bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-26. UNRAVELING ANTIGEN PRESENTATION IN CENTRAL NERVOUS SYSTEM ANTI-TUMOR IMMUNITY
Authors: Bowman-Kirigin Jay , Kobayashi Dale , Livingstone Alexandra , Saunders Brian , Schaettler Max , Liu Connor , Durai Vivek , Bowman-Kirigin Jay , Leuthardt Eric , Kim Albert , Zipfel Gregory , Osbun Joshua , Chicoine Michael , Murphy Kenneth , Zinselmeyer Bernd , Johanns Tanner , Dunn Gavin
Published: December 2020

The antigen presenting cell that primes T cells in the central nervous system (CNS) remains unknown. Outside the CNS, the conventional dendritic cell 1 (cDC1) subset presents antigen to and primes CD8 T cells. However, the steady-state CNS parenchyma is relatively devoid of all dendritic cell subsets, including cDC1. cDC1 are required for anti-tumor immunity a variety of other tumor types, but their role CNS tumors remains undefined. Using the orthotopic preclinical glioblastoma models, GL261 and CT2A, we characterized the role of cDC1 in the CNS anti-tumor immune response. While cDC1 are absent in the steady state brain, tumor presence drove recruitment of cDC1 into extravascular spaces within the tumor and adjacent brain parenchyma. We further found that while GL261-bearing wildtype mice experienced survival benefit following anti-PDL1 checkpoint blockade treatment, mice with cDC1 genetically deleted experienced no survival benefit. cDC1-deficient mice completely lacked neoantigen-specific CD8 T cells against the endogenously-primed GL261-neoantigen mutant Imp3, and possessed broad CD8 effector T cell defects compared to wild type mice. Furthermore, using a fluorescent tumor-associated reporter, we detected tumor-derived material within dendritic cells from the tumor, the lymphatic vessel-containing dura, and the cervical lymph nodes. We observed the human cDC1-equivalent CD141+ cDC within human brain tumors (not limited to GBM) and dura as well. We used the GBM-specific reporter, 5-aminoilevulinic acid/protoporphyrin IX (PPIX) fluorescent metabolite to resect the tumor, and observed PPIX specifically in conventional dendritic cell subsets that had infiltrated the resected tumor, but not within those same cell subsets in the periphery, nor in T cells within the tumor. These findings comport with the canonical understanding that cDC1 uptake antigen at the effector site and migrate to draining lymph nodes to prime effector CD8 T cells, and highlight the significant role that cDC1 play in CNS anti-tumor immunity in mice and humans.
IMMU-33. MULTI-ANTIGEN RECOGNITION CIRCUITS OVERCOME CHALLENGES OF SPECIFICITY, HETEROGENEITY, AND DURABILITY IN T-CELL THERAPY FOR GLIOBLASTOMA
Authors: Watchmaker Payal , Choe Joseph , Simic Milos , Gilbert Ryan , li Aileen , Krasnow Nira , Carrera Diego , Yu Wei , Downey Kira , Celli Anna , Cho Juhyun , Briones Jessica , Dannenfelser Ruth , Cardarelli Lia , Sidhu Sachdev , Roybal Kole , Lim Wendell , Okada Hideho
Published: December 2020

Treatment of solid cancers with chimeric antigen receptor (CAR) T-cells is challenging because of a lack of target antigens that are both tumor-specific and homogenously expressed. While epidermal growth factor receptor (EGFR)vIII represents a glioblastoma (GBM)-specific antigen, its expression is heterogeneous within the tumor resulting in tumor escape. In contrast, more homogenously expressed GBM-associated antigens (GAA), such as EphA2, are non-ideal because of expression in other normal organs, yielding potential cross-reactive toxicity. As a way to safely target GAAs in the tumor without attacking normal cells expressing the same GAAs outside of the brain, we adapted a novel synthetic Notch (synNotch) receptor system and established a “prime and kill” sequential two-receptor CAR circuit. A synNotch receptor recognizes a specific priming antigen; the heterogeneous GBM neoantigen EGFRvIII or a brain tissue-specific antigen to prime the local expression of a CAR that mediates cytotoxicity against a GAA (e.g. EphA2). In orthotopic GBM6 glioma model, a patient-derived xenograft (PDX) with heterogeneous expression of EGFRvIII, intravenous infusion of T-cells transduced with EGFRvIII synNotch→anti-IL-13Rα2/EphA2 tandem CAR circuit resulted in long-term (over 100 days) survival and eradication of the heterogeneous tumor in all of 12 mice in two independent experiments. In contrast, constitutive CARs targeting EGFRvIII or IL-13Rα2/EphA2 (as a tandem CAR) failed to exhibit long-term anti-tumor response. Moreover, T-cells transduced with synNotch-regulated CAR maintain a less differentiated state which is associated with higher durability compared with ones with constitutive CAR in vivo. T-cells transduced with a synNotch→CAR circuit primed by a brain-specific antigen, myelin oligodendrocyte glycoprotein (MOG), exhibited a precise and potent local control of intracranial PDX without evidence of priming in extracranial organs. These data support the utility of synNotch→CAR circuits in EGFRvIII-negative GBM cases. By integrating multiple imperfect but complementary antigens, we improve both the specificity and persistence of T-cells directed against GBM.
IMMU-38. PRECLINICAL VALIDATION AND MANUFACTURE OF IL-8 RECEPTOR-MODIFIED CD70 CAR T CELLS FOR CLINICAL TRIAL
Authors: Jin Linchun , Tao Haipeng , Na Meng , Karachi Aida , Mendez-Gomez Hector , Weidert Frances , Hou Alicia , Sayour Elias , Mitchell Duane , Huang Jianping
Published: December 2020

BACKGROUND

Chimeric antigen receptor (CAR) modified T cell therapy is a promising treatment strategy for cancer therapy. We developed IL-8 receptor-linked CD70CAR (8R-70CAR), aiming to enhance T-cell intratumoral trafficking and persistence, guided by IL-8-secreting tumors. The preclinical results show that 8R-70CAR T cells induce complete tumor regression and long-lasting antitumor immunity, which necessitate further clinical development of this technology.

