bluuebunny/crossref_metadata_2025 huggingface dataset:
TMOD-19. INDIVIDUAL SPECIFIC HUMAN GUT MICROBE COMMUNITIES INFLUENCE RESPONSE TO IMMUNOTHERAPY IN A HUMANIZED MICROBIOME MOUSE MODEL OF GLIOMA
Authors: Dees Kory , Koo Hyunmin , Humphreys J Fraser , Hakim Joseph , Crossman David , Crowley Michael , Nabors Louis , Benveniste Etty , Morrow Casey , McFarland Braden
Published: December 2020

Although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in GBM patients. Since recent studies have linked the gut microbial composition to the success with immunotherapy for other cancers, we utilized a novel humanized microbiome (HuM) model in order to study the response to immunotherapy in a pre-clinical mouse model of GBM. We used five healthy human donors for fecal transplantation of gnotobiotic mice since it is now recognized that microbe strain level differences render individual humans with a unique microbial community composition. After the transplanted microbiomes stabilized, the mice were bred to generate 5 independent humanized mouse lines (humanized microbiome HuM1-HuM5). Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome composition with significant differences in diversity and microbial composition among HuM1-HuM5 lines. We next analyzed the growth of intracranial glioma cells in the HuM lines. All HuM mouse lines were susceptible to GBM transplantation, and exhibited similar median survival ranging from 19-26 days. Interestingly, we found that HuM lines responded differently to the immune checkpoint inhibitor anti-PD-1. Specifically, we demonstrate that HuM1, HuM4, and HuM5 mice are non-responders to anti-PD-1 resulting in the death of the mice from the intracranial tumors, while HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls. Bray-Curtis cluster analysis of the 5 HuM gut microbial communities revealed that HuM2 and HuM3 were closely related. Detailed taxonomic comparison analysis at the top 5 across all HuM mouse lines revealed that Bacteroides cellulosilyticus was commonly found between HuM2 and HuM3 with high abundances. The results of our study establish the utility of humanized microbiome mice as avatars to delineate features of the host interaction with gut microbe communities needed for effective immunotherapy against GBM.
TMOD-26. ESTABLISHING A PATIENT-DERIVED, IN-VITRO ORGANOTYPIC SLICE CULTURE MODEL OF GBM
Authors: Rappoldt Liam , Weeks Adrienne , Ouellete Rodney , Roy Jeremy , Taylor Catherine , McCormick Craig , Attwood Kathleen , Kim Inhwa
Published: December 2020

Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumour. This tumour is universally fatal with a median survival of 15 months. Driving this pathology is an extremely heterogeneic tumour and complex tumour microenvironment. GBM research is primarily conducted using immortalized or primary cell lines due to their practicality and reproducibility. However, these cell lines do not effectively recapitulate the tumour microenvironment. Mouse models address these shortcomings but are laborious and expensive. We propose to utilize a patient derived organotypic culture model of GBM as an intermediary. We have utilized this model to test genetic manipulation via lentiviral transduction and the feasibility of utilizing this model to understand patient derived extracellular vesicles (EVs). We have sectioned and cultured patient derived organotypic models for 14 days without loss of viability. To determine if these organotypic cultures are amenable to lentiviral manipulation, tissue sections were transduced with far-red fluorescent lentivirus and efficiency determined by confocal laser scanning microscopy (CLSM) and flow cytometry (FC). To determine feasibility as a model for EVs, media obtained from patient-derived organotypic cultures was analyzed by western blot, nanoparticle tracking analysis (NTA), and nanoFlow Cytometry (nFC). In the future these EVs will be compared to those found in patient serum. The model of GBM has been lentivirally transduced to express a far-red fluorescent vector in approximately 15% of the slice, quantified by CLSM and FC. EV-sized particles positive for canonical EV markers have been identified in the media by NTA, nFC and western blot. Using lentiviral-mediated genetic engineering and emerging EV science, this organotypic slice culture models yields exciting utility in GBM research. The established organotypic slice culture model will likely be a valuable tool in the study of GBM biology and EV dynamics.
ATRT-06. SMARCB1 LOSS DRIVEN NON-CANONICAL PRC1 ACTIVITY REGULATES DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS (ATRT)
Authors: Alimova Irina , Danis Etienne , Weetall Marla , Pierce Angela M , Wang Dong , Serkova Natalie , Balakrishnan Ilango , Madhavan Krishna , Sanford Bridget , Michel Cole , Foreman Nicholas K , Baird John , Venkataraman Sujatha , Vibhakar Rajeev
Published: December 2020

