bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-20. RADIOMIC FEATURES IMPROVE PROGNOSTICATION OVER CONVENTIONAL MR DERIVED QUALITATIVE DESCRIPTORS IN PEDIATRIC SUPRATENTORIAL HIGH GRADE GLIOMA: COMPARISON OF MACHINE LEARNING TECHNIQUES
Authors: Lucas John , Hsu Chih-Yang , Becksfort Jared , Hwang Scott , Lu Zhaohua , Wang Yichuan , Chiang Jason , Tinkle Christopher , Gajjar Amar , Merchant Thomas , Patay Zoltan 
Published: December 2020

Abstract

PURPOSE/OBJECTIVES
Pediatric supratentorial high-grade glioma (stHGG) is a biologically heterogeneous disease defined by unique mutations, natural history and prognosis. Prior work by our group outlined a role for qualitative imaging features in aiding prognostication. We build on that work by evaluating the prognostic utility of radiomic features (RM) when paired with clinical factors. MATERIALS/

METHODS
Ninety-one patients age &lt; 21 years with stHGG treated between 1980–2007 were retrospectively reviewed. Prognostic clinical, qualitative imaging (Visually AcceSAble Rembrandt Images, VASARI), and treatment characteristics were evaluated in concert with manual and automatically segmented (DeepMedic), tumor-derived semi-quantitative radiomic features (Pyradiomics) extracted from MR images. Prognostic RM were limited to stable imaging features which were subsequently selected using bootstrapped least absolute shrinkage and selection operator (LASSO). Nonparametric descriptive statistics and prognostication model evaluation, incorporating RM and clinical variables, were developed using random forest (RF), Cox proportional hazards (CPH), and deep learning (deepsurv) algorithms and assessed for goodness of fit using (c-index).

RESULTS
A subset (N=80) of 386 intensity, shape, and texture derived RM were stable between pre-treatment MR. 28 RM features were independently predictive of survival when compared to models utilizing combinations of clinical, VASARI and had comparable model fit statistics. CPH, RF and deepsurv showed comparable utility in modelling RM features. Combined modelling of clinical, VASARI and RM features using CPH, RF, and deepsurv resulted in c-indices of 0.68, 0.67, 0.68, respectively.

CONCLUSION
RM features are stable and independently prognostic. Combined modelling of clinical, VASARI, and RM features improves prognostication in stHGG.
IMMU-06. T-CELL IMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS: DIVERSITY IN CELL SURFACE ANTIGEN AND HLA EXPRESSION NECESSITATES A MULTI-PRONGED APPROACH
Authors: Houke Haley , Zhu Xiaoyan , Mercer Kimberly S , Stripay Jennifer L , Chiang Jason , Baker Suzanne J , Roussel Martine F , Gottschalk Stephen , Krenciute Giedre 
Published: December 2020

Abstract
Cell surface or intracellular antigens expressed in pediatric brain tumors are potential targets for chimeric antigen receptor (CAR) or ab (T-cell receptor) TCR T-cell immunotherapy. At present it remains unknown what cell surface antigens are suitable CAR targets for pediatric brain tumors; in addition, cell surface expression of HLA class I, a molecule critical for ab TCR T-cell recognition, has not been systemically studied in these tumors. Therefore, we set out to assess expression of five CAR targets (IL13Ra2, HER2, EphA2, B7-H3, GD2) and HLA class I. We established and validated a flow cytometry-based method to profile CAR targets and HLA class I expression from pediatric patient-derived xenograft (PDX) samples. To date, we profiled 53 PDX samples, including medulloblastoma, HGG, DIPG, ATRT, and ependymoma. We found that antigen expression has high intra- and inter-PDX sample variability with B7-H3 and IL13Ra2 being most consistently expressed. We confirmed these findings using conventional IHC for B7-H3 with PDX samples and patient tissue microarrays. HLA class I was present on the cell surface of HGGs and DIPGs, however significantly down-regulated in 26 out of 36 other brain tumor types. Finally, matched fresh tissue and PDX sample analysis revealed that cells derived from PDX models are indeed representative of fresh tissue. Our results indicate that more than one antigen needs to be targeted to achieve a more complete tumor clearance. In addition, variable expression of HLA class I suggests that pediatric brain tumors have developed immune evasion strategies to prevent recognition by conventional T cells.
IMMU-16. INTRA-TUMOURAL IL-12 DELIVERY ENABLES CAR T-CELL IMMUNOTHERAPY FOR HIGH-GRADE GLIOMA
Authors: Agliardi Giulia , Liuzzi Anna Rita , Hotblack Alastair , De Feo Donatella , Núñez Nicolás , Friebel Ekaterina , Nannini Francesco , Roberts Thomas , Ramasawmy Rajiv , Stowe Cassandra , Williams Iwan , Siow Bernard , Lythgoe Mark , Kalber Tammy , Quezada Sergio , Pule Martin , Tugues Sonia , Becher Burkhard , Straathof Karin 
Published: December 2020

