bluuebunny/crossref_metadata_2025 huggingface dataset:
NCMP-18. FIXED PTOSIS AS A SYMPTOM OF MYOSITIS SECONDARY TO CHECKPOINT INHIBITION
Authors: Aaroe Ashley , Tummala Sudhakar
Published: November 2021

BACKGROUND

A growing number of patients with cancer receive checkpoint inhibitor (CPI) based immunotherapy. Peripheral nervous system toxicities including myositis, myasthenia gravis and inflammatory neuropathy are distinct from their non immunotherapy-related equivalents, with unique clinical presentations and therapeutic considerations.

METHODS

Patients with CPI myositis and non-fatigable ptosis were identified, and clinical data was retrospectively extracted from the electronic medical record in compliance with MD Anderson Cancer Center Institutional Review Board guidelines.

RESULTS

14 patients were identified. Average maximum creatine kinase (CK) was 3571 U/L (range 20-19,794). 9 patients had electromyography and nerve conduction studies documented in our system; all had electrodiagnostic evidence of myopathy and two had evidence of concomitant myasthenia gravis by electrodecrement. Two muscle biopsies revealed myositis with inflammatory T-cell infiltrate. 6 had positive anti-striated muscle antibody titers, 9/14 had concomitant myocarditis, 2 had hepatitis, 2 had pneumonitis and 1 had thyroiditis. All received high dose steroids, 11 received plasma exchange, 4 received rituximab, 4 received tacrolimus and 2 received tocilizumab. 7/14 patients died (50%). Mean time from initial neurology consultation for symptoms to death was 6.46 months (range .3-24). 5 patients had documented clinical stabilization or mild improvement on post-discharge follow-up.

CONCLUSIONS

While ptosis in patients receiving CPI can initially suggest myasthenia gravis, in patients with rapid onset and ultimately fixed deficits there should be a high index of suspicion for immunotherapy related restricted localized myositis. Myositis may coincide with other toxicities, such as myocarditis and pneumonitis, and can be fatal despite aggressive treatment. Deficits persist on post-discharge follow-up, suggesting protracted recovery for patients who survive.
NCOG-08. BIOPSY-ONLY GLIOBLASTOMA (BO-GBM) AS A HETEROGENEOUS GROUP OF PATIENTS
Authors: Harlay Vincent , Loundou Anderson , Boucard Céline , Petrirena Gregorio , Barrie Maryline , Campello Chantal , Autran Didier , Padovani Laeticia , Figarella Dominique , Boissonneau Sébastien , Dufour Henry , Baumstark Karine , Tabouret Emeline , Chinot Olivier
Published: November 2021

BACKGROUND

“Biopsy-only” glioblastoma is associated with a heterogeneous functional and survival outcome. It is an understudied group of patients which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients. Our objective was to explore treatment and prognosis of BO-GBM.

MATERIAL AND METHODS

Patients with BO-GBM included in a prospective regional glioma SIRIC cohort in 2014-2017 were retrospectively reviewed for patient characteristics, MRI finding, treatment allocation and delivery. PFS and OS were analyzed.

RESULTS

Of 535 patients included in the cohort, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. Of 158 patients, 18 were excluded for missing data leaving 139 patients for the present analysis. Fifty-four (39%) were referred to RT-TMZ, 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF), 17 (12%) were referred to palliative care. Groups differed at baseline for age (mean 60 and 68 years, for RT-TMZ, CT-UF respectively); KPS (70, 60 for RT-TMZ, CT-UF); mean tumor surface (793, 1420 mm2 for RT-TMZ, CT-UF); and tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively). Median OS was 14 months (95% CI, 9.65-18.71) and 8 months (95% CI, 4.62-7.67) for RT-TMZ, CT-UF respectively.

CONCLUSION

Inoperable GBM constitute a large and heterogeneous population in which one third of patients are amenable to standard of care, with survival outcome close to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis exhibit a poor survival outcome. Thus, reliable criteria are needed to help selecting patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.
NCOG-27. STATUS AS A CLINICAL TRIAL PARTICIPANT AND OUTCOME IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Pan Peter , Joanta-Gomez Adela , Iwamoto Fabio , Welch Mary , Haggiagi Aya , Donovan Laura , Barbaro Marissa , Yuen Carlen , Lassman Andrew
Published: November 2021

INTRODUCTION

Standard of care for glioblastoma consists of surgery, followed by combined chemoradiation and adjuvant chemotherapy, as per the seminal EORTC study from 2005. Clinical trial patients, being a population selected for functional status, hepatic function, renal function, and lack of other malignancies, may have improved outcome over the general treated population.

METHOD

Single center retrospective analysis of status as a clinical trial patient in the upfront setting and other clinical factors/biomarkers, analyzed for correlation with outcomes (PFS/OS) in IDH-wildtype glioblastomas.

