bluuebunny/crossref_metadata_2025 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

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

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

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

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 < 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

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<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<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

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

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 (>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

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

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

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<0.0001) and 20% (p<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

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.
IMMU-29. AIF1 IS A PROGNOSTIC BIOMARKER AND CORRELATED WITH IMMUNE INFILTRATES IN GLIOMAS
Authors: Chai Yi , Liu Wei , Wang Junhua , Hu Libo , Zhang Yuqi
Published: December 2020

Gliomas remain highly variable clinical behaviors, leading to emerging studies to identify prognostic factors. AIF1 (Allograft Inflammatory Factor 1) is critical for promoting both macrophage- and dendritic cells (DCs)-mediated inflammatory response and growth of vascular smooth muscle cells and T-lymphocytes. Through comparative analyses of primary LGG patients from The Cancer Genome Atlas (TCGA) dataset and Chinese Glioma Genome Atlas(CGGA) dataset, we reported that the expression level and methylation level of AIF1 gene vary among glioma patients and AIF1 expression or gene body methylation is significantly associated with glioma patient survival. Cox regression results confirmed that AIF1 played an independent predictor of survival in lower-grade glioma(LGG), with a cox coefficient of 0.251 indicating a worse prognosis. Moreover, AIF1 expression was positively correlated with infiltrating levels of CD4+ T and B cells, macrophages, neutrophils, and DCs in LGG and glioblastoma(GBM). AIF1 expression also showed strong correlations with specific immune cell markers in LGG and GBM. In addition, AIF1 expression potentially contributed to the regulation of glioma-associated macrophages and microglia. In conclusion, our findings suggested that AIF1 was correlated with prognosis and immune infiltrating levels, and it can be used as a prognostic factor in gliomas.
IMMU-30. UPREGULATED T CELL AND INTERFERON-Γ-RELATED GENE EXPRESSION IS ASSOCIATED WITH INCREASED SURVIVAL IN RECURRENT PEDIATRIC HIGH-GRADE GLIOMA
Authors: Davidson Tom , Hugo Willy , Wang Anthony , Kim Jiyoon , Li Gang , Prins Robert
Published: December 2020

Recurrent pediatric high-grade glioma (pHGG) is the leading cause of cancer-related mortality in children. Immunotherapy is a successful treatment approach for a growing number of cancers and is being investigated as a treatment strategy for pHGG. Immunotherapy has shown the most benefit in tumors with increased infiltrating T cells at baseline. Our recently published results revealed that neoadjuvant checkpoint inhibition in recurrent adult glioblastoma was associated with upregulation of a T cell and interferon-γ-related gene expression signature (Tcell-IFNγGES) and was correlated with a significantly extended overall survival (OS). In this study, we examined the immune landscape in recurrent pHGG and the association of Tcell-IFNγGES in the tumor with survival. We analyzed tumor RNAseq data collected at time of recurrence from a historical cohort of 42 pHGG patients from the Children’s Brain Tumor Tissue Consortium. We found a significant transcriptional enrichment of Tcell-IFNγGES in 54% of the tumors. The survival of patients with high Tcell-IFNγGES was observed to be significantly higher than patients with low Tcell-IFNγGES, (log-rank p=0.05). The 3-year OS for patients with low versus high Tcell-IFNγGE was 28.5% (95%, CI:13.7%-59.5%) compared to 50.2% (95%, CI:33.1%-76.1%). When patients were stratified by age, gender and race, low Tcell-IFNγGES was found to be a poor OS prognostic factor (hazard ratio=2.4 (1.14–5.14), p=0.02). This indicates a strong relationship of decreased Tcell-IFNγGES and increased risk of death. Future investigations are necessary to validate these findings, and to explore the value of Tcell-IFNγGES as a predictive biomarker for response to immunotherapy in pHGG.
IMMU-31. PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M DIFFUSE MIDLINE GLIOMAS (DMG)
Authors: Mueller Sabine , Taitt Jared , Bonner Erin , Lulla Rishi , Goldman Stewart , Banerjee Anu , Chi Susan , Whipple Nicholas S , Crawford John , Gauvain Karen , Nazemi Kellie , Watchmaker Payal , Nejo Takahide , Okada Kaori , Butterfield Lisa H , Nazarian Javad , Villaneuva-Meyer Javier , Molinaro Annette M , Prados Michael , Okada Hideho
Published: December 2020

OBJECTIVE

To assess safety and efficacy within a multi-center trial the H3.3K27M specific peptide vaccine with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ DMGs.