OBJECTIVE

To assess the toxicity of 8R-70CAR T cells, evaluate in vitro tumor recognition and expansion of the 8R-70CAR T cells, and develop clinically compliant SOPs for the CAR T cell manufacture.

METHODS

The m8R-70CAR (mouse), h8R-70CAR (human), and control CAR were constructed. Toxicology: C57BL/6J mice were intravenously injected with or without 2x106 m8R-70CAR T cells after total body irradiation (5Gy). The body weight, clinical signs, hematology, serum chemistry, serum cytokines, gross pathology, and histopathology of 12 vital organs were evaluated. Tumor recognition: T cells derived from GBM patients were transduced with h8R-70CAR and then co-cultured with CD70+ glioblastoma. INF-g production was measured. Ex vivo expansion: The G-Rex system was utilized for CAR T cell production, and the expansion of h8R-70CAR T cells was assessed by cell count.

RESULTS

No CAR T cell-related toxicity was observed in mouse study. In addition to a robust antitumor reactivity, the h8R-70CAR T cells present an auto-stimulative property that elicits greater ex vivo expansion compared to other CAR T cells tested. An approximately 1200-fold expansion was achieved during the 2 weeks CAR T cell production without additional stimulation, which allows production of the CAR T cells on a clinical trial scale using < 100mL of whole blood.

CONCLUSION

The 8R-70CAR T cells are effective, auto-stimulative, and safe. These properties are fundamental for successful clinical applications in cancer treatment. A phase I trial using the 8R-70CAR T cells in newly diagnosed GBM will be initiated soon.
IMMU-39. TIM-3 APTAMER IN COMBINATION WITH RADIOTHERAPY RESULTS IN ENHANCED SURVIVAL IN DIPG MODELS
Authors: Martinez-Velez Naiara , Garcia-Moure Marc , Puigdelloses Montserrat , Laspidea Virginia , Ausejo Iker , Ramos Luis Isaac , Becher Oren J , Pastor Fernando , M Alonso Marta
Published: December 2020

Pediatric diffuse midline gliomas-H3-K27M-mutant are aggressive brain tumours that arise during childhood. Despite new advances in genomic knowledge and the significant number of clinical trial testing new targeted therapies, patient outcome is still insufficient. Cancer immunotherapy is opening new therapeutic options representing a hope for this orphan disease. Aptamers are single-stranded nucleic acid ligands design to achieve a remarkable affinity and specificity to their targets, comparable to antibodies. TIM-3, is a potential immune checkpoint target, typically involved in T-cell exhaustion. Recent studies showed that TIM-3 is also expressed in tumour and glial cells and it plays an important role in brain tumour responses mediated by myeloid cells. In this work, we examined the anti-tumour effect of an aptamer against TIM-3 alone or in combination with radiotherapy. Of importance, we tested TIM-3 aptamer in a murine glioma and DIPG model, where we not observed any toxicity. TIM-3 administration increased overall survival but was unable to control the disease. Of importance, TIM-3 combination with radiotherapy improved the overall survival of treated mice when compared with single treatments leading to 50% of long-term survivors. TIM-3 aptamer administration increase T-infiltration in the tumour site compared to non-treated or library control. Mechanistic studies performed on day 16 showed an increase in CD8 effector cells, a decrease in T-regulators Foxp3+ cells and an increase in IFN-gamma expression suggesting the triggering of an antitumor-immune response. Rechallenge experiments demonstrated immune memory in the long-term responders that led to reject tumour re-implantation, confirming that TIM-3 aptamer treatment in combination with RT elicits specific antitumor immunity in mouse glioma models. These results suggest that immuno-therapies approaches in combination with radiotherapy would be worth exploring in the treatment of deadly DMG-H3K27-Mutant tumours.
IMMU-42. DUAL ACTIVATION OF THE cGAS-STING PATHWAY AND AIM2-INDUCED PYROPTOSIS BY TUMOR-TREATING FIELDS PRODUCES ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA
Authors: Chen Dongjiang , Sebastian Mathew , Hutchinson Tarun , Ghiaseddin Ashley , Warren Sonisha , Allen Annie , Jin Dan , Le Son , Tran David
Published: December 2020

OBJECTIVES

Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed Glioblastoma (GBM) patients and resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. In many patients, a transient stage of increased peritumoral edema is often observed early during TTFields treatment, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. We hypothesize that TTFields activate the immune system by triggering pyroptosis and type I Interferon (IFN) response.

