bluuebunny/crossref_metadata_2025 huggingface dataset:
EPID-26. ALIGNING THE CBTRUS HISTOLOGY GROUPS WITH 2016 WHO CLASSIFICATION OF TUMORS OF THE CENTRAL NERVOUS SYSTEM
Authors: Kruchko Carol , Patil Nirav , Cioffi Gino , Brat Daniel , Bruner Janet , McLendon Roger , Tihan Tarik , Barnholtz-Sloan Jill , Ostrom Quinn
Published: November 2021

BACKGROUND

The Central Brain Tumor Registry of the United States (CBTRUS) uses a histology grouping scheme modeled after the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) to classify cancer registry records for clinically relevant statistical reporting. Molecular studies have identified genetic features which precisely stratify tumor types, resulting in the 2016 update to the WHO Classification incorporating these markers. To continue providing clinically relevant statistics, the histology groupings have been aligned with the 2016 update. Resulting changes to groupings were assessed.

METHODS

In collaboration with four consulting neuropathologists the scheme was reviewed and realigned to the 2016 update. Obsolete histology nomenclature and ICD-O-3 codes were identified. Evaluation of the frequency of affected codes in the 2013-2017 data was conducted.

RESULTS

417,767 total cases of primary brain and CNS tumors were diagnosed during 2013-2017 in the US. After review of the CBTRUS grouping scheme, 67 codes were noted to be obsolete, 51 codes were re-classified and 12 new codes were incorporated. This reorganization could result in grouping assignment or reporting changes for 2,588 cases (0.6%). The histology groups most significantly affected were mesenchymal tumors and neuronal and mixed neuronal glial tumors.

CONCLUSIONS

The 2016 revision to WHO Classification has affected collection and reporting of CNS tumors. The CBTRUS data edits program is now undergoing revision, which will become the basis of reporting. Some histology-specific molecular markers require additional data to distinguish between cases. In collaboration with CBTRUS, the NAACCR SSDI Committee developed a new variable for collection of molecular information. This variable was included in Uniform Data Standards beginning on January 1, 2018 and will be available for reporting in 2021. A 2021 update to the WHO Classification is scheduled for release later this year, requiring further classification updates.
IMMU-01. CHARACTERIZATION OF TUMOR-INFILTRATING CD8+ T CELLS IN BRAIN METASTASES
Authors: Sudmeier Lisa , Hudson William , Hoang Kimberly , Nduom Edjah , Neill Stewart , Schniederjan Matthew , Olson Jeffrey , Ahmed Rafi
Published: November 2021

BACKGROUND

Use of immune checkpoint blockade (ICB) therapy has prolonged overall survival in patients with metastatic cancer. One potential strategy to improve the effectiveness of ICB is to target additional inhibitory receptors on exhausted CD8+ T cells, which may promote rescue of CD8+ T cells that do not respond to PD-1 pathway blockade alone. This therapeutic strategy requires knowledge of the inhibitory molecules expressed on tumor-specific CD8+ T cells. Toward achieving this goal, we characterized the phenotype of CD8+ T cells infiltrating brain metastases.

METHODS

We performed flow cytometry on 45 brain metastases samples, single cell RNA sequencing with T cell receptor (TCR) sequencing on 5 samples, and spatially-resolved transcriptomics on 8 samples.

RESULTS

Analysis of our scRNA-seq data revealed 4 populations of PD-1+ CD8+ T cells infiltrating brain metastases. One of these populations (cluster A) has a terminal effector exhausted phenotype suggesting that this population contains tumor-specific CD8+ T cells. Two of the other populations (clusters B and C) have a transcriptional profile that suggests they may contain stem-like CD8+ T cells. TCR sequencing shows that cells in cluster A do not express the same TCRs as cells in clusters B and C, suggesting that stem-like cells in clusters B and C are not the progenitors of the terminal effector cells in cluster A. Bystander cells expressing TCRs specific for viral antigens are found predominantly in clusters B and C, further supporting the hypothesis that cluster A contains tumor-specific cells. Spatial transcriptomics reveals that cluster A cells are infiltrating the tumor parenchyma while cluster B and C cells are predominantly in peri-tumoral inflammatory tissue.

CONCLUSIONS

Brain metastases are infiltrated by a population of terminally-differentiated effector CD8+ T cells which express co-inhibitory molecules that may be potential therapeutic targets to improve control of metastatic disease in the brain.
IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM
Authors: Miller Tyler , El Farran Chadi , Verga Julia , Couturier Charles , Chen Zeyu , Castro L Nicolas Gonzalez , D'Antonio Joshua , Petrecca Kevin , Suva Mario , Bernstein Bradley
Published: November 2021

Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.
IMMU-22. THE IMPACT OF MICROGLIA MODULATION ON GBM PROGRESSION IN SYNGENEIC MOUSE MODELS
Authors: Ritz Marie-Françoise , Shekarian Tala , Martins Tomás A , Schmassmann Philip , Hutter Gregor
Published: November 2021

BACKGROUND

The tumor immune microenvironment (TME) of Glioblastoma consists of almost myeloid-derived macrophages and microglia called TAMs. We have shown that the disruption of CD47-Sirpα-axis induces an antitumor activity of TAMs against GBM in immune-deficient mice, through increases of phagocytosis of tumor cells by TAMs. We have aimed to study the role of microglia and its activation/depletion on GBM progression, in the syngeneic GBM model in immune-competent mice. We have studied the interplay of innate and adaptive immune response after activation and depletion of microglia and the effect on tumor progression and outcome of the mice.