Loss of SMARCB1 is the hallmark genetic event that characterizes ATRT. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. To identify co-operating epigenetic factors, we performed an unbiased shRNA screen targeting 408 epigenetic/chromatin molecules in patient-derived ATRT cell lines and identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as essential for ATRT cell viability. Genetic and Chemical inhibition of BMI1 inhibited clonogenic potential and induced apoptosis in vitro. In vivo PTC 596 significantly decreased growth of intracranial orthotopic ATRT tumors as evaluated by T2 MRI imaging and significantly prolonged survival compared to control animals. Using RNA-seq and ChIP-Seq our studies show that BMI1 co-operates with SMARCB1 loss to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. We then used a doxycycline-inducible SMARCB1 expression system and performed Immunoprecipitation for BMI1, followed by and mass spectrometry analysis. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. Re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. CBX4 is implicated DNA damage response, tumor angiogenesis and self-renewal. CBX8 activates lineage-specific genes during differentiation of ESC. Our data suggest that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex. These studies identify the mechanistic basis of BMI1 co-operation with SMARCB1 loss in ATRT and establish BMI1 inhibition as a novel therapeutic approach in ATRT.
ATRT-07. HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL TRANSPLANTATION FOR AN ADULT PRESENTATION OF THE ATYPICAL TERATOID-RHABDOID TUMOR (ATRT)
Authors: Mrugala Maciej , Raghunathan Aditya , Leis Jose
Published: December 2020

BACKGROUND

ATRT is a rare primary CNS tumor occurring predominantly in children with the peak age of onset at less than 3 years old. Adult presentations are exceedingly rare, associated with poor prognosis and no standard therapies exist.

METHODS

Case presentation.

RESULTS

61 y old woman presented with headaches, sinus pressure, and cognitive decline. She was found to have a pineal tumor causing obstructive hydrocephalus. The patient underwent gross total resection of the tumor with pathology reported as ATRT. Her CNS staging, including CSF, was negative. She subsequently received radiotherapy to the resection bed. There was no consensus on what should be the next step in her therapy given lack of data in adults. Ultimately, we adopted a pediatric regimen and treated the patient with a combination of high-dose chemotherapy with cisplatin, cyclophosphamide, and vincristine followed by autologous stem cell transplantation (ASCT). This regimen called for up to 4 cycles of chemotherapy with ASCT and we had collected enough cells to complete 3 cycles. The patient completed 2 cycles of therapy with moderate toxicity. Her CNS imaging remained stable with no evidence of recurrence 14-months from the original diagnosis.

CONCLUSIONS

ATRT continues to be an exceedingly rare diagnosis in adults. No standard therapies exist and treatment decisions are challenging given lack of data and lack of prospective clinical trials. Pediatric regimens can frequently be adopted for adults although high-dose chemotherapy with ASCT can be challenging. Our case exemplifies the feasibility of treating ATRT in an adult in the most aggressive fashion.
DDEL-11. CONVECTION-ENHANCED DELIVERY OF EZH2 INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Sasaki Takahiro , Katagi Hiroaki , Goldman Stewart , Becher Oren , Hashizume Rintaro
Published: December 2020

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities.

OBJECTIVE

This study aims to assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models.

METHODS

The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography–mass spectrometry (LC/MS). We treated mice bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image and the therapeutic response was evaluated by animal survival.

RESULTS

LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P=0.0475).

CONCLUSION

Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.
DIPG-33. CHARACTERIZING THE NEURO-VASCULAR UNIT IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: El-Khouly Fatma E , Haumann Rianne , Breur Marjolein , van Zanten Sophie E M Veldhuijzen , Kaspers Gertjan J L , Hendrikse N Harry , Hulleman Esther , van Vuurden Dannis G , Bugiani Marianna
Published: December 2020

Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain-barrier (BBB). In this study we aim to compare the neuro-vascular unit (NVU) of DIPG to healthy pons tissue. End-stage DIPG autopsy samples (n=5) and age-matched healthy pons samples (n=22), obtained from the NIH NeuroBioBank, were immunohistochemically stained for tight-junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, and pericyte marker PDGFRβ. Claudin-5 stains were also used to determine vascular density and diameters. In DIPG, expression of claudin-5 and ZO-1 was reduced, and claudin-5 was dislocated to the abluminal side of endothelial cells. Laminin expression at the glia limitans was reduced in both pre-existent vessels and neovascular proliferation. In contrast to healthy pons, no PDGFRβ expression was detected. The number of blood vessels in DIPG was significantly reduced compared to healthy pons, 13.9±11.8/mm2 versus 26.3±14.2/mm2, respectively (P<0.01). Especially the number of smaller blood vessels (<10µm) was significantly lower (P<0.01). Distribution of larger blood vessels (≥10µm) did not differ between groups (P=0.223). Mean vascular diameter was 9.3±9.9µm for DIPG versus 7.7±9.0µm in healthy pons (P=0.016). Our study demonstrates evidence of structural changes in the NVU in end-stage DIPG. Chemotherapeutic inefficacy could be the result of reduced vascular density. However, further research is needed to determine meaning and extent of these changes and to determine whether these observations are caused by the tumor or the result of treatment.
EPCT-02. PBTC-051: FIRST IN PEDIATRICS PHASE 1 STUDY OF CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M IN PEDIATRIC SUBJECTS WITH RECURRENT/REFRACTORY BRAIN TUMORS
Authors: Lindsay Holly , Onar-Thomas Arzu , Kocak Mehmet , Poussaint Tina Young , Dhall Girish , Broniscer Alberto , Vinitsky Anna , MacDonald Tobey , Trifan Ovid , Fangusaro Jason , Dunkel Ira
Published: December 2020

BACKGROUND

CD40 is a co-stimulatory molecule expressed on antigen presenting cells (APCs). APX005M is a CD40 agonist monoclonal antibody which stimulates innate and adaptive anti-tumor immunity through activation of APCs, macrophages, and antigen-specific CD8+T-cells. Pediatric Brain Tumor Consortium study PBTC-051 is the first investigation of APX005M in pediatric patients and is evaluating the safety, recommended phase 2 dose (RP2D), pharmacokinetics, and preliminary efficacy of APX005M in children with central nervous system (CNS) tumors.

RESULTS

Accrual of patients with recurrent/refractory primary malignant CNS tumors (stratum 1) began in March 2018. 16 patients (2 ineligible) have enrolled on this stratum; 14 were treated. Dose escalation through 3 planned dose levels of APX005M was completed without excessive or unanticipated toxicities. The highest dose level (0.6 mg/kg q3 weeks) is the presumptive RP2D, and an expansion cohort is currently enrolling at this dose. 2 patients at dose level 3 have received >12 cycles of therapy. Grade 3 or higher adverse events at least possibly attributable to APX005M include 11 lymphopenia, 5 neutropenia, 5 leukopenia, 3 ALT elevations, 1 AST elevation, 1 thrombocytopenia, and 1 hypoalbuminemia. PK data will be available March 2020. Stratum 2 is now enrolling patients with post-radiation/pre-progression DIPG beginning at dose level 2, with 1 patient currently enrolled.

CONCLUSION

The CD40 agonistic antibody APX005M has demonstrated preliminary safety in pediatric patients with recurrent/refractory primary malignant CNS tumors and has a likely RP2D of 0.6 mg/kg q3 weeks in this population. Preliminary efficacy data are pending.
EPCT-07. DEBIO1347, AN ORAL FGFR INHIBITOR: RESULTS FROM A SINGLE CENTER STUDY IN RECURRENT/REFRACTORY FGFR ALTERED PEDIATRIC GLIOMAS
Authors: Sait Sameer Farouk , Gilheeney Stephen , Dunkel Ira , Karajannis Matthias
Published: December 2020

BACKGROUND

Oncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1–3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.

METHODS

Five children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior chemotherapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8–12 weeks.

RESULTS

All AEs were grade 1–2. Most common treatment-related adverse events were ALT increased, hypoalbuminemia and hyperphosphatemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (18 months and ongoing).

CONCLUSIONS

Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Further studies in this population are warranted.
EPEN-18. CROSS-SPECIES GENOMICS IDENTIFIES GLI2 AS AN ONCOGENE OF C11orf95 FUSION-POSITIVE SUPRATENTORIAL EPENDYMOMA
Authors: Zheng Tuyu , Ghasemi David R , Okonechnikov Konstantin , Korshunov Andrey , Sill Martin , Hübner Jens-Martin , Maaß Kendra K , Snuderl Matija , Gojo Johannes , Schüller Ulrich , Gerber Nicolas U , Hernáiz-Driever Pablo , Milde Till , Sturm Dominik , Chapman Rebecca , Grundy Richard G , von Deimling Andreas , Jones David T W , Kool Marcel , Pfister Stefan M , Sahm Felix , Kawauchi Daisuke , Pajtler Kristian W
Published: December 2020

