bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-57. WHOLE-GENOME SEQUENCING, METHYLATION ANALYSIS, AND SINGLE-CELL RNA-SEQ DEFINE UNIQUE CHARACTERISTICS OF PEDIATRIC TREATMENT-INDUCED HIGH-GRADE GLIOMA AND SUGGEST ONCOGENIC MECHANISMS
Authors: Lucas John , DeSisto John , Xu Ke , Donson Andrew , Lin Tong , Sanford Bridget , Wu Gang , Tran Quynh , Hedges Dale , Hsu Chih-Yang , Armstrong Gregory , Arnold Michael , Bhatia Smita , Flannery Patrick , Lemma Rakeb , Hardie Lakotah , Schuller Ulrich , Hoffman Lindsey , Dorris Kathleen , Levy Jean , Hankinson Todd , Handler Michael , Liu Arthur , Foreman Nicholas , Vibhakar Rajeev , Jones Kenneth , Allen Sariah , Zhang Jinghui , Baker Suzanne , Merchant Thomas , Orr Brent , Green Adam 
Published: December 2020

Abstract

BACKGROUND
Pediatric treatment-induced high-grade glioma (TIHGG) is among the most severe late effects observed in childhood cancer survivors and is uniformly fatal. We previously showed that TIHGG are divergent from de novo pediatric high-grade glioma (pHGG) and cluster into two gene expression subgroups, one stemlike and the other inflammatory. Here we systematically compared TIHGG molecular profiles to pHGG and evaluated expression and single cell sequencing profiles in order to identify oncogenic mechanisms and the cellular basis for the observed TIHGG gene expression subgroups. MATERIALS/

METHODS
450/850K methylation and mutational signature analysis was conducted in 36 TIHGG samples. Resultant data were analyzed for the presence of chromothripsis, distinct molecular alterations, and mutational signatures in a subset of 10 samples with whole genome sequencing data. Five TIHGGs underwent single-cell RNA-Seq analysis (scRNAseq).

RESULTS
26/36 TIHGG clustered with the pedRTK1 methylation class. TIHGG were characterized by an increased frequency of chromothripsis relative to pHGG (67% vs. 31%, p=0.036). FISH and WGS revealed frequent PDGFRA amplification secondary to enrichment in ecDNA. TIHGG were enriched for COSMIC mutational signatures 5 and 19 (p=0.0003) relative to pHGG. scRNAseq data showed that TIHGG tumors are composed of stem-like, neuronal, and inflammatory cell populations which may contribute to the previously described dominant expression profiles.

CONCLUSIONS
TIHGG represents a distinct molecular subtype of pHGG. Chromothripsis, leading to enriched expression of genes in extrachromosomal DNA, likely contribute to TIHGG oncogenesis. The dominant cell type (stem-like vs. inflammatory) may define the expression subgroup derived from bulk RNA-seq in heterogeneous tumors.
IMG-04. RESPONSE ASSESSMENT IN PEDIATRIC HIGH-GRADE GLIOMA: RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY WORKING GROUP
Authors: Erker Craig , Tamrazi Benita , Poussaint Tina Y , Mueller Sabine , Mata-Mbemba Daddy , Franceschi Enrico , Brandes Alba A , Rao Arvind , Haworth Kellie B , Wen Patrick Y , Goldman Stewart , Vezina Gilbert , Macdonald Tobey J , Dunkel Ira J , Morgan Paul S , Jaspan Tim , Prados Michael D , Warren Katherine E 
Published: December 2020

Abstract

INTRODUCTION
Response criteria for pediatric high-grade gliomas (pHGG) have varied historically and across clinical trials. Compared to adult HGG, pHGG response assessment has unique challenges. An international Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was established to develop pHGG response assessment criteria.

METHODS
Pediatric and adult neuro-oncologists, neuro-radiologists and experts in imaging informatics developed a consensus statement and established a unified response assessment for biopsy-proven pHGG, excluding DIPG. This was achieved by identifying major challenges, reviewing existing literature and current practices, and finally developing recommendations through an iterative process.