MATERIAL AND METHODS

We used different colonies of genetically modified immunocompetent mouse strains to genetically activate/deplete microglia in the tumor context. We generated Sall1 CreERT2/fl mice and Cre-negative littermates. The application of Tamoxifen in this constellation leads to the excision of the transcription factor Sall1 and subsequent enhanced microglia activity. Conversely, we generated Sall1 CreERT2 x Csf1r fl/fl animals and the respective heterozygous and Cre-negative littermates in which Tamoxifen treatment leads to inactivation of microglia through the deletion of Csf1r. Glioblastoma tumors were induced by intracerebral injection of GL261, CT2A, or retrovirus-induced PDGF-Akt in pups and Tamoxifen treatment was started once the tumors were detected.

RESULTS

We observed a survival advantage in tumor-bearing mice after activation of microglia in Sall1 CreERT/fl animals compared to Cre-negative littermates. Genetic depletion of microglia in this model resulted in a shorter lifespan in microglia-depleted animals compared to Cre-negative littermates. Furthermore, the iTME in these tumors is subjected to scRNAseq analysis to identify mechanistic insights.

CONCLUSION

Microglia are important players in tumor development and progression of glioblastoma in mouse models. These cells may be targeted in future immunotherapeutic approaches for patients.
IMMU-30. IDENTIFICATION OF COORDINATELY REGULATED IMMUNO-MODULATORY GENES USING SINGLE-CELL RNA SEQUENCING OF DECITABINE TREATED GLIOMA CELLS
Authors: Lai Thomas , Treger Janet , Rao Jingyou , Prins Robert , Everson Richard
Published: November 2021

INTRODUCTION

The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Our previous data has shown that the hypomethylating agent decitabine (DAC) is a strong sensitizer of GBM to NY-ESO-1 specific adoptive T-cell induced cytotoxicity. However, we hypothesized that DAC alters expression of other immuno-modulatory genes in addition to NY-ESO-1 that may also increase T-cell mediated killing in GBM. The extent of regulation of other immuno-modulatory genes to DAC demethylation has not yet been thoroughly investigated.

METHODS

We performed single-cell RNA sequencing on DAC and non-DAC treated glioma cells. We confirmed DAC treatment induced NY-ESO-1 expression with quantitative real-time PCR and demethylation using bisulfite sequencing. We analyzed our single-cell RNA sequencing data with Seurat and our customized R-based pipelines to identify coordinate differential expression of immuno-modulatory genes and their tumor subpopulations.

RESULTS

Using our single-cell data, we identified tumor subpopulations with coordinate differentially expressed immuno-modulatory genes including cancer testes antigens, antigen presentation proteins, and apoptosis regulators. Amongst these candidate genes, we validated their expression with qPCR and promoter demethylation with bisulfite sequencing and TA bisulfite cloning.

CONCLUSION

Exposure of glioma cells to DAC results in promoter demethylation of NY-ESO-1, with increased expression of CTA and other immunomodulatory genes. DAC treatment may therefore sensitize GBM to the immunotherapeutic targeting of these antigens and reveals a feasible strategy for clinical translation.
IMMU-34. CAMKK2 PROMOTES AN IMMUNOSUPPRESSIVE PROGRAM AND CHECKPOINT BLOCKADE RESISTANCE IN THE GLIOBLASTOMA TUMOR MICROENVIRONMENT
Authors: Tomaszewski William , Waibl-Polania Jessica , Racioppi Luigi , Sanchez-Perez Luis , Michael Gunn , Sampson John
Published: November 2021

BACKGROUND

Immunotherapy has demonstrated efficacy in several cancers but has shown only modest effects in Glioblastoma (GBM). This is linked to the anti-inflammatory nature of the tumor microenvironment (TME) and the pro-tumor functions of brain native cells. Targeting stromal cells, such as tumor associated macrophages (TAMs) and neurons, is a promising approach. Re-analysis of human and murine brain single cell-RNAseq (scRNAseq) datasets shows Calmodulin Dependent Kinase Kinase 2 (CaMKK2) is highly expressed in both neurons and TAMs. Loss of CaMKK2 polarizes TAMs to an immunostimulatory phenotype and reduces pro-tumor neuronal functions. Thus, we hypothesize that CaMKK2 promotes the pro-tumor nature of the GBM TME and immunotherapy resistance.