The majority of supratentorial ependymomas (ST-EPN) are driven by fusions between RELA and a zinc finger containing gene, C11orf95. Apart from fusions to the Hippo effector YAP1, which affects a small group of infant patients, the oncogenic mechanism of remaining ST-EPNs is unclear. Aiming at refining the molecular classification of ST-EPNs, we analyzed methylation profiles, RNA and DNA sequencing results as well as clinical data in a cohort of 617 ST-EPNs. Unsupervised clustering analysis of DNA methylation data revealed four distinct clusters that formed in addition to the known molecular groups ST-EPN-RELA and –YAP1. Tumors within these additional clusters were characterized by fusions of C11orf95 to numerous fusion partners different from RELA, e.g. MAML2, MAML3, NCOA2 and SS18, suggesting a general role of C11orf95 in tumorigenesis of ST-EPN. Transforming capacity of newly identified fusion genes was validated using an electroporation-based in vivo gene transfer technology. All fusion genes were sufficient to drive malignant transformation in the cerebral cortex of mice and resulting tumors faithfully recapitulated molecular characteristics of their human counterparts. We found that both, the partner gene and the zinc finger DNA binding domain of C11orf95, were essential to exert tumorigenesis. When exploring genes commonly upregulated in C11orf95 fusion-expressing tumors of human and murine origin, the Sonic Hedgehog effector gene Gli2 was identified as a promising downstream target. Subsequent co-expression of C11orf95:RELA and a dominant negative form of Gli2 indeed hampered tumorigenesis. We thus propose GLI2 as a potential therapeutic downstream target of C11orf95 fusion-dependent oncogenic signaling in ST-EPN.
EPEN-22. SINGLE-CELL RNA SEQUENCING IDENTIFIES UPREGULATION OF IKZF1 IN PFA2 MYELOID SUBPOPULATION DRIVING AN ANTI-TUMOR PHENOTYPE
Authors: Griesinger Andrea , Prince Eric , Donson Andrew , Riemondy Kent , Ritzman Timothy , Harris Faith , Amani Vladimir , Handler Michael , Hankinson Todd , Grundy Richard , Jackson Andrew , Foreman Nicholas
Published: December 2020

We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype and have a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples and used advanced machine learning techniques to identify distinct myeloid and lymphoid subpopulations. The myeloid compartment was difficult to interrupt as the data shows a continuum of gene expression profiles exist within PFA1 and PFA2. Through lineage tracing, we were able to tease out that PFA2 myeloid cells expressed more genes associated with an anti-viral response (MHC II, TNF-a, interferon-gamma signaling); while PFA1 myeloid cells had genes associated with an immune suppressive phenotype (angiogenesis, wound healing, IL-10). Specifically, we found expression of IKZF1 was upregulated in PFA2 myeloid cells. IKZF1 regulates differentiation of myeloid cells toward M1 or M2 phenotype through upregulation of either IRF5 or IRF4 respectively. IRF5 expression correlated with IKZF1, being predominately expressed in the PFA2 myeloid cell subset. IKZF1 is also involved in T-cell activation. While we have not completed our characterization of the T-cell subpopulation, we did find significantly more T-cell infiltration in PFA2 than PFA1. Moving forward these studies will provide us with valuable information regarding the molecular switches involved in the tumor-immune microenvironment and to better develop immunotherapy for PFA ependymoma.
ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL BASIS OF PINEOBLASTOMA THROUGH GENOMICS
Authors: Gudenas Brian , Englinger Bernhard , Liu Anthony P Y , Tong Yiai , Meredith David , Pfaff Elke , Lin Tong , Orr Brent A , Klimo Paul , Bihannic Laure , Paul Leena , Kumar Rahul , Bouffet Eric , Gururangan Sridharan , Crawford John R , Kellie Stewart J , Chintagumpala Murali , Fisher Michael J , Bowers Daniel C , Hassall Tim , Indelicato Daniel J , Ellison David W , Boop Frederick A , Merchant Thomas E , Chiang Jason , Robinson Giles W , Gajjar Amar , Alexandrescu Sanda , Jones David T W , Filbin Mariella G , Northcott Paul A
Published: December 2020

Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.
GCT-31. DIAGNOSTIC CAPABILITY OF CSF-PLAP ON INTRACRANIAL GERM CELL TUMOR
Authors: Okamoto Michinari , Yamaguchi Shigeru , Ishi Yukitomo , Motegi Hiroaki , Terashita Yukayo , Hirabayashi Shinsuke , Sugiyama Minako , Cho Yuko , Iguchi Akihiro , Manabe Atushi , Houkin Kiyohiro
Published: December 2020

BACKGROUND

Since the majority of intracranial germ cell tumor(GCT) is sensitive for chemoradiation, biopsy specimens are usually tiny and not enough for accurate pathological diagnosis. To supply complementary diagnostic information, a-fetoprotein or human chorionic gonadotropin-b are important biomarkers. Recently CSF-placental alkaline-phosphatase(PLAP) is also reported as an additional biomarker in intracranial GCT. This study’s purpose is to evaluate the significance of CSF-PLAP.

