bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-100. THE MEDIAN NERVE STIMULATION INDUCES LONG LATENCY GAMMA MODULATIONS IN THE PRIMARY SOMATOSENSORY CORTEX, WHICH DIFFERENTIATES THE CONSCIOUS STATE
Authors: Asman Priscella , Pellizzer Giuseppe , Sudhakar Tummala , Bastos Dhiego , Prabhu Sujit , Ince Nuri
Published: November 2022

OBJECTIVE

While the intraoperative assessment of the short-latency somatosensory evoked potentials (SSEPs) phase reversal in electrocorticogram (ECoG) is routinely used to locate the central sulcus (CS), its spatial-spectral patterns in the primary sensorimotor cortex and the relation to consciousness is not well characterized. Our goal was to evaluate the functional utility of using median nerve stimulation-induced ECoG sub-band modulations in pre-and post-CS to differentiate between anesthetized and awake states. Method: SSEPs were recorded from the sensorimotor cortex with ECoG during routine intraoperative cortical mapping of 8 patients in the anesthetized and awake states. We conducted a time-frequency analysis on the SSEP trace in each state to extract the spectral modulations up to 900Hz and contrasted their intensity in M1 and S1 to discern awake from anesthetized states.

RESULTS

We observed late gamma activity ranging from 60-250Hz, starting approximately 50ms after stimulation onset and extending up to 250ms. The late gamma activity was suppressed in the anesthetized state in both M1 (p< 0.01) and S1 (p=0.0369). Whiles in the awake state, the late gamma power increased significantly with respect to baseline both in M1 (p=0.0180) and S1 (p< 0.01). The difference in late gamma power between the anesthetized and the awake state was highly significant for M1 (p< 0.01) and for S1 (p< 0.01).

CONCLUSION

The results show that besides CS delineation, SSEPs long latency gamma modulations can serve as an additional biomarker to monitor the level of consciousness in neurosurgical practice.
NIMG-104. PRE-OPERATIVE LANGUAGE FUNCTIONAL MRI (FMRI) FOR LOCALIZATION OF THE RIGHT VENTRAL PREMOTOR CORTEX (VPMC) IN COMPARISON WITH DIRECT CORTICAL STIMULATION
Authors: Sahu Arpita , Vijan Antariksh , Shetty Prakash , Velayutham Parthiban , Moiyadi Aliasgar
Published: November 2022

PURPOSE

To assess the concordance of pre-operative language functional MRI (fMRI) for localization of the right ventral premotor cortex (vPMC) in comparison with Direct Cortical Stimulation.

METHODS AND MATERIALS

Prospective analysis was performed for 11 (n=11) patients with right-sided tumors who underwent language mapping by fMRI, followed by awake neurosurgery and intra-operative mapping by Direct Cortical Stimulation (DCS). Multi-paradigm language fMRI was performed using a standard 3-paradigm language protocol, with additional tongue movement paradigm on a Phillips Ingenia, 1.5T Scanner. The vPMC was identified as BOLD signal activation seen in at least two paradigms anterior to and discrete from the motor orofacial cortex. Pre-operative fMRI findings were validated intra-operatively using DCS with the intra-operative responses of anarthria (speech arrest) and dysarthria recorded separately.

RESULTS

We obtained moderate concordance (sensitivity) of 72.2% (n=8) for anarthria (speech arrest). The vPMC was the site of speech arrest in 75% cases (n=6), followed by the oro-facial motor cortex in the remainder (n=2, 25%). Higher frequency of vPMC activation was seen with Tongue Movement and Number Counting paradigms, while that of Broca’s area with Verb Generation. Tumour size >5cm, presence of peritumoral edema and intra-tumoral haemorrhage were some of the features associated with fMRI-DCS discordance.

CONCLUSIONS

vPMC detection by fMRI shows good concordance (sensitivity) with anarthria responses on Direct Cortical Stimulation. Thus, fMRI serves as a useful non-invasive tool in pre-operative planning for maximal safe resection of brain tumors.
NCMP-07. CASE SERIES OF REGULARLY SCHEDULED MANNITOL INFUSIONS SHOWING WITH PROLONGED CLINICAL BENEFIT FOR MANAGEMENT OF CEREBRAL EDEMA IN GLIOMAS
Authors: Chow Jared , Carrillo Jose , Kesari Santosh , Sharma Akanksha , Nguyen Minh , Truong Judy , Wagle Naveed
Published: November 2022

Gliomas account for the vast majority of malignant primary tumors arising in the central nervous system. Elevated intracranial pressure (ICP) may be a potentially devastating complication of brain tumors and hydrocephalus. Brain tumors may occupy significant space causing displacement and compression of delicate structures within a finite intracranial compartment. The compliance relationship is nonlinear and decreases as the combined volume of the intracranial contents increases. When these compensatory mechanisms have been exhausted, significant increases in pressure develop with relatively small increases in volume. The diagnosis of elevated ICP is generally based on clinical findings and corroborated by imaging studies and the patient's medical history. The best therapy for intracranial hypertension (ICH) is the resolution of the proximate cause of elevated ICP such as the evacuation of a blood clot, resection of a tumor, or cerebrospinal fluid (CSF) diversion in the setting of hydrocephalus. If these modalities have been exhausted or unavailable, osmotic diuretics such as mannitol can be utilized. This medication reduces brain volume by drawing free water out of the tissue and into the circulation, where it is excreted by the kidneys, thus dehydrating brain parenchyma. The common belief is that effects are usually present within minutes, peak at approximately one hour, and last 4 to 24 hours. We report a series of 33 patients treated for a minimum of 1 month of regularly scheduled maintenance infusions of Mannitol 1g/kg every two weeks, 64% showed improved clinical outcomes or stabilization of edema clinical symptoms. Patients expressed improvements in headaches, dizziness, and cognitive ability. This supports the bi-weekly maintenance use of Mannitol in glioma patients with symptomatic cerebral edema. A controlled trial should be supported. This series also suggest a mechanism of action with a more durable response than osmotic diuresis.
NCMP-18. NEUROLOGICAL SEQUELAE IN THE ID8 OVARIAN CANCER MOUSE MODEL: P38/JNK MAPK INHIBITION AS A POTENTIAL THERAPEUTIC FOR CANCER-RELATED COGNITIVE IMPAIRMENTS AND CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
Authors: Lomeli Naomi , Garcia Martha , Argueta Donovan , Gupta Kalpna , Bota Daniela
Published: November 2022

