bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-39. SIGNALING NETWORKS IN PEDIATRIC-TYPE DIFFUSE HIGH GRADE GLIOMAS
Authors: Herbst Sophie A , Ahn Ryuhjin , Agnihotri Sameer , Zapotocky Michal , White Forest M
Published: June 2023

Pediatric-type diffuse high grade gliomas are aggressive brain cancers in children which to date lack effective treatment options and remain largely understudied. Even though genomic markers including histone H3 K27M and G34R mutations have been identified, their functional implications on signaling networks remain to be described. Phosphoproteomics might be able to uncover activated signaling pathways which could open up new paths for treatment. Here we analyzed formalin-fixed paraffin-embedded (FFPE) sections from K27M mutated, G34R mutated and histone H3 wild type patient tumors (n = 14) using phosphoproteomics. Our workflow not only enables the comprehensive characterization of phosphoserines and threonines but also of phosphotyrosines which, despite being rare modifications (0.1-1% of all phosphorylations), are known to play an important role in cancer. We found that signaling networks were distinct between the different tumor subtypes. For phosphotyrosines, tumor subtype accounted for the largest source of variation in the data (44% of variance) as determined by principle component analysis. The separation by subtype could also be seen from serine and threonine phosphoproteomics and proteomics, but was not as striking as for the phosphotyrosine data. Differential abundance analysis, partial least squares discriminant analysis and self-organizing maps revealed deregulated signaling networks between subtypes. The most downregulated pathway in K27M compared to wild type tumors was enriched for proteins involved in the epigenetic regulation of gene expression (FDR<5%), which is in accordance with the remodeling of the epigenome taking place in K27M mutated tumors. In addition, we could identify signaling networks (e.g. EGFR signaling) which were activated in a few individual patients independent of their subtype and might be targetable. Our study provides insights into the signaling landscape of pediatric-type diffuse high grade gliomas. Recognizing deregulated signaling networks across subtypes and in individual patients could offer new avenues for personalized therapy.
DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)
Authors: Lazow Margot , Baxter Patricia , Stanek Joseph , Rodriguez Diana , Kumar Shiva Senthil , Palmer Joshua , Leach James , Mikael Leonie , Thomas Diana , Fuller Christine , Boué Daniel , Pierson Christopher , Breneman John , Li Xiao-Nan , Salloum Ralph , Ashley David , de Blank Peter , Hwang Eugene , Leary Sarah , Plant Ashley , Fisher Michael , Chi Susan , Crabtree Dorothy , Murali Mythili , Weetall Marla , Rance Mark , Maliakal Pius , Baird John , D’Silva Dhiren , O’Keefe Kylie , Leonard Jeffrey , Stewart Clinton , Mardis Elaine , Fouladi Maryam , Drissi Rachid
Published: June 2023

BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.
METB-02. DECIPHERING THE CELLULAR HETEROGENEITY OF INFANT-TYPE HEMISPHERIC GLIOMAS USING SINGLE-NUCLEI MULTI-OMICS
Authors: De Micheli Andrea J , Zápotocký Michal , Cavalli Florence M G , Guerreiro Stücklin Ana S
Published: June 2023