RESULTS

Murine GBM was orthotopically implanted into wild-type and CaMKK2-/- mice. CaMKK2-/- mice exhibited significantly prolonged survival. To determine if anti-tumor immune function was enhanced, we probed the TME using flow cytometry and scRNAseq. CaMKK2-/- mice showed increased abundance of precursor exhausted, potentially immune checkpoint blockade (ICB) responsive, CD8 T cells. Furthermore, T cell depletion abrogated the survival benefit observed in CaMKK2-/- mice. Considering these T cell phenotypes, we treated CaMKK2-/- mice with ICB, and indeed they were sensitive. To determine if the CaMKK2-/- survival phenotype and ICB response depended on CaMKK2 expression in hematopoietic or in non-hematopoietic cells, we utilized a reciprocal chimera model. Loss of CaMKK2 in the non-hematopoietic cells was more vital for survival and ICB response than in hematopoietic cells, suggesting a potential novel and unique role for CaMKK2 in brain native cells - potentially neurons - in coordinating ICB resistance.

CONCLUSIONS

We find that CaMKK2 exacerbates mortality and drives ICB resistance by limiting the anti-tumor response in GBM via both hematopoietic and brain native cells. Our findings identify a novel therapeutic target for GBM, and a unique role for CaMKK2 in the TME.
IMMU-43. IMMUNE CONTEXTURE OF ISOCITRATE DEHYDROGENASE STRATIFIED HUMAN GLIOMAS REVEALED BY SINGLE-CELL TRANSCRIPTOMICS AND ACCESSIBLE CHROMATIN
Authors: Gupta Pravesh , Dang Minghao , Hao Dapeng Hao , Bojja Krishna , Tran Tuan M , Shehwana Huma , Kamiya-Matsuoka Carlos , Li Jianzhuo , Audia Alessandra , Kassab Cynthia , Ott Martina , Gumin Joy , Al-enazy Sanaalarab , Balasubramaniyan Veerakumar , DeGroot John , Lang Frederick , Iavarone Antonio , Navin Nicholas E , Heimberger Amy B , Wang Linghua , Bhat Krishna
Published: November 2021

The immune cell composition of isocitrate dehydrogenase wild type (IDH-wt) glioma patients significantly differs compared to IDH-mutant (IDH-mut) yet a detailed and unbiased understanding of their transcriptomic and epigenetic landscapes remains elusive. To this end, we performed single-cell RNA-sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen IDH mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells (MDCs) and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells. As tissue macrophages exhibit multifaceted polarization in response to microenvironmental cues, we clarify the existence of microglia/macrophage functional states beyond M1/M2 paradigms exemplified by the presence of palmitic-, oleic- acid, and glucocorticoid responsive polarized states. We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation/phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas. Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut, and IDH-wt glioma-associated immune cells. In particular, we noted reduced microglial usage of an iron recycling SPIC transcription factor and Interferon Regulatory Factors (IRFs); IRF1 and IRF2 in IDH-wt relative to IDH-mut and NGBs. Unique features such as amplification of 11-Zinc Finger Protein accessibility were restricted to MDCs. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on CTLA-4, Layilin, and TIM-3 but no enrichment on PD1 was seen. In summary, our study provides unprecedented granular detail of transcriptionally and epigenomically defined glioma-specific immune contexture that can be exploited for immunotherapy applications.
IMMU-44. AN IMMUNOTHERAPEUTIC VACCINE COMPOSED OF IRRADIATED WHOLE TUMOR CELLS PULSED WITH MANNAN-BAM, TLR LIGANDS AND ANTI-CD40 ANTIBODY INDUCES POTENT IMMUNE RESPONSE IN PRECLINICAL GBM ANIMAL MODEL
Authors: Wang Herui , Medina Rogelio , Ye Juan , Lookian Pashayar , Uher Ondrej , Zenka Jan , Gilbert Mark , Pacak Karel , Zhuang Zhengping
Published: November 2021