Abstract
Treatment with T-cells redirected to tumour specificity with a chimeric antigen receptor (CAR) may be well suited to treat intracranial tumours due to the ability of T-cells to access the central nervous system and migrate to infiltrative sites of disease. In adult glioblastoma, a case report of local and distant eradication of intracranial and spinal tumour deposits following intraventricular infusion of IL13Ra2-CAR T-cells indicates the potential of this approach. However, in contrast to the sustained complete remissions observed in haematological malignancies, in the majority of patients with glioblastoma CAR T-cell therapy has not resulted in clinical benefit. Tumour heterogeneity and the highly immune inhibitory tumour microenvironment (TME) are likely key barriers to achieving durable anti-tumour immunity. Here use intra-tumoural administration of IL-12 to enable CAR T-cell immunity. We employed CAR-T cells targeting the tumour-specific epidermal growth factor variant III (EGFRvIII). In an immunocompetent orthotopic mouse model of high-grade glioma, we show that CAR-T cells alone failed to control fully established tumour, but when combined with a single, locally delivered dose of IL-12, durable antitumor responses were achieved. IL-12 not only boosted cytotoxicity of CAR T-cells, but also reshaped the TME driving increased infiltration of proinflammatory CD4+ T-cells, decreased numbers of regulatory T-cells (Tregs) and activation of the myeloid compartment. Critically, immunotherapy enabling benefits of IL-12 were achieved with minimal systemic effects. Our findings show that local delivery of IL-12 is an effective adjuvant for CAR-T cell therapy for high-grade glioma. Assessment of application in high-risk childhood brain tumours is ongoing.
IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY
Authors: Bouffet Eric , Sudhaman Sumedha , Chung Jiil , Kelly Jacalyn , Coblentz Ailish , Edwards Melissa , Lipman Tatiana , Zhang Cindy , Ercan Ayse Bahar , Sambira Lauren , Bendel Anne , Bielack Stefan , Koustenis Elisabeth , Blumenthal Deborah , Bowers Daniel , Broniscer Alberto , Bronsema Annika , Carroll Sara , Chiaravalli Stefano , Cole Kristina , Constantini Shlomi , De Mola Rebecca Loret , Dunn Gavin , Fröjd Charlotta , Gass David , Gauvain Karen , George Ben , Hijiya Nobuko , Hoffman Lindsey , Knipstein Jeffrey , Laetsch Ted , Larouche Valérie , Lassaletta Alvaro , Lindhorst Scott , Lossos Alexander , Luna-Fineman Sandra , Magimairajan Vanan , Mason Gary , Mason Warren , Massimino Maura , Mordechai Oz , Opocher Enrico , Oren Michal , Osborn Michael , Reddy Alyssa , Remke Mark , Roy Sumita , Sabel Magnus , Samuel David , Schneider Kami , Sen Santanu , Stearns Duncan , Sumerauer David , Thomas Gregory , Tomboc Patrick , Van Damme An , Wierman Margaret , Winer Ira , Yen Lee Yi , Zapotocky Michal , Ziegler David , Zimmermann Stefanie , Dvir Rina , Rechavi Gidi , Durno Carol , Aronson Melyssa , Taylor Michael , Dirks Peter , Pugh Trevor , Shlien Adam , Hawkins Cynthia , Morgenstern Daniel , Tabori Uri 
Published: December 2020

Abstract
Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (&gt;50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.
IMMU-22. PHASE IB IMMUNOTHERAPY CLINICAL TRIAL WITH THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Madrid Andres Morales La , Mora Jaume , Cruz Ofelia , Lopez Vicente Santa-Maria , Perez-Jaume Sara , Guillen Antonio , Paco Sonia , Carcaboso Angel M , Puerta Patricia , Salvador Noelia , Juan Manuel , Benitez-Ribas Daniel , Cabezon Raquel , Flórez-Grau Georgina , Molero Mari Carmen 
Published: December 2020

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a lethal condition, and therefore novel approaches are needed. Monocyte-derived dendritic cells (mDCs) pulsed with tumor antigens, as professional antigen-presenting cells, are a promising strategy for immunotherapy of invasive brain tumors.

