bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract
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&lt;0.01). Especially the number of smaller blood vessels (&lt;10µm) was significantly lower (P&lt;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

Abstract

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 &gt;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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

Abstract

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

Abstract
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 &gt;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

Abstract

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.