Despite numerous therapeutic advances, the treatment of glioblastoma multiforme (GBM) remains a challenge, with current 5-year survival rates estimated at 4%. Multiple characteristic elements of GBM contribute to its treatment-resistance, including its low immunogenicity and its highly immunosuppressive microenvironment that can effectively disarm adaptive immune responses. Hence, therapeutic strategies that aim to boost T-lymphocyte mediated responses against GBM are of great therapeutic value. Herein, we present a therapeutic vaccination strategy that promotes the phagocytosis of tumor cells, enhances tumor antigen presentation, and induces a tumor-specific adaptive immune response. This strategy consists of vaccinations with irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists (Mannan-BAM), TLR ligands [LTA, Poly (I:C), and R-848], and anti-CD40 antibody (collectively abbreviated as rWTC-MBTA). We evaluated the therapeutic efficacy of rWTC-MBTA strategy in a mouse syngeneic GL261 orthotopic GBM tumor model. rWTC-MBTA or vehicle control were administered subcutaneously over the right foreleg three days after intracranial injection of GL261 cells. Complete regression (CR) of intracranial tumors was achieved in 70% (7/10) of rWTC-MBTA treated animals while none survived in the control group. Immunophenotyping analyses of peripheral lymph nodes and brain tumors of rWTC-MBTA treated mice demonstrated: (1) increased mature dendritic cells and MHC II+ monocytes; (2) increased effector (CD62L-CD44+) CD4-T and CD8-T cells; (3) increased cytotoxic IFNγ-, TNFα-, and granzyme B-secreting CD4-T and CD8-T cells. Of note, the therapeutic efficacy of rWTC-MBTA disappeared in CD4-T and/or CD8-T lymphocyte depleted mice. Three mice that achieved CR were rechallenged with 50k GL261 cells intracranially 14 months after the last rWTC-MBTA treatment and all rechallenged animals resisted GL261 tumor development, confirming the establishment of long-term immunological memory against GL261 tumor cells. Collectively, our study demonstrated that rWTC-MBTA strategy can effectively activate antigen presenting cells and induce more favorable T-cell signatures in the GBM tumors.
INNV-05. MULTIDISCIPLINARY SPINE ONCOLOGY CARE ACROSS THE DISEASE CONTINUUM - UPDATES FOR THE BEDSIDE AND THE BOARDS
Authors: Dunbar Erin
Published: November 2021

In response to the increased prevalence and complexity of metastatic and primary spine oncology, there has been a resultant increase in stakeholders, treatments and outcomes. A subset of the global multidisciplinary authors will present a timely and concise review of the contents of NOP’s Volume-7, supplement-1, “Multidisciplinary Spine Oncology Care Across the Disease Continuum”. The first portion will review: Epidemiology, Tumor Types, Presentation, Initial Tumor-directed Management, Initial Symptom-directed Management, Subsequent Tumor-directed Management, Subsequent Symptom-directed Management, and Multidisciplinary Program Development and Resources for Stakeholders. The second portion will challenge the current state of care and engage the attendees toward developing initiatives needed for a future state of care. Attendees will receive an update for both the bedside and the boards.
INNV-40. REAL WORLD INTEGRATION OF THE NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE IN CLINICAL PRACTICE IN PATIENTS WITH IDH-WT GBM
Authors: Lim-Fat Mary Jane , Allen Marie , Smith Timothy , Youssef Gilbert , Andersen Brian , Akintola Oluwatosin , Berger Tamar , Budhu Joshua , Hsieh Annie , Aquilanti Elisa , Batchelor Tracy , Beroukhim Rameen , Chukwueke Ugonma , Castro L Nicolas Gonzalez , Lee Eudocia Quant , McFaline-Figueroa J Ricardo , Doherty Lisa , Stefanik Jennifer , Taubert Christina , Torres Alexandra , Wen Patrick , Reardon David , Nayak Lakshmi
Published: November 2021

BACKGROUND

The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM.

METHODS

We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3).

RESULTS

Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference.

CONCLUSIONS

Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.
INNV-43. MORE THAN WHAT MEETS THE EYE: ETMR AN UNDER RECOGNISED ATYPICAL BRAINSTEM PRIMARY. A RARE BRAIN TUMOR CONSORTIUM (RBTC) STUDY
Authors: Khan Sara , Solano-Paez Palma , Hansford Jordan R , Lu Mei , Al-karmi Salma , Leung Lydia , Plant-Fox Ashley , Spina Melina La , Andrew Eden , Dunham Christopher , Phillips Joanna , Ridola Rita , Sgouros Spyros , Hazrati Lili-Naz , Shago Mary , Hoffman Lindsey , Hawkins Cynthia , Bartel Ute , Mulchay Jean , Vibhakar Rajeev , Andre Nicolas , Bouffet Eric , Huang Annie
Published: November 2021

10% of all pediatric brain tumors arise in the brainstem. Amongst these gliomas are the most common while other entities are rare and infrequently described in the literature. In this study we investigated the prevalence of non-gliomatous tumors in the brainstem. Amongst the 1323 embryonal tumours received at the RBTC, we identified 17 cases of ETMRs (17/165) that presented as brainstem primaries. Previously grouped within CNS-PNETs, ETMR, is a new WHO diagnostic entity, characterized by C19MC alterations. ETMR is a disease of infancy, the clinical spectrum of which is poorly understood. ETMRs arise at multiple CNS locations including cerebrum being most common (60%,) followed by cerebellum (18%) and midline structures (6%); notably 10% were brainstem primaries, mimicking DIPG radiologically. All patients presented with a short history of progressive neurological symptoms, with most common signs and symptoms of cranial neuropathies, long tract signs and gait disturbance. Median age at diagnosis was 27 months (range 16-75months) with a male to female ratio of 0.9:1. Predominantly localized (M0-94%, M2-3 -6%) majority of patients underwent upfront biopsy or partial resection (15/17:88%), while complete tumor resection was achieved in 2 cases. All patients received heterogenous combination of chemotherapy with and without radiotherapy. Majority of patients progressed rapidly with median time to progression of 4 months and overall survival of < 13 months. The only long-term surviving patient had complete resection dose intensified chemotherapy and radiation (OS 202months). Primary ETMRs in the brainstem are under recognised entities and carry a dismal prognosis. Although rapidly progressive, prompt recognition, maximal resection and management with multimodal adjuvant therapy should be considered in cases with brainstem disease.
PATH-01. SMALL RNASEQ ANALYSIS OF MICRORNAS IN BRAIN METASTASIS
Authors: Jancalek Radim , Siegl Frantisek , Sana Jiri , Vecera Marek , Trachtova Karolina , Hendrych Michal , Vybihal Vaclav , Smrcka Martin , Hermanova Marketa , Kazda Tomas , Slaby Ondrej
Published: November 2021

