bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTH-37. PAK4 INHIBITION REPROGRAMS VASCULAR MICROENVIRONMENT AND IMPROVES CAR T IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Yang Fan , Binder Zev , O’Rourke Donald M , Fan Yi
Published: November 2021

Malignant solid tumors are characterized by aberrant vascularity that inhibits T cell adhesion to vasculature and impedes T cell delivery into the tumors, contributing to glioblastoma (GBM) resistance to T cell-based immunotherapy such as adoptive chimeric antigen receptor (CAR)–T transfer. Vascular abnormality is driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide functional screening of mesenchymal-like transcriptional activation in human GBM-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic programming and aberrant vascularization in tumor. Genetic ablation of PAK4 reprograms EC transcriptome and inhibits mesenchymal-like transformation. Interestingly, deficiency of PAK4 induces adhesion protein re-expression in tumor ECs, reduces vascular abnormalities in tumors, improves T cell infiltration into the tumors, and inhibits GBM growth in mice. Moreover, pharmacological PAK4 inhibition normalizes the tumor vascular microenvironment and sensitizes GBM to Egfrviii CAR–T cell immunotherapy. Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer exciting opportunities to recondition the vascular microenvironment and strengthen cancer immunotherapy.
EXTH-40. MULTIDIMENSIONAL INTERROGATION OF GLIOBLASTOMA MICROENVIRONMENT TREATMENT RESPONSE IN EXPLANT CULTURES
Authors: Shekarian Tala , Bartoszek-Kandler Ewelina , Zinner Carl , Schuerch Christian , Hutter Gregor
Published: November 2021

The immune tumor microenvironment (iTME) of glioblastoma (GBM) contains microglial, macrophage, other myeloid cell populations and as adaptive immune cells. Recent therapeutic strategies for GBM aim at targeting iTME components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of response and resistance. Here, we generated patient-derived, live 3D GBM bioreactors from different tumor regions to assess iTME treatment responses to microglia modulators and immune checkpoint inhibitors. Intact GBM tissue specimens from the tumor center and periphery were cultured for 7 days in the presence or absence of anti-PD1, anti-CD47 antibodies or their combination. Tissues were analyzed by CODEX highly multiplexed microscopy using an immune-centered 54-marker panel, and changes in cytokine and chemokine levels in culture supernatants were investigated. A computational pipeline for integrative therapy response assessment was implemented. Explant cultures from n=8 IDH wt GBM were subjected to this integrative personalized analysis. Tissue integrity after 3D bioreactor cultures was comparable to tissue taken directly after surgery. FFPE CODEX workflow was feasible with adequate staining quality in bioreactor cultures. 850'000 single cells were segmented and clustered. Cellular composition between tumor center and the peripheral invasion zone differed significantly in immune phenotypes, cytokine profile and response to innate, adaptive or combinatorial local immunotherapies. Multiplexed cytokine analysis revealed IFNγ response signatures in a subset of center samples, whereas the peripheral invasion zone displayed a blunted cytokine response. This cytokine signature corresponded to cellular composition shifts within specific cellular neighborhoods. CD4 and CD8 T cells were invigorated and left their vascular niche. Our study demonstrates that local immunotherapies enable an active antitumoral immune response within the tumor center, and provides a multidimensional personalized framework for immunotherapy response assessment.
EXTH-42. COMBINATION OF MAPK PATHWAY INHIBITORS AND IMMUNE CHECKPOINT BLOCKADE IN BRAF-MUTANT HIGH-GRADE GLIOMA
Authors: Park Jong-Whi , Grossauer Stefan , Wang Wei , Daynac Mathieu , Pitteri Sharon , Monje Michelle , Grant Gerald , Petritsch Claudia
Published: November 2021

BACKGROUND

Despite successes, clinical MAPK pathway inhibitors show limited anti-tumor activity in the majority of patients with BRAF-mutant high-grade glioma. Because of the presence of higher fraction of CD8+ tumor-infiltrating T cells in MAPK pathway-altered glioma, we explored the possibility that combined BRAF and MEK inhibition with immune checkpoint blockade enhances anti-tumor response.

METHODS

We engineered mice to carry BRAF V600E expression and CDKN2A deletion in various hemispheric areas. We treated syngeneic tumor-bearing mice with dabrafenib, trametinib, anti-PD-L1 and anti-CTLA-4 antibodies, and analyzed the tumor immune infiltrate by high-dimensional single-cell mass cytometry (CyTOF). RNA sequencing and Gene Set Enrichment Analysis were conducted using patient-derived BRAF-mutant glioma lines upon the inhibitor treatment.

