bluuebunny/crossref_metadata_2025 huggingface dataset:
PDTM-21. MULTI-MODAL PROFILING OF PEDIATRIC HIGH-GRADE GLIOMA SINGLE CELLS USING PATCH-SEQ
Authors: Gillespie Shawn , Arzt Marlene , Woo Pamelyn , Monje Michelle
Published: November 2019

Pediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry. One subpopulation of glioma cells participates in glutamatergic synaptic communication with neurons, and a distinct subpopulation of cells sense and respond to extracellular potassium flux of neuronal networks by an entirely distinct mechanism. Our data support a model in which both modes of electrical communication are critical to glioma growth, but current associations between the electrophysiological properties of a cell, its transcriptional profile and developmental state are correlational in nature. Patch-seq is needed to clarify the relationship between transcriptional profiles of quiescent/cycling stem-like cells and the observed electrophysiological behaviors. Put more simply, patch-seq will clarify where the synaptically-connected glioma cells exist along a developmental hierarchy.

METHODS

Here, we adapt a recently described technique called patch-seq to record the electrophysiological profiles of individual pediatric high-grade glioma cells by whole cell patch-clamp and subsequently isolate their mRNA for single cell sequencing by smart-seq2 and analysis using Seurat. In this way, we couple electrophysiological and transcriptomic profiles to unambiguously assign functional identities to cells with transcriptional profiles along a developmental hierarchy.

RESULTS

We report the successful adaptation of patch-seq for use with patient-derived diffuse intrinsic pontine glioma (DIPG) xenografts in acute brain slice preparations, enabling evaluation of single glioma cells integrated in intact neural circuitry.

CONCLUSIONS

Data synthesizing the electrophysiological and transcriptomic profiles of single glioma cells in the context of the developmental hierarchy will be presented.
PDTM-27. THE CRISPR-Cas9 SYSTEM-MEDIATED ENDOGENOUS GENE-REARRANGEMENT INDUCED C11orf95-RELA FUSION IN VITRO AND IN VIVO THAT LED TO DEVELOPMENT OF BRAIN TUMORS
Authors: Takadera Mutsumi , Ozawa Tatsuya , Yamamoto Tetsuya , Ichimura Koichi
Published: November 2019

Recent large-scale genomic studies of ependymal tumors have identified recurrent RELA and YAP1 fusion genes in supratentorial ependymomas. We have so far shown that C11orf95-RELA fusion was a potent oncogene capable of inducing human ependymoma-like tumors in the RCAS/tv-a retroviral gene transfer system. However, molecular mechanism underlying the tumor formation has not been fully investigated. Given that C11orf95-RELA fusion genes are caused by gene rearrangement between C11orf95 and RELA gene due to chromothripsis involving 11q, it has been suggested that expression of these fusion genes is regulated under the C11orf95 promoter. In this study, we developed a system to reproduce the oncogenic gene rearrangement using the CRISPR-Cas9 system and examined if consequent endogenous ependymoma fusion genes are competent to form brain tumor in mice. Initially, we designed guide RNAs on the human and mouse genomic loci corresponding to breakpoints observed in human RELA fusion positive ependymomas and introduced them into HEK293T or NIH3T3 cells. RT-PCR and immunoblot analyses revealed that a combination of multiple guide RNAs efficiently induced gene rearrangement between C11orf95 and RELA gene, resulting in C11orf95-RELA fusion protein. Subsequently, we introduced the same guide RNAs using a lentiviral gene transfer system into mouse brain. Brain tumor formation was observed around 2 months after the guide RNA delivery, indicating successful gene rearrangement followed by C11orf95-RELA fusion expression in vivo. These results thus firmly establish that a gene rearrangement is the mechanism to form the C11orf95-RELA fusion which is the direct driver of tumorigenesis. Furthermore, we found that endogenous YAP1-FAM118B fusion gene can be also induced with a similar experimental strategy to that of C11orf95-RELA fusion. Our system to simulate genomic event will provide insights into the tumorigenic mechanism of ependymomas that harbor various fusion genes.
PDTM-31. INVESTIGATING THE EFFECT OF H3G34V MUTATION ON DISTINCT GENOMIC H3K36 METHYLATION PATTERNS IN PEDIATRIC GLIOMA
Authors: Huang Tina , Piunti Andrea , Ozark Patrick , Barton Elizabeth , Qi Jin , Hashizume Rintaro , Shilatifard Ali , Saratsis Amanda
Published: November 2019

BACKGROUND

Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas (pHGGs). This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me is observed on H3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3G34V mutation in pediatric glioma on genomic H3K36me3 enrichment in vitro.

METHODS

Doxycycline-inducible short hairpin RNA (shRNA) against H3F3A was delivered via lentivirus to established H3G34V mutant pediatric glioma cell line KNS42, and H3G34V introduced into H3.3 wild type normal human astrocytes (NHA). Transfections were confirmed by western blot, fluorescent imaging, and flow cytometry, with resulting H3.3WT and H3K36me3 expression determined by western blot. H3.3WT, H3K36me3, and H3G34V ChIP-Seq was performed to evaluate effects of H3G34V mutation on genomic enrichment patterns.

RESULTS

Complete knockdown of H3G34V was achieved with DOX-induced shRNA, with no change in total H3.3, suggesting disproportionate allelic frequency of genes encoding H3.3 (H3F3A and H3F3B). Modest increase in H3K36me3 expression occurred after H3F3A-knockdown from KNS42, suggesting H3G34V alone impacts observed H3K36me3 levels. H3G34V knock-in to NHAs was verified via western blot. Distinct H3K36me3 genomic enrichment was observed with H3G34V on ChIP-Seq.