RESULTS

82 patients with IDH-wildtype glioblastoma were identified between 2014 and 2020, treated with standard of care or with an upfront clinical study (43% women; median age 66 years, range 35-91 years of age). 22 patients (27%) were treated with upfront clinical study. Status as a patient treated in an upfront clinical study did not correlate with outcome (hazard ratio HR PFS 0.99, CI 0.57-1.7, p=0.97; HR OS 1.09, CI 0.56-2.1, p=0.81). Frontal lobe was most frequently involved (n=36, 44%), followed by parietal lobe (n=33, 40%). Age was not a strong predictor of survival (R2 0.01). No statistically significant correlation was observed between outcome and laterality or location. MGMT promoter methylation was associated with improved PFS (HR 0.56, CI 0.33-0.94, p=0.03) and OS (HR 0.40, CI 0.19-0.85, p=0.02), with mPFS 6 months vs 9 months and mOS 16 months vs 20 months (unmethylated vs methylated respectively).

CONCLUSION

In this retrospective cohort of IDH-wildtype glioblastomas, age, tumor laterality, and tumor location were not significant predictors of outcome. MGMT promoter methylation predicted for superior PFS/OS. Patient selection for clinical studies are influenced by entry criteria, however at least in this retrospective review, status as a clinical study patient in the upfront setting did not correlate with outcome compared to patients treated with upfront standard of care.
NCOG-33. GROWTH DYNAMICS OF INCIDENTAL MENINGIOMAS - A 10-YEAR PROSPECTIVE STUDY
Authors: Strømsnes Torbjørn Austveg , Lund-Johansen Morten , Skeie Geir Olve , Skeie Bente Sandvei
Published: November 2021

There is no consensus for the management of incidental meningiomas. To evaluate the natural history, we assessed tumour growth dynamics during 10 years of active monitoring of 62 patients (45 female and mean age 63.9) harbouring 68 tumours. Radiological and clinical data was obtained was obtained biannually for two years, then annually the following eight. Thirty-six patients (38 tumours) were referred to treatment and/or died of unrelated causes (n=5) within 5 years. The remaining were monitored for up to 10 years. Mean overall survival was at 128 months (95% CI: 118.8-136.7). Median progression free survival was 34 months (95% CI: 14.7-53.3). Median time for growth requiring intervention was 46 months (95% CI: 23.5-68.5). All tumours with self-limiting growth at 5 years (57.9 %) were still stable or reducing in size at 10 years. Mean growth rate decreased from 0.27 cm3/year (95% CI: 0.10-0.43) during the early observation period (0-5 years) to 0.09 cm3/year (95% CI: -0.02-0.21) in the late observation period. No tumours were referred to treatment during the late observation period. Two patients, both with verified WHO2 grade meningiomas succumbed to the disease, seven and eight years after diagnosis. No other patients developed symptoms and none other of the 18 total mortalities were meningioma related. Most clinical and radiological events occur within 5 years after diagnosis. Our findings suggests that if tumour growth slows down during the first 5 years of monitoring, this trend will continue. Clinical follow-up should be sufficient when a self-limiting growth pattern has been established.
NCOG-42. SYMPTOM ONSET TO TIME OF DIAGNOSIS IN PRIMARY CENTRAL NERVOUS SYSTEM TUMOR PATIENTS: A REVIEW OF FINDINGS FROM THE NOB-NHS
Authors: Lindsley Matthew , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2021

Prior reports suggest the low prevalence of primary central nervous system (PCNS) tumors and the healthcare setting where patients seek care can contribute to diagnostic delays, potentially affecting prognosis. This descriptive report highlights findings from patient-reported data at presentation collected from a sample of 623 PCNS tumor patients. Participants were White (88%), males (56%), median age at diagnosis 41 (2-79) with high grade (HG) (66%) brain tumors (BT) (89%). Among BT patients, 30% reported ≥ 3 concurrent symptoms at presentation including headaches (40%), seizures (30%), and memory problems or difficulty with balance/walking (20% each). Over half (57%) had symptoms for < 6 months before diagnosis and 60% presented to the Emergency Room. Sixty-five percent of HG BT patients had symptoms for < 6 months prior to diagnosis compared to low grade (LG) tumors (40%) and had surgery in < 1 month from presentation (68% vs 51%, p < 0.01). More HG BT patients presented with weakness in the arms/legs than LG BT (14% vs 8%). Among spine tumor (ST) patients, 45% reported ≥ 3 concurrent symptoms at presentation including back pain (65%), sensory changes (45%), and weakness (40%). Almost half (46%) were symptomatic for > 1 year before diagnosis, presented in an outpatient clinic (64%) with 41% having surgery < 1 month from presentation. Younger (40% vs 16%) and HG ST patients (56% vs 21%) more often reported symptoms for < 6 months before diagnosis. HG ST patients more often presented to Emergency Rooms (67% vs 25%) and had surgery < 1 month from presentation (60% vs 36%). Further analysis of symptom presentation and clinical course is ongoing. Tumor location, grade, patient age and healthcare setting were associated with the time from clinical presentation to diagnosis. Development of aids providing guidance on diagnostic evaluation/treatment to front-line healthcare providers is warranted.
NCOG-44. FEASIBILITY AND UTILITY OF THE MONTREAL COGNITIVE ASSESSMENT IN ROUTINE CLINICAL EXAMS AND TELEHEALTH VISITS IN NEURO-ONCOLOGY
Authors: Jammula Varna , Vera Elizabeth , Rogers James , Christ Alexa , Leeper Heather , Acquaye Alvina , Briceno Nicole , Choi Anna , Grajkowska Ewa , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Smith-Cohn Matthew , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2021

