bluuebunny/crossref_metadata_2025 huggingface dataset:
The ultraluminous X-ray source bubble in NGC 5585
Authors: Soria R , Pakull M W , Motch C , Miller-Jones J C A , Schwope A D , Urquhart R T , Ryan M S
Published: December 2020

Some ultraluminous X-ray sources (ULXs) are surrounded by collisionally ionized bubbles, larger and more energetic than supernova remnants: they are evidence of the powerful outflows associated with super-Eddington X-ray sources. We illustrate the most recent addition to this class: a huge (350 pc × 220 pc in diameter) bubble around a ULX in NGC 5585. We modelled the X-ray properties of the ULX (a broadened-disc source with LX ≈ 2–4 × 1039 erg s−1) from Chandra and XMM–Newton, and identified its likely optical counterpart in Hubble Space Telescope images. We used the Large Binocular Telescope to study the optical emission from the ionized bubble. We show that the line emission spectrum is indicative of collisional ionization. We refine the method for inferring the shock velocity from the width of the optical lines. We derive an average shock velocity ≈125 km s−1, which corresponds to a dynamical age of ∼600 000 yr for the bubble, and an average mechanical power Pw ∼ 1040 erg s−1; thus, the mechanical power is a few times higher than the current photon luminosity. With Very Large Array observations, we discovered and resolved a powerful radio bubble with the same size as the optical bubble, and a 1.4-GHz luminosity ∼1035 erg s−1, at the upper end of the luminosity range for this type of source. We explain why ULX bubbles tend to become more radio luminous as they expand while radio supernova remnants tend to fade.
BIOM-17. BRAF MUTATION IS AN EARLY EVENT IN THE EVOLUTION OF A SUBSET OF GLIOBLASTOMAS AND IS ASSOCIATED WITH INCREASED PD-L1 EXPRESSION
Authors: Walsh Kyle , Xiu Joanne , López Giselle , Landi Daniel , Reitman Zachary , Mittal Sandeep , Brenner Andrew , Fonkem Ekokobe , Kesari Santosh , Phuphanich Surasak , Newton Herbert , Pandey Manjari , Lou Emil , Glantz Michael , Sumrall Ashley , Dunbar Erin , De La Fuente Macarena , Korn W Michael , Khasraw Mustafa , Ashley David
Published: December 2020

INTRODUCTION

BRAF is a RAF-family kinase that regulates MAPK/ERK signaling. Activating BRAF mutations, including V600E, are common in circumscribed low-grade gliomas of childhood and young adulthood, but are uncommon in infiltrative astrocytomas, including glioblastoma. Their role in glioblastoma initiation and progression requires analysis of large datasets given the low frequency (1.0%) in TCGA IDH-wild-type glioblastomas.

METHODS

Molecular profiling was done on 4679 FFPE gliomas by next-generation sequencing at Caris Life Sciences, of which 3170 underwent RNA-sequencing for gene fusion and 4603 DNA-sequencing for mutations. MGMT promoter methylation was tested by pyrosequencing and PD-L1 IHC was performed using the SP142 clone.

RESULTS

Excluding variants of uncertain significance, BRAF mutations/fusions were most common in pleomorphic xanthoastrocytoma (PXA; N=12/24, 50%), glioneuronal tumors (N=6/13, 46%), pilocytic astrocytoma (PA; N=15/48, 31%), and ganglioglioma (n=5/18, 28%). BRAF fusions were uncommon (N=17), most frequent in PA (N=8/31, 26%) where they were associated with older age at daignosis (P=0.043), and typically involved KIAA1549 as fusion partner (70%). BRAF-mutated/fused glioblastoma patients (N=59/3126, 2%) were younger than BRAF-wild-type glioblastoma patients (54 versus 59 years, P=3.5x10-3); more likely to be MGMT-unmethylated (75% versus 56%, P=5.0x10-3); and 3x more likely to express PD-L1 (55% versus 17%, P=2.1x10-10). In tumors harboring a V600E mutation, the variant allele frequency (VAF) was similar in glioblastoma as in PXA, PA, ganglioglioma, and glioneuronal tumors (median VAF=35%).

CONCLUSIONS

BRAF-mutated glioblastoma were 3x more likely to express PD-L1 than BRAF-wild-type glioblastoma. We observed no differences in BRAF V600E clonality in BRAF-mutated glioblastoma compared to BRAF-mutated PXA, PA, ganglioglioma, and glioneuronal tumors, suggesting BRAF mutation is an initiating event in the clonal evolution of a subset of glioblastoma. There is rationale to evaluate combined BRAF inhibition with checkpoint inhibition in BRAF-mutated glioblastoma, potentially synergizing the complete response profile of the former with the durable response profile of the latter.
COVD-07. THE IMPACT OF COVID-19 ON PATIENTS AND CAREGIVERS AFFECTED BY BRAIN TUMORS: THE PATIENT NAVIGATOR PERSPECTIVE
Authors: Walsh Kyle
Published: December 2020

BACKGROUND

Preliminary evidence indicates that glioma patients are at higher risk for COVID-19 complications due to systemic immunosuppression. Interruptions in cancer care may exacerbate patient and caregiver anxiety, but surveying patients/caregivers about their COVID-19 experiences is often limited by attainable sample sizes and over-reliance upon single-institution experiences.