CONCLUSIONS

We demonstrate that DOX-inducible knockdown of H3F3A in an H3G34V mutant pediatric glioma cell line, and H3G34V mutation transduction in wild-type NHAs, directly impacts H3K36me3 expression level. Further evaluation by ChIP-Seq analysis for restoration of wild-type genomic H3K36me3 enrichment patterns with H3G34V knockdown, and mutant H3K36me3 patterns with H3G34V transduction, is currently underway.
PDTM-33. EUROPEAN GENETIC ANCESTRY ASSOCIATED WITH RISK OF CHILDHOOD EPENDYMOMA
Authors: Zhang Chenan , Ostrom Quinn , Hansen Helen , de Smith Adam , Kline Cassie , Kruchko Carol , Vaksman Zalman , Diskin Sharon , Barnholtz-Sloan Jill , Ramaswamy Vijay , Taylor Michael , Bondy Melissa , Metayer Catherine , Wiemels Joseph , Walsh Kyle
Published: November 2019

BACKGROUND

Ependymoma is a histologically-defined central nervous system tumor most commonly occurring in children. Incidence differs by race/ethnicity, with individuals of European ancestry at highest risk. No large-scale genomic analyses of ependymoma predisposition have been conducted to date. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk.

METHODS

In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among admixed Hispanic and African-American subjects and estimated European substructure among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local European ancestry. We also re-analyzed CBTRUS data to examine subtype-specific differences in ependymoma incidence across racial/ethnic groups.

RESULTS

Each 20% increase in European ancestry was associated with 1.31-fold greater odds of ependymoma among Hispanic and African-American subjects (95% CI: 1.08–1.59, Pmeta=6.7×10–3). Among non-Hispanic whites, European ancestral substructure was also significantly associated with ependymoma risk. Local admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and genotype association analysis in the region identified an association upstream of R-spondin 4 that survived Bonferroni correction (P=2.2x10-5) but was not validated in an independent set of posterior fossa type A (PF-EPN-A) patients. In complementary CBTRUS analyses, American Indian/Alaskan Natives were at reduced risk relative to non-Hispanic whites (RR=0.64, 95% CI:0.46–0.87), as were African-Americans (RR=0.67, 95% CI:0.60–0.74) and Asian/Pacific Islanders (RR=0.86, 95% CI:0.73–1.00). Although overall ependymoma rates were similar in U.S. Hispanics (RR=0.96, 95% CI:0.88–1.05), lower rates were observed for myxopapillary ependymoma and other spinal ependymoma.

CONCLUSION

Inter-ethnic differences in ependymoma risk vary by histopathologic and potentially molecular subgroup, and are recapitulated in the genomic ancestry of ependymoma patients.
PDTM-35. MODELLING MEDULLOBLASTOMA WITH MOUSE MODELS AND HUMAN CEREBELLAR ORGANOIDS
Authors: Tiberi Luca
Published: November 2019

Malignant medulloblastoma (MB) is the most common brain tumor affecting children and it remains responsible for a high percentage of morbidity and mortality among cancer patients. During the past few years, studies on human MB and mouse models have uncovered the existence of four major MB groups, with specific pathological and molecular features: WNT, SHH, Group 3 and Group 4. Of the four groups, patients with Group 3 MB have the worst outcome with nearly 50% of the tumors metastatic at the time of diagnosis. Therefore, developing “humanized “ mouse model of Group3 Medulloblastoma would be of paramount importance for the identification and testing of new drugs for pediatric patients, tailored on the genetic condition of the patient itself. We performed an in-vivo screen to identify new cancer-inducing genes starting from the published genome-wide analyses of MB patients. This screen led to the identification of novel driver gene combinations required for tumorigenesis. To study Medulloblastoma in human cells, we generated human cerebellar organoids. Organoids are cellular structures that resemble whole organs and can be generated from pluripotent stem cells or isolated organ progenitors. We were able to induce cerebellar progenitors to self-form neuro-epithelial structures that mimic early human cerebellar plate, composed by cerebellar progenitors, cerebellar neurons (interneurons, Purkinje cells, and granule neurons) and glial cells. Notably, we have generated human putative iPSC-derived cancer organoids with gene combinations mimicking human Group3 MB. Indeed, organoids that mimic cancer can be used as an alternative system for drug testing that better recapitulate effects in human patients as compared to other in-vitro and in-vivo systems.
PDTM-37. GALECTIN-3 PROMOTES CXCR2 EXPRESSION IN MEDULLOBLASTOMA
Authors: Das Arabinda , Eskandari Ramin , Alshareef Mohammed , Kosnik Infinger Libby , Patel Sunil , Cachia David
Published: November 2019

Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The identification of cancer stem cell (CSC) populations in MB has play a vital role in drug resistance, and cancer relapse. Galectin-3 (Gal-3) a multifunctional β-galactoside-binding protein is known to participate in tumor progression and drug resistance. However, the exact role of Gal-3 in medulloblastoma tumor pathophysiology is yet unknown. In this study, we observed higher levels of stem/progenitor cell markers, such as Oct4, Sox2, CD133 and Nanog in MB slices. Among the Gal family, Gal-3 in particular was highly expressed in MB tumor slices. To further investigate Gal-3’s role in the pathophysiology of MB, we used either small interfering RNA (siRNA) to knock down Gal-3 expression or Gal-3 inhibitor, TD139 to suppress Gal-3 expression in ex vivo slice culture model. Upon suppressing Gal-3 in parental MB slices, drug resistance (MDR1and MPR1) and stem cell related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down-regulated in Gal-3-knockdown or Gal-3 inhibitor treated MB tumor slices, while CXCR2 overexpression in Gal-3-knockdown or Gal-3 inhibitor treated MB slices restored their viability. These results indicate that highly expressed Gal-3 may up-regulate CXCR2 to augment MB invasiveness and progression. Gal-3 may be a prognostic and innovative target for the treatment of MB.
PDTM-41. INHIBITION OF DNA DOUBLE STRAND BREAK REPAIR PATHWAYS AS A PROMISING THERAPEUTIC TARGET IN DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)
Authors: Pal Sharmistha , Bian Jie , Price Brendan , Chowdhury Dipanjan , Haas-Kogan Daphne
Published: November 2019