METHODS

After focal radiation therapy, participants 3–21 years of age were enrolled into two strata. Stratum A: newly diagnosed diffuse intrinsic pontine glioma (DIPG); Stratum B: other DMGs. H3.3K27M vaccine was administered with poly-ICLC IM every 3 weeks for 8 doses followed by every 6 weeks for a total of 96 weeks. Immuno-monitoring of peripheral blood mononuclear cell (PBMC) and imaging occurred every 3 months. Modified iRANO criteria were applied. PBMC samples were evaluated by mass cytometry.

RESULTS

From November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolled in Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60 % female) in Stratum B. Treatment was well tolerated (7 grade 3; 0 grade 4 related toxicities). Median number of vaccines per participant was 6 (range 1–11). Overall survival at 12 months was 40% (95% CI 22–73%) for Stratum A and 39% (95% CI 16–93%) for Stratum B. Among the 19 subjects with longitudinal immune cell assessments, 7 exhibited an expansion of K27M-reactive CD8+ effector memory T-cells correlating with prolonged survival (p=0.028).

CONCLUSION

H3.3K27M specific vaccine in combination with poly-ICLC is well tolerated. CyTOF-based immune monitoring of PBMCs facilitates sensitive high-throughput analysis. Further investigation is warranted to determine if this may be predictive of clinical outcomes.
LGG-02. A BRAIN TUMOR DIAGNOSED AFTER TRANSITION TO THE DEPARTMENT OF ADULT NEUROSURGERY FROM THE DEPARTMENT OF PEDIATRICS
Authors: Shibata Yasushi
Published: December 2020

The patient was a 17-year-old boy with a history of 4 non-febrile convulsions at 15 and 16 years of age. He visited the Department of Pediatrics at a pediatric hospital. An electroencephalogram showed right frontal spike discharge. MRI was performed and judged to show no abnormality. The pediatric doctor diagnosed him with epilepsy. At 17 years old, he was referred to our Department of Adult Neurosurgery for transition. Physical and neurological examinations showed no abnormalities. Brain MRI showed right frontal cortical small tumor, with T1 low, T2 high, diffusion-weighted imaging low, and partial contrast enhancement. We diagnosed him with a brain tumor and symptomatic epilepsy. We surgically removed a right frontal cortical tumor. A pathological examination finalized the diagnosis of dysembryoplastic neuroepithelial tumor. MRI confirmed the total removal of the tumor. Anticonvulsant was started before surgery. No epileptic seizure was observed, so the anticonvulsant medication was gradually tapered and stopped at two years after the surgery. No epilepsy nor recurrence has been observed thus far. The problem with the initial management of this case at the Department of Pediatrics in the pediatric hospital was that the brain tumor was missed despite an MRI examination. Had the transition not happened, this brain tumor might not have been diagnosed. A brain tumor is a rare disease, and epilepsy is a common disease. However, in cases of non-febrile convulsion, a brain tumor should be considered. Collaboration within a single department, hospital and local area should be established.
LGG-06. LONG-TERM OUTCOME OF NEWLY DIAGNOSED LOW GRADE GLIOMA
Authors: Sirachainan Nongnuch , Boongerd Attaporn , Pakakasama Samart , Anurathapan Usanarat , Hansasuta Ake , Songdej Duantida , Pongpicha Pongpak , Dhanachai Mantana , Hongeng Suradej
Published: December 2020

INTRODUCTION

Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children accounted for 30–50%. Regarding benign characteristic of disease, surgical management remains the mainstay of treatment. However, surgical approach is limited in some conditions such as location at brainstem or infiltrative tumor. Chemotherapy and radiation treatments have been included in order to control tumor progression. The 5-years survival rate is approach 90% especially in patients who receive complete resection. However, the outcome of children with LGG in low to middle income is limited. Therefore, the aim of the study was to determine long-term outcome of children with newly diagnosed LGG.

METHODS

A retrospective study enrolled children aged <18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was confirmed by histological findings of grade I and II according to WHO criteria.