METHODS

To explore how COVID-19 is impacting brain tumor patients/caregivers across the U.S., we performed semi-structured interviews with brain tumor patient navigators employed by two different 501(c)3 nonprofit organizations. A semi-structured interview guide was used, utilizing prompts and open-ended questions to facilitate dialogue. A core set of COVID-19 topics were covered, including: financial issues, coping strategies, geographic variability, variability by tumor grade/histology, disruptions in care continuity, accessing clinical trials, psychosocial issues, and end-of-life care. Interviews were audio-recorded, transcribed, and organized by discussion topic to identify emerging themes. Inductive sub-coding was completed using the constant comparison method, within and between transcripts.

RESULTS/CONCLUSIONS

Ten patient navigators were interviewed between April 15th and May 8th, with interviews lasting approximately one hour (range 38-77minutes). Navigators reported having contact with 183 unique brain tumor families during the pandemic (range 7–38 families per navigator). High concordance emerged across narratives, revealing important considerations for the neuro-oncology workforce. The most prominent theme was increased caregiver burden, attributed to maintaining social distancing by reducing visits from home-health aides and friends/family. A related theme that applied to both patients and caregivers was increased social isolation due to social distancing, suspension of in-person support groups, and church/temple closures. Accessing clinical trials was a recurrent issue, exacerbated by patients’ increasing unwillingness to travel. Glioblastoma patients, especially those with recurrent tumors, expressed greater reluctance to travel. Access to standard-of-care treatment was rarely interrupted, but reduced access to supportive services – especially physical and occupational therapy – was identified as an emerging COVID-related deficiency in clinical care.
CTIM-01. GLIOBLASTOMA RE-IRRADIATION: IMPACT OF CONCOMITANT CHEMOTHERAPY
Authors: Epaillard Nicolas , Hammoudi Nassim , Faron Matthieu , ammari Samy , Pallud Johan , Louvel Guillaume , Lezghed Naima , Garcia Gabriel , Bockel Sophie , Copaciu Razvan , Dezami Edouard , Knafo Steven , Benadhou Lyna , Abbar Baptiste , Seknazi Lauren , Abdayem Pamela , Simonaggio Audrey , Bourcier Kevin , Dhermain Frederic , Dumont Sarah
Published: December 2020

PURPOSE

Although the standard of initial treatment is well defined for glioblastoma, no recommendation exists in the relapse setting. This work focuses on the optimal strategy for recurrent glioblastoma.

METHODS

Retrospective monocentric analysis of all recurrent glioblastoma adult patients treated since 2000 in one center by re-irradiation, alone or combined with chemotherapy and/or surgery at first or second relapse.

RESULTS

Patient (n=61) median age was 55 (27 to 76), 44% were women. At diagnosis, 77% underwent surgical resection and 23% were biopsied. Most (95%) received a Stupp regimen. After a median follow-up of 31.1 months, 44 patients (72%) had died, median overall survival (mOS) was 39.8 months. Regardless of the time of treatment, patients treated with radiotherapy concomitant to bevacizumab (RTbev) showed superior survival data compared to patients treated with radiotherapy alone (RTalone). At first relapse, median progression free survival (mPFS) of RTbev was 9.9 versus 3.6 months for RTalone (OR=3.98 (3.14–61.81); p=0.001). At second relapse, mPFS of RTbev was 9.2 versus 5.4 months for RTalone (OR=2.31 (1.18–7.75); p=0.029), and mOS of RTbev was 15.2 versus 9.1 months for RTalone (OR=3.60 (2.17–18.13); p=0.001).

CONCLUSION

This retrospective monocentric analysis reports a favourable impact of bevacizumab adjunction to re-irradiation.
CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS
Authors: De La Fuente Macarena , Koru-Sengul Tulay , Heros Deborah , Miao Feng , Marrero Alain Fernandez , Tejera Dalissa , Liendo Michelle , Khan Aisha , Ayad Nagi , Ivan Michael , Komotar Ricardo
Published: December 2020

BACKGROUND

Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells.

METHODS

Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel.

RESULTS

A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed.