RESULTS
Categories for response assessment include complete response, partial response, minor response, stable disease and progressive disease. Refractory disease is excluded. Criteria used to determine response assessment include quantitative evaluation of measurable disease, qualitative assessment of diffusion imaging, presence or absence of new lesions, clinical status using performance score, and vascular endothelial growth factor inhibitor and/or corticosteroid use. Response is determined over 2-time points ≥ 8 weeks apart, and when progressive disease is unclear, guidance for repeat MRI imaging and/or utility of repeat biopsy is described. A number of recommendations are also given to standardize response assessment across clinical trials including MRI protocol sequence recommendations for brain and spine, definitions for measurable and non-measurable disease, and imaging time points with post-operative considerations. In addition, guidance is given for differentiating vasogenic edema versus tumor invasion in non-enhancing disease.

CONCLUSION
Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.
IMG-08. UNUSUAL IMAGING FINDINGS IN TWO CASES OF PAEDIATRIC LOW GRADE GLIOMA
Authors: Carruthers Vickyanne , Siddle Kathryn , Halliday Gail , Bailey Simon , Hill Rebecca 
Published: December 2020

Abstract
Low grade gliomas (LGG), including pilocytic astrocytoma (PCA), are the commonest paediatric brain tumours and their behaviour is well understood, typically following a benign course. BRAF fusion is common, particularly in PCA of the cerebellum and optic pathway. Here we present two patients whose LGG behaved in an unusual fashion. The first patient who was treated 6 years previously on LGG2 with vincristine and carboplatin for a tectal plate lesion was identified on routine imaging to have local tumour progression and underwent completion staging. This showed a new enhancing soft tissue abnormality within the spinal cord at the level of L2. Due to radiological dubiety both lesions were biopsied for histological and molecular analysis, confirming LGG of the tectal plate and finding the spinal lesion to be a myxopapillary ependymoma. The second patient presented with acute hydrocephalus following a 2 year history of neurocognitive impairments. He was found to have a large, complex tumour centred in and expanding the bodies of both lateral ventricles with significant mass effect. Radiologically this was most in keeping with a central neurocytoma but histological analysis confirmed it to be a PCA with KIAA1549-BRAF fusion. The first case demonstrates the utility of molecular analysis in confirming two distinct tumour types in one patient, in a situation where metastasis would not be expected and would significantly alter treatment and prognosis. The second is an example of how imaging can be misleading in a KIAA1549-BRAF fused PCA presenting as an intraventricular mass.
IMG-15. PEDIATRIC GLIOBLASTOMAS CONTRAST ENHANCEMENT PATTERN IS PREDICTIVE OF SURVIVAL
Authors: Sadighi Zsila , Pokhylevych Halyna , Gule-Monroe Maria , Chen Melissa , Fuller Greg , Gruschkus Stephen , Sandberg David , McGovern Susan , McAleer Mary Frances , Zaky Wafik , Khatua Soumen , Johnson Jason 
Published: December 2020

Abstract

BACKGROUND
Pediatric GBMs are rare, accounting for 3% of all pediatric CNS tumors. Despite advances in treatment, the outcomes for pediatric glioblastomas (GBM) have not significantly improved. Research suggests a link between enhancement patterns and survival in adult patients with glial tumors. We sought to study this relationship in a cohort of pediatric GBMs.

METHODS
A radiology database was searched for cases &lt; 22 years, pathology proven brain glioblastoma, and pre-surgical MR imaging available for review. Based on pre-treatment, T1-contrast enhanced MR images, size, and contrast enhancement patterns were characterized as focal, diffuse, or ring-like. The extent of resection was assessed by comparing pre- and post-surgery T2 hyperintensity and contrast enhancement.

RESULTS
64 eligible patients (age 2-21y, 14.6 + 5.4) were identified. The majority of lesions demonstrated enhancement on gadolinium-enhanced T1 imaging. (n=58/64; 90%). The lesions were categorized into six (9.4%) cases with focal enhancement, 37 (57.8%) cases with diffuse enhancement, and 15 (23.4%) with ring-like enhancement. Patients who received GTR/subtotal resection (STR) and had focal-enhanced GBMs had a significantly longer progression-free survival (PFS) – 14.1 months (p = 0.0308), comparing to diffuse and ring-like enhancing glioblastomas which had respectively 13.9 and 5.5 months of PFS.