New approaches to the treatment of diffuse intrinsic pontine gliomas (DIPGs) are desperately needed. DNA damage response is essential for cells to maintain genome integrity as DNA is damaged by both endogenous and exogenous stressors. Many cancer cells exhibit hyper-dependency on specific DNA repair pathways due to either defects in DNA repair mechanisms and/or high levels of endogenous stress leading to accumulation of DNA damage lesions. Identification of DIPG-specific DNA repair deficiencies and resultant dependencies may establish novel therapeutic strategies for DIPGs.

METHODS

To identify pathways critical for DIPG cell survival, genome wide CRISPR-Cas9 screen was performed on patient derived DIPG cell lines followed by gene set enrichment analyses. To monitor the effects of pathway inhibition on survival, apoptosis, DNA damage and repair, assays were performed to measure cell proliferation, cleaved-caspase3, gamma-H2AX and reporter based-DNA repair efficiency.

RESULTS

Our unbiased CRISPR approach to uncover vulnerabilities in DIPGs identified DNA double strand break (DSBs) repair pathways as essential for DIPG cell proliferation and survival. Further studies revealed high basal DSBs in DIPG cells compared to neural stem cells and primary astrocytes that suggest dependence of DIPG cell survival on specific DSB repair pathways. We confirmed the intrinsic reliance of DIPG cells on the specific DSB repair pathway of mutagenic end-joining, and defined a key role for DNA repair in suppressing endogenous DNA damage-induced apoptotic cell death.

CONCLUSION

DIPG cells have high endogenous DNA damage levels and escape catastrophic genomic instability and cell death by engaging DNA repair pathways, in particular the mutagenic end-joining DNA repair pathway. Inhibition of this specific DNA repair pathway represents a promising new avenue for the treatment of DIPGs.
PDTM-42. CROSS-PLATFORM PROFILING OF ctDNA USING ddPCR: STANDARDIZATION OF THE LIQUID BIOPSY FOR PEDIATRIC DIFFUSE MIDLINE GLIOMA
Authors: Li Daphne , Bonner Erin , Stallard Stefanie , Panditharatna Eshini , Huang Tina , Lulla Rishi , Koschmann Carl , Nazarian Javad , Saratsis Amanda
Published: November 2019

INTRODUCTION

Pediatric diffuse midline glioma (DMG) with histone H3 mutations (80%), are highly morbid tumors with poor response to therapy. We previously detected H3 mutations in circulating tumor DNA (ctDNA) from CSF derived from children with DMG and high grade glioma. Here, we describe a high-throughput, sensitive and specific approach for H3 mutation detection and quantification in plasma and CSF specimens, validated across multiple centers.

METHODS

DNA extracted from tissue-validated H3.3K27M specimens (4 tumor, 5 CSF, 4 plasma) and pediatric glioma cell lines (1 wild-type, 1 H3.3K27M) were used to standardize ddPCR workflows. ctDNA extracted from 500uL of CSF or plasma was pre-amplified using sequence-specific primers, then analyzed on RainDance and BioRad ddPCR systems using two sets of custom primers and fluorescent LNA probes (Assays A and B). H3 mutation allelic frequency (MAF) was determined across specimens, and validated through parallel analysis of additional matched H3.3K27M tumor tissue, CSF and plasma specimens (n=3).

RESULTS

ctDNA processing and detection was standardized across three institutions and two platforms with sensitive, specific and reproducible H3 mutation detection. H3K27M mutations were detected in as little as 0.3-2pg input DNA on both platforms, with comparable MAFs across instruments and assays. RainDance yielded greater overall positive droplet number detection (increased sensitivity). Differences in optimal sample input volume between platforms were circumvented by vacuum concentration or dilution to maintain equal input DNA. Assay A yielded superior specificity so was used for subsequent matched specimen analysis. Mutation detection in plasma, as in previous studies, remained challenging due to low [ctDNA], while CSF analysis yielded reliable results across assays and platforms.

CONCLUSIONS

We demonstrate the utility of liquid biopsy for identifying H3K27M mutations in plasma and CSF via ddPCR with low starting [DNA], representing a rapid, minimally invasive method for diagnosis and therapeutic monitoring of DMG.
QOLP-16. DISTRESSED (D TYPE) PERSONALITY, PREOPERATIVE PSYCHOLOGICAL DISTRESS, COGNITIVE FUNCTIONING, QUALITY OF LIFE, AND TREATMENT OUTCOMES OF GLIOMA PATIENTS: PROSPECTIVE STUDY
Authors: Pranckeviciene Aiste , Saudargiene Ausra , Deltuva Vytenis , Tamasauskas Arimantas , Bunevicius Adomas
Published: November 2019

BACKGROUND

This study aimed to evaluate impact of distressed (D type) personality on preoperative psychological distress, cognitive functioning and quality of life (QoL) as well as short-term and long-term treatment outcomes of glioma patients.