Infant-type hemispheric gliomas (IHGs) have recently been recognized as a new tumor entity. Compared to other types of pediatric gliomas, most IHGs distinctively harbor a fusion in a cluster of receptor tyrosine kinase (RTK) genes: the NTRK family, ROS1, ALK, or MET. Clinically, IHG patients appear to be associated with better outcomes compared to older children with high-grade tumors. While large-scale genomic studies have helped uncovered the complex molecular landscape and clinical features of IHGs, little is known about the underlying biology – specifically how tumor heterogeneity may explain the spectrum of clinical presentations and progression of the disease. Using single-nuclei multi-omic (RNA/ATAC-seq) profiling, we assembled a comprehensive atlas of IHG tumor cells from a cohort of patients spanning different age groups and RTK fusion subtypes. We measured that tumor single-nuclei transcriptomes clustered into distinct subpopulations and contained genes expressed by the normal brain cell lineages. Data integration with single-cell atlases from the developing brain allowed us to rank tumor cell subpopulations according to their developmental stage, with age- and fusion-specific differences. Using trajectory inference and gene expression velocity modeling, we describe a hierarchical and dynamic organization between subpopulations, potentially illustrating the role of phenotypic plasticity in glioma formation. Moreover, we measured in fragments of open chromatin a cell-type specific enrichment of binding sites for transcription factors known to regulate brain cell maturation. Taken together, our multi-modal atlas describes the cellular and functional heterogeneity of IHGs, paving the way towards a greater understating of its unique biology and clinical consequences.
METB-04. THE MOLECULAR CHARACTERIZATION INITIATIVE (MCI): A CLINICAL AND GENOMIC RESOURCE FOR THE PEDIATRIC BRAIN TUMOR COMMUNITY
Authors: Leary Sarah , Thomas Diana , Cottrell Catherine , Wang Yu , Rudzinski Erin , Ramirez Nilsa , Hawkins Douglas , Fouladi Maryam , Mardis Elaine
Published: June 2023

BACKGROUND

The Molecular Characterization Initiative (MCI) sponsored by the National Cancer Institute (NCI) as part of the Childhood Cancer Data Initiative provides free clinical molecular testing with return of results to treating institutions.

METHODS

The MCI was activated as an optional sub-study of the COG Project:EveryChild registry, eligibility screening, biology and outcome study. Eligibility for subjects with central nervous system (CNS) tumors included newly diagnosed benign and malignant tumors in subjects < 25 years. Clinical testing included exome sequencing of paired tumor/normal; DNA methylation array for CNS tumor classification; and targeted RNA sequencing for fusion detection. Required specimens were tumor (snap frozen, FFPE block or slides) and whole blood. Quality control confirming presence and percentage of tumor was confirmed by central pathologist. Minimum nucleic acid yield included 300ng DNA (frozen, 700ng from fixed tissue) and 500ng RNA.

RESULTS

In the first 10 months since activation 3/21/2022, 867 CNS subjects from 149 COG institutions have enrolled in the MCI, of which 675 (78% of enrolled) have submitted both required tumor and blood specimens. Adequate nucleic acids were extracted from 592 specimens (88% of submitted). For subjects with adequate nucleic acids, DNA exome and methylation classification results were returned for 99%; RNA fusion analysis was returned for 93%. Median time to return of results was 19 days from receipt of tumor specimens. Only 16% of CNS subjects were also participating in screening for COG therapeutic studies, including medulloblastoma (7%), low-grade glioma (6%) and high-grade glioma (4%). Genomic and annotated clinical data are available within the NIH-sponsored repository, dbGAP, through controlled access request by academic investigators.

CONCLUSIONS

The MCI represents an unprecedented resource of genomic and clinical data that is readily available to improve clinical diagnosis and support pediatric brain tumor research.
METB-12. CLINICAL MONITORING OF MEASURABLE RESIDUAL DISEASE BY CELL-FREE DNA IN PEDIATRIC BRAIN TUMORS
Authors: Crotty Erin , Cole Bonnie , Paulson Vera , Lockwood Christina , Leary Sarah
Published: June 2023