RESULTS

The transcriptome analysis demonstrated that antigen processing and presentation feature is strongly enriched upon dual MAPK pathway inhibition. Consistent with these molecular changes, dabrafenib and trametinib treatment led to dynamic changes in tumor-infiltrating immune cells, including CD8+ and CD4+ T cells. In line with this, combination of MAPK pathway and immune checkpoint inhibitors elicit a significant survival benefit over MAPK pathway inhibition alone in mice with orthotopic BRAF-mutant glioma.

CONCLUSIONS

Clinically relevant molecular targeted therapy by dabrafenib and trametinib and immune checkpoint blockade synergize in pre-clinical models.
EXTH-47. SAFETY AND EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION ON GLIOBLASTOMA MEASURED IN VITRO
Authors: O'Neal Christen , Scott Sydney , Stephens Tressie , McKernan Patrick , Chakraborty Arpan , Babu Anish , Evans Alexander , Glenn Chad , Battiste James
Published: November 2021

BACKGROUND

Although gross total resection (GTR) with chemoradiation is the standard of care for treating glioblastoma (GBM), tumor infiltration and treatment sequelae can impair activity of eloquent regions. Transcranial magnetic stimulation (TMS) has been explored as an adjunct therapy to rehabilitation for post-stroke motor deficits. TMS could be effective for postoperative rehabilitation in GBM, but its effect on GBM cells has not been evaluated. While TMS utilizes magnetic fields to induce electrical currents at low frequencies to cause neuronal excitation or inhibition, tumor-treating fields (TTF) utilize electrical currents with intermediate frequency to exert anti-mitotic effects, demonstrating promise as an adjunctive therapy in recurrent GBM. Although similarities exist between electrical and magnetic fields, the effects of magnetically induced electrical currents at low frequencies via TMS must be studied systematically in vitro on GBM cell lines.

METHODS

We studied the effect of theta burst stimulation (TBS), a form of patterned TMS, on in vitro G55 cell viability using colony forming assays. We compared TMS-treated cells to controls using a combination of parameters: continuous versus intermittent TBS (cTBS and iTBS), 300 versus 600 pulses, stimulation intensity of 32% versus 60%, and no pre-TMS chemotherapy versus 100 nM or 100 µM temozolomide (TMZ). Viability measurements between controls and TMS were analyzed using analysis of variance (ANOVA). Independent t-tests were used to analyze effects of stimulation parameters on viability percent difference within each TMZ condition.

RESULTS

There was no statistically significant increase in viability between control and TMS conditions for any of the stimulation parameters (+/- TMZ) while some showed decreased viability of GBM cells.

CONCLUSIONS

TMS did not significantly increase GBM viability compared to controls. Future studies include validation in other cell lines and characterization of the effects of stimulation parameters in conjunction with TMZ and dexamethasone, (often administered concurrently with GBM treatment).
EXTH-61. MODULATION OF THE IL-27 RECEPTOR SIGNALING PATHWAY IN GLIOBLASTOMA AND ONCOLYTIC VIROTHERAPY
Authors: Panagioti Eleni , Nowicki Michal , Goins William , Macias Jorge Jimenez , Escobar Julia , Zdioruk Mykola , Saini Shikha , Ligon Keith , Anderson Ana Carrizosa , Kuchroo Vijay Kumar , Lawler Sean , Chiocca E Antonio
Published: November 2021

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with median overall survival of 14-16 months. Glioblastoma progression involves multiple immunosuppressive pathways hindering the success of cancer immunotherapy. Oncolytic virotherapy is a promising approach to reprogram the glioblastoma microenvironment and restore anti-tumor immunity. Interleukin (IL)-27 receptor signaling pathway regulates development of effector T cells, IL-10 producing T regulatory type 1 (Tr1) cells and induction of co-inhibitory receptors associated with T cell exhaustion in cancer. In this study, we sought to tackle local and systemic GBM-induced immunosuppression using the novel rQNestin34.5v2 oncolytic herpes simplex virus type-1 (HSV-1), engineered to selectively replicate in glioma cells together with genetic disruptions of the IL-27 receptor signaling pathway. The antitumor activity of HSV-1 rQNestin34.5v2 was evaluated in IL-27ra-/- and wild-type C57BL/6 mice harboring orthotopic CT-2A and GL261 glioblastoma and in athymic nude mice harboring orthotopic patient derived glioblastoma xenografts (PDXs) selected from patients that had been treated in a clinical trial of intratumoral administration of HSV-1 rQNestin34.5v2 (ClinicalTrials.gov: NCT03152318). HSV-1 rQNestin34.5v2 exhibited superior capacity to infect glioma cells in vitro triggering release of proinflammatory cytokines and inducing immunogenic cell death in infected cells. Immune phenotyping of GL261 and CT-2A gliomas revealed astrocytes and microglia express the highest levels of IL-27R. Lack of IL-27R signaling decreased expression of the co-inhibitory receptors PD-1 and Tim-3 on circulating CD4+ T cells suggesting altered CD4+ T cell responses. In the tumor microenvironment, lack of IL-27R signaling decreased immune suppression as evidenced by reduced interleukin (IL)-10 secretion by glioma cells. Despite positive functional modifications on CD4+ T cells, global lack of IL-27R signaling promoted tumor growth accompanied by increased circulating myeloid derived suppressor cells (MDSCs) in the GL261 model. Experiments to address the immunoregulatory role of IL-27R signaling during HSV-1 rQNestin34.5v2 virotherapy-induced glioma tissue destruction are ongoing.
EXTH-67. THERAPEUTIC EFFICACY OF GC1118, A NOVEL ANTI-EGFR ANTIBODY, AGAINST GLIOBLASTOMA WITH HIGH EGFR AMPLIFICATION IN PATIENT-DERIVED XENOGRAFTS
Authors: Choi Seung Won
Published: November 2021