METHOD

One-hundred and seventy patients (93 men, mean age=51.1±14.5 years) participated in the study. Fifty-four (31.8%) patients were diagnosed with low grade (WHO grade I-II), and 116 (68.2%) with high grade (WHO grade III-IV) tumors. Psychological assessment was performed 2–3 days before surgery using a set of self-report questionnaires (NCCN Distress thermometer, EORTC-QLQ-C30, EORTCQLQ-BN20, HADS, DS-14) and a short battery of neuropsychological tests. Functional status at the discharge was assessed using the GOS. Follow-up period was 40 months.

RESULTS

Thirty-nine (22.9%) of patients met criteria for D type personality. D-type patients relative to non D-type patients reported significantly worse QoL, higher number tumor related symptoms, greater depression and anxiety symptoms, and demonstrated slowing of psychomotor speed in neuropsychological tests. However, no personality related differences were observed in level of functioning at time of discharge as well as long-term patients’ survival. Path analysis using SEM revealed non-direct impact of D-type personality traits on patients QoL (Chi-square value=16.73, df=13, p=0.212). The model indicated statistically significant indirect effects of D-type Negative Affectivity on QoL (IPC -0.285, 95% CI [-0.386; -0.178], p=0.003) and tumor related symptoms (IPC 0.196, 95% CI [0.117; 0.296], p=0.002) mediated via depression and anxiety. Social Inhibition was also indirectly associated with QoL (IPC -0.047, 95% CI [-0.120; -0.002], p=0.035) and symptoms (IPC 0.033, 95% CI [0.002; 0.097], p=0.032) through depression and anxiety.

CONCLUSION

D-type personality contributes to impairment of QoL and higher number of reported symptoms in glioma patients via increased susceptibility for depression and anxiety.
QOLP-18. A TIME-BASED MODEL OF EARLY PALLIATIVE CARE INTERVENTION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA, A SINGLE INSTITUTION FEASIBILITY STUDY
Authors: Johnson Margaret , Ramirez Luis , Herndon James , Massey Woody , Lipp Eric , Affronti Mary , Kim Jung-Young , Friedman Henry , Desjardins Annick , Randazzo Dina , Ashley David , Casarett David , Peters Katherine
Published: November 2019

OBJECTIVE

There is no validated model for delivering palliative care (PC) in the glioblastoma (GBM) population. The primary objectives were to assess the feasibility and determine the acceptability of a time-based model of integrated specialty PC to patients and providers. Secondary objectives were to estimate the impact on healthcare utilization and quality of life (QoL) compared to historical controls.

METHODS

We consented and referred patients to PC at their initial Neuro-Oncology consultation between 4/2018 and 5/2019. We conducted QoL assessments (NCCN Distress Tool; Functional Assessment of Cancer Therapy-Brain (FACT-BR); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); Epworth Sleepiness Scale (ESS)) at (1) baseline (2) immediately after chemoradiation, and (3) 6 months following chemoradiation. Ongoing PC follow-up was at the discretion of the PC provider. We administered the Edmonton Symptom Assessment System (ESAS) before and after PC visits. We measured patient and referring provider satisfaction using FAMCARE-16 and a PC departmental survey, respectively.

RESULTS

We did not meet our goal enrollment of 50 patients. 32 were offered participation, 12 consented and 8 attended at least one PC visit. The mean number of PC visits was 1.6. Mean age was 62 (42–79). 75% had a KPS ≥80. Of those that did not complete the study, 2 died and 5 either withdrew consent or declined further visits. At baseline, 91.7 % had a NCCN distress score ≥4. Patients were overall satisfied with the intervention.

CONCLUSION

Introduction of specialty PC at the time of GBM diagnosis is challenging. Participants reported their experience as overall positive. Results from referring providers are pending. Due to low-enrollment we did not pursue further statistical comparisons regarding healthcare utilization compared to historical controls.
QOLP-23. IDENTIFICATION OF CHARACTERISTICS THAT DETERMINE BEHAVIORAL AND PERSONALITY CHANGES IN GLIOMA PATIENTS
Authors: Zwinkels Hanneke , Dirven Linda , Bulbeck Helen , Grant Robin , Oberg Ingela , Koekkoek Johan , Habets Esther , Oliver Kathy , Pace Andrea , Rooney Alley , Taphoorn Martin
Published: November 2019

BACKGROUND

Glioma patients may experience behavioral and personality changes (BPC), which have a negative impact on the lives of both brain tumor patients and their relatives. The extent of BPC is currently unknown, and it is unclear if available assessment tools cover all aspects of BPC that are relevant for glioma patients. This study aimed to determine which characteristics of BPC are relevant for glioma patients.

METHODS

Possible characteristics of BPC were identified in the literature and based on expert opinion. Next, these 49 items were presented to patients and caregivers/former caregivers in an online survey launched via the International Brain Tumour Alliance. Participants were requested to indicate the relevance for each characteristic on a 4-point Likert scale ranging from ‘not at all’ to ‘very much’. In addition, they had to indicate which three characteristics had most impact on their daily life, and if characteristics were missing.

RESULTS

Completed surveys were obtained from 141 respondents, of which 36% were patients, 50% caregivers and 14% unknown. Most patients had grade II or IV glioma (29% vs 38%). Of 49 characteristics, 35 were reported as relevant in at least 25% (range all characteristics: 7–44%). Patients (n=50) and caregivers (n=70) rated different characteristics as most important. Common characteristics were lack of motivation, change in being socially active, not able to finish things and change in level of irritation. There were no characteristics reported to be missing by ≥5 respondents.