CONCLUSION

Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.
CTIM-14. PELAREOREP AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) WITH STANDARD CHEMORADIOTHERAPY/ADJUVANT TEMOZOLOMIDE FOR GLIOBLASTOMA MULTIFORME (GBM) PATIENTS: REOGLIO PHASE I TRIAL RESULTS
Authors: Kendall Jessica , Chalmers Anthony , McBain Catherine , Melcher Alan , Samson Adel , Phillip Rachel , Brown Sarah , Short Susan
Published: December 2020

BACKGROUND

Oncolytic viruses represent a novel treatment approach in GBM through oncolytic targeting as well as local immune activation. We designed a phase Ib, open-label study of intravenous reovirus (pelareorep) with GM-CSF alongside standard chemoradiotherapy to assess safety and tolerability.

METHODS

15 patients with newly diagnosed GBM were treated with GM-CSF 50mg subcutaneously (days 1–3) and pelareorep (days 4–5) in weeks 1 and 4 of chemoradiotherapy, and week 1 of adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Secondary objectives were to gain preliminary assessment of the activity of the combination and assess treatment compliance.

RESULTS

1 dose limiting toxicity (DLT) and 20 SAEs were experienced overall; median number of SAEs per patient was 2. Commonest SAEs were nervous system disorders, predominantly seizures. SARs included fever/flu-like episodes (n=5), fall (n=1) and headache (n=1). Two SUSARs occurred in dose level 2, classed as vascular disorders manifesting as hypotension episodes – one was a DLT. Suspected relationship of SARs: pelareorep (n=6); temozolomide (n=1); radiotherapy (n=1); all study drugs (n=1). 87% of patients (n=13) completed chemoradiotherapy without unplanned delays. Adjuvant treatment was delayed in 21% of cycles overall, with the majority due to inadequate haematology/biochemistry values (44% of delays). Pelareorep was omitted in 4 instances in 4 patients during chemoradiotherapy and omitted in 4 instances in 3 patients during adjuvant treatment.

CONCLUSION

We present the first clinical data using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM, suggesting that the combination is tolerable. Further analysis is underway and efficacy results will be ready for presentation at the conference. This work was supported by CRUK, The Brain Tumour Charity, Yorkshire Cancer Research and Oncolytics Biotech Inc.
CTNI-03. IMAGING FEATURES OF LEPTOMENINGEAL METASTASES OF NON-SMALL CELL LUNG CANCER: A SINGLE-CENTER REAL-WORLD STUDY
Authors: Zhen Junjie , Wen Lei , Li Shaoqun , Lai Mingyao , Shan Changguo , Cai Linbo
Published: December 2020

BACKGROUND

According to EANO-ESMO clinical practice guidelines, the MRI findings of LM are divided into 4 types, namely linear enhancement (type A), nodular enhancement (type B), linear combined with nodular enhancement (type C), and sign of hydrocephalus (type D).

METHODS

The MRI features of brain and spinal cord in patients diagnosed with NSCLC-LM in Guangdong Sanjiu Brain Hospital from 2010 until 2019 were investigated, and then were classified into 4 types. The imaging features were analyzed.

RESULTS

A total of 80 patients were enrolled in the study. The median age of the patients was 53.5 years old, and the median time from the initial diagnosis to the confirmed diagnosis of LM was 11.6 months. The results of enhanced MRI examination of the brain in 79 cases showed that the number of cases with enhancements of type A, B, C and D were 50 (63.3%), 0, 26 (32.9%) and 3 (3.8%), respectively, and that LM with metastases to the brain parenchyma was found in 42 cases (53.2%). The results of enhanced MRI examination of spinal cord in 59 cases showed that there were only enhancements of type A and C in 40 cases (67.8%) and 3 cases (5.0%), and no enhancement sign in the other 16 cases (27.2%).

CONCLUSION

MRI examination of brain and spinal cord will improve the detection rate of LM. The MRI features of NSCLC-LM in real world are mainly characterized by the linear enhancements of brain and spinal cord, followed by linear combined with nodular enhancement. The enhancements of type B and type D are rare in clinic. Almost half of the patients have LM and metastases to the brain parenchyma. Therefore, the differentiation of tumor metastases is needed to be paid attention to for the early diagnosis and the formulation of reasonable treatment plans.
CTNI-21. SCALP SPARING RADIATION WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATMENT FIELDS (SPARE) FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Miller Ryan , Song Andrew , Ali Ayesha , Bar-Ad Voichita , Martinez Nina , Glass Jon , Andrews David , Judy Kevin , Evans James , Farrell Christopher , Werner-Wasik Maria , Chervoneva Inna , Ly Michele , Palmer Joshua , Liu Haisong , Shi Wenyin
Published: December 2020

INTRODUCTION

Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide (TMZ) with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report our experience evaluating toxicity of scalp-sparing radiation with concurrent TTFields.

METHODS

This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Patients (age≥ 18 years) with KPS≥ 60 with newly diagnosed glioblastoma were eligible. Patients received concurrent scalp-sparing radiation (60 Gy/30 fx), standard TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and TTFields continuation. Radiotherapy was delivered through TTFields arrays. Primary endpoint was safety and toxicity of concurrent TTFields with chemoradiation.