METHODS

A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Cells were analyzed for the production of micronuclei and activation of both pyroptosis and STING pathways using immunostaining, quantitative PCR, ELISA and cytometry. Pre-treated mouse GBM cells were injected into mouse brain to monitor survive and immunophenotyping. GBM patients’ blood was collected, and PBMC were isolated and analyzed by single cell RNAseq.

RESULTS

TTFields resulted in a significantly higher rate of micronuclei structures released into the cytoplasm, which were co-localized with two upstream dsDNA sensors AIM2 and cGAS. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by LDH release assay, and through AIM2-recruited caspase1 activation and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway leading to the increase of type I IFNs and pro-inflammatory cytokines. In mouse model, double knocking down of STING/AIM2 eliminated the tumor suppression effects caused by TTFields. TTFields pretreated wild type cells successfully elevated dendritic cell level in mouse cervical lymph nodes which can be reversed by double knocking down.

CONCLUSIONS

These results provide compelling evidence that TTFields induces effective anti-tumor immunity in GBM cells and patients.
IMMU-44. PRE-DIAGNOSTIC EOSINOPHIL LEVEL AND GLIOBLASTOMA DEVELOPMENT IN PATIENTS WITH AND WITHOUT ATOPIC DISEASE
Authors: Bushara Omar , Guzner Alexander , Burdett Kirsten , Murday Patrick , Pollevick Matias , Scholtens Denise , Kumthekar Priya
Published: December 2020

BACKGROUND

Glioblastoma (GBM) is the most common primary malignant brain tumor and carries a very poor prognosis. Recent data report a negative association between the incidence of GBM and atopic disease. The underlying immunologic mechanisms of protection and the associated potential biomarkers are unclear. The aim of this retrospective study is to assess the relationship of eosinophil count to GBM risk by collecting eosinophil count in GBM patients with and without existing atopic disease.

METHODS

This is a retrospective study of 790 patients diagnosed with GBM from 2009–2019. Of those patients, 140 had laboratory values at least one year prior to diagnosis. Chart review was used to exclude patients with lymphoma, leukemia, other cancers, myelodysplastic syndromes, and unconfirmed drug, food, and adhesive reactions. 14 patients with chart-confirmed allergic rhinitis, asthma, or eczema and 47 controls were found. Wilcoxon rank sum test was used to compare the two groups.

RESULTS

The two groups did not differ in pre-diagnostic eosinophil counts (p=0.426). The two groups also did not differ in pre-diagnostic basophil, lymphocyte, neutrophil, or monocyte counts. Pre-diagnostic eosinophil to lymphocyte, monocyte to lymphocyte, and neutrophil to lymphocyte ratios also did not differ between the two groups. There were no other quantitative differences that would suggest a difference in immune cell profile.

CONCLUSIONS

In our study, the subset of GBM patients with atopic disease did not significantly differ in eosinophil count or other white blood cell subtypes when compared to GBM patients without atopic disease. Given that atopic disease is a known protective factor, and our atopic patients with GBM had normal eosinophil counts, we conclude that underlying immunologic factors such as eosinophilia may be protective from GBM as opposed to simply the presence of atopic disease. Prospective analysis to best understand eosinophil count as a surrogate for GBM risk is warranted.
IMMU-47. PROTEIN PHOSPHATASE 2A INHIBITION IN NK CELL THERAPY FOR TREATMENT OF MEDULLOBLASTOMA
Authors: Lu Rongze Olivia , Ho Winson , Chiou Brandon
Published: December 2020

Checkpoint immunotherapy (ICB) thus far has shown limited efficacy against brain tumors, such as medulloblastoma (MB). Its low mutational burden is thought to result in a paucity of neoantigen to trigger an effective T-cell response. Natural killer (NK) cells, can recognize tumor cells independently of neoantigens, making them appealing against MBs. Modulation of NK cells to enhance cytotoxicity against MBs could be a novel treatment strategy. Protein Phosphatase 2A (PP2A), a ubiquitous serine/threonine phosphatase, has been shown to inhibit IFNg and Granzyme B production by NK cells. We hypothesize that NK92, a transformed human NK cell line, has intrinsic activity against human MB cells and that inhibiting PP2A pharmacologically can enhance cytotoxicity of NK92 cells. We performed NK cytotoxicity assay and granulation assay against human MB cell line D425. We also used a small molecular inhibitor, LB100, to modulate PP2A activity in NK92. NK92 cells were co-cultured with D425, in increasing E:T (Effector:Target) ratio for 4 hours. D425 cells were pre-labeled with CellTrace Violet dye. The percentage of D425 (Violet+) cells in apoptosis (Cas3/7+) or necrosis (AAD+) were compared with different ET ratios to quantify NK mediated cell cytotoxicity. We also measured CD107a expression in NK92 to assess granulation with LB100 treatment. D425 cells were sensitive to NK92 killing. Percentage of D425 cells either apoptotic or necrotic increased with increasing ET ratio, suggesting that there was NK92 mediated cytotoxicity. Percentage of killed D425 cells ranged from 18% at baseline (without NK92) to 80% at ET ratio of 20. Inhibition of PP2A using LB100, enhanced NK92 degranulation. CD107a+ NK92 cells increased from 19% to 28% with 8uM of LB100. NK92 cells are cytotoxic against MB cells in vitro and inhibition of PP2A in NK cells can enhance their activity against MB cells.
IMMU-49. PREDICTING PATIENT-SPECIFIC ANTIGENS FOR MEDULLOBLASTOMA IMMUNOTHERAPY
Authors: Dyson Kyle , Yang Changlin , Trivedi Vrunda , Wildes Tyler , Grippin Adam , Mitchell Duane
Published: December 2020

BACKGROUND

Identification of tumor rejection antigens remains a major barrier to the development of effective immunotherapeutics and their application to pediatric brain tumors. To identify candidate antigen targets for medulloblastoma adoptive cellular therapy, we performed a comprehensive immunogenomic analysis of medulloblastoma transcription profiles and in silico antigen prediction across a broad array of antigen classes. We hypothesized that medulloblastomas are immunologically heterogeneous and express genes with limited normal tissue expression that may serve as targets for immunotherapy.