CONCLUSION

The majority of characteristics were rated as relevant in >25% of respondents, and patients and caregivers differed in which were most relevant. A clear definition based on these results is therefore difficult to establish. A next step would be to perform a cluster analysis of patients and caregivers separately, and discuss the results with experts, to reach consensus on an appropriate definition.
QOLP-26. PATIENT REPORTED SOCIAL FUNCTION AND SURVIVAL IN GLIOMA PATIENTS
Authors: Hardy Sara , Pandya Chintan , Mohile Nimish , Janelsins Michelle , Milano Michael
Published: November 2019

PURPOSE

Research among patients with cancer suggests that health related quality of life (HRQOL) may be more predictive of survival than performance status. Social function is a HRQOL outcome influenced by both physical and mental health. To our knowledge, no work has analyzed the potential association between survival and social function in patients with brain tumors.

METHODS

In the SEER Medicare Health Outcomes Survey, 158 patients were identified with 1) diagnosis of glioma between 1976 and 2013 2) no other cancer diagnosis 3) at least one post-diagnosis HRQOL survey. We examined the relationship between social function and mortality using a multivariable Cox proportional hazard model. We also examined factors correlated with social function score using linear regression.

RESULTS

At last follow up, 48% of the patients had died, 53% were female, 59% had trouble with ≥1 ADL, 53% were married, 27% had glioblastoma, 74% were white, and 32% had no reported comorbidities. Median time from cancer diagnosis to survey was 79 months and median age at survey was 60 years. For patients alive at last follow-up, there was a difference of >5 points for the social function subscale (38.2 vs 30.6) compared to those who died during the median 163 month follow up interval. On multivariable Cox proportion hazard model adjusting for covariates, higher social function scores were significantly associated with improved survival (5 point increase in score, HR 0.86, p = 0.0029). Worse social function was associated with patient-reported neurologic deficits in vision and speech and report of depression, but not marital status, sex, race, or patient-reported income.

DISCUSSION

Patient-reported social function score on post-diagnosis surveys, even after accounting for important clinical factors, was significantly associated with survival. The impact of patient reported social function in those with glioma should be further examined in confirmatory longitudinal studies.
QOLP-28. THE USE OF VIRTUAL REALITY FOR SYMPTOM MANAGEMENT: APPLICATION IN NEURO-ONCOLOGY
Authors: Leggiero Nicole , Armstrong Terri , Vera Elizabeth , Gilbert Mark , King Amanda
Published: November 2019

Patients with primary central nervous system (CNS) tumors are highly symptomatic due to the functional sequelae of their disease and an unfavorable prognosis. Virtual reality (VR) immersive technology has demonstrated benefit in improving patients’ symptom burden, such as distress, pain, anxiety, and fatigue. However, this has not been explored in a CNS tumor population. This project explored the potential use of VR for symptom management in CNS tumor patients. A descriptive analysis of MDASI-BT/MDASI-SP/PROMIS-Anxiety patient-reported outcomes (PROs) for 535 CNS tumor patients was performed to identify the common moderate-severe (> 4 on a 0–10 scale) symptoms. Additionally, a systematic review of literature was performed addressing the question “For adult patients with solid tumors, what effect does VR have on their self-reported symptoms, such as distress, anxiety and pain?” The systematic literature review resulted in 17 studies using VR in other solid tumor populations, which demonstrated improvement in pain, anxiety, and distress. However, study designs often lacked rigor and none incorporated any biomarkers to correlate with PROs. CNS tumor symptom review of our patient cohort revealed that the majority of the patients were Caucasian (83%) males (58%) with a median age of 50 years (range, 18–83). At the time of diagnosis, 35% had a gross total resection. Glioblastoma was the most common diagnosis (32%) and 50% had a high-grade glioma. The most prevalent moderate-severe symptoms in this sample was fatigue (34%), with (14%) anxiety, (18%) pain, and (19%) distress. Given the high symptom rate in our patients, the promising but limited data that VR technology could improve distress and other symptoms provides strong support for this intervention in the CNS tumor population. Further research is needed to assess feasibility and efficacy of VR, as well as incorporation of correlative biomarkers, to better determine potential improvement in patient symptom burden.
QOLP-29. MINDFULNESS MEDITATION PRACTICE IN MALIGNANT GLIOMA PATIENTS THROUGHOUT CONCOMITANT RADIATION AND TEMOZOLOMIDE: A FEASIBILITY STUDY
Authors: Randazzo Dina , Jackman Jenny , Herndon James , Affronti Mary , Lipp Eric , Cort Nicole , Desjardins Annick , Johnson Margaret , Landi Daniel , Ashley David , Friedman Henry , Glass Oliver , Porter Laura , Peters Katherine
Published: November 2019