MicroRNAs (miRNAs) are a well-known subclass of short non-coding RNAs responsible for posttranscriptional gene silencing and have been described as dysregulated in many cancers. They have also been shown to be both specific diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets. Therefore, specific miRNA expression patterns of BMs of various origins could serve as a promising diagnostic tool for determining both the original tumor and the prognosis in patients with BMs of unknown origin. For identifying significantly dysregulated miRNAs among BMs (n=90) with various origin and non-tumor brain tissues (n=12), small RNAseq analyses were used. cDNA libraries were prepared using QIAseq miRNA Library Kit and purified by Qiaseq beads. The final sequencing analyses were performed by Next 500/550 High Output v2 Kit-75 cycles using the NextSeq 500 instrument. For miRNA mapping and analysis, Miraligner and MirBase were used. Bioinformatic analysis of obtained sequencing data identified 472 significantly dysregulated miRNAs (logFc >2, adj.p-value< 0.05) between BM and non-tumor samples. The comparison of BMs origin from lung BMs (n = 26) with other BMs revealed 132 significantly dysregulated miRNAs, mainly miR-4662a-5p, miR-1179, miR-211-5p, miR-146a-5p, and miR-194-5p. The most significantly dysregulated miRNAs in breast BMs were miR-4728-3p, miR-211-5p, miR-184, miR-365b-5p, and miR-2115-3p. In BMs originating from melanoma, miR-200c-3p, miR-141-5p, miR-200b-5p, miR-514a-3p, and miR-200b-3p showed the most aberrant expression. We have demonstrated that miRNA profiling could be a potent tool for the partition of brain metastases based on their origin. We found that miRNA signatures corresponding to particular origins are rather distinct from the profiles of the rest of BMs. Our results suggest that after validation, miRNA profiling can be used to identify the origin of brain metastases and potentially for the refinement of the diagnosis. Supported by the Ministry of Health of the Czech Republic, grant nr. NV18-03-00398.
PATH-09. THE SEARCH FOR A NOVEL SUBTYPE OF GLIOBLASTOMA AND ITS CELL-OF-ORIGIN
Authors: Chen Yu-Jung , Iyer Swathi , Xie Xuanhua , Parada Luis
Published: November 2021

Glioblastoma (GBM) has been computationally classified into three molecular subtypes (i.e., classical, proneural and mesenchymal). However, these subtypes lack strong biological and clinical implications. Therefore, our group has proposed to classify GBM according to its cell of origins. We have previously shown that different cell of origins give rise to biologically and transcriptionally distinct subtypes of GBM. We termed tumors that derived from subventricular zone (SVZ) neural stem cells as type 1 tumors and that from oligodendrocytic progenitor cells (OPC) as type 2 tumors. Based on murine lineage transcriptional profiles, we have also identified corresponding human GBM (40-50% of the TCGA GBM samples) tumors with conserved lineage properties. However, a majority of the TCGA GBM tumors remains unexplained by the cell-of-origin model. This study aims to search for other distinct GBM subtypes by addressing the tumorigenic potential of a putative stem progenitor population in the murine basilar pons. By using a recently reported Nestin transgenic mouse line (Nestin- C reERT2; e G FP-H2B; h D TR, or CGD in short), we have shown that conditionally deleting the commonly mutated glioma genes, Nf1 f/f ; Tp53 f/f and Pten f/+ (NPP), in pontine GFP+ cells, give rise to tumors that histologically resembles human GBM. Further transcriptomic analysis showed that a subset of these tumors highly express lineage markers of the differentiation-committed oligodendrocytic precursors (COP). We further probed the TCGA GBM database and identified 5% of the tumors to be enriched with our CGD pontine tumor-derived signature. In summary, our results showed that CGD-NPP cells can give rise to a previously uncharacterized tumor subtype with enrichment of COP lineage markers. Therefore, we propose COP as another cell of origin for GBM and that COP-derived tumor may contribute to a novel tumor subtype of the GBM classification.
PATH-10. MULTI-OMICS PROFILING AND MACHINE LEARNING PROPOSE A REFINED MOLECULAR CLASSIFICATION SYSTEM FOR GLIOMA
Authors: Zhou Cheng , Zhou zhaoming , Wen Lei , Lai Mingyao , Cai Linbo
Published: November 2021