RESULTS

A total of 40 patients, female to male ratio was 1:1.35 and mean (SD) for age was 6.7 (4.0) years. The most common location was optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%). Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The 10-year progression free survival was 74.1±11.4% and overall survival was 96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used in progressive disease. The outcome was excellent.
LGG-16. PILOMYXOID ASTROCYTOMA OF THE CERVICAL SPINAL CORD IN A 7-YEAR-OLD ARMENIAN BOY: A CASE REPORT
Authors: Avagyan Anna , Sargsyan Lilit , Hoveyan Julia , Iskanyan Samvel , Bardakhchyan Samvel , Danielyan Samvel , Tamamyan Gevorg
Published: December 2020

BACKGROUND

Pilomyxoid astrocytoma (PMA) is a glial tumor that occurs predominantly in the hypothalamic-chiasmatic region and rarely in spinal cord. It has similar features as pilocytic astrocytomas, with some distinct histological characteristics and worse prognosis. The 2007 WHO recognized PMA as a Grade II glioma due to its aggressive behavior and dissemination tendency, but according to 2016 version grading of the pilomyxoid variant is under research. Here we report a case with a rare location, aggressive behavior and rapid progression. CASE PRESENTATION: A 7-year-old boy presented with headache, nausea, vomiting. Imaging revealed an intramedullary tumor extending from C2 to C6 with hydrocephalus. A ventriculo-peritoneal shunt and complete surgical resection were performed with significant improvement in the patient’s condition. Histopathological findings were consistent with pilomyxoid variant of pilocytic astrocytoma, with negative BRAF V600E and MGMT. Three months later, the follow-up imaging revealed disease recurrence with leptomeningeal metastases, for which the patient received standard-dose craniospinal irradiation 35.2 Gy with boosts to tumor bed and metastatic sites 49.6 Gy and 54 Gy respectively. 11 months later tumor progression was revealed with new metastatic lesions in the bones. Patient received 6 cycles of chemotherapy with TMZ and Avastin, but continued to suffer disease progression on therapy and he succumbed to his disease at 24 months from diagnosis.

CONCLUSION

Given the rarity of documented patients with spinal pilomyxoid astrocytoma with rapid progression, as well as the lack of certain WHO classification and treatment guidelines, this case report might be useful for development of more efficient treatment strategies.
LGG-22. EVALUATION OF IMMUNE AND GENOMIC CHARACTERISTICS IN PEDIATRIC OPTIC NERVE GLIOMA (ONG)
Authors: Campbell Ashley A , Silverman Andrew M , Moisander-Joyce Hanna , Wu Cheng-Chia , Mansukhani Mahesh , Zanazzi George , Turk Andrew , Canoll Peter D , Garvin James H , Kazim Michael , Gartrell-Corrado Robyn D
Published: December 2020

Pediatric optic nerve glioma (ONG) is a rare, sight-threatening tumor. We previously reported clinical, radiologic, histopathologic, and molecular characteristics of pediatric ONG patients treated at Columbia University Medical Center between 2000–2017. Here we evaluate this cohort and one additional patient using quantitative multiple immunofluorescence (qmIF) and next generation sequencing (NGS) using the Columbia Combined Cancer Panel (CCCP). For qmIF, 4 micron immuno-blank slides were stained for CD3, CD8, CD68, CD163, HLA-DR, and Olig2. QmIF images were analyzed and data were processed in R studio and compared based on tumor mutation and treatment history. QmIF failed in 1 case and CCCP failed in 2 cases. CCCP confirmed KIAA1549:BRAF fusions in 2 patients, identified NF1 in 2 patients, and demonstrated both a KIAA1549:BRAF fusion and SETD2 mutation in the added case. Qualitative analysis showed immune infiltrate across cases included macrophages (CD68+, 1.6–6.5% of all cells) and T cells (CD3+, 0.4% to 1.5%). Non-cytotoxic T cells (CD3+CD8-) comprised 60.7–100% of the T cell compartment. There was no difference when comparing mutation groups. However, patients who previously received radiation had increased CD3+, specifically CD3+CD8- cells compared to non-irradiated patients (p=0.01 and p<0.01, respectively) while CD3+CD8+ and CD68+ cells were not different between groups (p=0.49 and p=0.27, respectively). In summary, qmIF analysis showed increased tumor infiltration by non-cytotoxic T cells in previously irradiated pediatric ONG patients compared to non-irradiated patients, while there was no difference in macrophages of cytotoxic T cells. This type of analysis may be useful in designing immunotherapeutic strategies for pediatric ONG.
LGG-27. TARGETED THERAPY FOR PEDIATRIC LOW-GRADE GLIOMAS AND PLEXIFORM NEUROFIBROMAS WITH TRAMETINIB
Authors: Nguyen Tiffany , McMahon Kathleen , Hemenway Molly , Levy Jean Mulcahy , Foreman Nicholas , Dorris Kathleen
Published: December 2020