With a bleak prognosis for malignant glioma, maintaining quality of life (QoL) and decreasing distress of the patient are important in the clinical care of the patient. Mindfulness meditation is a mind-body therapy that has been recently investigated in the oncology field as a non-pharmacological strategy to ameliorate cancer symptoms and to improve QoL. This practice has not been studied in the primary brain tumor population. We initiated a pilot study among newly diagnosed brain tumor patients with the hypothesis that mindfulness meditation practice may benefit the patient by decreasing stress and anxiety and provide a means to cope with their new diagnosis. The specific aim of this pilot study is to determine the feasibility of a mindfulness meditation program to this population during standard of care chemoradiation and to determine whether it merits additional research in a subsequent trial. The intervention consists of six weekly one hour telephone-based mindfulness sessions followed by one in- person mindfulness session consisting of: mindfulness and healing, understanding stress, abiding in kindness, working with difficult emotions, finding peace, going forward and living fully. Subjects are provided with downloadable guided meditations. We plan to enroll fifteen newly diagnosed WHO grade III or IV malignant glioma subjects prior to their 6 week chemoradiation course. We will determine the percentage of subjects approached vs enrolled, number of sessions that each subject attends, completion of study questionnaires and satisfaction of the subjects. QoL surveys include: Functional Assessment of Cancer Therapy- Brain, Functional Assessment of Cancer Therapy- Cognitive Function, Pittsburgh Sleep Quality Index, Functional Assessment of Chronic Illness Therapy-Fatigue and the Five Facet Mindfulness Questionnaire – short form. 13 subjects have been approached and 8 signed consent over a two-month period. We will provide final study results at time of presentation.
QOLP-32. PATTERNS OF CARE AT END OF LIFE IN PATIENTS WITH GLIOMA
Authors: Barbaro Marissa , Blinderman Craig , Iwamoto Fabio , Kreisl Teri , Welch Mary , Odia Yazmin , Donovan Laura , Evans Katharine , Lassman Andrew
Published: November 2019

OBJECTIVE

To understand patterns of care at end of life in glioma patients.

BACKGROUND

Patients with gliomas often inquire about end-of-life issues. Understanding common clinical outcomes of tumor progression and end-of-life circumstances may reduce anxiety among patients and caregivers and inform care planning.

METHODS

Following IRB approval, we retrospectively analyzed circumstances surrounding death among patients with intracranial gliomas at Columbia University Irving Medical Center from 1/2014-2/2019, including immediate cause and location of death and implementation of palliative measures. Information unavailable from the medical record was supplemented by caregivers.

RESULTS

Data were available for 152 patients (95 men, 57 women; median age at death 61.5 years). Failure to thrive with transition to supportive care (n=117, 77%) was the most common immediate cause of death. Others included infection (19, 13%; with pulmonary (12, 8%), urinary tract (5, 3%), CNS (4, 3%), and GI (2, 1%) sources); seizures (8, 5%); intracerebral hemorrhage (5, 3%); cerebral edema (4, 3%); pulmonary embolism (4, 3%); autonomic failure (2, 1%); hemorrhagic shock (2, 1%); respiratory failure of unknown cause (2, 1%); pulmonary edema (1, 1%); and cardiac arrhythmia (1, 1%). Ten patients had multiple causes of death. Seventy-three patients (48%) died at home with hospice. Other locations were inpatient hospice (40, 26%); acute care hospital (34, 22%) including 27 (18%) with and 7 (5%) without comfort measures; skilled nursing facility (4, 3%) including 3 (2%) with and 1 (1%) without comfort measures; or religious facility (1, 1%) with comfort measures. Acute cardiac and/or pulmonary resuscitation was performed in 20 patients (13%); 8 (5%) died with no comfort measures.

CONCLUSIONS

Failure to thrive with transition to supportive care was the most common (77%) immediate cause of death followed by infection (13%). Hospice and/or palliative measures were implemented in 95% of patients, though resuscitative efforts were performed in 13%.
QOLP-35. OUTCOMES AND CORRELATIONS BETWEEN LEGACY QUALITY OF LIFE MEASURES (EORTC-C30/EORTC-BN20) AND THE ELECTRONIC QUALITY OF LIFE MEASURING SYSTEM NIH-PROMIS IN GLIOBLASTOMA PATIENTS
Authors: Walbert Tobias , Schultz Lonni , Snyder James , Suneja Aarushi
Published: November 2019

BACKGROUND

Health-related quality of life (QoL) and patient reported outcomes are essential to guide patient-care. The NIH sponsored electronic Patient-Reported Outcomes Measurement Information System (PROMIS) is well established in multiple cancers but not in Glioblastoma (GBM). The aim of this study was to analyze the association of the PROMIS measures with the European Organization for Research and Treatment of Cancer core instrument (EORTC-QLQ-C30) and the brain tumor specific EORTC QLQ-BN20 questionnaire (EORTC-BN20) in GBM patients.

METHODS

Newly diagnosed patients with GBM were enrolled prospectively to assess association between both tools. The PROMIS modules were selected to reflect the quality of life domains assessed in the EORTC- QLQ-C30 and EORTC-BN20 questionnaires. Pearson’s correlation coefficients were computed between the PROMIS and EORTC-C30/ EORTC-BN20 measures. Due to multiple responses over time, the p-values for the correlation coefficients were adjusted. Because of the large number of correlations computed and many with p-values less than 0.05, the magnitude of the correlation was considered. Correlations greater than 0.5 or less than -0.5 were consider to be “strong” associations, while correlations between 0.3 and 0.499 (or -0.3 and -0.499) were consider to be “moderate”.

RESULTS

43 patients with 124 PROMIS/EORTC responses were included in this analysis. The PROMIS measures had strong associations with the QoL functioning and fatigue measures from the EORTC-C30 and future uncertainty, communication deficit, motor dysfunction, social satisfaction and drowsiness from the EORTC-BN20 (all p< 0.001 and correlation >0.5).

CONCLUSIONS

There are strong and moderate correlations in the majority of PROMIS assessments and the EORTC tools. The PROMIS toolkit may be used to assess core features of the EORTC surveys. GI symptoms, seizures and itchy skin do not correlate. Given the prior documented shorter assessment time, the PROMIS toolkit may be a feasible alternative to established legacy tools to assess QoL in GBM patients.
QOLP-40. END-OF-LIFE CARE FOR GLIOBLASTOMA PATIENTS IN JAPAN
Authors: Omura Tomoko , Miyakita Yasuji , Ohno Makoto , Takahashi Masamichi , Fujimoto Kenji , Omura Takaki , Sato Hitomi , Narita Yoshitaka
Published: November 2019

BACKGROUND

Despite aggressive treatment with surgery and chemo-radiation therapy, it is difficult to cure patients with glioblastoma (GBM). The end-of-life (EOL) phase of patients with GBM, and related problems, have not yet been adequately studied. Unlike in other countries, most cancer patients died in the hospital (84%) in 2017, but the Japanese government has recommended palliative home care and the number of deaths at home has recently been increasing. This study explores the current situation of EOL care for GBM patients in Japan.

