patients who should be screened and treated for their psycho-oncological needs.
QOLP-28. COMPARING KNOWLEDGE OF AND BELIEFS ABOUT PALLIATIVE CARE AMONG NEURO-ONCOLOGY PATIENTS, CAREGIVERS, PROVIDERS AND A NATIONALLY-REPRESENTATIVE U.S. SAMPLE
Authors: Johnson Margaret , Khasraw Mustafa , Kim Jung-Young , Cort Nicole , Herndon James , Ramirez Luis , Lipp Eric , Landi Daniel , Desjardins Annick , Friedman Henry , Ashley David M , Affronti Mary , Casarett David J , Peters Katherine B
Published: November 2021

INTRODUCTION

There is increasing recognition that palliative care (PC) can benefit patients with advanced cancers. However, early referral to PC is not yet a reality for patients diagnosed with a primary brain tumor. We hypothesize that lack of knowledge and/or misperceptions regarding PC by patients, caregivers, or their providers remain barriers.

METHODS

This is an IRB-exempt, one-time QR-accessible REDcap questionnaire administered to patients, caregivers, and providers at the Preston Robert Tisch Brain Tumor Center between September 2020 and May 2021. We administered 9 questions regarding knowledge and beliefs about PC from the Health Information National Trends Survey 5, Cycle 2: results of this nationally representative U.S. sample are publicly available and used for comparison.

RESULTS

We had 141 survey respondents: 25 providers, 59 patients, and 57 caregivers. The median patient and caregiver ages were 49 (21-74) and 50 years (24-73), respectively. Caregivers were more likely female (55.2 %) and identified as a spouse or domestic partner (58.2%). Providers, were equally distributed by years of experience. Compared to patients and caregivers, providers reported more baseline knowledge of PC (p< 0.0001, p< 0.0001) and better understood the role of PC in pain/symptom management (p=0.0038, p=0.0087) and social/emotional support (p=0.0044, p=0.0279). Interestingly, most providers (76.0%) disagreed with the statement “the goal of palliative care is to give patients more time at the end of life.” Compared to a general U.S. sample (n=1,162) our patients (n=39) were better informed in only 2 of 9 questions. Whereas, caregivers (n=48) were better informed in 6 of 9 questions.

CONCLUSION

Neuro-oncology providers were knowledgeable, but a minor gap in understanding the goal of PC was identified. Caregivers were overall more knowledgeable than patients. However, Neuro-oncology patients, had similar knowledge and beliefs compared to a nationally representative sample. PC interventions should prioritize filling knowledge gaps for Neuro-oncology patients.
RTID-05. THE MULTI-ARM GLIOBLASTOMA AUSTRALASIA (MAGMA) TRIAL
Authors: Kong Benjamin , Sim Hao-Wen , Koh Eng-Siew , Gan Hui , Barnes Elizabeth H , Yip Sonia , Nowak Anna K , Lau Peter , Cuff Katharine , Khoo Eric , Lwin Zarnie , Cooper Adam , Dowling Anthony , Linton Anthony , Harrup Rosemary , Dunlop Tracey , Hovey Elizabeth , Parkinson Jonathon , Jeffree Rosalind , Hall Merryn , Tu Emily , Andrew Diana , Simes John , Gedye Craig
Published: November 2021

BACKGROUND

Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide.

METHODS

Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities.

PROGRESS

Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.