Accurate molecular stratification of glioma patients is key to an optimal design of therapeutic strategy to maximize patient survival. Here we leveraged multi-omics analysis of glioma and detailed clinical follow-up to build a refined classification system for glioma patients using support vector machines. The model input included the number of non-synonymous mutations in cancer driver genes, the number of non-synonymous mutations in cancer related genes, the transcriptomic grouping information, the immune infiltrations predicted by RNA-seq dataset, the site of tumor occurrence, as well as other well-known markers including IDH mutation status and 1p19q co-deletion status. We validated key model predictions using TCGA and CGGA datasets. Our refined classification system outperforms current state-of-the-art framework used in clinic. Taken together, we propose a refined molecular classification for glioma combining multi-omics profiling and machine learning approaches.
PATH-25. H3 K27M-MUTANT DIFFUSE NON-MIDLINE GLIOMA: REPORT OF A CASE WITH EXTENDED FOLLOW-UP
Authors: Donev Kliment , Sundararajan Vanitha , Johnson Derek , Ida Cristiane
Published: November 2021

H3 K27M-mutant diffuse gliomas without midline involvement are extremely rare and their clinical behavior remains elusive due to limited reported follow-up data. We describe an H3 K27M-mutant diffuse non-midline glioma patient with extended follow-up. A 34-year-old woman presented with headache, memory loss, periods of changes in taste and smell, and confusion. Imaging studies revealed an 2.3 cm expansile T2/flair hyperintensity with patchy postcontrast enhancement centered in the left amygdala without associated restricted diffusion and no involvement of the midline structures. The tumor was debulked and consisted of a mitotically active infiltrating astrocytic glioma without tumor necrosis or microvascular proliferation, consistent with anaplastic astrocytoma. Targeted 187-gene neuro-oncology NGS testing detected an H3F3A K27M mutation along with a PTPN11 and a PPM1D mutation. FISH 1p/19q-codeletion testing was negative. MGMT promoter was unmethylated. The patient was treated with chemoradiation with temozolomide for 6 weeks followed by 12 cycles of temozolomide. Four years after initial resection, an area of increased post-contrast enhancement indicating tumor recurrence/progression was noted. Partial resection of the recurrent tumor revealed a mitotically active infiltrating astrocytic glioma with tumor necrosis consistent with glioblastoma. Molecular profiling of the recurrent tumor by the neuro-oncology NGS panel detected similar mutational profile (identical H3F3A K27M and PTPN11 mutation; different PPM1D mutation) with an additional SOS1 mutation. The patient completed 4 cycles of Lomustine and although clinically stable, imaging studies showed slight increase in residual tumor size concerning for tumor progression. Lomustine was discontinued, Bevacizumab therapy was initiated and patient was enrolled in clinical trial (NCT02525692). Despite tumor progression, this patient has had a relatively long disease course (5 years) suggesting that H3 K27M-mutant non-midline diffuse gliomas although molecularly similar, may follow a more favorable clinical course than their midline counterparts possibly due to the hemispheric location, which is more amenable for surgical resection.
PATH-46. DIAGNOSTIC IMPACT OF THE CNS TUMOR METHYLATION PROFILING IN A NEUROPATHOLOGY CONSULT PRACTICE
Authors: Wu Zhichao , Abdullaev Zied , Pratt Drew , Chung Hye-Jung , Skarshaug Shannon , Zgonc Valerie , Perry Candice , Pack Svetlana , Saidkhodjaeva Lola , Nagaraj Sushma , Tyagi Manoj , Xi Liqiang , Raffeld Mark , Papanicolau-Sengos Antonios , O’Donnell Kayla , Chinquee Joseph , Newford Michael , Gilbert Mark , Sahm Felix , Suwala Abigail K , von Deimling Andreas , Nassiri Farshad , Zadeh Gelareh , Ruppin Eytan , Quezado Martha , Aldape Kenneth
Published: November 2021

DNA methylation profiling coupled with the application of CNS tumor methylation classifier has contributed to precise and accurate diagnostics for a range of tumor types involving the central nervous system. The impact and characteristics of methylation profiling on tumor diagnosis has not been fully assessed in the setting of neuropathology consultation practice. A consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice were profiled over 2-year period and analyzed using the DKFZ/Heidelberg CNS tumor methylation classifier. Among the 1,045 cases received from outside institutions for consultation, the classifier was able to refine a histologically diagnosed entity (e.g. medulloblastoma) in 13.3% (n = 139) cases. A substantially new diagnosis was able to be rendered in an additional 17.9% (n = 187) cases, many of which could be confirmed using orthogonal methods. A “suggestive” (0.30-0.84) classifier score was found in 23% (242) cases and we found that complementary methods (UMAP, t-SNE and nearest-neighbors) were able to resolve this uncertainty in 118 cases. We found tumor purity significantly associated with varied classifier score (p = 1.53e-11). Computational tumor purity adjustment by deconvolution on a subset of gliomas provided a proof-of-concept to resolve diagnostics in the setting of low tumor purity. Overall, this work directly assesses the benefit of methylation classification in a set of diagnostically challenging CNS tumors, addresses tumor purity diminished methylation signal and provides complementary approaches to address diagnostics in cases of low-confidence classifier scores.
NIMG-05. DIFFERENCES IN VASCULARITY BETWEEN RECURRENT GLIOBLASTOMA AND BRAIN METASTASIS USING DYNAMIC CONTRAST ENHANCED MRI
Authors: Bashat Dafna Ben , Blumenthal Deborah , Limon Dror , Aizenstein Orna , Bressler Idan , Bokstein Felix , Artzi Moran
Published: November 2021