METHODS
Our Ib pilot study explored the use of immunotherapy with mDCs for the treatment of newly diagnosed DIPG. Patient′s mDCs were extracted after irradiation and were primed with an allogenic tumor lysate from five patients with K27M-mutated DIPGs. The principal goal of this study was to establish the feasibility and safety of the intradermic administration of these mDC vaccines in patients with DIPG. In the absence of progression, patients received maintenance boosts of tumor lysate. Additionally, we evaluated the non-specific and antitumoral immune response generated in peripheral blood mononuclear cells (PBMC) and in cerebrospinal fluid (CSF) cells.

RESULTS
Nine patients were included in the study (2016–2018). Vaccines fabrication was feasible and administered in all cases without grade 3 or 4 toxicities. KLH (9/9 patients) and antitumor (8/9 patients) specific responses were identified in PBMC. Immunological responses were also confirmed in T-lymphocytes from the CSF of two patients. Twenty-four month overall survival and progression free survival was 33.3% (95 % CI 13.2% to 84.0 %) and zero, respectively.

DISCUSSION
These results demonstrate that mDC vaccination is feasible, safe, and generates a DIPG-specific immune response detected in PBMC and CSF. There was a trend in improved OS when compared to historic controls. This strategy shows a promising immunotherapy backbone for future combination schemas.
IMMU-23. A NOVEL MASS CYTOMETRY-BASED MULTI-PARAMETER CHARACTERIZATION OF NEOANTIGEN-REACTIVE CD8+ T-CELLS IN PATIENTS PARTICIPATING IN PNOC007 H3.3K27M PEPTIDE VACCINE CLINICAL TRIAL
Authors: Taitt Jared , Nejo Takahide , Watchmaker Payal , Almeida Neil , Okada Kaori , Shahin Maryam , Gilbert Ryan , Molinaro Annette , Prados Michael , Mueller Sabine , Okada Hideho 
Published: December 2020

Abstract

BACKGROUND
We have identified an HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG). We sought to characterize vaccine-reactive CD8+T-cells subpopulations using their precise activation and developmental status to find their associations with clinical outcomes.

METHODS
Mass cytometry (CyTOF) analysis was performed on patient-derived peripheral blood mononuclear cells collected at baseline as well as pre-specified time points throughout the study. Each cell subtype was characterized via tSNE-clustering based on their expression profiles and quantified as a fraction of total CD45+cells. H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-HLA-A2 dextramer along with a panel of T-cell and myeloid markers.

RESULTS
Among all 29 patients enrolled, we analyzed samples from all 19 DIPG and 9 of 10 non-brainstem DMG cases, of which 18 had longitudinal samples available (range: 2–5). Utilizing a novel CyTOF-based immuno-monitoring platform, the expansion of H3.3K27M-reactive CD8+T-cells, defined as a 25% increase at any time-point relative to baseline, was observed in 7 of these 18 patients. Survival analyses indicated that the expansion of H3.3K27M-reactive CD8+T-cells, particularly the effector-memory phenotype, positively correlated with longer overall survival (OS) (median: 16.1 vs 9.7 months, p=0.03), whereas an abundance of early and monocytic myeloid-derived suppressor cells at baseline correlated with shorter OS among DIPG patients (9.5 vs 14.3 months, p=0.002).

CONCLUSION
Our novel immuno-monitoring approach offers insight into how vaccine-induced immune responses impact clinical outcomes.
IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY
Authors: Chandramohan Vidyalakshmi , Evangelous Tyler , Lipp Eric S , Hora Bhavna , Bigner Darell D , McLendon Roger E , Ashley David M 
Published: December 2020

Abstract

BACKGROUND
Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches.

MATERIAL AND METHODS
In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV).

RESULTS
The analysis indicates intratumoral CD3+ LYMPHS are commonly &lt;5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis.

CONCLUSION
PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.
LGG-01. CLINICAL MANAGEMENT AND GENOMIC PROFILING OF PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA
Authors: Mobark Nahla A , Alharbi Musa , Balbaid Ali Abdullah O , Al-Habeeb Lamees , AlMubarak Latifa , Alaljelaify Rasha , AlSaeed Mariam , Almutairi Amal , Alanazi Fatmah A , Bashawri Yara , Ahmad Maqsood , Al-Banyan Ayman , Alotabi Fahad E , Barakeh Duna , AlZahrani Malak , Al-Khalidi Hisham , Ajlan Abdulrazag , Ramkissoon Lori A , Ramkissoon Shakti H , Abedalthagafi Malak 
Published: December 2020