Conventional response monitoring relies on imperfect tools like MRI and cerebrospinal fluid (CSF) cytology to detect measurable residual disease (MRD) in children with brain tumors. “Liquid biopsy” techniques provide a minimally-invasive method for MRD detection by identifying fragments of cell-free DNA (cfDNA) shed from tumor cells following cell death. Early detection of MRD has been proposed as a clinically actionable biomarker that may allow clinicians to reliably detect tumor versus treatment effect, intensify therapy prior to relapse, and minimize toxicity. Our center is currently evaluating low-pass whole genome sequencing (LP-WGS) in children with brain tumors receiving standard of care therapy for real-time MRD assessment. Following informed consent, patients are enrolled on the Seattle Children’s Hospital Tissue Banking and Biology Protocol, and CSF samples are collected prospectively by lumbar puncture during routine clinical care. LP-WGS is performed in a CAP/CLIA certified environment with return of results to the referring clinician. In addition to feasibility as a prognostic and predictive biomarker, correlative studies will investigate if neuroinflammatory and immunologic profiles change with the presence of MRD using CNS cytokine signatures, including CXCL-12, CCL-2, MMPs, CD163, and GFAP. Preliminary cfDNA studies of children with embryonal tumors suggest LP-WGS is both a sensitive and clinically valuable test to detect tumor-associated copy number variants (CNVs). Thirty of thirty-one (97%) of CSF samples from 17 patients demonstrated adequate cfDNA for LP-WGS testing. Key CNVs detected included monosomy 6, isodicentric chromosome 17, and amplifications of MYCN and TTYH1. Among 8 samples obtained at initial tumor staging, LP-WGS detected tumor in 7/8 (1 negative ATRT without CNVs), whereas only 2/8 were positive by cytology. Two samples acquired additional chromosomal alterations at progression beyond those observed in the original tumor. Future prospective clinical trials are warranted to determine how MRD will transform clinical care and patient outcomes.
RARE-02. OBSERVATIONAL REGISTRY STUDY OF TREATMENT PRACTICES AND LONG-TERM OUTCOMES OF CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMAS (PN) INITIATING SELUMETINIB IN REAL-WORLD PRACTICE IN THE UNITED STATES (US): STUDY DESIGN AND METHODOLOGY
Authors: Waanders Angela , Yohay Kaleb , Fang Shona , Wahlstrom Svea , Bornhorst Miriam , Meade Julia , Vallance Kelly , Rodriguez Randolph de la Rosa
Published: June 2023

Selumetinib (ARRY-142886, AZD6244) is an oral, allosteric MEK1/2 inhibitor approved in the US for children aged ≥2 years with NF1 and symptomatic, inoperable PN, based on results from the pivotal SPRINT study. Aims of the US Selumetinib Registry study [NCT05683678] include understanding treatment practices and assessing short- and long-term safety and effectiveness outcomes of selumetinib treatment in children with NF1-PN in real-world US practice. Clinical and non-clinical factors affecting outcomes will also be explored. This observational registry study of pediatric patients with NF1-PN will be conducted in up to 22 US centers. Eligible patients will be 2–18 years old at the time of selumetinib initiation (on/after April 10, 2020), and not currently participating in a clinical trial. Patients will be divided into three cohorts: Cohort 1 – treatment discontinued before enrollment, Cohort 2 – treatment initiated before enrollment and currently on treatment, Cohort 3 – treatment initiation intended within 3 months of enrollment. Patients will be followed for ≥36 and up to 60 months. Primary objectives are to describe patient demographics and disease characteristics (including diagnosis criteria and related manifestations, diagnostic tests and results, and PN-related morbidities), selumetinib treatment course, short- and long-term effectiveness and safety, and disease course and treatment following discontinuation. Key secondary objectives include measures of quality of life, pain and physical functioning before, during, and after selumetinib. Target enrollment is 200 patients with a 24-month enrollment period and will begin in 2023. The US Registry study will facilitate understanding of treatment practices and assess short and long-term outcomes of selumetinib for NF1-PN in a real-world setting.
RARE-05. MOLECULAR HETEROGENEITY OF PEDIATRIC CHOROID PLEXUS CARCINOMAS
Authors: Zaytseva Margarita , Papusha Ludmila , Yasko Ludmila , Karachunskiy Alexander , Novichkova Galina , Druy Alexander
Published: June 2023

BACKGROUND:

Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li–Fraumenisyndrome, though only about a half of CPCs develop fromsyndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course.

METHODS:

This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted5.2 years (absolute range 2.8–12.6 years).

RESULTS:

All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. Inseven tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0±17.9% vs. 85.7±13.2%; p=0.009. Transcriptomically, the cohort split into two polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3±17.8% vs. 100%; p=0.012.