METHODS

CSF-PLAP was obtained from the patients with the intraventricular and periventricular tumor before any adjuvant therapy. Definitive diagnoses were made by histopathological information and/or their clinical courses; GCT(germinoma or non-germinomatous GCT(NGGCT)) or other tumors. In GCT, the relationship between CSF-PLAP and tumor reduction volume was evaluated. Tumor volumes were calculated on gadolinium-enhanced T1-weighted magnetic resonance imaging before and after initial chemoradiotherapy.

RESULTS

Between 2005 and 2019, 42 patients were studied: 24 with GCT and 18 with others. CSF-PLAP value in patients with GCT was significantly higher than those with others: the Specificity was 88% and the sensitivity was 95% at the cutoff value of 8.0 pg/ml. For GCT patients, CSF-PLAP value tended to be higher in germinoma(n=12, mean 4756 pg/ml), compared to the value in NGGCT(n=7, mean 332 pg/ml), although there was no statistical difference. There was a significant positive correlation between initial CSF-PLAP value and tumor reduction volume.

CONCLUSION

CSF-PLAP is a useful tumor marker for GCT differentiating from the other tumors located in intraventricular and periventricular region and CSF-PLAP value might correlate with the volume of germinomatous component of the tumor.
GCT-42. CLINICAL CHARACTERISTICS OF LOCALIZED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS (NGGCT) PATIENTS ENROLLED ON ACNS1123 WITH RELAPSE: A CHILDREN’S ONCOLOGY GROUP (COG) STUDY
Authors: Dhall Girish , Wu Shengjie , Onar-Thomas Arzu , Shaw Dennis , MacDonald Shannon , Murphy Erin , Khatua Soumen , Bartels Ute , Fangusaro Jason
Published: December 2020

ACNS1123 was a Children’s Oncology Group Phase 2 study that was undertaken to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients. Between May 2012-Jan 2017, 107 eligible patients were accrued to Stratum 1 (NGGCT stratum). Sixty-six (61.7%) patients achieved a complete/partial response (CR/PR) to induction chemotherapy and received 30.6Gy whole ventricular field irradiation followed by 54Gy tumor-bed boost achieving a 2-year progression-free survival rate of 89% (95% CI:81%-97%) and overall survival rate of 92% (95% CI:86%- 99%). Eight patients progressed; 6 had a spinal relapse and 2 patients had a local plus spinal relapse. Seven of eight patients had marker elevation at relapse and data was not available in one patient. At diagnosis, location was pineal in six cases, suprasellar in one, and bifocal in one case. Four patients had beta HCGβ and AFP elevation and two each had HCGβ and AFP elevation alone at diagnosis. Only two patients had HCGβ or AFP >1000 (HCGβ 3550 in one patient and AFP of 1340 in another). All eight patients were CR by markers; four had radiographic CR and four had a PR. Five patients had surgery at diagnosis: two had embryonal carcinoma, one germinoma, and two mixed germ cell tumor with malignant elements on histology. A consistent significant risk factor could not be identified to explain excess of spinal failures seen in our cohort.
GCT-57. ARE MELATONIN LEVELS A RELIABLE MARKER FOR INTRACRANIAL GERM CELL TUMORS POST TREATMENT DEFICIENCY?
Authors: Cappellano Andréa M , Fujita Alex M M , Silva Nasjla S , Almeida Daniela B , Amaral Fernanda G
Published: December 2020

BACKGROUND

Pineal is the melatonin-producing gland, with this hormone importantly acting as a central and peripheral chronobiotic, antioxidant and in energy metabolism. The urinary dosage of 6-sulfatoxymelatonin (aMT6s), a melatonin metabolite, is an indirect marker to estimate the total melatonin nocturnal production, ranging in clinically normal individuals from 10–50 micrograms(ug). The purpose of this study was to evaluate aMT6s in patients with diagnosis of intracranial germ cell tumors (iGCT) treated at IOP/GRAACC/UNIFESP.

METHODS

After an interview to collect data about therapies employed and medications, night urine samples (from 8:00pm to first void in the morning) were collected and analyzed by ELISA.