OBJECTIVES

Chemotherapy-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) are neurological sequelae of platinum-based chemotherapy. To examine the contribution of cancer itself and additional neurological impairment with chemotherapy, we used the ID8 syngeneic ovarian cancer mouse model and assessed cognition and hyperalgesia +/- cisplatin treatment. We examined the effect of p38 and c-JUN N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) inhibition on cisplatin-induced neuronal damage.

METHODS

B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 m¬¬¬g/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. Cognition was assessed longitudinally at 69d by the open field test (OFT), novel object recognition (NOR) at 75d and 104d, and novel place recognition (NPR) at 106d post-ID8 implantation. Hyperalgesia was assessed at 113d. Primary mouse and rat hippocampal neurons were pre-treated with VX-745 or SP600125, followed by cisplatin, and neuronal morphology was assessed.

RESULTS

OvT+VEH mice had detectable abdominal tumors 90d post-implantation. At 75d, OvT+VEH and OvT+CIS had impairments in NOR, with discrimination ratios (DR)= 0.52, 0.51, respectively. OvT+VEH showed trending differences vs. OvT+CIS (DR=0.39, DR=0.62, p=0.079) on NOR on 104d, and impairments on NPR on 106d (DR=0.41, DR=0.63, p=0.03). Cisplatin decreased mechanical (p< 0.05) and cold hyperalgesia (p< 0.07, n.s.) in OvT+CIS vs. OvT+VEH. VX-745 and SP600125 pre-treatment in mouse and rat hippocampal neurons prevented cisplatin-induced dendritic branching and spine density loss (p< 0.05).

DISCUSSION

While cisplatin transiently increased anxiogenic behavior, cognitive impairments, and hyperalgesia in OvT+CIS, these deficits persisted longitudinally in OvT+VEH, suggesting ovarian cancer may evoke sensory and progressive neurocognitive deficits in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer mice +/- cisplatin, and whether VX-745 and SP600125 administration ameliorates CRCI/CIPN in this model.
NCMP-19. VON HIPPEL-LINDAU DISEASE ASSOCIATED INTRACRANIAL HEMANGIOBLASTOMAS IN PREGNANCY: TREATMENT CHALLENGES AND OUTCOMES
Authors: Gvazava Nanuli
Published: November 2022

Von Hippel-Lindau disease is an autosomal dominant disorder characterized by development of variety of benign and malignant tumors and cysts including brain stem, cerebellum, spinal cord as well as pancreas, kidneys, and retina. The most common tumors associated with the disorder are hemangioblastomas. Symptomatic CNS hemangioblastomas maybe the first presentation of Von Hippel-Lindau disease. Initial presentation during pregnancy is uncommon and presents unique challenges with regard to early diagnosis and management. We report a case of a young woman with cerebellar hemangioblastoma, complicated by obstructive hydrocephalus, who first presented with signs and symptoms of increased intracranial pressure during pregnancy and was eventually diagnosed with Von Hippel-Lindau disease. We propose increase on size of Von Hippel-Lindau disease related hemangioblastomas during pregnancy and explore the pathophysiology of this disorder. Specific diagnostic challenges imposed by pregnancy and approach to management of these complex patients are also reviewed. Increase in tumor size as well as rare but life-threatening complications such as tumor hemorrhage are most likely to happen during the 3rd trimester of pregnancy. Unfortunately, non-specific symptoms like nausea and vomiting, which are common obstetric complaints, can be confounding and pose challenges to early diagnosis. Careful neurological examination is critical in pregnant patients with new onset neurological symptoms. When a hemangioblastoma is suspected, pregnant patients should be screened for Von Hippel-Lindau disease to identify other potentially life-threatening tumors, and when near term, elective delivery should be considered to avoid both maternal and fetal complications. In complicated cases such as obstructive hydrocephalus, CSF diversion may be indicated and will result in rapid symptom improvement and prevention of severe neurologic sequelae. Unlike sporadic hemangioblastomas, surveillance may be the preferred approach in Von Hippel-Lindau in the absence of symptoms, as these patients have multiple tumors and a high risk of recurrence, making repeat surgeries of unclear benefit.
NCOG-02. STEREOTACTIC RADIOSURGERY (SRS) FOR BRAIN METASTASES FROM MELANOMA: AN EVALUATION OF OUTCOMES AT A UK TERTIARY CENTRE
Authors: Haris Puteri Abdul , Al-Salihi Omar , Blythe Kirsty , Chia Kazumi , Hassan Sheila , Sisodia Caroline , Brazil Lucy
Published: November 2022

INTRODUCTION

Brain metastases (BM) are common in melanoma and historically associated with poor prognosis. Targeted systemic treatment have improved prognosis, and stereotactic radiosurgery (SRS) may offer an effective and less neurotoxic option. We evaluated the outcomes and potential prognostic factors of patients treated with SRS.