BACKGROUND

Targeted therapy aimed at modulating the RAS/RAF/MEK/ERK pathway is of increasing interest for patients with plexiform neurofibromas and low-grade gliomas. Trametinib is an FDA-approved MEK inhibitor that has little published pediatric experience to date.

METHODS

A retrospective chart review of patients treated with trametinib for low-grade gliomas (LGG) and/or plexiform neurofibromas (PN) between 2015–2018 was conducted at Children’s Hospital Colorado. Data collected included patient demographics, lesion location, Neurofibromatosis type 1 (NF1) status, best response of PN/LGG to trametinib, duration of trametinib therapy, and reported toxicities at least possibly attributed to trametinib.

RESULTS

Thirty (57% male; 73% NF1) patients were identified. Sixteen (53%) patients had PN only, 12 (40%) had LGG only, and two (7%) patients had both PN and LGG. The most common LGG location was the optic pathway/hypothalamus (72%). The most common location of PN was the face (63%). Two-thirds (8/12) of patients with LGG had a BRAF alteration or NF1 mutation. The median age at start of trametinib therapy was 9.9 years (range, 2.0 – 18.8 years). The median duration of trametinib therapy was 0.8 years (range 0.1 – 2.9 years). The most commonly reported adverse event was rash. No patients developed retinal toxicity or cardiotoxicity. Only two (7%) patients discontinued for toxicity and one (3%) for progressive disease.

CONCLUSIONS

Trametinib can be administered without significant toxicity to children with PN or LGG. Clinical benefit is noted in this cohort; however, prospective clinical trials are necessary to characterize efficacy formally.
LGG-29. TREATMENT FOR RECURRENT OPTIC PATHWAY PILOCYTIC ASTROCYTOMA
Authors: Nonaka Masahiro , Miyata Mayuko , Yamamura Natsumi , Asai Akio
Published: December 2020

Chemotherapy after biopsy or partial resection of the tumor is widely accepted as first-line therapy for optic pathway pilocytic astrocytoma. However, there is no standard of care for recurred tumors. We investigated our cases which showed recurrence after initial therapy. Retrospective analysis of four recurrent optic pathway pilocytic astrocytoma cases was performed. All patients underwent partial resection or biopsy of the tumor, and all received carboplatin and etoposide- based chemotherapy as initial treatment. Mean age at first therapy was 2.3 years old, and mean time from initial therapy to recurrence of the tumor was 5.6 years. Two patients were totally blind at the time of recurrence, and other two had partial visual field losses. One patient underwent total resection of the tumor, and other three patients underwent partial resection followed by chemotherapy. Visual function in patients with visual acuity did not deteriorate after removal of the recurrent tumor. There was no recurrence of the tumor who underwent total resection.　All of the three patients who had partial resection followed by chemotherapy recurred. Mean time from first recurrence to second recurrence was 1.8 years. After second recurrence, all patients underwent radiation therapy. One patient died due to malignant transformation of the tumor. For recurrent optic pathway pilocytic astrocytoma, prognosis may be better if total resection of the tumor without deteriorating the vision is possible.
LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR
Authors: Lazow Margot A , Lawson Sarah A , Salloum Ralph , Hummel Trent R , Smiley Natasha Pillay , DeWire-Schottmiller Mariko D , Fouladi Maryam , de Blank Peter M
Published: December 2020

Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.
LGG-45. A REPORT OF IDH-MUTANT BRAINSTEM ASTROCYTOMAS IN YOUNG ADULTS
Authors: Chang Ellen , Tamrazi Benita , Cotter Jennifer , Margol Ashley
Published: December 2020