Cognitive dysfunction (CD) is common among primary brain tumor (PBT) patients and adds to the overall symptom burden. Standardized assessments able to be incorporated into routine clinical in-person and telehealth care are needed. Here, we report the feasibility, utility, and satisfaction with use of the Montreal Cognitive Assessment (MoCA) in telehealth and clinical settings by trained clinical providers. Feasibility and provider satisfaction were assessed through survey responses, and patient performance on the MoCA, after a reliability check, was reported through descriptive statistics. Seventy-nine MoCAs on 71 patients were completed in clinic (n=55) or telehealth (n=24). Majority of patients were white (83%) males (54%) with high grade PBTs (66%), and half of patients had completed at least a college education. In clinic, providers (n=9) reported the MoCA took 5-20 minutes to complete, was easy to incorporate into routine practice (78%), believed it was accurate in assessing cognition (67%), and was useful in determining treatment (88%). The average in-person MoCA score was 25 (range: 6 to 30), with 31% of scores classified as abnormal (≤26). In telehealth, providers (n=11) found the administration of the MoCA prior to attending participation in the telehealth visit helpful (75%), discussed the results with their clinical team (75%) and patient (63%), and believed the MoCA was accurate in assessing cognition remotely (63%). On average, patients took 13 minutes (9-22) to complete testing, with three tests discordant on reliability scoring and one patient unable to complete testing. The average telehealth MoCA score was 26 (12-30), with 29% of scores classified as abnormal. Overall, testing was feasible in both clinical and telehealth settings, and providers reported satisfaction with its use. Future studies should evaluate validity in a larger sample and include analysis of relevant cut-off scores, impact of disease, tumor treatment, and genomic predispositions.
NCOG-49. UNMET NEEDS AND WISH FOR SUPPORT OF FAMILY CAREGIVERS OF PRIMARY BRAIN TUMOUR PATIENTS
Authors: Pointon Lucy , Grant Robin , Peoples Sharon , Erridge Sara , Sherwood Paula , Klein Martin , Boele Florien
Published: November 2021

BACKGROUND

Most primary brain tumour patients rely on informal caregivers (i.e. family members or friends) for practical and emotional support. While caregiving can be rewarding, it may lead to significant burden. To develop support it is therefore vital to distinguish between unmet needs, and an actual wish for support. Study aims: 1) identify the presence and magnitude of caregivers’ unmet needs; 2) examine associations between unmet needs and wish for support; 3) evaluate perceived usefulness of caregiver needs screening in clinical practice.

METHODS

Family caregivers of primary brain tumour patients were recruited and asked to complete an adapted version of the Caregiver Needs Screen (CNS) which consisted of 33 common issues in neuro-oncology caregiving (scale 0-10), and the wish for support (yes/no). Participants ranked (0-7) their experience of using the CNS with a study-specific evaluation questionnaire. Descriptive and correlational analyses were applied.

RESULTS

Caregivers (N=79) reported between 1-33 unmet needs (M=17.20, sd=7.98) but did not always wish for support (range 0-28, M=4.71, sd=6.63). Most distressing items were changes in patient’s memory or concentration (M=5.75, SD=3.29), followed closely by patient’s fatigue (M=5.58, SD= 3.43), and recognising signs of disease progression (M=5.23, SD= 3.15). A weak correlation was found between the total number of unmet needs and wish for support (r=0.296, p=0.014). Caregivers most often wished for support with recognising disease progression (N=24, 34.78%), and least often with managing spiritual issues (N=0, 0%). Caregivers evaluated the CNS tool positively (mean item scores ranging 4.19-6.21 out of 7).

CONCLUSIONS

Family caregivers experience distress resulting from many neuro-oncology specific needs, but this is not directly related to a wish for support. Caregiver needs screening could be useful to tailor support to suit caregivers’ preferences in clinical practice.
EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS
Authors: Price Gabrielle , Sudhir Sweta , Brusco Concetta , Bouras Alexandros , Tsankova Nadejda , Hadjipanayis Constantinos
Published: November 2021

Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.
EXTH-19. INTEGRATION OF PLASMONIC GOLD NANOSTARS AND LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR SPECIFIC AND AMPLIFIED ABLATION OF BRAIN TUMORS
Authors: Srinivasan Ethan , Chongsathidkiet Pakawat , Odion Ren , Liu Yang , Sankey Eric , Vo-Dinh Tuan , Fecci Peter
Published: November 2021

INTRODUCTION

Laser interstitial thermal therapy (LITT) is an effective minimally-invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT while better conforming to tumor boundaries and protecting surrounding tissue.