We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.
EXTH-70. ESTABLISHMENT OF INTRAVENTRICULAR SHH INHIBITION AS A THERAPEUTIC OPTION IN YOUNG PATIENTS WITH MEDULLOBLASTOMA
Authors: Kresbach Catena , Schoof Melanie , Leven Tara , Holst Lea , Yorgan Timur , Wrzeszcz Antonina , Rutkowski Stefan , Schüller Ulrich
Published: November 2021

Medulloblastoma is the most common malignant brain tumor in children. The embryonal tumor arises in the posterior fossa and disseminates via the cerebrospinal fluid. Medulloblastoma divides in four molecular subgroups, one of which is characterized by mutations in the sonic-hedgehog (SHH) -pathway. SHH inhibition provides an elegant way of targeted therapy. The small molecule Vismodegib allosterically inhibits Smoothened (SMO), an upstream activator of SHH. Unfortunately, Vismodegib has shown to cause irreversible premature epiphyseal growth plate fusions in preclinical studies and clinical trials, preventing its systemic application in children (Kimura et al. 2008; Robinson et al. 2017). We established an intraventricular therapy with Vismodegib, combining the benefits of targeted drug delivery and minimizing systemic side effects. In a mouse model for SHH medulloblastoma, we compare intraventricular, oral and placebo treatment regarding effects on survival, tumor biology, and bone morphology. Math1-cre::Ptch1 Fl/Fl mice show a homozygous loss of PTCH1 in Math1-positive cells, resulting in SHH-pathway overactivation and development of SHH medulloblastomas. At postnatal day 11-13, Math1-cre::Ptch1 Fl/Fl mice were randomized in four treatment arms: group A (n= 9) received placebo intrathecally, B (n= 9) received Vismodegib 200 mg/kd/d orally, C (n= 19) received Vismodegib 0.2 mg/kg/d intrathecally, and D (n= 8) received Vismodegib 1.6 mg/kg/d intrathecally. Kaplan-Meier survival analysis showed a significant survival benefit for 1.6 mg/kg/d intraventricular Vismodegib compared to placebo (p= 0.012). Bone histology and X-ray analysis of intraventricular treated mice showed intact femoral and tibial growth plates, in contrast to orally treated mice that developed skeletal malformations. Further analyses such as DNA sequencing, gene expression analysis, and histological evaluation are ongoing and will add to the picture of the anti-tumor effects of intraventricular SHH-inhibition. Based on the preliminary experimental results, we conclude that intrathecal application of a SMO-inhibitor might evolve as a promising new way of targeted treatment of SHH medulloblastomas.
EXTH-74. INCREASING CANCER CELL MEMBRANE PERMEABILITY THROUGH APPLICATION OF TUMOR TREATING FIELDS (TTFIELDS)
Authors: Voloshin Tali , Koltun Bella , Koren Lilach , Porat Yaara , Volodin Alexandra , Kaynan Noa , Klein-Goldberg Anat , Paz Rom , Brant Boris , Zemer-Tov Efrat , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: November 2021

INTRODUCTION

Tumor Treating Fields (TTFields) are intermediate frequency, alternating electric fields with anti-mitotic effects on cancerous cells. TTFields are delivered non-invasively through arrays placed on the skin at the tumor region. TTFields therapy is approved in several territories for treatment of glioblastoma (GBM) and mesothelioma. Recently, TTFields have been shown to increase GBM cell membrane permeability. The current study aimed to explore this effect in multiple cell lines and examine the potential benefits of combining TTFields with other anticancer agents.