RESULTS

Twenty patients between 5–42 years old (mean 20.9 years), all male, were analyzed. Thirteen patients had diagnosis of Germinoma, 1 with Imature Teratoma, 5 NGGCT and 2 Mature Teratoma. The first site was pineal (N=15) and bifocal (N=5). The treatment was surgery/biopsy/2º look surgery in 17 patients associated with chemotherapy/ radiotherapy, except in 2 (pure teratoma-surgery only) and 1 (chemo only). Three patients had diagnosis by tumor markers treated with chemo only (N=1) and chemotherapy/radiotherapy (N=2). The levels of aMT6s were between 0.2–3.2ug in all participants, except in one (14.8ug-biopsy, chemo and RT).

CONCLUSION

aMT6s levels found in most patients are below the expected for the general population suggesting that this is an appropriate marker for pineal tumors with melatonin deficiency. It may contribute to support future studies in this area and adoption of follow-up protocols, with eventual hormone supplementation and consequently improved quality of life.
HGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS
Authors: Dodgshun Andrew , Fukuoka Kohei , Edwards Melissa , Bianchi Vanessa , Sexton-Oates Alexandra , Larouche Valerie , Magimairajan Vanan , Lindhorst Scott , Yalon Michal , Mason Gary , Crooks Bruce , Constantini Shlomi , Massimino Maura , Chiaravalli Stefano , Ramdas Jagadeesh , Mason Warren , Shamvil Ashraf , Farah Roula , Van Damme An , Opocher Enrico , Hamid Syed Ahmer , Ziegler David , Samuel David , Cole Kristina A , Tomboc Patrick , Stearns Duncan , Thomas Gregory , Lossos Alexander , Sullivan Michael , Hansford Jordan R , Jones David , Mackay Alan , Jones Chris , Ramaswamy Vijay , Hawkins Cynthia , Bouffet Eric , Tabori Uri
Published: December 2020

Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
HGG-50. TWO CASES OF H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA OF CERVICAL SPINAL CORD
Authors: Kuroha Masae , Tamura Kaoru , Inaji Motoki , Hashimoto Satoka , Kobayashi Daisuke , Tanaka Yoji , Nariai Tadashi , Maehara Taketoshi
Published: December 2020

BACKGROUND

“Diffuse midline glioma, H3 K27M-mutant’ was newly categorized as a separate pathological entity in the 2016 WHO classification, based on recently discovered mutation. Spinal cord glioma with H3 K27M-mutant is rare, so we reported the clinical course of two cases. CASE 1: A 17-year-old male presented with posterior headache and right limbs paralysis. MRI showed cervical spinal cord with expansion, T2-weighted high intensity and a part of enhancement. The biopsy revealed a diffuse midline glioma, H3 K27M-mutant. He received bevacizumab plus radiotherapy-temozolomide. In a few months, he had quadriplegia and cranial nerve paralysis and needed respirator. There was not expansion of mass, but intracranial dissemination. CASE 2: A 16-year-old male presented with posterior neck pain and right limbs paralysis. On brain stem and cervical spine, MRI findings were same to case 1. The biopsy was undergone and revealed H3 K27M mutation. He received bevacizumab in addition to radiotherapy-temozolomide. Although he also had quadriplegia, the progression of tumor has stopped. He has received chemotherapy with respirator at home.

DISCUSSION

It was previously reported that the prognostic factors for diffuse midline glioma were tumor location, H3 K27M-mutation and age, but there are few relevant studies. The consensus on the treatment is also not clearly determined. Because the cervical spinal cord gliomas are rapidly advanced miserably, we added bevacizumab to standard radiotherapy-temozolomide for initial treatment. In addition, whole brain and spine radiation may be considered to avoid dissemination. Multicenter study is important to collect information and improve treatment of H3 K27M-mutant glioma.
IMG-17. RADIOMICS CHARACTERIZATION OF FOUR PEDIATRIC BRAIN TUMOR SUBTYPES IN PDX MOUSE MODELS
Authors: Serkova Natalie , Stukova Marina , Henehan Samuel , Steiner Jenna , Pierce Angela , Griesinger Andrea , Veo Bethany , Alimova Irina , Venkataraman Sujatha , Green Adam , Dahl Nathan , Foreman Nicholas , Vibhakar Rajeev
Published: December 2020

BACKGROUND

Previously, we have reported on the development of advanced magnetic resonance imaging (MRI) protocols for mouse brain tumors. The goal of this follow-up pre-clinical study was to develop a machine-learning MRI classifier (radiomics) for four subtypes of childhood brain tumor in patient-derived xenograft (PDX) mice.

METHODS

MRI scans on orthotopic medulloblastoma, ependymoma, ATRT and DIPG PDX (each n=12 animals) were performed on the animal 9.4 Tesla scanner with an in-plane resolution of 47 microns. Image segmentation, as well as shape and texture based radiomics descriptors were modeled using a modified COLIAGE software for tumor classification and to characterize tumor habitat of each tumor subtype.