METHODS

Retrospective study of patients treated with linac-based SRS for BM from melanoma in a UK tertiary centre between August 2017-September 2021. Overall survival (OS), intracranial progression-free survival (IPFS), and prognostic factors were evaluated using Kaplan–Meier analysis, log-rank test, and Cox proportional-hazards model.

RESULTS

Median follow up was 32 months. 69 patients were included. Median age was 59 years old (range 30-93), and 63% were male. 99% had performance status of 0/1. 45% had BRAF mutation, and 68% had stable extracranial disease at SRS. 62 patients had first-line treatment with SRS. 133 BM were treated, with mean volume of 0.39 cm3(range 0.02-18.82). Median prescription dose was 23 Gy (range 14-24Gy), prescribed to 100% isodose. Median OS and IPFS from SRS was 18 months (95% CI 5-31), and 12 months (95% CI 6-18), respectively. 6 months and 1 year local control (LC) rate were 79% and 64 %, respectively. 91% had out-of-field recurrences. Patients with BRAF mutation had shorter IPFS compared to BRAF WT (7 months vs 18 months, HR 2, p=0.04). 36% were on BRAF inhibitors, and IPFS were longer for patients on immunotherapy within 3 months of SRS (15 months vs 4 months, HR 2.6, p=0.03). There was non-significant trend towards shorter OS and IPFS for patients who were male, ≥ 65 years old, BRAF mutant, progressive extracranial disease, > 4 BM, and total volume of ≥ 5cm3.

CONCLUSION

SRS demonstrates good OS and LC for treatment of BM from melanoma. Prospective studies should establish the synergistic effects between targeted treatment and SRS.
NCOG-18. OVERALL SURVIVAL VARIATION DUE TO THE TIMING OF POST-SURGICAL RADIATION IN HIGH-GRADE GLIOMAS
Authors: Lowman Allison , Bobholz Samuel , Duenweg Savannah , Kyereme Fitzgerald , Cochran Elizabeth , Coss Dylan , Connelly Jennifer , Mueller Wade , Agarwal Mohit , Banerjee Anjishnu , LaViolette Peter
Published: November 2022

PURPOSE

Grade III and IV astrocytomas and glioblastomas are recognized as high-grade gliomas with aggressive heterogenous natures that carry with them a low overall survival (OS). Standard treatment currently involves surgical resection followed by radiation (RT) and concomitant chemotherapy. Despite this standard pathway, there is often disagreement in the optimal timing of radiation initiation post-surgery. In this study, we examined a subset of patients diagnosed with primary high-grade gliomas that underwent radiation following surgery at varying time frames.

METHODS

53 patients from our brain cancer bank with surgical diagnosis of high-grade gliomas were retrospectively analyses for this study. All patients were grouped into three cohorts based on the timing of the initiation of radiation post-surgery. Group 1 RT < 4 weeks, Group 2 RT 4-5 weeks, and Group 3 RT > 5 weeks post-surgery. Overall survival was calculated in days from initial surgical resection to time of death.

RESULTS

Across the three patient cohorts, Group 1 included 9 patients (mean OS 430 days), Group 2 had 18 patients (mean OS 597 days), and Group 3 had 26 patients (mean OS 895 days). Overall survival trended towards a difference between the three radiation timing groups, with Group 3 showing better survival outcomes compared to Group 1 (p=0.07).

CONCLUSIONS

This current study demonstrates a positive outcome with increased time between surgical intervention and initiation of radiation and concomitant chemotherapy. While we did not correct for additional treatment outside of standard clinical care, we would expect to observe similar trends. Despite these promising results for treatment planning, future research in larger cohorts is necessary to investigate possible molecular markers that may also impact treatment response and overall survival.
NCOG-19. TUMOR INVASION INFLUENCES ON COGNITIVE FUNCTION IN RIGHT CEREBRAL HEMISPHERIC GLIOBLASTOMAS
Authors: Nakajima Riho , Kinoshita Masashi , Okita Hirokazu , Nakada Mitsutoshi
Published: November 2022

INTRODUCTION

Glioblastoma cells broadly infiltrate into surrounding brain parenchyma. In this study, we investigated the influence of tumor invasion on cognitive function in glioblastomas, using diffusion tensor imaging (DTI) .

METHODS

Participants were 32 patients with right hemispheric glioblastoma who underwent surgery in Kanazawa University Hospital (mean age, 61.8 years). We evaluated the differences in p-map and q-map, which represent diffusion isotropy and anisotropy with the patients' preoperative DTI. The patients were divided into two groups: less-invasive and highly-invasive types. Following clinical and demographic factors were collected retrospectively: age, sex, volume of enhanced lesion, tumor location, and methylation status of MGMT promoter. Several kinds of cognitive functions mediated by right cerebral hemisphere were assessed preoperatively. All these factors were compared between two groups. Moreover, voxel-based lesion symptom (VLSM) analyses were performed to investigate brain regions relate to decline of cognitive function by tumor invasion.

RESULTS

All clinical and demographic factors were not significantly different between two groups. Tumor cells significantly infiltrated to insula and basal ganglia in highly-invasive group. Verbal fluency, executive function, attention, and social cognition were impaired in highly-invasive group (p=0.0067, 0.036, 0.0064, and 0.030, respectively). Score of verbal fluency and social cognition were significantly lower when tumor infiltrated to the medial frontal region including cingulate cortex, and deep part of posterior middle and inferior frontal gyrus. Invasion to the sagittal stratum influenced on deterioration of attention and executive function.