METHODS

Immunologic heterogeneity was assessed using several published algorithms and approaches implemented within the R programming language. Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Patient-specific tumor associated antigens (TAA) were selected only if expressed >1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database was below 1 TPM. Patient-specific HLA and TAA sequences were extracted from RNA-seq data for prediction with eight MHC class I and four MHC class II affinity algorithms. Only expressed mutations and personalized TAAs were used for antigenic epitope predictions. All epitopes were screened against a human reference proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Public mass-spec data was also screened for protein-level antigen expression.

RESULTS

Although absolute immune cell content is predicted to be low, immune gene-signature analysis revealed subgroup-specific differences. Antigen prediction analysis revealed most patients express few candidate neoantigen targets passing all filtering criteria. Importantly, cancer testis antigens as well as previously unappreciated neurodevelopmental antigens were found expressed across all medulloblastoma subgroups and most patients. Protein level antigen expression was confirmed for some predicted TAAs.

CONCLUSION

Medulloblastomas are immunologically cold yet subgroups have distinct immune cell gene-signatures. Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for development of medulloblastoma cellular therapies.
IMMU-50. BBB CROSSING NANO-IMMUNOMEDICINE COMBINATION THERAPY TO TREAT BRAIN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Sun Tao , Yang Jiyuan , Gamburg Maximilian , Ljubimov Vladimir , Grodzinski Zachary , Black Keith , Holler Eggehard , Kopeček Jindřich , Ljubimova Julia
Published: December 2020

INTRODUCTION

Lack of standard treatment of Primary Central Nervous System Lymphoma (PCNSL) was acknowledged in phase III intergroup study (HOVON 105/ALLG NHL 24). PCNSL incidence is increasing for unknown reasons, particularly among persons over 65 years. One of the major limitations of successful treatment of PCNSL is the blood-brain barrier (BBB), which prevents drug delivery into the brain.

METHODS

Polymer nanoconjugate based on biodegradable poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) was used for treatment of BALB/C mice with intracranially inoculated murine A20 lymphoma. PHPMA-based nanoconjugates have defined synthesis strategy for BBB transcytosis, tumor targeting, and cancer cell killing. Nano immunodrug PHPMA/AP-2/Fab’/c-Myc inhibitor/H6 conjugate contains multiple AP-2 peptides for efficient delivery across the BBB and Fab’ fragments of αCD20 mouse Ab for CD20 receptor crosslinking on PCNSL cells. c-Myc inhibitor bound via a disulfide bond is transferred to the cytoplasm followed by cleavage. The therapeutic efficacy and survival were evaluated together with spectral flow cytometry and RNA-seq bioinformatic analysis of tumor tissues.

RESULTS

Nanoconjugates were able to penetrate BBB and accumulate in brain parenchyma. The best survival results were obtained for the group where nanoconjugate with αCD20 Fab’ causing tumor cell apoptosis and c-Myc antisense inhibitor was combined with αPD-1 checkpoint inhibitor. Survival compared to PBS-treated controls was significant (P=0.0006 by ANOVA). Ex vivo analysis of A20 brain lymphoma tissue after treatment with nanoconjugates demonstrated reduction of Tregs, associated with downregulation of IL-10 and IL-1β in plasma. Spectral flow cytometry revealed activation of tumor infiltrating T lymphocytes and M1 macrophages in lead nanodrug treated groups. RNA-seq data correlated with flow cytometry results indicating the activation of genes linked to IFN-γ pathway important for anti-tumor response and M1 macrophage activation. Immunostaining confirmed a marked increase of M1-specific iNOS expression in the nanodrug-treated tumors. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921
IMMU-51. NEUROLOGIC IMMUNE-RELATED ADVERSE EVENTS MIMICS, RISK FACTORS, AND MECHANISMS: CLIPPERS AND ASEPTIC MENINGITIS
Authors: Yuen Carlen , Rezania Kourosh , Park Deric , Reder Anthony
Published: December 2020

Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint blockade. It is imperative to distinguish between irAEs and their mimics for successful treatment. We present the first case of CLIPPERS-like lesions in a patient with thymic cancer, thymoma, and a family history of neuromyelitis optica, following treatment with pembrolizumab. The brainstem lesion was in the anatomic location of the respiratory and cardiac centers. We also present a second case of aseptic meningitis irAE in a patient with prior graft-versus-host-disease following a single dose of nivolumab. These cases add to the growing evidence of CNS complications from immune checkpoint inhibitors. Risk factors for irAEs are not well established, and we explore potential risk factors and a possible mechanism from dysfunctional regulatory T cells.
INNV-05. TUMOR TREATING FIELDS (TTFIELDS) TREATMENT PLANNING FOR A PATIENT WITH ASTROCYTOMA IN THE SPINAL CORD
Authors: De Los Santos Jennifer , Arvatz Smadar , Zeevi Oshrit , levi Shay , Bomzon Zeev , Marciano Tal
Published: December 2020

BACKGROUND

The use of Tumor Treating Fields (TTFields) following resection and chemoradiation has increased survival in patients with Glioblastoma. Randomized data provide strong rationale for planning TTFields transducer array placement to maximize TTFields dose at the tumor in a patient-specific manner. Here we present a case demonstrating the use of numerical simulations for patient-specific TTFields treatment planning for a spinal tumor.