Abstract
Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1 3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). BRAF V600E mutations were observed in only 2/37 patients, while H3F3A (K27M) histone mutations were not detected. Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR) currently he is disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG which may represent a genomically-distinct subgroup of pLGGs that could be targeted with oral target therapy crizotinib. Taken together, we reveal the genetic characteristics of pLGG Saudi patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG. Our study proves the possibility of using genetic profiling to guide optimal treatment strategies for pLGG in Saudi population
LGG-03. INCIDENCE AND OUTCOME OF PEDIATRIC IDH-MUTANT GLIOMA
Authors: Yeo Kee Kiat , Alexandrescu Sanda , Cacciotti Chantel , Krzykwa Emily , Clymer Jessica , Chordas Christine , Zimmerman Mary Ann , Chi Susan , Warren Katherine , Wright Karen 
Published: December 2020

Abstract

INTRODUCTION
The incidence of IDH mutations in pediatric glioma is unclear. Recent publications suggest rates ranging between 0–20%. Therapy poses challenges as it is unclear if the biology and prognosis of pediatric IDH-mutant gliomas are identical to adults.

METHODS
We performed an IRB approved, systematic retrospective search for IDH-mutant gliomas in the Dana-Farber Cancer Institute/Boston Children’s Hospital database between 2009–2018, analyzing incidence, demographics, histology, co-occurring genetic alterations and outcome.

RESULTS
We identified 575 patients with glioma, ages 0–21 years. Of these, 394 underwent biopsy/resection (0–9 years:n=204; 10–21 years:n=190), with 294 genetic testing. Fifteen of 294 tumors (5%) were IDH1-mutant. Among patients 0–9 years and 10–21 years, 1/156 (0.6%) and 14/138 (10%) had IDH1-mutant tumors, respectively. Among patients 10–21 year old, 13/115 low-grade gliomas were IDH1-mutant (11%). High-grade gliomas accounted for the remaining 23, with one IDH1-mutant glioma (4%). Most common co-occurring genetic alterations for diffuse astrocytoma (n=12) were TP53 (n=9) and ATRX (n=2). Three patients with IDH1-mutant oligodendrogliomas had 1p/19q deletion. Eleven IDH1-mutant patients were evaluable for outcomes with median follow-up of five years. Five-year radiation-free, progression-free and overall survival for patients with low-grade histology were 76% and 100%, respectively. One patient with high-grade glioma recurred 1.2 years after upfront chemo-radiation and died soon after recurrence.

CONCLUSION
IDH-mutant gliomas comprise a small proportion of pediatric gliomas. Incidence rate is higher in the second decade of life. Comparative analyses between pediatric IDH-mutant gliomas and adult historical cohorts are currently underway, evaluating outcomes, radiation therapy and frequency of malignant transformation.
LGG-09. CORRELATING GENETIC SIGNATURE OF PILOMYXOID ASTROCYTOMAS AND PILOCYTIC ASTROCYTOMAS WITH QUALITATIVE AND QUANTITATIVE MR IMAGING CHARACTERISTICS
Authors: Fadel Sandra Abi , Omay Zeynep Erson , Darbinyan Armine , Bronen Richard , Fulbright Robert , Mahajan Amit , Aboian Mariam 
Published: December 2020

Abstract

PURPOSE
Pilomyxoid astrocytomas are predominantly located in supra-chiasmatic region and are more clinically aggressive than pilocytic astrocytomas, although recent WHO 2016 classification placed them into the grade I/II category. In our study, we describe imaging correlation of PMA to their genetic signature.

MATERIALS AND METHODS
We identified 12 pediatric patients with pathologically proven PMA, PA, and PA with myxoid features in an IRB approved study. Three of the tumors had whole exome somatic and germline sequencing. Qualitative MRI characteristics of location, size, enhancement, edema, T2 and T1 intensity, and multifocality were assessed.

RESULTS
Among the PMA, 3 cases were found to have KIAA1549-BRAF fusion, 1 case BRAF V600E mutation, and 2 cases had wildtype BRAF. The BRAF wildtype tumors had atypical imaging features with intraventricular extension of tumor, involvement of frontal lobe parenchyma and one tumor demonstrating increase in size and development of enhancement at 5 years. Whole exome sequencing of BRAF wildtype tumors identified somatic truncation mutations in NF1 R1534X and R1513X with wildtype germline NF1 and missense mutations in KMT2C and GLTSCR1. Among PAM, one was BRAF wildtype with mutations i PTCH1 M956V and PTPN1 (A72V) and demonstrated atypical features of intratumoral hemorrhage on presentation. Among PA, one was positive for KIAA1549-BRAF, one was BRAF wildtype.

CONCLUSIONS
BRAF wildtype PMA and PA demonstrate atypical tumor localization and are associated with atypical genetic mutations on whole exome sequencing. On the contrary, presence of KIAA1549-BRAF fusion or BRAF V600E mutation within PMA and PA correlates with classic qualitative imaging characteristics.