METHODS

TTFields were delivered to GBM (U-87 MG), uterine sarcoma (MES-SA), and breast adenocarcinoma (MCF-7) cell lines for 72hr across a range of frequencies (50-500kHz). Cytotoxicity of TTFields was examined by cell counts, and intracellular accumulation of 7-aminoactinomycin D (7-AAD) was measured by flow cytometry. Exposing the cells to 7-AAD at different time points relative to TTFields application cessation was used to determine the kinetics of cell membrane permeability. The potential of TTFields to facilitate intracellular accumulation of anthracycline chemotherapeutics was tested in chemotherapy-sensitive and chemotherapy-resistant cells.

RESULTS

Elevated intracellular accumulation of 7-AAD was observed in all examined cell lines treated with TTFields, at an optimal frequency that differed from that for maximal TTFields-induced cytotoxicity. No intracellular accumulation of 7-AAD was seen for measurements performed after termination of TTFields application, indicating that increased cell membrane permeability by TTFields was temporary and reversible. Lastly, the accumulation of chemotherapeutic agents in chemotherapy-resistant cancer cells was elevated to the same extent as in matched chemotherapy-sensitive cells when TTFields were delivered concomitant with chemotherapy.

CONCLUSIONS

TTFields increased cancer cell permeability in a transient and reversible manner across multiple cancer cell types. The increased permeability enhanced intracellular accumulation of chemotherapeutics, even within chemotherapy-resistant cells.
EXTH-75. APPLICATION OF TUMOR TREATING FIELDS (TTFIELDS) TO THE HEAD AND TORSO OF MICE WITH THE DEDICATED INOVIVO SYSTEM
Authors: Davidi Shiri , Blatt Roni , Munster Mijal , Shteingauz Anna , Porat Yaara , Zeidan Adel , Marciano Tal , Bomzon Zeev , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: November 2021

INTRODUCTION

Tumor Treating Fields (TTFields) therapy is an approved anti-cancer treatment for glioblastoma and mesothelioma. TTFields are delivered to patients continuously by two sets of arrays placed on opposite sides of the body at the tumor region to generate two perpendicular electric fields. Previously, in vivo studies of TTFields were limited due to the lack of a dedicated system that could maintain continuous and adequate contact of the arrays with the animal’s skin as well as the stress imposed on the animals by individual housing and the motility limitations they experience during treatment.

METHODS

Different electrode layouts were explored to optimize the intensity of the electric fields delivered to the target locations (therapeutic threshold >1 V/cm). The ability of various adhesive materials and wire coiling prevention strategies to increase TTFields device usage was examined. Stress reduction with different housing methods was evaluated via clinical examination of the animals.

RESULTS

Optimal array layouts were identified based on simulation data for TTFields delivery to the torso or the head of the mouse. Compacting conductors into a single printed circuit cable connected to a novel electric swivel machine resulted in fewer wire entanglements, and the improved adhesives resulted in fewer array replacements, overall elevating device usage. Improved cage design permitted pairs of mice to maintain social interactions while individually housed. Less weight loss was seen for animals housed in the dyadic relative to the standard solitary cages, indicating reduced stress.

CONCLUSIONS

The inovivo system provides means for continuous delivery of therapeutic levels of TTFields to the head and torso of mice while minimizing animal stress and increasing device usage. The new head arrays enable application of TTFields to the head of mice for the first time, allowing expansion of glioblastoma treatment research.
EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE
Authors: Yang Yuanfan , Brown Michael , Stevenson Kevin , lopez Giselle , Kornahrens Reb , Zhang Gao , Gromeier Matthias
Published: November 2021

Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.
EXTH-81. STING ACTIVATION PROMOTES ROBUST IMMUNE RESPONSE AND TUMOR REGRESSION IN GLIOBLASTOMA MODELS
Authors: Berger Gilles , Knelson Erik , Nowicki Michal , Mooney David , Chiocca E Antonio , Barbie David , Lawler Sean
Published: November 2021

The immunosuppressive tumor microenvironment in glioblastoma presents a major barrier to effective application of immunotherapeutic approaches in this disease. Although immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease glioblastoma remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties, but has not been well investigated in glioblastoma to date. Here we investigated the presence of STING pathway components in glioblastoma patient specimens and cell lines by Western blotting and immunostaining. The functionality of the pathway was determined by ELISA, and immune infiltrates, and animal survival were investigated in mouse glioblastoma models after treatment with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature, and appears to be activated as evidenced by elevated phosphoTBK1 staining. We show that human GBM cells do not respond agonists, but that GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.
QOLP-02. HEALTH-RELATED QUALITY OF LIFE (HRQOL) AMONG PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMA (PN) IN THE UNITED STATES: PERSPECTIVES OF THE PATIENTS AND CAREGIVERS
Authors: Yang Xiaoqin , Yoo Hyun Kyoo , Amin Suvina , Cheng Wendy , Sipsma Heather , Sundaresan Sanjana , Zhang Lujia , Duh Mei Sheng
Published: November 2021

BACKGROUND

PNs occur in 30-50% of pediatric patients with NF1, often resulting in debilitating pain, mobility limitations, significant disfigurement, and may be life-threatening. Real-world evidence on the HRQoL of pediatric NF1 PN patients is limited.