DISCUSSION
Our data suggests that the contrast enhancement pattern is a significant prognostic factor for survival in pediatric GBM. Patients with GTR/STR who had focal-enhancing GBMs had a significantly longer progression-free survival (p=0.03) comparing to other enhancement patterns.
IMG-16. WHOLE TUMOR DIFFUSION KURTOSIS IMAGING ANALYSIS FOR DISCRIMINATING PEDIATRIC POSTERIOR FOSSA TUMORS: ACCURACY AND REPEATABILITY
Authors: Voicu Ioan Paul , Napolitano Antonio , Carboni Alessia , Caulo Massimo , Carai Andrea , Vinci Maria , Miele Evelina , Rossi Sabrina , Cacchione Antonella , Vennarini Sabina , Ferretti Elisabetta , Mastronuzzi Angela , Tomà Paolo , Colafati Giovanna Stefania 
Published: December 2020

Abstract

PURPOSE
Diffusion kurtosis imaging (DKI) has not yet been tested for pediatric brain tumors. Estimating diffusion values from whole-tumor based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and to assess VOI-based DKI accuracy in discriminating among pediatric posterior fossa tumors.

MATERIALS AND METHODS
We retrospectively analyzed 34 children (19 M, 15F, mean age 7.48 years) with posterior fossa tumors who underwent preoperative 3T MRI including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor (VOI), the area of maximum tumor diameter and a smallROI.Inter-observer variability was assessed with coefficient of variation (COV) and Bland-Altman plots. VOI-based DKI metrics accuracy in discriminating among tumor histology and for tumor grading were assessed with MANOVA and ROC analyses respectively. Correlation between grading accuracy and inter-observer variability was assessed with Spearman’s rho.

RESULTS
Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14) and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai’s trace: p&lt;0.001) and were accurate for tumor grading (AUCs of 0.919, 0.986, 0.996, 0.842 and 0.926 for RK, MK, AK, FA and MD respectively). VOI-based COV was significantly correlated to AUC values (R=-0.900, p&lt;0.037).

CONCLUSIONS
DKI-derived metrics are useful for pediatric posterior fossa tumor discrimination and grading. VOI-based diffusion measurements present improved repeatability compared to ROI-based measurements and are significantly correlated to diagnostic accuracy.
IMG-22. A DEEP LEARNING MODEL FOR AUTOMATIC POSTERIOR FOSSA PEDIATRIC BRAIN TUMOR SEGMENTATION: A MULTI-INSTITUTIONAL STUDY
Authors: Tam Lydia , Lee Edward , Han Michelle , Wright Jason , Chen Leo , Quon Jenn , Lober Robert , Poussaint Tina , Grant Gerald , Taylor Michael , Ramaswamy Vijay , Ho Chang , Cheshier Samuel , Said Mourad , Vitanza Nick , Edwards Michael , Yeom Kristen 
Published: December 2020

Abstract

BACKGROUND
Brain tumors are the most common solid malignancies in childhood, many of which develop in the posterior fossa (PF). Manual tumor measurements are frequently required to optimize registration into surgical navigation systems or for surveillance of nonresectable tumors after therapy. With recent advances in artificial intelligence (AI), automated MRI-based tumor segmentation is now feasible without requiring manual measurements. Our goal was to create a deep learning model for automated PF tumor segmentation that can register into navigation systems and provide volume output.

METHODS
720 pre-surgical MRI scans from five pediatric centers were divided into training, validation, and testing datasets. The study cohort comprised of four PF tumor types: medulloblastoma, diffuse midline glioma, ependymoma, and brainstem or cerebellar pilocytic astrocytoma. Manual segmentation of the tumors by an attending neuroradiologist served as “ground truth” labels for model training and evaluation. We used 2D Unet, an encoder-decoder convolutional neural network architecture, with a pre-trained ResNet50 encoder. We assessed ventricle segmentation accuracy on a held-out test set using Dice similarity coefficient (0–1) and compared ventricular volume calculation between manual and model-derived segmentations using linear regression.

RESULTS
Compared to the ground truth expert human segmentation, overall Dice score for model performance accuracy was 0.83 for automatic delineation of the 4 tumor types.