In recent years, several automatic methods have been proposed to differentiate between brain tumor recurrence and treatment-related changes following radiotherapy, based on conventional and advanced MRI methods. Vascular parameters extracted from dynamic contrast-enhanced (DCE) were suggested as potential markers for disease progression. Yet, most studies that proposed machine-learning methods or relayed on threshold values of DCE for classification, did not analyze separately Glioblastoma (GBM) and brain metastasis, and often offer the same method/threshold values, neglecting the different vascularity of these two tumor types. Understanding and quantifying the differences between tumors type can improve early diagnosis of recurrence and may improve the reliability of identifying treatment-related changes. The aim of this study was to quantify vascular parameters of tumor recurrence and to assess differences between GBM and brain metastasis, specifically metastasis of breast cancer. METHOD: 41 MRI scans were included: 24 from patients with GBM: 20 with recurrence and 4 with treatment-related changes, and 17 scans from patients with brain metastasis of breast cancer: 10 with recurrence and 7 with treatment-related changes (diagnosis were based on radiological follow-up/histopathology, when available). MRIs were performed on a 3.0 Tesla MRI scanner (Siemens MAGNETOM Prisma) and included T1, T1+contrast, and DCE images. DCE analysis was performed using DUSTER and Ktrans, Vp and Kep pharmacokinetic parameters were compared between groups. RESULTS: Patients with GBM often demonstrated both tumor recurrence and areas with treatment-related changes. Significantly differences were detected between tumor recurrence and treatment-related changes, and higher Vp and Ktrans were detected in recurrent GBM as compared to recurrent breast cancer metastasis. Cutoff for differentiation between tumor recurrence and treatment-related changes will be presented specifically for each tumor type. To conclude, when defining quantitative threshold values for clinical decision-making, the inherent differences between primary and metastatic brain tumors should be taken into account.
NIMG-12. MR SUSCEPTIBILITY IMAGING FOR DETECTION OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Nazem Amir , Guiry Samantha , Pourfathi Mehrdad , Ware Jeffrey B , Anderson Hannah , Iyer Srikant Kamesh , Moon Brianna F , Fan Yi , Witschey Walter R , Rizi Rahim , Bagley Stephen J , Desai Arati , O’Rourke Donald M , Brem Steven , Nasrallah MacLean , Nabavizadeh S Ali
Published: November 2021

BACKGROUND

Tumor-associated macrophages (TAMs) are a key component of glioblastoma (GBM) tumor microenvironment. Considering the differential role of different TAM phenotypes in iron metabolism with the M1 phenotype storing intracellular iron, and M2 phenotype releasing iron in the tumor microenvironment, here we investigated non-invasive quantitative susceptibility mapping (QSM) and T2* MRI relaxometry to quantify iron as imaging biomarkers for TAMs in adult patients with GBM.

METHODS

In this prospective study, 21 adult patients with GBM were enrolled between 2016 to 2019. Patients underwent a 3D single echo gradient echo sequence in addition to standard anatomical sequences on a 3 Tesla MRI. QSM images were reconstructed using the morphology-enabled dipole inversion (MEDI) algorithm. In 3 subjects, ex vivo imaging of surgical specimens was performed on a Bruker 9.4 Tesla 8.9 cm vertical bore MR using 3D multi-echo GRE scans, and R2* (1/T2*) maps were generated by a pixel-wise monoexponential fitting. Each specimen was stained with hematoxylin and eosin, as well as with CD68, CD86, CD206, and L-Ferritin.

RESULTS

Significant positive correlation was observed between mean susceptibility for the tumor enhancing zone and the L-ferritin positivity percent (r =0.56, p=0.018) and the combination of tumor’s enhancing zone and necrotic core and the L-Ferritin positivity percent (r=0.72; p=0.001). Moreover, the mean susceptibility significantly correlated with positivity percent for CD68 (ρ=0.52, p=0.034) and CD86 (r=0.7 p=0.001), but not for CD206 (ρ=0.09; p=0.7). There was a positive correlation between mean R2* values and CD68 positive cell counts (r =0.6, p=0.016). Similarly, mean R2* values significantly correlated with CD86 (r=0.54, p=0.03) but not with CD206 (r=0.15, p=0.5). High mean susceptibility in the necrotic core was associated with inferior PFS (hazard ratio,4.5, p=0.016).