RESULTS

We report the first eighteen patients on trial. Majority were male (66.7%) with median age 59 years (34 to 77). Median KPS was 90 (70–100). Median follow-up was 6.0 months (1.4 to 18.0). Twelve (66.6%) patients had unmethylated MGMT, five (27.8%) were methylated, and one patient’s status was not obtained. Scalp dose constraints were achieved, with mean dose having a median value of 7.4 Gy (4.3–13.2), D20cc median 23.2 Gy (17.7–36.8), and D30cc median 20.3 Gy (14.8–33.4). Only one possible Grade 3 toxicity was observed in a patient who experienced a seizure in month six of the maintenance phase. Skin toxicity (erythema or dermatitis) was limited to Grade 1 (83.3%) or 2 (5.6%) during the concurrent phase and resolved spontaneously or responded to topical medications. Other Grade 1 events included fatigue (47.3%), cognitive impairment (31.6%), pruritis (52.6%), headache (26.3%), dizziness (15.8%), and nausea (26.3%). Other Grade 2 events included fatigue (21.1%) and headache (10.5%). Nine patients (50%) had progression, with median PFS of 7.6 months (2.2–9.6 months).

CONCLUSIONS

Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.
CTNI-27. FIRST-IN-PEDIATRICS PHASE I STUDY OF GDC-0084 (PAXALISIB), A CNS-PENETRANT PI3K/mTOR INHIBITOR, IN NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) OR OTHER DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Tinkle Christopher , Huang Jie , Campagne Olivia , Pan Haitao , Onar-Thomas Arzu , Chiang Jason , Klimo Paul , Boop Rick , Patay Zoltan , Shulkin Barry , Lucas John , Merchant Thomas , Upadhyaya Santhosh , Robinson Giles , Vinitsky Anna , Stewart Clinton , Gajjar Amar
Published: December 2020

BACKGROUND

GDC-0084 is an oral, highly selective and potent inhibitor of class I PI3K and moderate inhibitor of mTOR, with an established adult maximum tolerated dose (MTD) of 60 mg/day and evidence of brain tumor penetration in adult recurrent glioblastoma.

METHODS

We used a rolling-6 design to evaluate the safety and pharmacokinetic (PK) properties and establish the pediatric MTD of once-daily GDC-0084 administered after focal RT in children with newly diagnosed DIPG and histone H3 K27M-mutant DMG. Non-compartmental plasma PK analyses were performed using samples collected on cycle 1 days 1–3 after single-dose and day 28 at steady-state.

RESULTS

Twenty-five patients have been enrolled, 16 of whom were treated at study dosage levels of 27 mg/m2 (n=11) and 35 mg/m2 (n=5). Two dose limiting toxicities (DLTs) observed at 35 mg/m2 were grade 3 mucositis and grade 3 rash. Grade 3 hyperglycemia was the only DLT at 27 mg/m2. The most frequent grade 3 or 4 adverse events attributed to GDC-0084 were rash (5 patients), neutropenia (4), and hyperglycemia (2). After single-dose, GDC-0084 exposures (AUC0-48h) at 27 and 35 mg/m2 were 3399±1301 and 4462±2868 hr·ng/mL, respectively. Mean GDC-0084 half-life was 20.6±9.1 hr, comparable to that observed in adults.

CONCLUSIONS

The dosage of 27 mg/m2 has been established as the pediatric MTD of GDC-0084, which is approximately equivalent to 80% of the adult MTD. At 27 mg/m2, GDC-0084 is well tolerated in children where the spectrum of toxicities is similar to those observed in adults and consistent with this class of agents.
CTNI-58. A PROSPECTIVE TRIAL OF RESECTION AND SURGICALLY TARGETED RADIATION THERAPY FOR INITIAL OR SALVAGE TREATMENT OF AGGRESSIVE MENINGIOMA
Authors: Rogers Leland , Nakaji Peter , Youssef Emad , Smith Kris , Thomas Terry , Zabramski Joseph , Dardis Christopher , Pinnaduwage Dilini , McBride Heyoung , Brachman David
Published: December 2020

INTRODUCTION

Achieving durable local control (LC) for aggressive or recurrent meningiomas remains problematic. Resection (R) alone is insufficient and even with the addition of radiation therapy (RT), outcomes are suboptimal in many series.

OBJECTIVE

Hypothesizing R plus Surgically Targeted Radiation Therapy (STaRT) may improve LC, we evaluated a permanently implanted brachytherapy device consisting of Cs-131 seeds positioned within modular resorbable collagen carrier/spacer tiles (GammaTile, GT Medical Technologies, Tempe AZ).