MATERIALS AND METHODS

The 12nm GNS were synthesized using reduced HAuCl4 with Na3C6H5O7 seeds, mixed with AgNO3, C6H8O6, and HAuCL4, and coated with polyethylene glycol then functionalized with methoxy PEG thiol. CT-2A glioma cells were intracranially implanted into mice, followed 18 days later by IV injection of GNS. PET-CT was performed at 10-minutes, 24-, and 72-hours post-GNS administration, with autoradiography (AR) and histopathology (HP) on sacrifice after the last scan. To test the impact of GNS on LITT coverage capacity in appropriately sized ex vivo models, we utilized agarose gel-based phantoms incorporating control and GNS-infused central “tumors” in multiple shapes. LITT was administered with the NeuroBlate System.

RESULTS

In vivo, GNS preferentially accumulated within intracranial tumors on PET-CT at the 24- and 72-hour timepoints. AR and HP confirmed high GNS accumulation within tumor. Ex vivo, in cuboid tumor phantoms, the GNS-infused phantom heated 5.5x faster than the control, rising 0.49°C per minute compared to 0.09°C. In a split-cylinder tumor phantom with half containing GNS, the GNS-infused border heated 2x faster and the surrounding area was exposed to 30% lower temperatures. In a GNS-infused star-shaped phantom, the heat spread contoured along phantom boundaries.

CONCLUSIONS

Our results provide evidence for use of GNS to improve the specificity, efficiency, and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors, and the GNS-infused phantom experiments demonstrate increased rates of heating within the tumor model, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.
EXTH-20. SINGLE-CELL DRUG ACTIVITY MAPPING IN GLIOBLASTOMA IDENTIFIES EXTENDED DRUG RESPONSE HETEROGENEITY AND THERAPY-INDUCED CELLULAR PLASTICITY
Authors: Panovska Dena , Antoranz Asier , Creemers Pieter-Jan , Derweduwe Marleen , Nasari Pouya , Orlando Gabriele , Van Gassen Sofie , Claeys Annelies , Verbeke Tatjana , Solie Lien , Sciot Raf , Clement Paul , Van der Planken David , Verfaillie Michiel , Rousseau Frederic , Schymkowitz Joost , Saeys Yvan , Ligon Keith , De Vleeschouwer Steven , De Smet Frederik
Published: November 2021

Glioblastoma (GBM) remains a highly malignant and incurable brain tumour. The inability to achieve clinical improvements in GBM treatment can be attributed to the excessive heterogeneity and plasticity of GBM cells, which is reflected by the presence of various cellular states within each tumour. How each of these tumour cell subtypes respond to therapy remains largely unknown. In this work, we developed a functional diagnostic analysis pipeline to measure therapeutic activity in GBM tumour cells at single-cell resolution using mass cytometry by time-of-flight (CyTOF). By applying an optimised GBM-specific and therapy-tailored antibody panel, we measured therapeutic activity upon exposure to ionising radiation (RT) or a small molecule MDM2 inhibitor (AMG232) in a cohort of patient-derived GBM cell lines (n=14). As such, extended heterogeneity in drug responsiveness was reflected by diverse degrees of alterations in cell cycle progression and apoptotic signalling, in addition to shifts in tumoral phenotypic states implying therapy-induced plasticity. A similar approach was used to measure drug activity in freshly resected tumour samples (n=18) harvested from different tumour regions (core or invasive front) within hours following surgery. Accordingly, we identified highly variable fractions of responsive tumour and microenvironmental cell populations in a patient-specific way. The ability to measure drug activity at single-cell resolution in a patient-tailored manner by applying a genotype-agnostic method, paves the way for advanced precision cancer medicine in GBM by offering a novel approach to more precisely select eligible patients for prospective clinical trials.
EXTH-24. TUMOR PHARMACOKINETICS, PHARMACODYNAMICS AND RADIATION SENSITIZATION IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA TREATED WITH THE SECOND-GENERATION HDAC INHIBITOR, QUISINOSTAT
Authors: Lo Cascio Costanza , Margaryan Tigran , Melendez Ernesto Luna , McNamara James , Knight William , Himes Sarah , Sanai Nader , Tovmasyan Artak , Mehta Shwetal
Published: November 2021

BACKGROUND

Class I Histone deacetylases (HDACs) are highly expressed in glioblastoma (GBM) and are considered promising therapeutic targets for cancer treatment. Quisinostat is a class I HDAC inhibitor with high specificity for HDAC1 and 2. In this study, we evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and radiation sensitization properties of quisinostat in orthotopic and flank human glioma models of GBM.