METHODS

Patients ages 8-18 years with NF1 PN (treatment-naïve/new on selumetinib [≤ 1 month of use]) and their caregivers were recruited through Children’s Tumor Foundation to participate in an online cross-sectional survey (12/2020-1/2021). HRQoL measures included Pediatric Quality of Life Inventory (PedsQL; Acute version), Pain Interference Index (PII), and Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity functioning subscales. Patients provided self-reported responses; caregivers provided proxy responses and patient characteristics. Agreement between patient-reports and caregiver proxies was assessed using intra-class correlation coefficients (ICCs).

RESULTS

61 patient-caregiver dyads participated in the survey. Patients were mostly white/Caucasian (90.2%), 50.8% female, with a median (range) age of 13.0 (11-16) years. Most were treatment-naïve (96.7%), with NF1 and PN diagnosis for > 5 years (91.8%, 82.0%). On the PedsQL (range: 0-100; higher=better; healthy patient mean scores typically > 80), patient-reported mean scores were 50.3, 56.1, 60.7, and 63.7 for school, emotional, social, and physical functioning; mean total score= 58.5. Caregiver-proxy mean scores ranged from 49.9-61.5 across subscales; mean total score= 55.4. Among patients reporting pain in the last 7 days, PII mean scores (range: 0-6; higher=more interference) were 3.0 (patient-reports) and 2.9 (caregiver proxies). Among patients with movement difficulty in the past 7 days, mean PROMIS scales t-scores (distribution mean= 50; higher=better) were 40.2 and 39.5 (patient-reports), and 35.6 and 30.1 (caregiver proxies), for mobility and upper extremity functioning. ICCs were very good, ranging from 0.85-0.93 across HRQoL measures.

CONCLUSION

NF1 PN can have substantial negative impact on pediatric patients, as demonstrated across various HRQoL domains, highlighting the importance of collecting patient-centered outcomes to guide treatment decisions.
QOLP-10. A LONGITUDINAL OBSERVATIONAL STUDY OF EXERCISE BEHAVIOR IN GLIOBLASTOMA PATIENTS TREATED WITH TUMOR-TREATING FIELDS
Authors: Peters Katherine , Affronti Mary , Kim Jung-Young , Patel Mallika , Johnson Margaret , Bartlett David , Cort Nicole , Lipp Eric , Iden Deborah , Broadwater Gloria , Herndon James , Landi Daniel , Khasraw Mustafa , Desjardins Annick , Friedman Henry , Ashley David M
Published: November 2021

Glioblastoma (GBM) patients can use tumor-treating fields (TTFs) with adjuvant temozolomide (TMZ) to treat their disease. TTFs involve wearing transfixed transducers to the shaved scalp, and the transducers are wired to a battery pack that is either fixed or carried (weighing 2.7 pounds). EF-14 clinical trial did evaluate health-related quality of life with standardized patient-report outcome measures but did not measure exercise behavior. We sought to evaluate the exercise behavior of GBM patients using TTFs. We consented GBM patients who intended to use TTFs with adjuvant TMZ after completion of chemoradiation. After informed consent and before starting TTFs, patients completed a self-administered questionnaire, Godin Leisure-Time Exercise Questionnaire, to assess exercise behavior/physical function. To calculate our primary outcome of total exercise behavior, the frequency of exercise sessions per week within each intensity category was multiplied by the average reported duration, weighted by an estimate of the MET, summed across all intensities, and expressed as average MET-hr/wk. Prior work has defined that physical function can be compared as < 9 MET-h/wk vs. ≥ 9 MET-h/wk. We evaluated at baseline and up to 24-week exercise behavior in patients with TTFs vs. historical controls not using TTFs. We enrolled 19 total GBM patients, with 14 proceeding to use TTFs. Of the 14 patients on TTFs, seven patients (50%) completed ≥ 9 MET-h/wk of exercise, and this level was maintained 8, 16, and 24 weeks after starting TTFs. Six months after the completion of chemoradiation, mean MET-h/wk was decreased in the TTFs group (n=6) (10.71 sd=7.06) vs. historical controls (n=38) (27.35 sd=46.94). TTFs did not interfere with exercise behavior in our GBM cohort, but when compared to GBM patients not utilizing TTFs, there could be a long-term impact on exercise behavior. More research is needed to evaluate exercise behavior in GBM patients using TTFs.
QOLP-15. FEASIBILITY OF AN ELECTRONIC PATIENT REPORTED STEROID TOXICITY MONITORING PROGRAM IN PATIENTS WITH MALIGNANT GLIOMAS
Authors: Macher Jared , Wasilewski Andrea
Published: November 2021

OBJECTIVE

To determine the feasibility of a longitudinal, electronic, patient-reported survey of steroid toxicity in patients with malignant glioma (MG).