METHODS

We retrospectively examined the clinical course and EOL phase of 166 consecutive patients who were treated in our hospital between 2010 and 2017. RESULT: In total, 107 patients died; 27 (25.7%) at home, 24 (22.8%) in hospice care, 8 (7.6%) in nursing homes, 46 (43.9%) in hospitals (long-term care hospitals [LTCH; 19.8%], our hospital [13.3%], and other neurosurgical hospitals [10.4%]). According to our previous research, in 2001–2005, 6% of GBM patients died at home, 3% in hospice case, and 91% in the hospital. The KPSof patients who started palliative home care or transferred to another hospital was 50–60. The median survival time and length of EOL phase for patients who died at home were 498 and 76.5 days; 395 and 103 days in hospice care; 533 days and 149 days in LTCH; 374 days and 52 days in our hospital; 338 and 75.5 days in other neurosurgical hospital; and 557 days and 37 days in nursing homes, respectively.

CONCLUSION

The number of GBM patients who died at home in Japan is increasing, and we must consider the problems of the EOL phase and improve the quality of EOL care.
QOLP-41. ASSESSING CAREGIVERS’ OF PATIENTS WITH PRIMARY BRAIN TUMORS EXPERIENCES WITH AND NEEDS RELATED TO SEIZURE MANAGEMENT
Authors: Warren Paula , Ejem Deborah , Taylor Richard , Edwards Rebecca , Dionne-Odom James , Nabors Louis , Bakitas Marie
Published: November 2019

Family caregivers of persons with primary brain tumors report high levels of distress. Information is limited, however, regarding family caregivers’ experiences and needs concerning the risk and management of seizures in this population. In this qualitative descriptive study, we conducted one-on-one interviews to describe the experiences of family caregivers’ of persons with primary brain tumors who have had and who have not yet had a seizure. We sought information on how they coped with this issue and what information they needed regarding management of out-of-the-hospital seizures. We conducted 15 interviews using study-specific interview protocols; 10 caregivers with seizure experience and 5 caregivers without seizure experience. Caregivers were, on average, 52 years old, predominately white (93.3%), college graduates (66.7%), and were employed full-time (53.3%). The relationship between caregiver and care recipient was spouse (46.7%), other family member (46.7%), and friend (6.6%). Most caregivers provided care everyday (46.7%) and for more than 8 hours per day (33.3%). Themes emerged around three major domains: 1) caregiver challenges regarding seizures, 2) desired resources/information about seizures, and 3) timing of delivery of these resources. Caregivers often reported being fearful of seizures and the majority (93%) expressed difficulty with knowing when to call EMS. In terms of desired resources, opinions were split between preferring written materials versus online resources with most participants (87%) stating that videos or graphics detailing seizures would be helpful. In terms of delivery timing, most (66.7%) thought that training should come after diagnosis versus at the time of diagnosis citing reasons such as too much other information to absorb and overall inability to focus. Future studies will use this information to develop and pilot a seizure-focused supportive caregiver intervention that is tailored and caregiver-directed and that can be incorporated into standard neuro-oncology clinical practice.
RDNA-01. TUBULIN AND MICROTUBULES AS MOLECULAR TARGETS FOR TTFIELD THERAPY
Authors: Kalra Aarat , Patel Sahil , Bhuiyan Asadullah , Rezania Vahid , Lewis John , Shankar Karthik , Tuszynski Jack
Published: November 2019

TTField (Tumor-treating field) therapy utilizes low intensity intermediate frequency AC electric fields to reduce the spread of cancer. While it has attained FDA approval for the treatment of recurrent glioblastoma multiforme, the exact molecular targets of TTField therapy are not well understood. Microtubules are pipe-like polymers of the highly charged (–31 e) and strongly dipolar (dipole moment 1666 D) protein, α, β- tubulin. Studies on the electrical properties of microtubules have recently gained interest, with them being modelled as molecular targets of TTFields. Here, we experimentally show that while tubulin polymerized into microtubules leads to an increase in solution capacitance, unpolymerized tubulin has no appreciable effect. To the best of our knowledge, we present the first experimental quantification of the capacitance of a 20 μm-long microtubule. Using these results, we calculate the resonant frequency of a microtubule meshwork in a cell-like environment to be in the TTField regime. Our results utilize high ionic strength solutions and cell-like concentrations of tubulin to show the potential of microtubules as the targets of TTField action and as intracellular charge-storage devices. We conclude with a hypothesis of an electrically-tunable cell, where the dielectric properties of the cytoskeleton alter local and global charge storage and transport.
RDNA-05. RADIOTHERAPY PROMOTES ONCOPROGRESSIVE CROSSTALK BETWEEN GLIOBLASTOMA TUMOR CELLS AND M2 MACROPHAGES VIA THE NLRP3 INFLAMMASOME PATHWAY
Authors: An Shejuan , Rooney Michael K , Miska Jason , Lee Chang Catalina , Zhang Peng , Han Yu , Lopez-Rosas Aurora , Lesniak Maciej S , Sachdev Sean
Published: November 2019

PURPOSE

Radiotherapy (RT) is an essential component in the adjuvant treatment of glioblastoma (GBM); however, despite an initial benefit in tumor control, recurrence is nearly universal. The inflammasome is a multimeric cytosolic complex that has been shown to be activated in immune cells following RT. We investigated the relationship of inflammasome activation and disease progression after RT in GBM.