METHODS

In vitro drug-uptake and PK-PD correlation experiments were conducted in patient-derived glioma stem cell (GSC) lines. Pilot PK studies were performed in mice to optimize the dosing regimen and administration route (subcutaneous (s.q.), intraperitoneal (i.p.) and oral gavage). Athymic mice with intracranial or flank tumors were treated with the most optimized treatment schedule to evaluate plasma PK profile and brain/tumor distribution of quisinostat. The drug levels in plasma, normal brain, and tumor-tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Western blot analysis and immunocytochemistry were performed to assess changes in acetylated histone, Ki67 (proliferation) and cleaved caspase 3 (cell death) levels. Tumor-bearing mice were randomized to four cohorts – vehicle, radiotherapy, quisinostat monotherapy, and quisinostat plus radiotherapy.

RESULTS

Quisinostat exhibited potent growth inhibition in multiple GSC lines (IC50 ~60 nM), radiosensitization, increased histone acetylation, and decreased expression of key stem cell markers. Significant toxicity was observed at 10 mg/kg s.q. dosing while the same dosing via i.p. route was tolerated relatively well. The unbound concentration of quisinostat was 19 nmol/L, 0.03 nmol/kg and 0.03 nmol/kg in plasma, tumor, and brain tissue, respectively, at 2 hours post-dose. Pharmacodynamic changes were observed in flank but not in intracranial tumors.

CONCLUSION

Our data indicate low free quisinostat levels in the brain primarily due to drug instability.
EXTH-36. ELECTROCONVULSIVE SEIZURE-INDUCED CHANGES IN THE TUMOR MICROENVIRONMENT PROMOTE SURVIVAL IN GLIOMA-BEARING MICE
Authors: Sita Timothy , Hurley Lisa , Drumm Michael , Tommasini-Ghelfi Serena , Mahajan Akanksha , Dussold Corey , Murnan Kevin , Sachdev Sean , Horbinski Craig , Stupp Roger , Stegh Alexander
Published: November 2021

PURPOSE

Growing evidence indicates that the neurotransmitters dysregulated in psychiatric disorders are similarly dysregulated in glioblastoma (GBM) biology. GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to augment progression, and catabolize serotonin to drive proliferation and inhibit anti-tumor immunity. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to correct these dysregulations and can additionally improve medication blood-brain barrier (BBB) penetrance. We hypothesized that seizure-induced changes in the glioma microenvironment occur with ECT, slowing tumor progression, increasing BBB permeability, and prolonging overall survival in glioma-bearing mice.

METHODS

C57BL6 mice were orthotopically injected with CT-2A-Luc mouse glioma cells. Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week. Intracranial progression was monitored via bioluminescent signal from CT-2A-Luc xenografts. BBB permeability was assessed by subjecting mice to ECT or sham treatment immediately following intravenous injection of sodium fluorescein.

RESULTS

Intracranial progression was maximally reduced in ECT-treated mice relative to sham-treated mice after 17 ECT treatments (ECT radiance 2.6 x 109 photons/second versus sham 4.7 x 109 photons/second, p=0.013), which was further confirmed by both decreased tumor weight and tumor size on histologic evaluation. This translated into an improvement in overall survival from median 29 days in sham-treated mice to 38 days in ECT-treated mice (p=0.0018). Mean seizure duration was 41.8 seconds and positively correlated with overall survival (Pearson coefficient r=0.63, p=0.028). Brain parenchymal uptake of sodium fluorescein was significantly higher in ECT-treated mice (mean relative increase in ECS to sham radiance of 1.47, p< 0.05).

CONCLUSION

Repeated ECT slows tumor progression and prolongs overall survival in C57BL6 mice bearing CT-2A-Luc xenografts. The BBB is compromised immediately following ECT. ECT merits further oncologic investigation as a potential therapeutic in GBM.
EXTH-43. IL-13RΑ2 IMMUNOCONJUGATE TARGETED THERAPY FOR H3K27M-MUTANT MIDLINE GLIOMAS
Authors: Rechberger Julian , Porath Kendra , Schrecengost Randy , Sarkaria Jann , Daniels David
Published: November 2021

High grade gliomas are devastating diseases. In the pediatric population, diffuse midline gliomas with the H3K27M mutation (H3K27M DMG) are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains a death sentence despite standard clinical care. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in H3K27M DMG and GBM versus normal brain tissue, posing a potentially promising therapeutic target for both tumors. In this study, we investigated the pharmacological effects of a novel peptide-toxin conjugate, IL13.E13K-PE4E (also known as GB-13), that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. We demonstrated that IL13.E13K-PE4E was a potent killer of cultured H3K27M DMG and GBM cells in vitro. Intratumoral administration of IL13.E13K-PE4E via convection-enhanced delivery (CED) decreased tumor burden and prolonged survival in both H3K27M DMG and GBM murine xenograft models. Furthermore, we observed enhanced drug tissue retention and volume of distribution after CED, suggesting IL13.E13K-PE4E is capable of covering the target area and remaining at the site of infusion long enough to impart therapeutic effects. In summary, administration of IL13.E13K-PE4E demonstrated a potent pharmacological response in H3K27M DMG and GBM models both in vitro and in vivo in a manner strongly associated with IL13Rα2 expression, underscoring the potential of IL13Rα2 targeted therapy in a subset of these tumors.
EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?
Authors: Schmassmann Philip , Martins Tomás A , Stanczak Michal , Ritz Marie-Françoise , Shekarian Tala , McDaid Marta , Läubli Heinz , Hutter Gregor
Published: November 2021

Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
EXTH-51. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING ARTIFICIAL INTELLIGENCE (AI)-DIRECTED IDENTIFICATION OF THE GBM STATE
Authors: Tran David , Le Son , Ma Bo , Falk Darin , Zolotukhin Serge
Published: November 2021

BACKGROUND

Profound heterogeneity has severely hampered therapeutic advancements in GBM. Remarkably, however, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common state. The GBM state embodies network restructuring forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSCs). Successful targeting of the GBM state promises to circumvent the heterogeneity.

METHODS

To decipher the GBM state, we applied NETZEN, an AI suite integrating a deep neural network with gene network-based ranking, to first generate the reference GBM gene network from TCGA’s entire GBM RNAseq collection, and then identify the altered master regulatory gene subnetwork in GBM using a dataset containing >30 diverse patient-derived GSC lines and their paired differentiated cells, 6 astrocyte and 3 neuronal precursor cell lines. To develop a gene therapy against the GBM state, we screened a rAAV capsid library through GBM patient-derived xenografts (PDX) to identify variants with specific tropism for GBM cells that can deliver targeting constructs intratumorally.

RESULTS

We discovered a putative GBM state anchored by developmentally restricted master regulators. To validate its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed improved tumor control and survival compared to controls (p< 0.05 in all lines). More notably, when the core GBM state was forcibly reconstructed in astrocytes, transformation into GSC-like cells occurred, as measured by single-cell analysis, neurosphere formation, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel rAAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based rAAV platform to target key master regulators of the validated GBM state.

CONCLUSIONS

The GBM state is established by a developmental master regulator subnetwork permitting the creation of a first-of-its-kind, heterogeneity-agnostic GBM therapy. This AI-directed R&D program can be expanded to target other tumors.
EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION
Authors: Miller Julie , Cahill Daniel , Melamed Lisa , Nagashima Hiroaki
Published: November 2021

Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.
EXTH-62. COMBINATORIAL THERAPY TARGETING TRANSCIPTION AND IMMUNO-METABOLISM IN RECURRENT GLIOBLASTOMA
Authors: Dighe Pratiksha , Woo Rinette , Salomonis Nathan , Bhattacharjee Anu , Nosrati Mehdi , Desprez Pierre , Dickinson Larry , McAllister Sean , Soroceanu Liliana
Published: November 2021

Recurrent glioblastomas (GBM) are notoriously difficult to treat, and in spite of aggressive chemo- and radiation therapy they inevitably recur in almost all GBM patients within 14 months following initial diagnosis. To interrogate pathways driving therapeutic resistance, we compared matched primary and recurrent IDH wild type glioblastoma samples from a cohort of patients, using RNA-Seq. Our analyses showed that pathways involved with tumor immune and metabolic reprogramming were up-regulated in recurrent GBMs compared to untreated, primary samples. Based on these findings, we tested the anti-tumor efficacy of over 20 rationally selected targeted therapeutic agents alone and in combination in a high-throughput drug screen assay designed to measure long term cell viability of primary tumorspheres from patients who underwent surgery for recurrent GBM. Top performing drug combinations from these screens were validated in vivo using patient-derived intracranial mouse models of glioma. Our data demonstrated that the combination of the transcriptional/metabolic inhibitor TG02 and the dual PI3K/mTOR inhibitor GDC-0084 significantly prolonged in vivo survival of tumor bearing mice, performing better than either drug alone. Notably, both inhibitors are undergoing human clinical trials as single agents with positive initial safety profiles and superior blood brain barrier penetrance. RNA Seq and functional assays of tumor samples from treated mice showed that only the combination treatment (TG02 + GDC-0084) significantly inhibited expression of immunomodulatory cytokines driving tumor progression, including those identified by us to be overexpressed in recurrent human GBM samples. Overall, these data suggest that combining TG02 and GDC-0084 is an effective treatment for recurrent GBMs. Furthermore, our results support the use of a translational research platform consisting of a personalized pharmaco-genomics testing, using patient-derived tumor samples towards designing more effective treatment for recurrent GBM patients.
EXTH-73. PROTEASOME INHIBITION EXPOSES SELECTIVE VULNERABILITY IN CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Miyake Yohei , Kawazu Masahito , Wakimoto Hiroaki , Tateishi kensuke , Yamamoto Tetsuya
Published: November 2021