METHODS

Treatment planning was performed for a 48 year old patient following T10-L1 laminectomy, gross total resection, and postoperative chemoradiation for an anaplastic astrocytoma of the spinal cord. An MRI at 3 weeks following chemoradiation showed tumor recurrence. Based on the post-chemoradiation MRI, a patient-specific model was created. The model was created by modifying a realistic computational phantom of a healthy female. To mimic the laminectomy, the lamina in T10-L1 was removed, and the region assigned electric conductivity similar to that of muscle. A virtual mass was introduced into the spinal cord. Virtual transducer arrays were placed on the model at multiple positions, and delivery of TTFields simulated. The dose delivered by different transducer array layouts was calculated, and the layouts that yielded maximal dose to the tumor and spine identified.

RESULTS

Transducer array layouts, in which the arrays were placed on the back of the patient with one array above the tumor and one array below the tumor, yielded the highest doses at the tumor site. Such layouts yielded TTFields doses of over 3.4mW/cm3 which is well above the threshold dose of 1.1 mW/cm3 reported previously [Ballo et al Red Jour 2019].

CONCLUSIONS

These data represent the first ever study on utilizing numerical simulations in order to plan treatment for a spinal tumor in a patient-specific manner. This is an important milestone in the developing a framework for TTFields dosimetry and treatment planning.
INNV-11. GLIOBLASTOMA IN THE OLDER PERSON – HOW DO WE DECIDE ON TREATMENT?
Authors: Lorimer Cressida , Chalmers Anthony , Johnson Margaret , Brock Juliet
Published: December 2020

The incidence of glioblastoma (GBM) peaks in the 7th and 8th decades of life. Multiple treatment options exist for older patients with GBM however, the assessment of older patients prior to treatment decisions is poorly researched and lacks standardization. In order to address this issue we performed a cross-sectional electronic survey distributed to all full members of the Society for Neuro-Oncology. There were 116 respondents from a total of 1515 recipients (8% response rate). The survey was distributed during the peak of COVID-19 which undoubtedly affected response rates. 97% of respondents were clinicians with 86% academic. 72% had been in practice > 10 years and the majority saw 5–10 new GBM cases per month. 95% of respondents were from the USA, with involvement from Japan, Australia, Canada and Italy. 37% of respondents routinely perform a cognitive or frailty screening test. Of these, MMSE and MoCA were the most commonly used. Of those who performed a screening test, the majority reported that the results changed their treatment decision in approximately 50% of cases. 50% of respondents have access to a multidisciplinary team during their clinic, with physical therapy being the most available. When making treatment decisions, participants ranked performance status as the most important clinical factor. Considering the heterogeneity of this patient population, we argue that performance status is a crude measure of vulnerability within this cohort. In the first survey of this kind, we have shown a disparity in assessment techniques across the international neuro-oncology field and the impact performing a cognitive screen has on decision making. Older patients with GBM represent a unique clinical scenario because of the complexity of distinguishing neuro- oncology related symptoms from general frailty. There is a need for specific geriatric assessment models tailored to the older neuro-oncology population in order to facilitate treatment decisions.
INNV-21. EFFECTIVE REGIMEN OF HIGH-DOSE METHOTREXATE PLUS TEMOZOLOMIDE FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A SINGLE-CENTER RETROSPECTIVE STUDY
Authors: Zhang Jun-ping , Ge Jing-jing , Li Cheng , Qi Shao-pei , Xue Feng-jun , Gao Zhi-meng
Published: December 2020

OBJECTIVE

To evaluate the efficacy and safety of high-dose methotrexate combined with temozolomide in the treatment of newly diagnosed primary central nervous system lymphoma.

METHODS

A retrospective study was performed to analyze the clinical data of patients with primary central nervous system lymphoma treated with high-dose methotrexate plus temozolomide in the Department of Neuro-oncology, Capital Medical University, Sanbo Brain Hospital from May 2010 to December 2018.

RESULTS

A total of 41 patients were identified. Median age was 57 years (range, 27–76 years). The maximal extent of surgery was total resection in 6, partial resection in 8, and biopsy in 27 patients. Of the 35 patients with evaluable lesions, 32 achieved complete response (CR) and 3 achieved partial response. CR rate was 91.4%. The median follow-up time was 36.5 months (range, 4.9–115.4 months). After treatment, the median progression-free survival (PFS) was 45.1 months. PFS rate at 1, 2, 5 years were 85.4%, 70.1% and 43.8%, respectively. The OS rate at 1, 2, 5 years were 92.7%, 82.4% and 66.5%, respectively. The median PFS of patients younger than 65 years was better than that of patients ≥65 years (98.8 months vs 27.9 months, p=0.039). There was no association between efficacy and extent of resection (p=0.836). After disease progression, 6 of the 21 patients received radiotherapy. There was no statistical difference in OS between the patients with or without radiotherapy (36.9 months vs 28.4 months). The main severe adverse events were myelosuppression (36.6%) and elevated transaminase (34.1%). Three patients were discontinued due to drug-related toxicities.