BACKGROUND

Corticosteroids are frequently used for management of cerebral edema in MG, with side effects resulting from prolonged use or high dosage. Corticosteroid use is common and may negatively impact quality of life (QOL) and survival in MG.

DESIGN/METHODS

We prospectively enrolled patients with MG receiving neuro-oncologic care at the University of Rochester with or without their caregivers on an IRB-approved study. Subjects received 12 weekly electronic questionnaires through a secure health portal focused on symptoms of corticosteroid toxicities, dosing and functional status. Weekly toxicity scores were calculated based on the number of reported toxicities (0-17). Completed questionnaires were reviewed by a care team member to inform clinical management. Corticosteroid dosing adjustments were documented in the medical record. Feasibility was defined as an overall questionnaire completion rate of 70%.

RESULTS

11 patient/caregiver pairs were enrolled (11 patients, including 9 with caregivers). Median patient age was 58. Patient tumors were glioblastoma (82%), anaplastic astrocytoma (9%) and anaplastic oligodendroglioma (9%). Phase of treatment was concurrent (55%), adjuvant (36%) and recurrence (9%). Median dexamethasone does at study start and conclusion were 4mg/day and 3mg/day. Median weekly toxicity score was 5/17 (range: 0-14). The most common toxicities were muscle weakness, sleep disturbance and weight gain and were reported by 82% of participants. Overall questionnaire completion rate was 81%. Ten percent of questionnaires resulted in clinically significant symptoms requiring follow-up from a provider.

CONCLUSION

Patients with MG experience frequent corticosteroid toxicities. Electronic corticosteroid toxicity monitoring is feasible in patients with MG and may lead to changes in management. Future studies are needed to assess utility of this tool and impact on QOL and survival.
QOLP-33. EVIDENCE OF FINANCIAL TOXICITY IN PRIMARY CENTRAL NERVOUS SYSTEM TUMOR PATIENTS: CORRELATIONS BETWEEN EMPLOYMENT STATUS, SYMPTOM BURDEN AND HEALTH-RELATED QUALITY OF LIFE
Authors: Christ Alexa , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Grajkowska Ewa , Jammula Varna , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri , Leeper Heather
Published: November 2021

SIGNIFICANCE AND AIMS

Financial toxicity (FT) after a cancer diagnosis is the consequence of decreased earnings and increased spending. In patients with primary central nervous system (PCNS) tumors, the correlation between FT and factors such as symptom burden, psychological distress, and health-related quality of life has not been extensively studied. We assessed employment status and several patient illness factors in a PCNS tumor cohort.

METHODS

Patient and disease characteristics and patient-reported outcomes (PROs) were collected from adults diagnosed with PCNS tumors between 9/2016-12/2019. Descriptive statistics and regression analyses were used to describe PROs.

RESULTS

Of 277 patients, 77 (28%) reported being unemployed due to tumor diagnosis. They reported difficulty walking (64%) and performing usual activities (64%). This group had lower general health status (p< 0.001) and higher tumor-related symptom severity (p=0.004) than employed patients. Unemployed patients reported high symptom burden with an average of 6 moderate-severe symptoms for those with brain tumors and 10 for those with spine tumors. Both brain and spine tumor patients who were unemployed reported increased mood-related interference (p=0.020), as well as moderate-severe anxiety (30%) and depression (25%) compared to employed patients (15% vs 8%, respectively). Unemployed brain tumor patients reported worse scores in cognitive and neurologic symptom subscales (p< 0.001).

CONCLUSIONS AND IMPLICATIONS

These data provide indirect evidence that financial toxicity that correlates with high symptom burden across several domains and lower health-related quality of life. Future research work will include the COST questionnaire to further evaluate the implications of FT in the PCNS tumor patient population.
RBIO-05. THE IMPACT OF STEREOTATIC RADIOSURGERY (SRS) FOR THE RESIDUAL LESIONS OF PINEAL NON-GERMINOMATOUS GERM CELL TUMORS (NGGCTS) FOLLOWING CONVENTIONAL RADIOTHERAPY: A RETROSPECTIVE STUDY
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Li Shaoqun , Cai Linbo
Published: November 2021

OBJECTIVE

To evaluate the safety and efficacy of stereotatic radiosurgery (SRS) in treating residual lesions of pineal non-germinomatous germ cell tumors (NGGCTs) after conventional radiotherapy.