METHODS

From 2/2013-2/2018 recurrent and newly diagnosed aggressive meningiomas were treated on a prospective single-arm study (NCT#03088579). At completion of maximum safe resection the tumor bed was lined with collagen tiles imbedded with Cs-131, delivering 60–80 Gy at 5 mm depth. No additional local therapy was given absent progression.

RESULTS

35 meningiomas in 28 patients were treated; 29 recurrent (22 prior R+RT, 6 R only, and 1 RT only) and 6 without prior therapy. WHO grade was I in 2 patients, II in 28, and III in 5. Median age was 66 years (range 37–82), KPS 80 (70–100), female: male ratio 15:13. Mean time for implantation was 5 minutes. At a median radiographic follow-up of 25.5 months (range 0.1–71) LC was 80% (28/35) and median time to progression had not been reached (95% CI > 35.6 months). LC at 12/24/36/48 months was 100/89/72/72% for all tumors, 100/93/79/79% for Grade II, and 100/50/0/0% for Grade III, respectively. No patient receiving STaRT as their initial RT failed. Median overall survival was 50 months. Four symptomatic adverse events occurred, 2 wound breakdowns requiring surgery and 2 radiation-related brain changes, medically treated.

CONCLUSION

R+STaRT demonstrates favorable safety and LC outcomes in this single-arm prospective trial that includes heavily pre-treated patients. A commercial version of the device recently received FDA clearance for use in newly diagnosed malignant or recurrent intracranial neoplasms including meningiomas.
CTNI-61. PILOT STUDY OF REPEATED PLANNED GLUCARPIDASE FOLLOWING HIGH DOSE METHOTREXATE (HD-MTX) IN CNS LYMPHOMA (CNSL)
Authors: Schaff Lauren , Lobbous Mina , Sener Ugur , Gavrilovic Igor , Miller Alexandra , Stone Jacqueline , Piotrowski Anna , Skakodub Anna , Madzsar Juli , Schumpp Alyssa , Acosta Edward , Ryan Kevin , Carlow Dean , DeAngelis Lisa , Nabors Louis , Grommes Christian
Published: December 2020

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.
DDRE-01. ACQUIRED AND INTRINSIC RESISTANCE TO VEMURAFENIB IN BRAFV600E-DRIVEN MELANOMA BRAIN METASTASES
Authors: de Gooijer Mark C , Zhang Ping , Buil Levi C M , Freriks Stephan , Li Gang , Beijnen Jos H , van Tellingen Olaf
Published: December 2020

BRAF V600-mutated melanoma brain metastases (MBMs) are responsive to BRAF inhibitors, but clinical responses are less durable than those of extracranial metastases. We studied the impact of the drug efflux proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB) on the efficacy of vemurafenib against BRAFV600E-mutated A375 MBMs. We intracranially implanted A375 tumor cells in wild-type and Abcb1a/b;Abcg2-/- mice. We characterized the tumor BBB, analyzed drug levels in plasma and brain lesions after oral vemurafenib and determined the efficacy against brain metastases and subcutaneous lesions. MRI shows that A375 MBMs disrupt BBB integrity, but vemurafenib accumulation in MBMs was still reduced by P-gp/BCRP. Vemurafenib is also less efficacious against MBMs in wild-type mice compared to Abcb1a/b;Abcg2-/- mice. Vemurafenib efficacy against subcutaneous A375 tumors was similar in both strains. Even in Abcb1a/b;Abcg2-/- mice, A375 MBMs rapidly developed resistance, which was unrelated to pharmacokinetic issues or insufficient inhibition of MAPK/PI3K pathways. Taken together, these studies demonstrate that although the BBB is disrupted in MBMs, P-gp/BCRP still limit the efficacy of vemurafenib. Moreover, the response to vemurafenib is less and of shorter duration also due to rapidly acquired resistance, most likely by resorting to non-canonical growth signaling.
EPID-07. ACCESS TO GLIOBLASTOMA CLINICAL TRIALS FOR RURAL PATIENTS IN THE UNITED STATES FROM 2010–2020
Authors: Nevel Kathryn , Capouch Samuel , Arnold Lisa , Peters Katherine , Mohile Nimish , Thomas Alissa
Published: December 2020

BACKGROUND

Patients in rural communities have less access to optimal cancer care and clinical trials. For GBM, access to experimental therapies, and consideration of a clinical trial is embedded in national guidelines. Still, the availability of clinical trials to rural communities, representing 20% of the US population, has not been described.

METHODS

We queried ClinicalTrials.gov for glioblastoma interventional treatment trials opened between 1/2010 and 1/2020 in the United States. We created a Structured Query Language database and leveraged Google application programming interfaces (API) Places to find name and street addresses for the sites, and Google’s Geocode API to determine the county location. Counties were classified by US Department of Agriculture Rural-Urban Continuum Codes (RUCC 1–3 = urban and RUCC 4–9 = rural). We used z-ratios for rural-urban statistical comparisons.