CONCLUSION

The present study revealed that tumor invasion extending beyond the enhanced lesion causes deterioration of cognitive functions such as verbal fluency, executive function, attention, and social cognition in right hemispheric glioblastoma.
NCOG-20. BRAIN ATROPHY IN GLIOBLASTOMA PATIENTS FOLLOWING TREATMENT WITH CHEMORADIATION OR CHEMORADIATION WITH ANTI-ANGIOGENIC THERAPY IN NRG/RTOG 0825 PARTICIPANTS
Authors: Akintola Oluwatosin , Dietrich Jorg , Muzikansky Alona , Gardner Melissa , Youssef Gilbert , Huang Raymond , Gerstner Elizabeth , Wen Patrick Y , Parsons Michael , Gilbert Mark , Rogers Leland , Lieberman Frank , Wendland Merideth , Puduvalli Vinay , Shrieve Dennis , Stieber Volker , Pugh Stephanie , Mehta Minesh
Published: November 2022

BACKGROUND

The clinical trial NRG/RTOG 0825 sought to determine if the addition of bevacizumab to temozolomide and radiation improves survival in patients with newly diagnosed glioblastomas. Tertiary objectives included measuring the effect of the addition of bevacizumab to standard chemoradiation on neurocognitive function and quality of life. In this study, we describe brain atrophy changes as measured by ventricular volume expansion.

METHODS

We analyzed longitudinal MRI brain studies obtained from NRG/RTOG-0825. Volume changes in the contralesional (non-tumor) lateral ventricle were measured. Patients were included if they had either a scan at post operative (week 0) or post radiation baseline (week 10). Patients were also required to have at least one follow-up MRI brain scan 6 months or more from their baseline scans (at Week 0 or Week 10). Volumes were delineated using tissue segmentation in Slicer software.

RESULTS

177 patients were identified with eligible baseline scans at Week 0 and 162 patients at Week 10. For participants analyzed at 6 months from the Week 0 scan, mean ventricular volume increased by 54.70% (SEM: 3.21%, t = 6.41, p < 0.001, N = 135). For patients analyzed at 6 months from the Week 10 scan, mean ventricular volume increased by 31.89% (SEM: 2.52%, t = 3.96, p < 0.001, Nf117).

CONCLUSIONS

This study presents evidence of progressive brain volume loss in patients with glioblastoma treated with standard chemoradiation with or without anti-VEGF therapy. This is one of the largest sample sizes of volumetric analysis in real world patients with glioblastoma. These volume changes begin early in the disease course and may precede treatment. Next directions include correlating these volumetric changes with neurocognitive score changes, quality of life scores and analyzing these changes by treatment arm.
NCOG-35. A SINGLE INSTITUTION SERIES ON PINEAL PARENCHYMAL TUMORS OF INTERMEDIATE DIFFERENTIATION (PPTID)
Authors: Webb Mason , Campian Jian , Sener Ugur
Published: November 2022

INTRODUCTION

First classified in 2000, pineal parenchymal tumor of intermediate differentiation (PPTID) is an uncommon intracranial malignancy. Given recent codification and rarity, there is no consensus on management and treatment is often provider dependent.

METHODS

Within an institutional database, we identified 10 patients with PPTID diagnosed between 2009 and 2022. Medical records were reviewed for demographic data, presenting symptoms, extent of disease, surgical interventions, radiation therapy, and chemotherapy. Progression free survival, overall survival, and neurocognitive outcomes were reviewed.

RESULTS

Median age at diagnosis was 36 (range 13-73), 40% women, 60% Caucasian. Nine patients had tumor involvement limited to the pineal region and one patient had multifocal intracranial tumor involvement with leptomeningeal disease. Two patients had gross total resection (GTR) alone, three had GTR followed by adjuvant radiation therapy (RT), two had subtotal resection (STR) followed by craniospinal irradiation (CSI), two had biopsy followed by adjuvant RT, and one had biopsy with CSI and chemotherapy. At median follow up of 31 months (range 3-88 months), only one patient, who had received biopsy, CSI, and chemotherapy, had progression of disease and no patients are deceased. Two patients treated with CSI had adverse neurocognitive outcomes, which was not observed with focal RT.

CONCLUSIONS

Our limited case series suggests GTR followed by surveillance, GTR followed by focal RT, and any extent resection followed by CSI may all achieve durable disease control in patients with PPTID. Treatment selection should be individualized and potential neurocognitive toxicities should be considered.
NCOG-36. DOSIMETRY AND COGNITIVE FUNCTION AFTER RADIATION THERAPY IN LOW GRADE GLIOMAS
Authors: Asha Wafa , Koro Sami , Asha Wafa , Wei Wei , Chen Yanwen , Murray Eric , Murphy Erin , Suh John , Chao Samuel , Angelov Lilyana , Peereboom David
Published: November 2022

PURPOSE

We found that cognitive function remained stable following radiotherapy with concurrent and adjuvant temozolomide (RT+TMZ) in low-grade glioma (LGG) patients evaluated prospectively up to 2 years. This study evaluates the effects of radiotherapy dosimetry on neurocognitive function in a larger group of molecularly defined LGG patients treated with radiotherapy (RT).

METHODS

A total of 39 LGG patients were evaluated with comprehensive psychometric tests at baseline (prior to RT) and at various time intervals following RT. Patients served as their own controls by evaluating change in scores over time. Dosimetric parameters included mean and maximum dose to the pituitary, mean and maximum dose to the hypothalamus, mean dose to contralateral hippocampus, brain, cochlea, and PTV volume. Correlation between dosimetry and neurocognitive tests were assessed by Spearman correlation for the baseline correlation and Cox proportional hazard regression analysis for the survival analysis.