METHODS

The patients admitted to Guangdong Sanjiu Brain Hospital from 1 January 2008 to 31 December 2018 who diagnosed with pineal NGGCTs pathologically or clinically were retrospectively analyzed. Among those, the patients received conventional radiotherapy with or without SRS were included. The residual lesions after radiotherapy were defined with a maximum diameter > 10mm. Prognosis related parameters such as local control rate, progress-free survival, overall survival and treatment-related toxicity were determined.

RESULTS

The median follow-up time was 34 months (range 8-142 months). The objective response rate and disease control rate were 71.4% and 95.2%, respectively. Three-year progression-free survival rate was 85.2% and 3-year total survival rate was 88.0%. The univariate analysis revealed that both age and concurrent chemotherapy were not correlated with the prognosis (P=0.286, 0.824). Partial tumor resection before radiotherapy and chemotherapy, AFP >500ng/ml, and no more than 4 cycles of adjuvant chemotherapy were poor prognostic factors (P=0.037, 0.010, 0.006). Moreover, no acute radiation response was observed after treatment with SRS. Only 1 out of 27 patients (3.7%) had brain neurotoxicity related to a prolonged course of radiochemotherapy.

CONCLUSION

SRS for residual lesions of NGGCTs following conventional radiotherapy appears to be well tolerant and improved local control. However, the therapeutic efficacy of conventional radiotherapy combined with SRS warrants further investigations in a large-scale randomized controlled clinical trials.
RBIO-06. MECHANISM OF ACTION AND ASSOCIATED EFFECTS OF TUMOR TREATING FIELDS (TTFIELDS) ON LIVING CELLS USING SIMULATIONS
Authors: Marciano Tal , Levi Shay , Fedorov Eduard
Published: November 2021

Following FDA approval, TTFields treatment has become a commonly used modality for treating patients with Glioblastoma (GBM) and Mesothelioma. From the early 2000’s, extensive research has been performed in in-vitro systems for studying the effects of TTFields on living cells. These studies have shown that multiple cellular functions are affected by TTFields. However, the physical mechanism by which the fields exert effects on cells are not well understood. We propose an analytical model for predicting the geometric and electrical parameters enabling amplification of the electric field in the living cells. This amplification favors the emergence of local heating, dielectrophoretic (DEP) force, or electrostatic pressure at TTFields frequencies. This model is supported by simulations of cells in different configurations. Computational studies were performed with Comsol Multiphysics software. Cell models were constituted of cytoplasm, membrane and extracellular matrix. A field of 1V/cm was generated at different frequencies between 10kHz and 1GHz. Maximal field amplification of X20 of the applied field (@200 kHz) was observed in a model of confluent cells with 5nm intercellular distance. Such field amplification could create electrostatic pressure on the membrane potentially leading to its deformation and to stress on the cytoskeleton. Analytical calculations show the field gradient could result in DEP forces of ~10pN on the membrane. Such force could potentially disrupt the membrane or junctions. Results show that a 10nm pore in membrane would lead to a 450 times amplification in the pore’s vicinity, potentially resulting in forces of between 0.1pN and 100pN on intracellular structures. Those forces are sufficient for disrupting microtubules. Specific Absorption Rates of up to 106 W/kg were observed in the vicinity of the pore, suggesting that strong thermal effects may also explain the effect of TTFields on cells. Our generic analytical model predicts the conditions for field amplification at TTFields frequencies.
RTID-08. MACHINE LEARNING TO UNCOVER SIGNATURES OF VULNERABILITY IN GLIOBLASTOMA UMBRELLA SIGNATURE TRIAL (GUST)
Authors: Peng Sen , Lee Matthew , Tang Nanyun , Ahluwalia Manmeet , Fonkem Ekokobe , Fink Karen , Raizer Jeffrey , Walker Christopher , Dhruv Harshil , Berens Michael
Published: November 2021

Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. A contingency of an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely-most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potential better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status and whole transcriptome data. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM.

Surgical Therapies
SURG-02. NEUROSURGICAL RESECTION FOR LOCALLY RECURRENT BRAIN METASTASIS
Authors: Hulsbergen Alexander , Abunimer Abdullah , Ida Fidelia , Kavouridis Vasileios , Cho Logan , Tewarie Ishaan , Mekary Rania , Schucht Philippe , Phillips John , Verhoeff Joost , Broekman Marike , Smith Timothy
Published: November 2021

BACKGROUND

In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population.

METHODS

Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM).

RESULTS

Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with >24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (p < 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, p < 0.05) but similar ICC (hazard ratio 1.11 in both groups, p > 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes.