CONCLUSIONS

High-dose methotrexate combined with temozolomide is effective in the treatment of primary central nervous system lymphoma, with a low incidence of severe adverse reactions. This efficacy may be better than the historical control of methotrexate alone or methotrexate plus rituximab.
INNV-26. SERVICE RECONFIGURATION INTO AN URGENT ELECTIVE PATHWAY FOR THE MANAGEMENT OF GLIOBLASTOMA PATIENTS IMPROVES OUTCOMES, COSTS AND PATIENT EXPERIENCE AND ADJUNCT USE: A SINGLE CENTRE SIX YEAR REVIEW
Authors: Sun Rosa , Sharma Shivam , Watts Colin , Wykes Victoria
Published: December 2020

BACKGROUND

Glioblastomas (GB) are grade four gliomas, the most common form of neoplasms arising in the brain. GBs are known for their aggressiveness; despite widespread research, limited advances have been made to improve survival. Between 2014–2019, a service reconfiguration for suspected GB referrals within our centre has been achieved. We have gone from a predominantly emergency admission and surgery based service for GB, to an urgent elective admission pathway. This is backed by weekly MDTs, neuro-oncology specialist led clinics, with imaging and pre-assessment clinic as part of a one-stop-shop model. Improved planning through elective admissions has also helped us achieve increased use of intra-operative adjuncts, including neuro-monitoring and the use of 5-ALA. The aim of this study is to describe a single centre experience of improvements made across six years through a combination of service reconfiguration and an increase use of intra-operative adjuncts.

METHODS

Patients with histological confirmed, primarily diagnosed GBs between 01/01/2014 and 31/12/2019 were extracted from the pathology database. Information including survival, treatment (surgical, oncological) and use of adjunct, admission status, length of stay (LOS), extent of resection and surgical complications were extracted manually. Inpatient admission costs were estimated.

RESULTS

From 2014 to 2019, we achieved an increase in elective admissions (28.1% to 90.3%, p< 0.001), which has led to a greater proportion of patients undergoing resective surgery (68.4% to 81.9%, p= 0.041), reduction in median length of stay (9 to 3 days, p < 0.001) and deceased overall costs. An increased use of intra-operative adjuncts has improved the proportion of total and gross resections (p< 0.001).

CONCLUSIONS

A switch from emergency to a MDT-based, urgent pathway with increased use of intra-operative adjuncts has resulted in improved technical outcomes and cost savings for the trust. This change has high potential to improve survival in patients on further follow-up.
INNV-29. PROFESSIONAL PRACTICE MODEL FOR ADVANCED PRACTITIONERS IN NEURO ONCOLOGY
Authors: Cone Christina , Affronti Mary
Published: December 2020

BACKGROUND

Neuro-oncology advanced practitioners (APs - nurse practitioners, physician assistants) require specialization beyond the scope of population-based generalist training and education. There are no specialty standards or certifications for neuro-oncology APs, no formal training programs, and no literature that addresses the competency requirements of neuro-oncology APs. The burden of AP turnover at an academic medical center ambulatory neuro-oncology practice was as high as 50%. This quality improvement project’s purpose was to develop a professional practice model (PPM) to support the professional development and retention of APs.

METHODS

Using the Focus, Analyze, Develop, Execute and Evaluate (FADE) quality improvement methodology the authors (1) reviewed literature and relevant professional organizations to identify possible professional competencies for neuro-oncology APs, (2) analyzed data to develop evidenced-based practice domains, (3) used purposive sampling to recruit a team of neuro-oncology experts, (4) conducted a Delphi study with the experts to gain consensus on practice domains and professional competencies, and finally (5) utilized the Delphi study results to create a PPM for neuro-oncology APs.

RESULTS

The authors recruited twenty-three participants (39% were physicians, 57% were APs, and 4% were administrators) for the Delphi study, which was executed via electronic transmission using Qualtrics. Participants reached consensus on six domains of practice (Medical Knowledge, Interprofessional Collaboration/Communication, System-based Practice, Professionalism, Practice-based learning, Patient/family-centered care) and fifty corresponding competency statements after two rounds of the Delphi. With the implementation of the PPM and the development of standardized onboarding, the AP turnover rate decreased from 50% to 12% in just two years.

CONCLUSION

This QI project successfully created a PPM for a neuro-oncology AP team. The PPM supports neuro-oncology APs by validating their unique skill set that combines several specialties. The PPM provided the framework to standardize orientation/training, evaluate performance, and promote job satisfaction and retention.
NCMP-07. TREATMENT-INDUCED CEREBRAL NECROSIS IN GLIOMAS: THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER (OSUCCC) EXPERIENCE
Authors: Rayi Appaji , Alnahhas Iyad , Palmer Joshua , Raval Raju , Slone Wayne , Ong Shirley , Giglio Pierre , Puduvalli Vinay
Published: December 2020

INTRODUCTION

Treatment-induced cerebral necrosis (TN) is a challenging complication encountered in neuro-oncology. Diagnosis and treatment of TN remains poorly defined.