CONCLUSION:

CPCs split into at least two molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates withsurvival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.
RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Abu-Arja Mohammad H , McGlynn Mary Claire , Zaghloul Mohammed Saad , Elhemaly Ahmed , Bertrand Kelsey , Gajjar Amar , Ronsley Rebecca , Cappellano Andrea M , Dassi Natalia , Czogala Malgorzata , Graham Richard , Baglivo Sofi Jares , Dhall Girish , Nagabushan Sumanth , Abdelbaki Mohamed S
Published: June 2023

PURPOSE

Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs.

METHODS

We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI) using SPSS software.

RESULTS

We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up.

CONCLUSIONS

Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.
OUTC-01. ESTABLISHING THE PSYCHOMETRIC VALIDITY OF ATTENTIONAL MEASURES APPLIED TO THE PAEDIATRIC NEURO-ONCOLOGY POPULATION: A SYSTEMATIC REVIEW
Authors: Verity Sarah , Hagan Alexander
Published: June 2023

BACKGROUND: Associated with hydrocephalus, cranial irradiation, and certain chemotherapeutic agents, impairment in attention is a common feature of childhood brain tumour survivorship. Attentional processes are implicated in a number of cognitive functions, supporting sustained and selective attention, inhibition of competing stimuli, and management of divided attention (multi-tasking). Acquired attentional deficit reported in childhood survivors of brain tumour is correlated with reduced academic attainment, slowed intellectual development, poor peer relationships, and lower overall quality of life. Accurate identification of tumour-related attentional impairment is a prerequisite to access appropriate rehabilitative intervention. Despite this, no attentional measures have been adequately normed on the paediatric brain tumour population. As such, there exists little agreement as to which measure is most suitable for current research or clinical practice. AIM: This prospective study will assess the utility of common measures of childhood attention used in the paediatric Neuro-Oncology population. METHOD: Comprehensive database searches will be conducted to identify relevant articles that address the validity, reliability, and capability of attentional measures currently used within paediatric Neuro-Oncology populations. The psychometric properties and clinical utility of each measure will be reviewed using a purpose-developed evaluative tool. The strengths and limitations of particular measures when applied to this clinical population will be discussed. Recommendations for the utility for and against measures in future research or clinical application will be provided. FINDINGS: Analyses of these data continues with an aim to present initial findings by May 2023.
OUTC-03. IMPACT OF TREATMENT EXPOSURES AND SOCIOECONOMIC STATUS ON NEUROCOGNITIVE PERFORMANCE IN CHILDREN WITH BRAIN TUMORS
Authors: Chang Leslie , Patel Palak , Peterson Rachel , Acharya Sahaja
Published: June 2023

PURPOSE

To investigate the impact of treatment exposures and socioeconomic status on neurocognitive performance in children with brain tumors.

METHODS

Eligible patients included those diagnosed with a brain tumor at <22 years of age with ≥ 1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age standardized measures of intellectual function. Neurocognitive outcomes included Wechsler indices of full-scale intelligent quotient (IQ), working memory (WM), and processing speed (PS). Neurocognitive decline was defined as a negative slope. Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models.

RESULTS

Eligible patients (n=152) had a mean neurocognitive follow-up of 50.2 months and median age at diagnosis of 9.6 years. PS was most frequently impaired in patients (37.5%) followed by IQ (20.6%) and WM (16.5%). Patients with public insurance had eight-fold increased odds of impaired IQ compared to those with private insurance (Odds Ratio [OR]: 7.59, p<0.001). Patients treated with CSI had eight-fold increased odds of impaired IQ (OR: 7.86, p=0.003) and almost six-fold increased odds of impaired WM (OR: 5.66, p=0.028) compared to those treated without RT. After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, p=0.012). Patients treated with both chemotherapy and RT demonstrated the greatest decline whereas those treated without either demonstrated no decline in any of the neurocognitive measures.