RESULTS

Patients were followed for a median of 60 months. Overall, patients showed group mean test scores similar to their initial performances following radiotherapy on all psychometric measures. There was a significant correlation between mean dose to cochlea (p=0.006), pituitary (p=0.035), mean PTV volume (0.019) and neurocognitive outcome..

CONCLUSION

Cognitive function remained stable following radiotherapy in LGG patients evaluated prospectivelys. There was a significant correlation between specific dosimetric endpoints and neurocognitive outcomes over time. Further study needs to be done in a larger population to validate these findings.
NCOG-38. PEMBROLIZUMAB (ANTI-PD-1) INDUCED LIMBIC ENCEPHALITIS PRESENTING AS EPISODIC APHASIA
Authors: Zahid Anza , Poursheykhi Meryim , Tremont Ivo W
Published: November 2022

PD-1 immune checkpoint inhibitors (ICI) have been associated with neurological immune-related adverse events including meningioencephalitis and limbic encephalitis that can manifest as paraneoplastic syndromes. We present a case of pembrolizumab (Anti-PD-1) induced limbic encephalitis presenting as episodic aphasia. A 62-year-old man with poorly differentiated papillary thyroid carcinoma with extensive brain, lung, lymphatic metastases, post total-thyroidectomy, radioiodine therapy, chemotherapy with dabrafenib and trametinib, and stereotactic radiation presented with recurrence of brain metastasis 1 year after diagnosis of a 2.1 cm metastatic lesion in the left parieto-occipital region. The metastases had initially improved in size and number with radiation, followed on serial MRI Brain - that were stable. Biopsy of recurrence revealed a poorly differentiated cancer. He was subsequently treated with pembrolizumab for 6 months for refractory carcinoma. Two months after treatment initiation, he reported episodic behavioral arrest, confusion, and expressive aphasia, initially concerning for seizures. Continuous EEG monitoring revealed non-epileptogenic left-sided foci and no seizures were captured. Patient empirically started on levetiracetam and clobazam - however, episodes persisted. Lumbar puncture revealed lymphocytic pleocytosis (10-14 cells), elevated protein (48-68 mg/dL), negative cytology, flow cytometry, and viral studies including JC virus. Paraneoplastic panel in serum and cerebrospinal fluid were negative. Repeat MRI findings were most consistent with radionecrosis and on contrary improvement of the previous metastatic lesions. This rose suspicion for pembrolizumab-induced encephalitis and he received high dose steroids with minimal response but great clinical improvement with IVIG and induction/maintenance therapy with rituximab. Marked reduction in aphasic episodes were noticed thereafter. PD-1 ICI-related encephalitis is diagnosis of exclusion that should be considered in patients with encephalopathy or neurological deficit following 3 months of treatment initiation and response to immunosuppressive therapy. Higher incidences reported in males. Early recognition is crucial to prevent long-term neurological damage. Outcomes depend on patient characteristics and timeline of presentation.
NCOG-44. FAMILY CAREGIVER CONSTRUCTS AND OUTCOMES IN NEURO-ONCOLOGY: A SYSTEMATIC REVIEW
Authors: Boele Florien , Hertler Caroline , Dirven Linda , Piil Karin , Sherwood Paula
Published: November 2022

BACKGROUND

As a first step to reach consensus on the key constructs and outcomes in neuro-oncology caregiver research, we performed a systematic review to evaluate the constructs that are being evaluated in research studies and how these have been assessed.

METHODS

All peer-reviewed publications with primary data reporting on outcomes of family caregivers of adult primary brain tumour patients were eligible. Electronic databases PubMed/ Medline, Embase, Web of Science, Emcare, Cochrane Library, and PsycINFO were searched up to September 2021. Using Covidence, title and abstract screening, full text review, and data extraction were done by two researchers independently, with a third guiding consensus. Constructs as reported in each study, and how these were assessed were the primary result.

RESULTS

Searches yielded 1090 unique records, with 213 remaining after title/abstract screening. Of these, 157 publications met inclusion criteria, comprising 120 unique studies. These originated from 18 countries and were published between 1996-2022. Most were observational (75%) cross-sectional (61%) studies, reporting on quantitative methods (62%). Twenty-seven different constructs were assessed and mapped along the Caregiver Health Model categories: caregiver health, needs, tasks, beliefs and attitudes, and environment. Seventeen questionnaires were used > 2 times to measure the same construct, with the vast majority of questionnaires only used across one or two studies.

DISCUSSION

Neuro-oncology caregiving research is a field gaining traction, but lags behind in clear definition of key constructs, and consistency in assessment of these constructs. Developing consensus or guidance will improve comparability of studies, meta-analyses, and advance the science more quickly.
NCOG-47. SYMPTOMATOLOGY OF PRIMARY BRAIN TUMOR PATIENTS AT CLINICAL TRIAL INITIATION: SNAPSHOT FROM THE NCI NOB-NATURAL HISTORY STUDY
Authors: Vera Elizabeth , Penas-Prado Marta , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2022