RESULTS

We identified 406 interventional treatment trials for GBM at 1491 unique sites. 8.7% of unique sites were in rural settings. Rural sites opened an average of 1.7 trials/site and urban sites 2.8 trials/site from 1/2010–1/2020. Rural sites offered more phase II trials (63% vs 57%, p= 0.03) and fewer phase I trials (22% vs 28%, p= 0.01) than urban sites. Rural locations were more likely to offer federally-sponsored trials (p< 0.002). There were no investigator-initiated or single-institution trials offered at rural locations, and only 1% of industry trials were offered rurally.

DISCUSSION

Clinical trials for GBM were rarely open in rural areas, and were more dependent on federal funding. Clinical trials are likely difficult to access for rural patients, and this has important implications for the generalizability of research as well as how we engage the field of neuro-oncology and patient advocacy groups in improving patient access to trials. Increasing the number of clinical trials in rural locations may enable more rural patients to access and enroll in GBM studies.
EPID-31. CONTEMPORARY MANAGEMENT OF GRADE 2 AND 3 GLIOMA IN ALBERTA AND MANITOBA, 2012–2016: COMPARISON OF TOLERABILITY AND OUTCOMES ACROSS CHEMOTHERAPY REGIMENS
Authors: Walker Emily , Easaw Jay , Davis Faith , Pitz Marshall
Published: December 2020

BACKGROUND

Grade II/III glioma are a significant source of morbidity and mortality, with disease behaviour ranging from relatively mild to aggressive. Phase 3 clinical trial data informed contemporary treatment paradigms, but the perceived differences in tolerability between temozolomide-based regimens and procarbazine, CCNU, and vincristine (PCV)-based regimens has resulted in different treatment approaches across centres. We compared the frequency of progression and adverse drug events (ADE) among patients given these two regimens.

METHODS

Grade II/III glioma patients were identified through cancer registries in Alberta and Manitoba. Clinical data was obtained through electronic medical records. We estimated the distribution of patient age and sex, molecular data, treatment details, ADE, and patient outcomes across groups treated by temozolomide or PCV.

RESULTS

From 2012–2016, 344 patients were identified. Of these, 51% received chemotherapy: 26 received PCV (5/6 cycles completed by 85%), 142 received temozolomide (5/6 cycles completed by 78%). PCV resulted in grade 3/4 ADE in 38% of cycles, most commonly bone marrow toxicity. Temozolomide resulted in grade 3/4 ADE in 6% of cycles, most commonly nausea and rash. Clinical progression events occurred in 23% and 30% of PCV and temozolomide patients, respectively. Radiological progression events occurred in 50% and 52% of PCV and temozolomide patients, respectively.

CONCLUSION

Systemic therapy is commonly given to patients with grade II/III glioma, with more temozolomide use compared to PCV. All patients had high completion rates of treatment despite more frequent grade 3/4 adverse events in patients treated with PCV. The frequency of progression was similar across groups.
EXTH-04. INTRATHECAL (IT) DELIVERY OF TYPE I POLARIZED DENDRITIC CELL VACCINE (DC1) ERADICATES TUMOR GROWTH IN BREAST CANCER (BC) XENOGRAFT MODEL WITH BRAIN METASTASES (BM) AND LEPTOMENINGEAL DISEASE (LMD)
Authors: Law Vincent , Kodumudi Krithika , Snyder Colin , Czerniecki Brian , Forsyth Peter
Published: December 2020

BACKGROUND

Approx. 5% of BM will also develop LMD. Currently there is no effective treatment for BC-associated BM/LMD. As systemic therapies do not prevent the disease recurrence and eventual death, the better option would be direct-targeted approach. We have shown that there is a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune response in BC patients (pts). In a clinical setting, administration of class II HER2 peptide-pulsed Type I polarized dendritic cell vaccine (HER2-DC1) partially restored anti-HER2 Th1 immune responses with pathologic complete response in HER2+ BC patients. In this study, we examined the IT delivery of HER2/HER3- DC1 in BC-LMD model.

METHODS

Luciferase-labeled HER2+ TUBO BC cell line was injected into the cisterna magna of BALB/c mice to develop BM/LMD. We developed a technique, coined the “Top Hat” (TH) for mouse model that mimics the Ommaya reservoir in BC-pts. The TH essentially allows us to administer IT treatment directly into CSF. BC-BM/LMD bearing mice were given HER2- and Her3 peptide-pulsed Type I polarized DC1 through the TH.