METHODS

We performed survival analysis for patients with recurrent GBM using the TCGA dataset, stratifying according to expression of inflammasome pathway molecules Caspase 1 (CASP1), IL-1β, and NLRP3. IL-1β expression and colocalization with CD11b+ myeloid cells were analyzed at different time points following RT in a murine glioma GL261 model. We detected the secreted IL-1β, CASP1 activity, and NLRP3 expression in both tumor and infiltrating immune cells, and the downstream effects of their interplay, including cellular apoptosis, proliferation, and viability.

RESULTS

High expression of CASP1, IL-1β, and NLRP3 are associated with poor survival in recurrent GBM. In a mouse model, recurrent tumors after treatment with RT display higher levels of the inflammasome effector molecule IL-1β, which colocalizes with infiltrating CD11b+ myeloid cells. Using a co-culture system of tumor cell and M2 macrophages, we found that RT enhances inflammasome activation in both cell types, and this interaction restores the proliferative capacity of surviving tumor cells following treatment. RT induces the inflammasome pathway activation in the setting of an associated immune microenvironment rich in tumor-associated macrophages and myeloid-derived suppressor cells (TAM/MDSCs) and not in tumor cells alone.

CONCLUSIONS

Inhibition of the oncoprogressive crosstalk between GBM tumor cells and M2 macrophages, possibly through disruption of the inflammasome pathway, might be a potential therapeutic strategy with RT.
RTHP-07. CYBERKNIFE HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY FOR THE PATIENTS OF RECURRENT GLIOBLASTOMA WITH BEVACIZUMAB TREATMENT FAILURE
Authors: Tabei Yusuke , Sato Kengo , Ichi Shunsuke
Published: November 2019

BACKGROUND

The prognosis for patients with recurrent glioblastoma after Bevacizumab (Bev) treatment is extremely poor. No effective treatment has been established.

PURPOSE

We retrospectively investigated the efficacy and safety of hypofractionated stereotactic radiotherapy with Cyberknife (CK-HSRT) for recurrent glioblastoma after Bev treatment in our institution.

METHODS

GTV (Gross tumor volume) was set in the FLAIR abnormal high signal area that resulted in the contrast lesion and invasive recurrence, and PTV (Planning target volume) = GTV + 2 mm. As aimed CK dose,30 Gray(Gy) in 5 fraction was performed on PTV. Bev(10mg/kg biweekly) was continued after CK. The case background, treatment effect, survival and adverse events were investigated for 21 cases from January 2013 to the end of May 2018.

RESULTS

The median age was 69 (range;31–85) years, and The D95% marginal dose was 27.5 (23–35) Gy in 5 (3–8) divisions. Median PTV was 112 (2–305) ml. The median time to progression after CK was 3.9 months, and the median overall survival after CK was 10.9 months. Early treatment-related adverse events included hair loss in the irradiated area, seizures, headache, nausea and vomiting. As late treatment-related adverse events, symptomatic cerebral radiation necrosis was not observed, but 2 cases of symptomatic cerebral infarction and a case of cerebral hemorrhage were observed. All cases were treated conservatively.

CONCLUSION

CK-HSRT may be well tolerated and effective as a salvage treatment for the patients with recurrent glioblastoma after Bev.
RTHP-08. FAILURE TO COMPLETE STANDARD RADIATION THERAPY IN GLIOBLASTOMA PATIENTS: PATTERNS FROM A NATIONAL DATABASE WITH IMPLICATIONS FOR SURVIVAL AND THERAPEUTIC DECISION MAKING
Authors: Yusuf Mehran , Gaskins Jeremy , Gilbert Mark , Woo Shiao , Burton Eric
Published: November 2019

BACKGROUND

Approximately 5%-10% of patients with newly diagnosed glioblastoma (GBM) will fail to complete standard radiotherapy (SRT). We sought to determine the impact on survival and to identify risk factors for failure to complete SRT.

METHODS

A cohort of 17,451 adults with GBM were identified from the National Cancer Database. The cohort was restricted to patients diagnosed between 2005 to 2012 that were started on conventionally fractionated RT of 1.8 to 2.0 Gy per fraction to a dose of < 66Gy and. Patients were stratified by RT dose achieved: (a.) completed RT > 58Gy, (b.) nearly completed RT > 50Gy - < 58Gy, and (c.) did not complete RT < 50Gy.

RESULTS

Radiotherapy completion rates correlated with survival, 87% of patients completed RT and had a median OS of 13.5 months, 4% were near completers (median OS 5.7 months), and 9% did not complete RT (median OS 1.9 months). Risk factors for not completing SRT were: older age, biopsy alone, government insurance, high comorbidity score and lower income zip code (all OR > 1 and p-values < 0.05). Twenty-eight percent of patients > 80 yrs did not complete SRT (OR 2.99, 95% CI 2.36–3.80, relative to 40–49 yrs) and 19% of 70-79-yrs did not complete SRT (OR 1.99, 95% CI 1.63–2.42).

CONCLUSIONS

Failure to complete SRT was associated with decreased survival in our cohort. Risk factors for failure to complete SRT, include older age, biopsy alone and substantial comorbidities. Other studies have shown SRT is discontinued primarily due to clinical deterioration and/or disease progression. Therefore, these patients should be considered for alternative therapeutic management such as hypofractionated radiotherapy.