Central nervous system lymphoma (CNSL), including primary and secondary CNSL, has a poor prognosis despite standard intensive chemotherapy. Since the majority of CNSL tumors are highly dependent on NF-κB signaling pathway for survival, Bruton’s kinase inhibitors, which target upstream in the NF-κB pathway, have demonstrated favorable clinical response in PCNSL patients. However, early recurrence is frequently observed. Therefore, novel therapeutic strategies are required in this progressive CNS disease. To understand the underlying tumor biology and explore a novel therapeutic strategy of CNSL, we previously established a panel of patient-derived xenograft (PDX) models, from both immunocompetent and Epstein-Barr virus (EBV)-positive CNSL patients. We confirmed that these PDX models highly recapitulated the phenotypic and genetic features of patient tumors. Using 19 PDX models, including 17 originally established PDXs, we found that NF-κB pathway related genomic alterations and AKT/mTOR signaling did not correlate with sensitivity to BTK inhibitors. We also found that RelA/p65 dephosphorylation as a biomarker of CNSL cells, which are responding to ibrutinib. Through high-throughput and NF-κB pathway-targeted drug screenings, we discovered that proteasome inhibitors suppressed cell viability across all CNSL models. The therapeutic effect, observed at a lower nanomolar range, was mediated by inhibition of the canonical NF-κB and AKT/mTOR pathways and was reversed by silencing of MYD88/CD79B in immunocompetent CNSL or LMP1 in EBV-positive CNSL. The second-generation proteasome inhibitor marizomib prolonged overall survival in CNSL orthotopic xenograft models through simultaneous suppression of RelA/p65 and AKT/mTOR signaling. Proteasome inhibition deregulated Mcl-1 and mediated caspase-dependent apoptosis, which was further enhanced by Bcl-2 family inhibition. Our results demonstrate the potential of proteasome inhibition as a novel therapeutic strategy in patients with immunocompetent and EBV-positive CNSL.
EXTH-80. PBI-200: IN VIVO EFFICACY OF A NOVEL, HIGHLY CNS-PENETRANT NEXT GENERATION TRK INHIBITOR
Authors: Pal Kollol , Regina Anthony , Elagoz Aram , Albert Vincent , Boudreault Johnathan , Ouellet Marc , Pilote Louise , Bruneau-Latour Nicolas , Wang Hong , Tao Limei , Bellavance Edith , White Peter , Ciblat Stephane , Leef Jordan , Bishop Robert
Published: November 2021

TRK kinases (TRK) are clinically validated targets for cancers harboring NTRK gene fusions. However, approved TRK inhibitors (TRKi) give rise to mutations reducing long-term clinical efficacy, and display limited CNS penetration that may impact their ability to address primary brain tumors (PBT), including high-grade gliomas. Second generation compounds in development address some resistance mutations, but are not sufficiently CNS penetrant. PBI-200 is a novel, orally active TRK inhibitor designed to overcome resistance, with high CNS penetration. In vitro assays demonstrate picomolar- to nanomolar potency against both wild-type TRK and the major acquired resistance mutations. A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Importantly, drug concentrations in the brains of PBI-200 treated mice showed an approximately 4-fold brain/plasma ratio (BPR). In contrast, BPR of other TRKi were < 0.17, indicating that only PBI-200 achieved sustained drug levels in brain. PBI-200 demonstrated statistically superior CNS efficacy and survival in a KM12-Luc intracranial murine model, as compared to other TRKi (chi-squared 45.6, p < 0.0001). By day 41, 50% of mice in the PBI-200 group remained alive, whereas mice in the other treatment groups had died on or before day 32. Of note, no gross or histopathological CNS adverse effects were observed in a 14d CNS Field Observation Battery study. Finally, PBI-200 was the most selective TRKi in a 125 kinase panel (ThermoFisher) with only 1 off-target kinase inhibited > 60% at 1 micromolar. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).
QOLP-06. THE CHALLENGE OF FACING A NEW MALIGNANT GLIOMA DIAGNOSIS: PATIENT EXPERIENCES LEARNING ABOUT THEIR ILLNESS AND COMMUNICATING WITH THEIR PROVIDERS IN THE NEURO-ONCOLOGY CLINIC
Authors: Mesa Michelle , Kaslow-Zieve Emilia , Traeger Lara , Temel Jennifer , Forst Deborah
Published: November 2021

BACKGROUND

Patients with newly diagnosed malignant gliomas (MG) face the sudden and unexpected news that they have a terminal neurological illness. However, little is known about these patients’ experiences learning about their illness and communicating with their oncology providers.

METHODS

We conducted semi-structured interviews with patients with MG who had recently completed chemoradiation, to explore patient-clinician communication and evaluate how patients process information about their diagnosis. We excluded patients with marked cognitive dysfunction, with eligible patients required to have a Mini-Mental Status Exam score of 24/30 or greater. We terminated enrollment once we reached thematic saturation, after a total of 9 patient interviews. We thematically analyzed qualitative data to describe patterns common to the patients’ experiences.