METHODS

In this single institution, retrospective study, consecutive patients with gliomas and TN between 01/01/2012 and 04/20/2020 at the OSUCCC were identified. Details of the tumor treatment, molecular markers, radiological and pathological findings of TN, as well as treatment, recurrence rate and management upon recurrence were collected.

RESULTS

Of the 53 patients analyzed, 37 had glioblastoma, 7 had anaplastic oligodendroglioma and 9 had grade II or III astrocytoma. MGMT promoter hypermethylation was present in 31/50 (59%) and IDH mutation in 17/53 (32%). Diagnosis of TN was based on histology in 43/53 (81%) or clinical/radiographic features in 10/53 (19%). Worsening of focal weakness (36%), seizures (9%) or being (30%) were common presentations at TN diagnosis. Patient with right compared to left hemisphere involvement were more symptomatic at TN diagnosis. (p=0.049). Bevacizumab (BEV) (51%), resection (28%), steroids only (9%) or Laser Interstitial Thermal Therapy (6%) were used to treat TN. Steroids were weaned off in 20/27 (74%) after receiving BEV. Among all treatments, BEV was significantly associated with a better outcome (resolution or partial improvement of enhancement in 84.6%) (p=0.0006, Bonferroni corrected p< 0.005). TN Recurrence occurred in 36%, 70% and 100% of the patients treated with BEV, resection and LITT respectively. The median duration to TN recurrence was 10 weeks (range: 3–70 weeks). Initial treatment used for TN, MGMT methylation and IDH mutation status did not predict TN recurrence. (p=0.074; p=0.819; p=0.607 respectively).

CONCLUSIONS

BEV appears to be a superior treatment to control TN overall. Recurrence of TN in patients previously treated with BEV was 36%. There was no difference in the risk of developing recurrent TN based on MGMT or IDH status.
NCMP-10. IDH MUTATION STATUS AND THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM IN ASTROCYTOMA PATIENTS
Authors: Mandel Jacob , Youssef Michael , Yust-Katz Shlomit , Patel Akash , Jalali Ali , Ludmir Ethan , Wu Jimin , de Groot John
Published: December 2020

OBJECTIVE

Examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients.

BACKGROUND

The risk of venous thromboembolism (VTE) is high for patients with gliomas (10–30%). Unfortunately, biomarkers and predictive models for development of a VTE in brain cancer have not been validated. Prior research has suggested that IDH wildtype gliomas are at higher risk for development of VTE compared to IDH mutant tumors.

DESIGN/METHODS

We conducted a retrospective chart review of glioma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC). We obtained demographics, date of tumor diagnosis, initial pathology, IDH status (mutated or wildtype), extent of initial resection, KPS at time of initial resection, history of VTE, development of VTE, type of VTE (PE/DVT), KPS at time of VTE, treatment for VTE, bleeding complications, glioma treatments, date of last follow up and/or death.

RESULTS

We identified 282 astrocytoma patients consisting of 49 IDH mutant and 233 IDH wildtype astrocytomas. Glioblastoma was the histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45 (19.3%) of the IDH wild type astrocytomas (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p =0.8663).

CONCLUSIONS

IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.
NCMP-13. LEPTOMENINGEAL DISEASE FOLLOWING RESECTION OF INTRAVENTRICULAR MELANOMA METASTASIS DIAGNOSED THROUGH CIRCULATING TUMOR CELLS
Authors: Wang Christopher , Limia Melissa , Forsyth Peter , Liu James
Published: December 2020

Leptomeningeal disease in the setting of malignant melanoma metastatic to the brain provides a dismal prognosis. The relationship between intraventricular metastatic tumor seeding following surgical resection and development of leptomeningeal disease (LMD) is not completely clear, although there appears to be correlation. While the mechanisms that drive the development of LMD is not well understood, monitoring of cerebrospinal fluid (CSF) for circulating tumor cells (CTCs) in high risk patients may allow for early intervention for LMD prior to radiographical diagnosis. This report describes a patient with metastatic melanoma who developed ventricular trapping from an intraventricular melanoma metastasis. The patient underwent endoscopic assisted resection of the tumor. Due to concern for leptomeningeal seeding given the location of the tumor and use of surgical resection, CSF analysis was performed. CTC count was increased shortly after surgical resection along with cytology that was suspicious for malignancy. Due to the increase in CTCs, the patient was treated for LMD with whole brain radiation therapy and intrathecal pembrolizumab. Subsequent CSF analysis revealed clearing of malignant cells in the CSF. The patient developed symptoms consistent with LMD approximately 9 months after the surgery and died 21 months after resection of his brain metastasis. This case illustrates a rare occurrence of an intraventricular melanoma metastasis, and the use of CTC presence within the CSF to diagnose LMD for early intervention. This emphasizes that the risk of developing LMD must be considered with intraventricular metastasis or ventricular exposure during tumor resection, and that CTCs may be an effective factor to monitor for early development of disease with possible prolonged survival benefit.
NCMP-14. SKULL BASE OSTEOMYELITIS DUE TO COMMUNITY-ACQUIRED ASPERGILLUS FUMIGATUS MIMICKING RECURRENT CHONDROSARCOMA
Authors: Lillehei Kevin , Kleinschmidt-Demasters B K
Published: December 2020