Clinical trial endpoints include response/survival, but also treatment tolerance and clinical benefit. Few reports exist on the frequency and type of disease-related symptoms and functions and treatment-associated symptomatic toxicities at clinical trial initiation. The MD Anderson Symptom Inventory-Brain Tumor self-reports from patients at baseline of a clinical trial initiation were retrospectively evaluated for the presence of severe ratings ( ≥ 7 for symptom, ≥ 6 for interference) of Reeve's toxicity symptoms (TS) (pain, fatigue, nausea, insomnia, anxiety, dyspnea, anorexia, depression, vomiting, neuropathy, constipation, diarrhea) and RANO-COA Collaborative core disease-related symptoms (DRS) (pain, perceived cognition, difficulty communicating, seizure, physical function, role/social functioning). A total of 137 baseline assessments from 132 patients for 10 clinical trials were evaluated. Patients were primarily white (82%) males (67%), with median age 48 years (range: 19-76), initiating treatment for a recurrent (86%) high grade (95%) tumor. Thirty-six percent reported severe TS (range: 1-9) and 48% reported DRS (range: 1-8), both with a median of 2 symptoms. All 12 TS and 7 DRS were reported as severe (TS range: 3%-23%); DRS range: 1%-25%); most common were fatigue (23%), insomnia (12%), and anxiety (10%) for TS, and role/social function-work (25%), physical function-walking (24%), and role/social function-usual activity (20%) for DRS. Those ≤ 4 weeks since recurrence more frequently reported TS (53%) or DRS (62%). TS were more common if treatment initiation closely followed a previous treatment (0-4 weeks: 45%). Baseline symptom occurrence and functional limitations and their severity at clinical trial initiation are critical to understanding tolerability and clinical benefit. For TS, baseline adjustments are warranted for anticipated symptomatic toxicities. High disease-related symptom severity necessitates symptom management and supportive care approaches for patients entering clinical trials and promotes symptomatic improvement measures as trial endpoints along with traditional measures such as tumor reduction and prolongation of survival outcomes.
EXTH-11. TELOMERASE INHIBITION IS AN EFFECTIVE THERAPEUTIC STRATEGY IN TERT PROMOTER-MUTANT GLIOBLASTOMAS MODELS WITH LOW TUMOR BURDEN
Authors: Kageler Lauren , Aquilanti Elisa , Watson Jacqueline , Baird Duncan , Jones Rhiannon , Hodges Marie , Wen Patrick Y , Meyerson Matthew
Published: November 2022

Glioblastoma targeted therapeutics have been challenging to develop due to significant inter- and intra-tumoral heterogeneity. While many activated oncogenes in glioblastoma are subclonal, TERT promoter mutations commonly occur as clonal events and are found in up to 80% of IDH-wildtype glioblastomas. Given the high prevalence and clonal nature of TERT promoter mutations in glioblastoma, telomerase is considered a promising therapeutic target for this deadly cancer. Prior studies have validated this hypothesis, demonstrating that knockout of the transcription factor GABPA, which selectively binds to the mutant TERT promoter, as well as base editing-mediated correction of TERT promoter mutations, are selectively toxic to TERTpromoter mutant glioblastomas. However, an important limitation of this strategy is that cancer cell death does not occur immediately after telomerase ablation, but rather after several cell divisions required to reach critically short telomeres. We therefore hypothesize that telomerase inhibition would only be effective in low tumor burden glioblastomas. In this study, we used CRISPR interference to knock down TERT expression in TERT promoter-mutant glioblastoma cell lines and patient derived models. We then measured cell viability and assessed for features of telomere crisis by measuring telomere length and chromatin bridge formation. Lastly, we used a doxycycline inducible CRISPR interference system to knock down TERT expression in vivo early and late in the tumor formation process. We demonstrated that TERT promoter-mutant glioblastoma cells are sensitive to telomerase inhibition and undergo telomere crisis. In vivo, tumor formation is only inhibited when TERT knockdown is induced shortly after tumor implantation, but not when tumor burden is high. This work supports the idea that telomerase inhibition would be a suitable therapeutic strategy for glioblastoma patients with low tumor burden, for example in the adjuvant setting after surgical debulking and chemoradiation.
EXTH-15. DRUG SCREENING ON PATIENT GBM CELL CULTURES IDENTIFIES OMACETAXINE MEPESUCCINATE AS A POTENT ANTI-GLIOMA AGENT WITH THE ABILITY TO CROSS THE BLOOD-BRAIN-BARRIER
Authors: Ntafoulis Ioannis , Koolen Stijn L W , den Hollander Chelsea W J , Ju Jie , Kers Trisha , van den Bosch Thierry P P , Panth Kranthi , Mezzanotte Laura , Mustafa Dana A M , Stubbs Andrew P , Dirven Clemens M F , Leenstra Sieger , Lamfers Martine L M
Published: November 2022

INTRODUCTION

Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM.

METHODS

The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS.

RESULTS

Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice.

CONCLUSIONS

At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.
EXTH-17. COMBINATION OF HDAC INHIBITOR AND PI3K/MTOR INHIBITOR SYNERGISTICALLY INDUCES APOPTOSIS IN DIPG
Authors: Barnett Katie , Kwon HyukJean , Raabe Eric , Eberhart Charles
Published: November 2022

Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brain tumor characterized by epigenetic dysregulation with median survival of 9-11 months. Currently, radiation is the only therapy option, and therefore calls for a new, effective treatment method. RG2833 is a brain penetrant, selective HDAC 1/3 inhibitor. Western blot confirmed that RG2833 treatment alone downregulates the NFkB pathway in multiple DIPG cell lines. We showed that RG2833 treatment decreases expression of NFkB regulated anti-apoptotic genes XIAP, BCL-2, and BCL-XL in vitro. In vivo results in DIPG flank tumors confirmed that BCL-2 and BCL-XL expression are decreased with RG2833 treatment. We have also confirmed through Western blot that RG2833 treatment induces p16, p21, and p27 expression, which negatively regulate cell cycle progression, in multiple DIPG cell lines. RNAseq data showed that PI3K/mTOR pathway is upregulated in DIPG after RG2833 treatment. Paxalisib is a brain penetrant PI3K/mTOR inhibitor currently in clinical trials for DIPG. We hypothesized that RG2833 and paxalisib combination treatment would yield synergistic effects. RG2833 synergizes with paxalisib to suppress growth as measured by CellTiterBlue. ZIP synergy scores calculated by SynergyFinder were 10.5 for SUDIPG06 and 9.2 for HSJD007. Western blot demonstrated that combination treatment induced c-PARP and FOXO1 in the SUDIPG06 cell line, and decreased p-RB expression in HSJD007 cell line. Induction of c-PARP indicates increased apoptosis, and decreased p-RB expression indicates decreased cell proliferation. In vivo experiments evaluating the efficacy of combination treatment are in progress. Our data suggest the combination of RG2833 and paxalisib may be a promising treatment option for DIPG.
EXTH-18. TARGETING THE ADENOSINERGIC IMMUNE SUPPRESSION PATHWAY IN HIGH GRADE GLIOMA SYNERGIZES WITH INNATE IMMUNE CHECKPOINT BLOCKADE
Authors: Chetty Senthil Lakshmana , Liu Yifan , Cole Allison , Cruz Joselyn Cruz , Hoffmeyer Eric , Vibhakar Rajeev , Venkataraman Sujatha , Mitra Siddhartha
Published: November 2022

Immune response in the tumor microenvironment is modulated by the conversion of eATP to AMP to adenosine via the ecto-enzymes CD39 and CD73. Overexpression of CD73 in tumors leads to an increase in extracellular adenosine concentration and decrease in eATP, resulting in immune suppression. In this study, CD73 knockouts were created in adult and pediatric glioma cell lines (DIPG17, T3691, BT245) and used to quantify the effects of CD73 knockout on macrophage phagocytosis in the presence of extracellular AMP. In cell line DIPG17, CD73 knockout significantly increased phagocytosis with and without external AMP compared to the WT. In the WT condition, addition of AMP significantly reduced phagocytosis, while this decrease was not significant in the CD73-KO. The addition of anti-CD47 antibody significantly increased phagocytosis with external AMP in the WT condition. Similar results were obtained with cell line T3691. However, CD73 knockout combined with anti-CD47 treatment and external AMP showed significantly greater phagocytosis than the WT condition. This suggests that a combination of anti-CD73 and anti-CD47 treatment may be more effective in the tumor microenvironment. Lastly, in cell line BT245, CD73 knockout significantly increased phagocytosis as seen in the other cell lines. However, no significant difference was observed between WT and CD73-KO with extracellular AMP or anti-CD47. In vivo studies were conducted in orthotopic xenograft mouse models with DIPG17 CD73 knockout cells. Combination treatment with anti-CD47 antibody significantly decreased tumor burden and prolonged survival in the CD73-KO tumors compared to anti-CD47 treated DIPG17-WT tumors. We conclude that the CD73 adenosinergic pathway and the CD47-SIRPα pathway may present a target for immunotherapy in pediatric and adult gliomas.
EXTH-21. DEVELOPMENT OF THERAPEUTIC STRATEGIES BY PATHWAY-BASED MULTI-OMICS APPROACH AND MASTER KINASE ANALYSIS IN GLIOBLASTOMA MULTIFORME
Authors: Oh Michael , Hasanain Mohammad , Migliozzi Simona , Garofano Luciano , D'Angelo Fulvio , Stefano Anna Luisa Di , Lerond Julie , Sarkaria Jann , Ceccarelli Michele , Sanson Marc , Lasorella Anna , Iavarone Antonio
Published: November 2022

Current transcriptomic classification of Glioblastoma Multiforme (GBM) has been ineffective to predict survival and therapeutic vulnerabilities. Recently, we proposed a four-group functional classification of GBM that included proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic subtypes with prognostic and therapeutic implications as the mitochondrial subtype carries the best survival and exhibits distinct sensitivity to mitochondrial OXPHOS inhibitors. To uncover novel therapeutic targets for each functional GBM subtype, we focused on protein kinases for their attractive features as both drivers and drug targets, with current availability of 62 FDA-approved inhibitors available for cancer precision therapeutics. We designed an unbiased integrative, machine learning-based proteomics/phosphoproteomics network for the identification of Master Kinases (MKs) responsible for effecting key phenotypic hallmarks of each of the four GBM subtypes. Here we report the identification and validation of protein kinase C delta (PRKCd) and DNA-PKcs as MKs that sustain the glycolytic/plurimetabolic and proliferative/progenitor GBM subtypes, respectively. Genetic and pharmacologic inactivation of PKCd in GBM patient-derived organoids of the glycolytic/plurimetabolic subtype blocked glucose uptake and lipid accumulation, resulting in marked anti-tumor effects. We also validated the role of PKCd in oncometabolic processes at the intersection between insulin, IGF, and lipid metabolism. DNA-PKcs was qualified as MK for the proliferative/progenitor GBM subtype, which is characterized by high basal level of replication stress. Biochemical experiments showed activation of DNA-PK in GBM patient-derived organoids of the proliferative/progenitor subgroup. Targeting DNA-PK in proliferative/progenitor GBM organoids with the clinically tested DNA-PKcs inhibitor nedisertib in association with gamma irradiation, the essential component of the standard of care for patients with GBM, led to an unsustainable level of DNA damage and massive GBM cell death selectively in this GBM subtype. As DNA-PKcs inhibitors have been introduced into clinical trials, our findings suggest that pre-selection of patient with PPR tumors is likely to enhance therapeutic success.
EXTH-30. PHARMACOKINETICS- AND PHARMACODYNAMICS-BASED EVALUATION OF QUISINOSTAT AS A RADIOSENSITIZER IN PRECLINICAL MODELS OF GBM
Authors: Cascio Costanza Lo , Margaryan Tigran , Melendez Ernesto Luna , McNamara James , Knight William , White Connor , Opachich Zorana , Ganta Niddhi , Giff Alexis , Sanai Nader , Tovmasyan Artak , Mehta Shwetal
Published: November 2022

Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. Class I HDACs mediate chromatin compaction and are frequently overexpressed in GBM. Hence, there has been considerable interest in HDAC inhibitors (HDACi) for the treatment of malignant brain tumors. However, to date almost all HDACi tested clinically have failed to provide significant therapeutic benefit to primary and recurrent GBM patients. These HDACi are broad-spectrum with poor or unknown pharmacokinetic profiles and narrow therapeutic window. Isoform specificity for HDACi is important given that not all HDAC enzymes are equally expressed in GBM. Recently, we uncovered the functional importance of HDAC1 in therapy-resistant glioma stem cells, where we found that its expression increases with brain tumor grade and is correlated with decreased survival. While no class I HDAC isoform-specific inhibitors are currently available, the second-generation HDACi quisinostat harbors high specificity for HDAC1. In this study, we assessed the pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of human GBM. In vitro analyses conducted in patient-derived glioma stem cell (GSC) lines revealed that quisinostat exhibited potent growth inhibition, induced global histone hyperacetylation, elevated DNA damage, cell death and cell cycle arrest. To determine the efficacy and drug distribution profile of quisinostat in vivo, athymic mice with orthotopic or flank tumors were treated with an optimized treatment schedule. At various timepoints during treatment, plasma and brain/tumor tissue were collected to measure total and unbound drug levels by liquid chromatography tandem mass spectrometry (LC-MS/MS), coupled with transcriptomic and pharmacodynamic analyses of tumor tissues. We demonstrate quisinostat is a brain-penetrant molecule that reduces tumor burden in flank and orthotopic models of GBM, and significantly extends survival when administered with radiation. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation for the treatment of GBM.
EXTH-42. DUAL ROLES OF PKR ORCHESTRATE ONCOLYTIC HSV SENSITIVITY AND ANTIGEN-SPECIFIC T CELL EXPANSION
Authors: Hong Bangxing , Sahu Upasana , Mullarkey Matthew P , Hong Evan , Guangsheng Pei , Yan Yuanqing , Otani Yoshihiro , Fan Huihui , Zhongming Zhao , Kaur Balveen
Published: November 2022

The host immune system has developed many mechanisms to defend against and clear virus infections, including PKR, cGAS-STING and TLR-MyD88 signaling pathways. Compromised anti-viral mechanisms in tumor cells allows for infection, replication and lysis by oncolytic viruses. However, compromised antiviral mechanisms, together with immune cells and the tumor microenvironment (TME), limit the sensitivity of oncolytic virus in tumor cells. We generated a novel oncolytic Herpes simplex virus, oHSV-shPKR which disables tumor-intrinsic PKR signaling. oHSV-shPKR significantly increases oHSV infection and lysis in both oncolytic virus-resistant and sensitive glioblastomas (GBMs). Infection of oHSV-shPKR in GBMs induces G2/M cell cycle arrest and inhibits tumor cell growth. oHSV-shPKR increases activation of antigen presentation cells through type I interferon signaling activation and its immune-stimulatory function to increase tumor-antigen specific CD8 T-cell expansion, including cytotoxic T lymphocytes. Preclinical studies showed that oHSV-shPKR intra-tumoral injection significantly inhibits human GBM patient derived xenograft (PDX) tumor growth in immune-deficient NSG mice and murine orthotopic GBM tumor growth in immunocompetent mice. The results demonstrate that the novel oHSV-shPKR has the potential to be used in clinical applications for both oHSV-resistant and sensitive GBM treatment.
EXTH-55. DELIVERY OF CAS9/SGRNA RIBONUCLEOPROTEIN CONJUGATE VIA VIRUS-LIKE PARTICLES FOR EFFICIENT GENE EDITING OF TRANSCRIPTION FACTOR BRACHYURY IN GLIOBLASTOMA
Authors: Hsu Wesley , Lu Baisong , Hu Yunping
Published: November 2022

Brachyury, a transcription factor that is a critical driver during normal embryonic development, is highly expressed in glioblastoma (GBM) but rarely expressed in normal adult tissues. Recent evidence suggests that brachyury plays a crucial role in regulating GBM cell proliferation and stemness, implying the potential of brachyury as a therapeutic target. However, like other transcription factors, brachyury is not readily inhibited pharmacologically due to the absence of ligand-accessible small-molecule binding pockets, and a direct inhibitor of brachyury has not been identified. Our team has recently developed a novel virus-like particle (VLP)-based system by fusing aptamer-binding protein to the lentiviral nucleocapsid protein within the group-specific antigen, which allows for efﬁcient packaging of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) for gene editing. Our data suggests that our VLP-mediated Cas9/gRNA RNP allows for transient expression of Cas9 in patient-derived GBM cells while maintaining effective gene editing efficiency (∼40%). Our strategy results in 90% knockdown of brachyury in vitro with subsequent inhibition of GBM cell proliferation and stemness as well as enhanced susceptibility of tumor cells to radiation via increased cleavage of caspase-3. In addition, our in vivo results using a xenograft mouse model further demonstrates that transduction with VLP-packaged Cas9/brachyury gRNA inhibits GBM progression. Our findings demonstrate that our novel VLP-based system allows for efficient delivery of Cas9/gRNA RNP-based brachyury gene editing technology and represents a novel treatment strategy for GBM.