CONCLUSIONS
In this multi-institutional study, we present a deep learning algorithm that automatically delineates PF tumors and outputs volumetric information. Our results demonstrate applied AI that is clinically applicable, potentially augmenting radiologists, neuro-oncologists, and neurosurgeons for tumor evaluation, surveillance, and surgical planning.
IMMU-01. IMMUNE CHECKPOINT INHIBITION FOR PEDIATRIC CNS TUMORS: A SINGLE INSTITUTION EXPERIENCE
Authors: Cacciotti Chantel , Choi Jungwhan , Zimmerman Mary Ann , Tierney Elise , Chordas Christine , Clymer Jessica , Chi Susan , Yeo Kee Kiat 
Published: December 2020

Abstract

INTRODUCTION
Immune checkpoint inhibition through PD-1 and CTLA-4 blockade has shown efficacy in some adult malignancies and is being investigated in pediatrics. We describe our institutional experience with immune checkpoint inhibition in pediatric CNS tumors.

METHODS
We performed a retrospective chart review of patients with recurrent, progressive, or refractory pediatric CNS tumors treated with immunotherapy at Dana-Farber/Boston Children’s Hospital between 2018–2019.

RESULTS
Eleven patients were identified, with median age of 11 years (range:3–9). Diagnoses included DIPG (n=3), HGG (n=4), ependymoma (n=1), craniopharyngioma (n=1), HGNET (n=1) and NGGCT (n=1). Eight patients had recurrent disease (5 local; 3 disseminated); three had refractory disease (non-recurrent). Nine patients were treated with combination therapy (ipilimumab/nivolumab); two patients received monotherapy with either nivolumab or pembrolizumab. Median time from initial diagnosis-to-treatment was 8 months (range 0.8–156). Ten patients received radiation therapy (RT) prior to immunotherapy, with one receiving concurrent RT. Median duration of treatment was 6.1 months (range:1–19). Therapy was discontinued in nine patients: seven due to disease progression and two due to adverse events (colitis, transaminitis). Other pertinent toxicities included type 1 diabetes, hypothyroidism and skin toxicity. Based on iRANO criteria, best responses included partial (n=4), stable (n=6) and progressive disease (n=1). Durable response (&gt;12months) was noted in two patients (HGG and progressive NGGCT).

CONCLUSION
Immune checkpoint inhibition appears to have clinical benefit and is relatively well tolerated in this cohort of patients. Results from recently completed prospective clinical trials will be critical to inform clinical decisions.
IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL NEUROTOXICITY CORRELATES WITH PRETREATMENT AND ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS
Authors: Gust Juliane , Wilson Ashley , Finney Olivia , Hartsuyker Kendra Jae , Narayanaswamy Prabha , Wu Vicky , Garden Gwenn , Annesley Colleen , Gardner Rebecca 
Published: December 2020

Abstract

OBJECTIVE
Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is complicated by neurotoxicity in approximately 40% of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAP and S100b. We now hypothesize that NFL is also a useful biomarker of neuronal injury related to abnormal blood-brain-barrier and glial function.

METHODS
We used the Mesoscale Discovery platform to measure CSF and serum NFL levels in a consecutive cohort of 43 pediatric patients with B cell ALL who received CD19-directed CAR T cells. In addition, we will present expansion cohort measurements of NFL and GFAP (N=95).

RESULTS
CSF NFL levels prior to CAR T cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 for severe vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338) and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum, pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL, range 1–7.5pg/mL). However, there was no correlation with neurotoxicity, history of CNS radiation, peripheral neuropathy, stem cell transplant, or number of prior chemotherapies. Day 7 serum NFL levels did not change significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254).

CONCLUSION
We conclude that CSF NFL is promising biomarker of CAR T neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.
IMMU-07. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Brown Brandon , Tambaro Paolo , Mahadeo Kris , Khazal Sajad , Tewari Priti , Petropoulos Demetrios , Slopis John , Sadighi Zsila 
Published: December 2020

Abstract

INTRODUCTION
Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution.

METHODS
We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients with IEC products from 2018–2019 at MDACC.

RESULTS
Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids.