Skull base chondrosarcomas are often low grade tumors that do not metastasize, but are locally invasive and often recur locally. Thus, when patients with these tumors re-present with new onset symptoms, even decades later, recurrent tumor is presumed. A 50 year old woman with skull base chondrosarcoma initially diagnosed 30 years prior developed the subacute onset of worsening confusion and vision, with progressive blindness. Imaging disclosed a bony-erosive skull base mass without associated sinusitis/sinus opacification; additional small cerebral infarcts were identified. She had been on physiologic replacement therapy for panhypopituitarism since the original surgery, but had not received recent radiation therapy or chemotherapy and did not have neutropenia. RESULTS: Biopsy disclosed a chronic inflammation and necrotic debris; only on permanent sections were septated, 45-degree angle-branching fungi identified in one area. These had morphological features of, and were polymerase chain reaction-proven, Aspergillus fumigatus. No recurrent tumor was present. Given the lack of perceived risk factors, further questioning of the patient and her mother disclosed that precisely 1 year prior to surgery she and her family had participated in “cleaning out an old very dirty and dusty barn” in southern Colorado without the use of face masks; only the proband experienced sequelae. Anti-fungal therapy (voriconazole) was recommended although patient use was intermittent and symptoms have progressed. CONCLUSION: Community-acquired Aspergillus infections due to exposure to silage or barn detritus contaminated by fungal hyphae is almost never seen today, in comparison to opportunistic infections due to known risk factors of neutropenia and/or steroid usage. Replacement therapy may have added to this patient’s risk. Infections all too often mimic recurrent tumor.
NCMP-15. CNS LYMPHOMA: THE GREAT MIMICKER
Authors: Bazer Danielle , Kowalska Agnes
Published: December 2020

INTRODUCTION

Primary central nervous system lymphoma (PCNSL) is a variant of non-Hodgkin lymphoma, affecting the brain, leptomeninges, eyes, and spinal cord. PCNSL is a progressive disease with symptom onset occurring over weeks that presents with varied signs and symptoms, including focal neurological deficits, mental status changes, behavioral changes and seizures. Tissue diagnosis is imperative, though MRI, ophthalmologic and CSF evaluation can aid in diagnosis. PET scan and bone marrow biopsy are important for assessing metastatic spread following diagnosis.

CASE PRESENTATION

We present a case series, comprised of three patients with atypical presentations of CNS lymphoma. Patient 1. 64 year old male presented with facial muscle weakness, vertigo, and diplopia. Initial MRI showed an old thalamic and new internal capsule infarcts. EMG suggested sensorimotor peripheral neuropathy consistent with Guillain-Barre Syndrome, leading to treatment with a five day course of IVIG. His MRI findings gradually worsened, ultimately revealing leptomeningeal enhancement of the bilateral vestibulococchlear nerves, facial nerves and the trigeminal nerves. Patient 2. 66 year old male with a past medical history of primary cutaneous anaplastic T cell lymphoma stage 1 EA, status post field radiation, presented with aphasia and ataxia. Brain MRI showed extensive, enhancing hyperdensities in the midbrain, suggestive of multiple sclerosis, prompting treatment with steroids. He continued to clinically worsen, prompting tissue diagnosis. Patient 3. 66 year old male presented with recurrent syncopal episodes and aphasia, found to have a 4 cm extra axial mass in the left temporal region on MRI suggestive of a meningioma.

CONCLUSION

All three patients eventually underwent brain biopsy with a final histologic diagnosis of PCNSL. Due to the highly variable initial presentation of this condition and the wide range of pathologies it mimics, CNS lymphoma should be included in the differential diagnosis of patients presenting with atypical neuroimaging or clinical findings.
NCMP-19. SIDE EFFECTS FROM CHEMOTHERAPY VERSUS SYMPTOMS FROM COVID-19 INFECTION
Authors: Du Senxi , Hrachova Maya , Kong Xiao-Tang
Published: December 2020

INTRODUCTION

Adverse effects from chemotherapy such as high dose methotrexate (HD-MTX) are seen during and after chemotherapy. During this coronavirus disease 2019 (COVID-19) pandemic period, COVID-19 infection symptoms following chemotherapy due to immune compromise could mimic chemotherapy associated side effects. Differentiation on time is needed for correct management.

CASE REPORT

A 50-year old male with clinical history of ocular lymphoma underwent HD-MTX therapy. Before admission, his routine COVID-19 test was negative. After receiving HD-MTX, he developed fatigue, nausea and vomiting. The symptoms resolved before discharge. Next day after discharge, he developed diarrhea, fatigue, subjective fever and feeling cold. His temperature was normal. His symptoms have been persistent for 4-5 days and have resolved gradually and spontaneously. Family members have had no symptoms. The patient denies COVID-19 contact history. The above symptoms were considered adverse effects from chemotherapy. The patient did not seek medical attention. Prior to admission for next cycle of HD-MTX, COVID-19 test was found positive. Chemotherapy was on hold. The patient started home quarantine. The patient has been doing well and practiced COVID-19 infection precaution at home.

DISCUSSION

The fatigue, nausea and vomiting during HD-MTX treatment are adverse effects from chemotherapy while the diarrhea, fatigue, subjective fever and chills developed after discharge are symptoms of COVID-19 infection. Our case highlights the importance of keeping in mind and differentiating between side effects from chemotherapy and symptoms of COVID-19 viral infection in cancer patients who receive chemotherapy.