RESULTS AND DISCUSSION

BM/LMD mice were randomized into following groups: 1) systemic Her2-DC1 2) IT Her2-DC1 3) IT Her2-/Her3-DC1. The median survival (MS) of control mice was 10 days and systemically treated mice was 19 days. IT Her2-DC1 animals did significantly better than both control and systemic treated groups (MS: 63 days; p< 0.0001) and overall survival (OS): 44%. Interestingly, mice given IT Her2-/Her3-DC1 had the best OS (78%). Surviving animals were eventually disease free. Mice that had complete tumor regression were immune to subsequent rechallenge with TUBO cells. Immune cell infiltration in the of CSF, spinal cord and tissues of experimental mice are currently ongoing.

CONCLUSIONS

Our preclinical data supports the clinical relevance of using intrathecal delivery of DC1 vaccine as a potential treatment for BM and LMD of BC-pts.
EXTH-28. MOLECULAR CHARACTERIZATION OF HUMAN GLIOMAS AND IDENTIFICATION OF NEOPLASMS RESPONSIBLE FOR NEW BIOPHARMACEUTICALS OBTAINED FROM ANIMAL VENOM: A TRANSLATIONAL APPROACH
Authors: Barreto dos Santos Natalia , da Silva Monize Valeria , de Lima Munhoz Jaqueline , da Rocha-e-Silva Thomaz A A , Sutti Rafael , Verinaud Liana , Araujo João Luiz Vitorino , Raposo Catarina
Published: December 2020

Gliomas correspond to approximately 80% of primary malignant brain tumors in adults. Associate histopathological classification to the identification of the molecular profile of these tumors is a great strategy to predict the tumor’s behavior and its responsiveness to the treatments. Studies have shown the potential of using biopharmaceuticals against cancer. Our research group has recently found two main subfractions isolated from Phoneutria nigriventer spider venom (PnV) (called SF1 and SF11) that can act decreasing the number of migrating cells during transwell assay. Therefore, the present study aimed to characterize, as regards molecular identity, the responsiveness of glioma samples collected from patients to the molecules purified from the PnV, in order to improve diagnostic and prognostic predictions, as well as contribute to the development of new drugs. After consent of the patients, samples of the tumors clinically diagnosed as glioma were collected during the surgical procedure to cultivation, that were performed until 10 passages to establish a lineage before use. To analyze its responsiveness to PnV in a migration assay, cultured human glioblastoma (1-JA63) cells were treated with PnV-isolated (HPLC) subfractions (SF1 and SF11 at 1 µg/ml) for 12 and 48 h (control stayed in IMDM) in a transwell system. SFs (mainly SF1) treatment induced a significant reduction in the number of migrating cells after 48 hours of exposure, in comparison to the control (untreated). Ongoing trials continue the establishment of another tumor samples of gliomas and migration tests with PnV subfractions will be carried out, to compare their effects in relation to other degrees of the disease also correlating the tumor response to the drug with the molecular profile. The results will contribute to the development of a potential individualized therapy also adding information about the correlation between the molecular identity of the tumor and its prognosis.
EXTH-42. SPIDER VENOM COMPONENTS DECREASE GLIOBLASTOMA CELL MIGRATION AND INVASION THROUGH RHOA-ROCK AND NA+/K+-ATPASE β2: POTENTIAL MOLECULAR ENTITIES TO TREAT INVASIVE BRAIN CANCER
Authors: Raposo Catarina , dos Santos Natalia Barreto , Caballero Marcus , Bonfanti Amanda , da Rocha-e-Silva Thomaz A A , Sutti Rafael , Verinaud Liana
Published: December 2020

Glioblastoma (GB) cells have the ability to migrate and infiltrate the normal parenchyma, leading to the formation of recurrent tumors often adjacent to the surgical extraction site. We recently showed that Phoneutria nigriventer spider venom (PnV) has anticancer effects mainly on the migration of human GB cell lines (NG97 and U-251). The present work aimed to investigate the effects of isolated components from the venom on migration, invasiveness, morphology and adhesion of GB cells. The involvement of RhoA-ROCK signaling and Na+/K+-ATPase β2 (AMOG) was also evaluated. Human (NG97) GB cells were treated with twelve subfractions (SFs - obtained by HPLC from PnV). Migration and invasion were evaluated by scratch wound heling and transwell assays, respectively. Cell morphology and actin cytoskeleton were shown by GFAP and phalloidin labeling. The assay with fibronectin coated well plate was made to evaluate cell adhesion. Western blotting demonstrated ROCK and AMOG levels and a ROCK inhibitor was used to verify the involvement of this pathway. Two (SF1 and SF11) of twelve SFs decreased migration and invasion compared to untreated control cells. Both SFs also altered actin cytoskeleton, changed cell morphology and reduced adhesion. SF1 and SF11 increased ROCK expression and the inhibition of this protein abolished the effects of both subfractions on migration, morphology and adhesion (but not on invasion). SF11 also increased Na+/K+-ATPase β2. All components of the venom were evaluated and two SFs were able to impair human glioblastoma cells. The RhoA effector, ROCK, was shown to be involved in the mechanisms of both PnV components. It is possible that AMOG mediates the effect of SF11 on the invasion. Further investigations to isolate and biochemically characterize the molecules are underway. Support: FAPESP #2015/04194-0; CNPq #431465/2016–9.
IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE
Authors: Yang Fan , Brem Steven , Fan Yi
Published: December 2020

Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.
IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION
Authors: Gupta Pravesh , Dang Minghao , Bojja Krishna , M Tuan Tran , Shehwana Huma , Kamiya-Matsuoka Carlos , Li Jianzhuo , Kassab Cynthia , Ott Martina , Gumin Joy , Maheshwari Atul , de Groot John , Lang Frederick , Balasubramaniyan Veerakumar , Navin Nicholas , Heimberger Amy , Wang Linghua , Bhat Krishna
Published: December 2020

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.
INNV-15. COMPARISON OF READIBAND™ ACTIGRAPH AND ASSOCIATED SLEEP/WAKE CLASSIFICATION ALGORITHMS WITH PATIENT-REPORTED SLEEP QUALITY AND FATIGUE IN GLIOBLASTOMA
Authors: Tipps Megan , Tierney Meghan , Monson Caitlin , Jackson Kelsey , Banerji Nilanjana , Ellenberger Amy , Trusheim John
Published: December 2020

INTRODUCTION

Fatigue and sleep disturbances are among the most common side-effects reported by patients with glioblastoma and contribute significantly to the quality-of-life for this population. Non-invasive monitoring of long-term sleep patterns and fatigue levels in this population would allow for comparison between iatrogenic sleep disturbances, disease progression, treatment tolerance, and self-reported levels of fatigue. Here, we describe initial results from the implementation of the Readiband™ Sleep Tracker (Fatigue Science), a wearable actigraph device, for monitoring sleep patterns and fatigue in patients with newly diagnosed glioblastoma.

PATIENTS AND METHODS

Patients were prospectively enrolled and asked to wear the Readiband™ Sleep Tracker for a maximum of twelve months or until disease progression. Patients were also asked to report fatigue levels and sleep quality via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Pittsburg Sleep Quality Index (PSQI) questionnaires. Demographic, pathologic, and clinical information was abstracted from electronic medical records.

RESULTS

When data across all participants was combined, FACIT-F and PSQI scores were negatively correlated (r= -0.78, p< 0.001). Significant correlations were also seen between the Readiband™ measures for alertness, sleep quality, and sleep efficiency (p< 0.05 for all). However, we did not observe any correlations between the Redaiband™ measures and subjective survey responses. Interestingly, when patients were sub-divided based on tumor recurrence, we did see significant correlations between both survey scores and sleep quality and sleep efficiency measures (p< 0.05 for all) in patients that recurred during the study period.

CONCLUSION

The Readiband™ Sleep Tracker is a convenient and viable approach for monitoring sleep and fatigue in glioblastoma patients. Our preliminary findings suggest that actigraph measures may be a better indicator of subjective sleep quality and fatigue levels in specific sub-sets of this population. Ongoing research is exploring other clinical factors that might impact the accuracy of Readiband™ measures.
INNV-22. PROSPECTIVE ANALYSIS OF UTILIZATION OF TELEMEDICINE IN NEURO-ONCOLOGY
Authors: Kalra Aman
Published: December 2020

OBJECTIVE

to offer neuro-oncology care to patients in rural/suburban settings that may not otherwise have access to urban amenities, specialists, and clinical trials. To test the feasibility of telemedicine in Neuro-Oncology by measuring cost savings, travel time savings, and burden of care. To screen patients for clinical trials.

BACKGROUND

Neuro-Oncology services are primarily available only at tertiary care hospitals. This increases the burden of care for patients who live in suburban and rural areas, as they have to travel long distances for their care. Hence, some families and patients do not seek care as travel time increases the stress on patients and their caretakers who are already dealing with the devastating diagnosis of a brain tumor. Similarly, these patient groups do not have access to clinical trials.

METHODS

To help ease above hardships on patients, we built a telemedicine Neuro-Oncology program that is studying the quality of care compared with daily routine visits in the cancer center. We are enrolling 30 patients in each cohort of the study, cohort A, telemedicine visits and cohort B, regular clinic visits for a total of 60 patients after obtaining written consent. We are providing them survey identifying quality measures of care (24 questions). The survey is provided to the patients and their caregivers at the end of their visit.

RESULTS

Survey answers are inputted into Survey Monkey. After the completion of 60 total patient visits, surveys will be evaluated and the results will be analyzed.

CONCLUSION

We are looking for the long-term feasibility of utilizing telemedicine care in rural/suburban settings for Neuro-Oncology patients. We anticipate that there will be cost savings, travel time savings and reduction in burden of care without compromising patient satisfaction or quality of care provided. We are also studying the feasibility of screening patients for clinical trials.