RESULTS

The mean tumor volumes were 11.2 mm3. Each MRI scan was segmented into three regions: (i) well defined tumor (including distant metastases); (ii) peritumoral edema; (iii) tumor necrosis. 360 radiomics features (capturing co-occurrence, grey-level dependence and directional gradients) were obtained for each region. The model classified four subtypes with high accuracy while achieving sufficient segmentation accuracy despite the small lesion size. A subset of fourteen tumoral, six peritumoral and five distant MRI radiomics features were found to be predictive of the tumor sub-type (p=0.0017) independently of tumor anatomical location.

CONCLUSIONS

MRI protocols followed by radiomics feature analysis discriminated among specific radiological features for four distinct orthotopic PDX models: medulloblastomas exhibit low ADC values, high angiogenesis and cortical metastases as compared to ependymomas (high levels of edema and olfactory bulb metastases), ATRT (the highest level of necrosis) and DIPG (highest T2 signal intensities and spinal metastases).
IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSET PRIMARY INTRACRANIAL MELANOMA
Authors: Oba Utako , Koga Yuhki , Kawaguchi Riichiro , Nakashima Kentaro , Akagi Yojiro , Hata Nobuhiro , Yamamoto Nanae , Kohashi Kenichi , Masuda Satohiro , Iihara Koji , Oda Yoshinao , Ohga Shouichi
Published: December 2020

Primary intracranial malignant melanoma (PIMM) is an uncommon cancer in childhood, that accounts for approximately 1% of melanoma, and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients have a chance to receive the early diagnosis and curable resection of the isolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old girl with PIMM who received nivolumab therapy after an administration of dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa levels declined and circulating CD8+HLA-DR+T cells increased, indicating the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid nivolumab concentrations attained to 1.2% of serum ones. The present case demonstrated the safety and modest effect of nivolumab for CNS melanoma. Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatric patients need a more intensified CNS-specific immunotherapy.
IMMU-26. DISEASE CONTROL IN A PEDIATRIC PATIENT WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) AND SOMATIC HIGH MICROSATELLITE INSTABILITY (MSI-H) WITH PD-1 INHIBITOR NIVOLUMAB (NIVO) ONLY AND NO FOCAL RADIOTHERAPY (RT)
Authors: Larkin Trisha , Blatt Jason , Gururangan Sridharan
Published: December 2020

Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) have recently been shown to be a promising option for the management of recurrent mismatch repair (MMR) deficient GBM following radiotherapy. We report a case of a 9-year-old boy who presented with a 6 week history of frontal headaches and was found to have a left frontal lobe mass. Pathology obtained from a gross total resection (GTR) was consistent with classic GBM, WHO Grade IV. Neuroimaging four weeks following initial resection was remarkable for local recurrence. The patient underwent another GTR of the tumor at our center. While pathology again confirmed GBM, GlioSequencing of tumor tissue from second resection showed MSI-H, NF2 mutation p.R338H, NF1 mutations p.R2450* and pI193Yfs*11, TP53 mutations p.R213* and p.R273C, EGFR mutation, and multiple variants of uncertain significance. Germline testing was negative for MMR deficiency or other deleterious mutations. Parents opted to defer radiotherapy and consented to monotherapy treatment with Nivolumab (Opdivo, BMS pharmaceuticals, USA), a PD-1 inhibitor, at a dose of 3 mg/kg administered every two weeks. Our patient is now 22 months post-second resection and continues to receive Nivolumab without evidence of recurrent disease or adverse autoimmune effects from PD-1 blockade. He has remained in school with good academic performance and has exhibited no regression of functional status during the entirety of his treatment course. This case provides evidence of possible efficacy of PD-1 blockade without focal radiotherapy in this child with GBM and somatic MSI instability.
IMMU-28. IMMUNOGENOMIC ANALYSIS REVEALS LGALS1 CONTRIBUTES TO THE IMMUNE HETEROGENEITY AND IMMUNOSUPPRESSION IN GLIOMA
Authors: Chen Qun , Cai Jinquan , Han Bo , Meng Xiangqi
Published: December 2020

Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma.
LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Barbour Mustafa , Huang Michael Angelo
Published: December 2020

INTRODUCTION

Low grade gliomas (LGG) are the most common pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK) pathway as the primary oncogenic driver for this group of tumors has led to a shift towards the use of BRAF and MEK inhibitors.

METHODS

Herein we performed a chart review of seven pediatric LGG treated with trametinib, a MEK inhibitor. While most were treated in the relapse setting, one patient was treated for de novo LGG as a result of experiencing multiple severe adverse effects to conventional agents.