IDH-mutant astrocytomas are well-recognized in the adult population and while increasingly identified, are rare in children and young adults. These tumors typically arise in cortical locations, however cases of these tumors occurring in the brainstem have been reported in the adult literature. Here we present two cases of young adults with IDH-mutant astrocytomas of the brainstem. Patient 1 was initially diagnosed with an infiltrative low grade glioma (LGG) of the brainstem at 19 years of age based on conventional magnetic resonance imaging and magnetic resonance spectroscopy characteristics. She was treated with LGG therapy and had stable disease for over three years. At the time of disease progression she underwent biopsy and pathology was consistent with an anaplastic astrocytoma, IDH1 R132S mutant. Despite treatment she experienced rapid disease progression and died six months later. Patient 2 is a 17-year-old male who underwent up-front biopsy of an infiltrating brainstem lesion; pathology was consistent with diffuse astrocytoma, IDH1 R132H mutant. He was treated with focal irradiation and chemotherapy and continues to have stable disease 26 months post diagnosis. To our knowledge, this is the first report of IDH-mutant astrocytomas occurring the brainstem in young adult patients. Both patients’ tumors harbored accompanying TP53 mutations, but not ATRX mutations. These two cases reveal the importance of obtaining biopsies for brainstem tumors to perform molecular characterization and appropriate prognostication.
LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY
Authors: Robison Nathan , Pauly Jasmine , Malvar Jemily , Gardner Sharon , Allen Jeffrey , MacDonald Tobey , Aguilera Dolly , Baxter Patricia , Bendel Anne , Kilburn Lindsay , Leary Sarah , Bowers Daniel , Dorris Kathleen , Gauvain Karen , Alva Elizabeth , Cohen Kenneth , Nazemi Kellie , Tan Yi Juin , Margol Ashley , Dhall Girish , Rosser Tena , Davidson Tom , Plant Ashley , Ullrich Nicole , Bandopadhayay Pratiti , Agar Nathalie , Ligon Keith , Sposto Richard , Wright Karen , Kieran Mark
Published: December 2020

BACKGROUND

RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model.

OBJECTIVE

The primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately.

METHODS

Children aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements.

RESULTS

Fifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response.

CONCLUSION

Binimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.
LGG-56. INFANTILE HEMISPHERIC BRAIN TUMOR WITH A GOPC-ROS1 FUSION GENE: A CASE REPORT
Authors: Taniguchi Rieko , Natsume Atsushi , Kawashima Nozomu , Tanioka Shinji , Muramatsu Hideki , Hamada Motoharu , Ichikawa Daisuke , Imaya Masayuki , Narita Kotaro , Kurimoto Michihiro , Shiba Yoshiki , Aoki Kosuke , Ohka Fumiharu , Hirato Junko , Wakabayashi Toshihiko , Takahashi Yoshiyuki
Published: December 2020

INTRODUCTION

Infantile hemispheric gliomas with ROS1 fusion genes have been reported to have a relatively poor prognosis. Treatment using a ROS1 inhibitor is expected to generate less toxicity and effective for brain tumors with ROS1 fusion genes. CASE PRESENTATION: A one-month-old female presented with a seizure, and a large hypervascular mass in the right hemisphere was found on MRI. The tumor was not biopsied over concerns of an increased risk for bleeding. The mass was clinically diagnosed as an atypical teratoid rhabdoid tumor. She received neoadjuvant chemotherapy using the modified EU-RHAB protocol. The tumor gradually decreased to 70% of its original size with a reduction of vascularity. A near-total resection (> 95%) was performed at eight months of age. Pathological examination revealed the unusual histology with immunostaining positive for INI-1, GFAP, synaptophysin, neurofilament, and slightly positive for NeuN. MIB-1 labeling index was 6%. The pathological diagnosis was a glioneuronal tumor with desmoplastic infantile ganglioglioma-like features, suggestive of low grade. She received adjuvant chemotherapy with carboplatin and vincristine, which is the standard treatment for low-grade gliomas, and achieved a partial response. The GOPC-ROS1 fusion gene was detected in the tumor by FoundationOneⓇ CDx.

CONCLUSION

Chemotherapy may effectively reduce the size of an infant’s brain tumor which is initially considered to be inoperable. A gene profile should be performed as soon as possible in order to direct appropriate management.