CONCLUSIONS

In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.
SURG-13. THE TENTATIVE APPLICATION OF EN BLOC CONCEPT IN THE PEDIATRIC BRAIN TUMOR: EXPERIENCE FROM A LARGE PEDIATRIC CENTER IN CHINA
Authors: Cao Liangliang , Ma Jie
Published: November 2021

BACKGROUND

The less allowable blood loss and tolerance of intraoperative blood loss of children lead to the high rate of massive blood transfusion. The surgical concepts of en bloc resection may contribute to the improvement of brain tumor resection.

OBJECTIVE

To investigate the effects of en bloc concept on short outcomes of pediatric brain tumors and factors associated with the application of en bloc concept.

METHODS

According to the surgical concept involved, the patients were divided into three subgroups-complete en bloc concept, partial en bloc concept and piecemeal concept. The matching-comparison(en bloc group consisting of the first two subgroups and piecemeal group) was conducted to investigate the effect of the en bloc concept on the short-term outcomes. Then the patient data after January 2018, when the en bloc concept was routinely integrated into brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept.

RESULTS

In the en bloc group, the perioperative outcomes, including hospital stay(p=0.001), PICU stay(p=0.003), total blood loss(p=0.015), transfusion rate(p=0.005) and complication rate(p=0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, like encasing nerve or pass-by vessel, finger-like attachment, ratio of “limited line” and ratio of “clear line” remained independent predictors for the application of en bloc concept in our medical center.
TAMI-01. BRAIN METASTASES: CURRENT LITERATURE REVIEW
Authors: Raval Ruchi , Pandya Aadi , Behl Jaspreet , Raval Sumul
Published: November 2021

PURPOSE

As more information is gathered about brain metastases, it still remains that the current prognosis of brain metastases is very poor. Due to this, it is imperative that physicians are aware of the most important components regarding brain metastases. This literature review will encompass the most current literature in order to highlight the most crucial information.

METHODS

All mentioned studies and literature reviews cited in the paper were obtained through various sites, and were published between 1996 and 2017. The main components that were required from the papers reviewed included where in the body the brain metastases originated from, where in the brain they tended to spread to, what the signs and symptoms typical of patients with brain metastases are, and what the options are in terms of treatment.

RESULTS

Using the results from a variety of studies performed within the past three decades, it is apparent that brain metastases most commonly originate from, in order of increasing frequency, lung cancer, breast cancer, melanoma, and colorectal cancer. In addition, it is reaffirmed that the magnetic resonance imaging (MRI) is the best diagnostic tool to be used when dealing with brain metastases. The most frequent signs and symptoms of a brain metastases include cognitive changes, headaches, weakness, and seizures. Finally, supportive treatment includes use of corticosteroids, antiepileptic drugs (AEDs), and anticoagulation therapy. Definitive treatment for brain metastases varies based on size, location, and prevalence in the brain, but the most effective options include chemotherapy, radiation therapy, and surgery.

CONCLUSIONS

The study’s results confirm the need for more research to be done regarding brain metastases, and better options to increase the survival of patients.
TAMI-04. OLFACTORY RECEPTOR 5B21 DRIVES BREAST CANCER BRAIN METASTASIS THROUGH STAT3/NFΚB/CEBPΒ PATHWAY
Authors: Li Mao , Schweiger Markus , Ryan Daniel , Nakano Ichiro , Carvalho Litia , Tannous Bakhos
Published: November 2021

Olfactory receptors (ORs), responsible for the sense of smell, play an essential role in various physiological processes outside the nasal epithelium, including cancer. In breast cancer, however, the expression and function of ORs remain understudied. We established a breast cancer metastasis model by intracardiac injection of MDA-MB-231 (231P) in immunocompromised mice and produced a series of derivative cell lines from developed metastatic sites, including the brain-seeking clone (231Br). We examined the significance of ORs transcript abundance in primary and metastatic breast cancer to different tissues, including the brain, bone, and lung. While 20 OR transcripts were differentially expressed in distant metastases, OR5B21 displayed high expression in all three metastatic sites with respect to the primary tumor, especially in brain metastasis with 13 fold higher than the primary site. Metastatic clones showed distinguishing higher invasion biological characteristics compared to parental cells in vivo and in vitro. Knockdown of OR5B21 significantly decreased the invasion and migration of MDA-MB-231 Brain-seeking metastatic cell as well as metastasis to different organs, including the brain, while overexpression of OR5B21 had the opposite effect. Mechanistically, OR5B21 expression was associated with epithelial to mesenchymal transition through the STAT3/NFkB/CEBPβ signaling pathway. We propose OR5B21 (and potentially other ORs) as a novel oncogene contributing to breast cancer brain metastasis and a potential target for adjuvant therapy.