RESULTS

Median age was 14 years old (range: 5 to 17 years). Six of seven patients had tissue for molecular characterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1 had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549-BRAF fusion. Average duration on treatment was 8 months (range: 3 to 31 months). Disease control was achieved in 6 of 7 subjects, with one PR as best response. One patient with concurrent BRAF V600e and PTPN11 mutations progressed on trametinib and was switched to dual BRAF and MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patients required dose reduction and/or intermittent dose interruption.

CONCLUSION

Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.
LINC-07. PREVALENCE AND SPECTRUM OF EARLY ENDOCRINE DISORDERS IN SURVIVORS OF PEDIATRIC EMBRYONAL BRAIN TUMORS (PEBT): EXPERIENCE FROM INDIA
Authors: Prasad Maya , Nair Kalasekhar Vijayasekharan , Krishnatry Rahul , Chinnaswamy Girish , Gupta Tejpal , Rao Sudha
Published: December 2020

BACKGROUND

Survivors of pediatric brain tumors are at high risk of developing endocrine disorders, potentially impacting growth,development and quality of life.

METHODS

etrospective audit of 2-year survivors of PEBT(3-18years at diagnosis)viz. medulloblastoma(MB),Central nervous system Primitive neuro-ectodermal tumors(CNS-PNET) and atypical teratoid/rhabdoid tumor(ATRT) treated January 2006-December 2017 at Tata Memorial Centre,Mumbai, with surgery, cranio-spinal irradiation(CSI; 35Gy in high-risk MB,CNS-PNET,ATRT and 23.4Gy in average-risk MB with tumor boost 19.8Gy)and six cycles of adjuvant chemotherapy(cyclophosphamide,cisplatin and vincristine).Patients were followed up by a paediatric endocrinology team specialized in management of PEBT.

RESULTS

Of 249 PEBT treated during this period,88 are alive in remission >2 years (69-MB, 15-CNS PNET,4-ATRT),median age at diagnosis 6 years. At a median follow-up of 5.6 years (range 3- 12.5years),63 patients(72%) had at least one endocrine disorder,26(29.%)≥2 hormonal deficiencies. The most common endocrine disorders were central hypothyroidism(57%),growth hormone deficiency(40%), central hypogonadism(5%)and central hypoadrenalism (3.5%).The median time to develop hypothyroidism was 2.8 years(range 5months to 8.5 years) from CSI. Growth hormone replacement therapy began after a median period of 4.2 years(range-1.5 to 11.5years) from CSI. Higher dose of CSI was associated with development of endocrine disorder (odds ratio [OR] 2.71; 95% CI, 1.03 to 7.04,p-0.04).

CONCLUSIONS

The high incidence of endocrine deficits in survivors of PEBT necessitates early and lifelong monitoring. Early and appropriate management is crucial to achieve full growth potential.
LINC-20. INFANT BRAIN TUMOURS IN HONG KONG
Authors: Shing Matthew M K , Ku Dennis T L , Chan Godfrey C F , Luk C W , Yau Jeffrey P W , Fu Eric , Yan Carol L S , Ling Alvin S C
Published: December 2020

OBJECTIVES

To review the clinical features, pathology and survivals of infants with brain tumours.

METHODS

A retrospective review of the clinical findings, pathology, treatment and survival outcome in infants with brain tumours.

RESULTS

From 1999 to 2018, there were 507 children (<18 years) who were diagnosed to have brain tumours in Hong Kong. The patients were treated in five public hospitals. The clinical data were collected by the Hong Kong Paediatric Haematology and Oncology Study Group, and were cross-checked with the data of the Hong Kong Cancer Registry. In this group of patients, there were 36 infants (birth to 365 days of age) i.e. 7.1% of the whole group. Both benign and malignant brain tumours were included, while non-neoplastic lesions were excluded. On average, there was 1.89 cases per year. The pathology of the tumours were astrocytoma (n= 8), medulloblastoma (n=6), germ cell tumour (n=6), PNET (n=5), ATRT (n=4), choroid plexus tumours (n=3), ependymoma (n=2), craniopharyngioma (n= 1) and ganglioglioma (n= 1). These infants were treated according to their clinical conditions and prognosis, with operation, chemotherapy or both. Radiotherapy was withheld or postponed to older age. Some patients only received palliative care due to the poor neurological status or prognosis. The overall survivals of children younger than 18 years old vs infants were 67.3% (±2.3) vs 50.5%(±9.2) respectively, while the event free survivals were 64.4% (±2.4) and 43.5% (±8.8) at 10-years respectively.

CONCLUSION

Infants with brain tumours have different pathology and inferior outcome.