RESULTS

Most patients were male (6/9, 66.7%), with median age of 55 years (range 26-72) and had a diagnosis of glioblastoma (6/9, 66.7%). The majority of patients described a positive experience communicating with their providers, noting that information was delivered clearly, and visits were not rushed. Despite this, patients found it difficult to absorb and process the large volume of new information, particularly in the setting of their shock and dismay about the diagnosis and their ongoing neurological deficits. Emergent themes included concerns about the impact of the disease on their loved ones, struggles in coping with uncertainty, and worries about preserving their quality of life and functioning. Additionally, patients described their efforts to balance their knowledge about their poor prognosis with their desire to maintain hope, with many patients expressing a goal to “beat the odds” or exceed expectations with respect to their survival.

CONCLUSION

Although patients with newly diagnosed MG describe effective communication with their providers, they face many challenges coping with their terminal diagnosis. Supportive interventions aimed at this population are needed.
QOLP-13. RETROSPECTIVE REVIEW OF HOSPICE CARE UTILIZATION IN GLIOBLASTOMA PATIENTS IN A TERTIARY CARE CENTER
Authors: Puri Sushant , Heron David , NIcholas Martin , Huber Michael , Tuite Jason , Puri Sushant
Published: November 2021

BACKGROUND

Glioblastoma is a highly aggressive grade IV tumor of the brain. Standard of care is maximal safe resection followed by radiation therapy and chemotherapy. Despite optimal management, majority recur, and the median survival is 2-3 years. Hospice is a philosophy of care to alleviate end-of-life suffering, and it can also relieve caregiver fatigue.

METHODS

This is a retrospective chart review in a tertiary care center. IRB approval was obtained from the Office for the Protection of Research Subjects. ICD-10 code for malignant gliomas C71.9 was used to query EMR at UIC from 2015-2020. Patients with primary glioblastoma that had their entire neuro-oncologic care at UIC were included in the data analysis. Patient’s age < 18 years, unknown date of death, or those who transitioned to a different facility were excluded. Data included were demographic (including marital status as a proxy for social support), insurance, ethnicity, tumor characteristics, and treatments provided. End-of life quality measure assessed were (1)no chemotherapy < 2w, (2)hospice status < 7 days, (3)no hospital admission > 30 days (4)no ICU admission < 14 days.

RESULTS

48 patients with primary glioblastoma were identified and out of those, a total of 35 patients received entirety of neurooncological care at our center. Date of death was available for 13 patients. 9 patients had been referred to hospice and 4 were not. Demographic variables were similar except social support – patients referred to hospice were more likely to be married. End-of-life quality measures were met in all patients in hospice group (9/9) but only in half of those not referred to hospice (2/4).

DISCUSSION

Social support has an impact on enrollment of hospice care. Including goals of care discussion earlier in the treatment would require a multi-disciplinary team with additional involvement of supportive care, nurses, and social workers.
QOLP-18. QUALITY OF LIFE IN GLIOMAS WHO UNDERWENT AWAKE SURGERY DEPENDS ON RETURN TO SOCIAL LIFE, ABILITY OF MOVEMENT AND VERBAL FLUENCY
Authors: Nakajima Riho , Kinoshita Masashi , Okita Hirokazu , Nakada Mitsutoshi
Published: November 2021

Awake surgery is performed aiming for maintaining postoperative quality of life (QOL) by preserving brain function. Nowadays, it is not known whether QOL is certainly maintained in gliomas who underwent awake surgery, and which brain functions contribute to maintain their postoperative QOL. Here we investigated QOL following awake surgery, and to determine their background and functional factors influencing on QOL. Totally 80 patients with gliomas were matched our inclusion criteria. SF-36 was performed for assessment of QOL. Three component scores including physical component summary (PCS), mental component summary (MCS), and role/social component summary (RCS) were calculated, and were compared them with that of normal healthy controls. Additionally, neurological/neuropsychological functions were evaluated at pre- and post-operative six months. Multiple regression analyses were used to investigate functional and sociodemographic/clinical factors influencing on SF-36. RCS but not PCS and MCS in patient group was significantly lower than that of normal controls (p< .0001). Then, we investigated sociodemographic/clinical factors influencing on RCS, and found two significant factors, returning to social life and malignancy grade (p=0.011 and 0.022, respectively). The primary reasons for difficulty in returning to social life were functional deficits including aphasia and paresis. Among functional factors, RCS significantly related to motor function and verbal fluency (p= 0.0042 and 0.040, respectively). To support the results, RCS in deficit group for movement and verbal fluency was significantly low than in non-deficit group (Wilcoxon test, p=0.037 and 0.044, respectively). Among factors influencing on RCS, sociodemographic/clinical factors were returning to social life and malignancy grade, while functional factors were motor function and verbal fluency.