CONCLUSION
ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.
IMMU-13. DUAL IGF1R/IR INHIBITOR IN COMBINATION WITH GD2-CAR T-CELLS AS A POTENT THERAPEUTIC STRATEGY FOR H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: de Billy Emmanuel , pellegrino Marsha , De Angelis Biagio , Businaro Pietro , Orlando Domenico , Pericoli Giulia , Petrilli Lucia Lisa , Rossi Sabrina , Ferretti Roberta , Maestro Nicola , Massimi Luca , Pezzullo Marco , De Stefanis Cristiano , Rota Rossella , Ferrari Francesco , Salviato Elisa , Carai Andrea , Caruana Ignazio , Locatelli Franco , Mastronuzzi Angela , Quintarelli Concetta , Vinci Maria 
Published: December 2020

Abstract
Diffuse midline gliomas (DMG) are aggressive paediatric brain tumors for which there is no effective treatment. Recent pre-clinical studies suggest that adoptive transfer of chimeric antigen receptor (CAR) T-cells targeting the disialoganglioside antigen GD2 (GD2-CAR) has a significant therapeutic potential for H3K27M-mutant DMG. Still, some tumor cells resist to treatment suggesting that a multimodal approach may be necessary to treat more efficiently the disease. Our aim was to identify chemical compounds that, in combination with CAR T-cells, would enhance anti-tumor efficacy. After having confirmed the GD2 expression in tissue samples and patient-derived H3K27M-mutant DMG cells, we developed a high throughput cell-based assay to screen 40 kinase inhibitors in combination with T-cells expressing the GD2-CAR.CD28.4-1BB.z construct. The screening led to the identification of the dual IGF1R/IR antagonists, BMS-754807 and linsitinib, which, in combination with GD2-CAR T-cells, improved antitumor activity by 25% (p&lt;0.0001) and 20% (p&lt;0.0001) respectively, compared to GD2-CAR T-cells alone. The two compounds inhibited tumor cell proliferation through IGF1R/IR dependent mechanisms at a concentration which did not affect CAR T-cell expansion. Linsitinib, but not BMS-754807, decreased GD2-CAR T-cells exhaustion and increased their memory profile. Furthermore, linsitinib attenuated the expression of 10 out of 71 DMG genes involved in immunomodulation (e.g. IL33, VEGFC, STAT5A) and regulated upon tumor/CAR T-cells co-culture. Finally, we confirmed the anti-tumor activity of the new linsitinib/GD2-CAR T-cells combination strategy in a DMG H3K27M-mutant 3D culture model. Our work supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for H3K27M-mutant DMG therapy.
IMMU-20. EVALUATION OF CAR T CELLS IN EPENDYMOMA
Authors: Nellan Anandani , Donson Andrew , Calhoun Jacob , Griesinger Andrea , Fry Terry , Foreman Nicholas 
Published: December 2020

Abstract

BACKGROUND
Ependymoma is the third most common pediatric brain tumor and current treatment still results in a 10-year relapse rate of over 70% in the highest risk groups. The treatment refractory nature of ependymoma to standard therapies strongly supports the development of novel interventions. Ependymoma tumor cells express HER2 and there are active clinical trials treating children with ependymoma using local delivery of second-generation HER2 CAR T cells.

METHODS
Two high-risk patient-derived ependymoma cell lines, MAF811 and MAF928, that display HER2 surface expression are used for testing. We tested second-generation HER2-BBz CAR T cells in vitro and in vivo.

RESULTS
HER2 CAR T cells effectively kill ependymoma tumor cells in culture, but this strategy cannot eradicate the same tumor cells in mice when implanted in the fourth ventricle of the brain. HER2 CAR T cells proliferate and traffic into the tumor, but this causes a dramatic influx of immune cells, tumor swelling and lethal toxicity in a subset of mice. Mice that survive this initial tumor swelling, display significant tumor shrinkage but all tumors eventually start growing again. Ependymoma tumor cells release high amounts of inflammatory chemokines that strongly attract neutrophils and monocytes to the tumor, compared to other brain tumors, and can downregulate HER2 expression to escape recognition by CAR T cells.

CONCLUSION
The immunosuppressive microenvironment as well as tumor heterogeneity make HER2 CAR T cells ineffective in ependymoma. Studying these two hurdles in CAR T cell therapy is critical to effectively treat brain tumors with CAR T cells.