CONCLUSION

MR Susceptibility Imaging can quantify the iron content of GBM and provide a non-invasive method for TAM quantification and phenotyping.
NIMG-16. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS
Authors: Li Xianqi , Andronesi Ovidiu
Published: November 2021

Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging in patients due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For initial training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
NIMG-19. SYNTHETIC ISOCITRATE DEHYDROGENASE-MUTANT GLIOBLASTOMAS FROM GENERATIVE ADVERSARIAL NETWORK PROVIDE MORPHOLOGIC VARIABILITY AND DIAGNOSTIC PERFORMANCE SIMILAR TO REAL DATA: DEVELOPMENT AND VALIDATION
Authors: Park Ji Eun , Kim Ho Sung , Eun Dain
Published: November 2021

BACKGROUND

Generative adversarial network (GAN) creates synthetic MRI data that may provide morphologic variability to assess molecular characteristics of glioblastomas.

PURPOSE

To investigate the ability of GAN-based generation of isocitrate dehydrogenase (IDH)-mutant glioblastomas to provide morphologic variability and improve molecular prediction.

METHODS

GAN was retrospectively trained on 110 IDH-mutant high-grade gliomas. Paired contrast-enhanced T1-weighted and FLAIR synthetic MRI data were generated. Diagnostic models were developed from 80 IDH-wild type glioblastomas and 38 IDH-mutant patients, (real model), 38 IDH-mutant GAN-generated synthetic data (synthetic model), or both combined (augmented model). Two neuroradiologists independently assessed real and morphologic characteristics of contrast-enhancement patterns, the presence of necrosis, and margins and type of non-enhancing region. Significant predictors of IDH mutation were selected from multivariable logistic regression, and diagnostic performance was validated in 44 separate patients, 33 with IDH-wild type and 11 with IDH-mutant glioblastomas.

RESULTS

Synthetic IDH-mutant glioblastomas were similar to real tumors on Turing tests, with an area under the curve (AUC) of 0.67–0.71. Significant predictors of a more frontal or insular location (odds ratio [OR], 1.34 vs. 1.52; highest P = .04) and distinct non-enhancing tumor margins (OR, 2.68 vs. 3.88; P < .001) were similar for the real and synthetic models, with the synthetic (AUC, 0.958) and augmented (AUC, 0.899) models having higher diagnostic performance than the real model (AUC, 0.864) in the training set. The diagnostic accuracy was higher for the synthetic and augmented models (90.9% [40/44] each for both observers) than for the real model (84.1% [37/44] for one observer and 86.4% [38/44] for the other).

CONCLUSIONS

The GAN-based synthetic images yield morphologically variable IDH-mutant glioblastomas and may be useful as realistic training sets.
NIMG-23. MACHINE LEARNING METHODS IN GLIOMA GRADE PREDICTION: A SYSTEMATIC REVIEW
Authors: Bahar Ryan , Merkaj Sara , Brim W R , Subramanian Harry , Zeevi Tal , Kazarian Eve , Lin Ming , Bousabarah Khaled , Payabvash Sam , Ivanidze Jana , Cui Jin , Tocino Irena , Malhotra Ajay , Aboian Mariam
Published: November 2021

PURPOSE

Machine learning (ML) technologies have demonstrated highly accurate prediction of glioma grade, though it is unclear which methods and algorithms are superior. We have conducted a systematic review of the literature in order to identify the ML applications most promising for future research and clinical implementation.

MATERIALS AND METHODS

A literature review, in agreement with PRISMA, was conducted by a university librarian in October 2020 and verified by a second librarian in February 2021 using four databases: Cochrane trials (CENTRAL), Ovid Embase, Ovid MEDLINE, and Web of Science core-collection. Keywords and controlled vocabulary included artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. Screening of publications was done in Covidence, and TRIPOD was used for bias assessment.

RESULTS

The search identified 11,727 candidate articles with 1,135 articles undergoing full text review. 86 articles published since 1995 met the criteria for our study. 79% of the articles were published between 2018 and 2020. The average glioma prediction accuracy of the highest performing model in each study was 90% (range: 53% to 100%). The most common algorithm used for cML studies was Support Vector Machine (SVM) and for DL studies was Convolutional Neural Network (CNN). BRATS and TCIA datasets were used in 47% of the studies, with the average patient number of study datasets being 186 (range: 23 to 662). The average number of features used in machine learning prediction was 55 (range: 2 to 580). Classical machine learning (cML) was the primary machine learning model in 68% of studies, with deep learning (DL) used in 32%.

CONCLUSIONS

Using multimodal sequences in ML methods delivers significantly higher grading accuracies than single sequences. Potential areas of improvement for ML glioma grade prediction studies include increasing sample size, incorporating molecular subtypes, and validating on external datasets.