CONCLUSION

After treatment for pediatric brain tumors, public insurance, an indicator of low socioeconomic status, was associated with impairment in IQ with a large effect size similar to that of CSI. Chemotherapy was associated with decline in IQ with a small effect size. Combined chemotherapy and RT had additive effects on neurocognitive decline in IQ, WM, and PS.
OUTC-04. SUBSEQUENT CNS MALIGNANCY AMONG SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)
Authors: Galvin Robert , Chen Yan , Yuan Yan , Cooney Tabitha , Howell Rebecca , Smith Susan , Arnold Michael , Conces Miriam , Leisenring Wendy , Robison Leslie , Armstrong Gregory , Neglia Joseph , Turcotte Lucie
Published: June 2023

Subsequent malignant neoplasms (SMNs) of the central nervous system (CNS) following childhood cancer are a frequently fatal late effect of cancer therapy. We used the CCSS (5-year childhood cancer survivors, diagnosed 1970-1999) to assess whether temporal changes in therapy have reduced CNS SMN risk. Twenty-year cumulative incidence rates (95% confidence interval) were estimated, and standardized incidence ratios (SIR, 95% CI) were calculated comparing observed to expected rates from SEER. Multivariable models assessed demographic and treatment-related risk factors for CNS SMN. Among survivors diagnosed between 1970-1979 (N=6223), 1980-1989 (N=9680), and 1990–1999 (N=8999) with median follow-up of 40.5, 32.2, and 22.6 years, respectively, 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas. Malignant gliomas (N=131) were the most common SMNs. Cranial radiotherapy (CRT) exposure decreased by treatment decade, with the proportion of survivors receiving no CRT increasing from 23.0% (1970s), to 45.7% (1980s), and 66% (1990s). Decreases in >0–10Gy exposure (39.0% to 14.1%) and 20.1–30Gy (19.2% to 2.4%) were observed while those receiving >30Gy CRT has not substantially changed (12%, 11.1%, and 8.8%, respectively). Twenty-year cumulative incidence and SIR for development of SMN were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant differences between treatment eras, including when stratified by attained age. Multivariate analysis showed increased risk for all CRT dose levels >10Gy and for primary diagnoses of medulloblastoma/PNET (HR 3.6, 2.0-6.6) and astrocytoma (HR 2.4, 1.4-3.9). Three-year cumulative incidences of death after SMN, by treatment decade, were 70%, 73%, and 69%, respectively. In conclusion, CNS SMN incidence has not decreased despite fewer survivors being treated with CRT, and CNS SMNs remain a significant source of mortality for affected patients.
HGG-10. A SAFETY AND EFFICACY STUDY OF NOVOTTF-100A FOR PEDIATRIC HIGH-GRADE GLIOMA: RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE FIRST THREE CASES
Authors: Makimoto Atsushi , Terashima Keita , Nishikawa Ryo , Fujisaki Hiroyuki , Kurihara Jun , Ihara Satoshi , Adachi Jun-ichi , Enokizono Mikako , Morikawa Yoshihiko , Yuza Yuki
Published: June 2023

BACKGROUND

The safety and efficacy of Tumor-Treating Fields (TTFields) therapy for pediatric diffuse high-grade glioma (HGG) are uncertain. Despite differences between adult GBM and pediatric HGG in terms of genetic etiology, both have certain clinical behaviors in common, allowing TTFields therapy to be tested in pediatric HGG.

METHODS

The present study [jRCTs032200423] aims to evaluate the safety of NovoTTF-100A in pediatric HGG and conduct an exploratory analysis of its efficacy. The target population is ten children aged 5 to 17 years with newly diagnosed supratentorial HGG or its first-recurrence following frontline therapy. After completion of surgical resection of the tumor and radiation therapy, all the patients will receive TTFields therapy using NovoTTF-100A for 28 days per course for up to 26 courses until the end-of-therapy criteria (including disease progression) are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various efficacy parameters and quality of life. In total, the ten patients will be enrolled by September 2023.

RESULTS

The planned interim analysis, which was done in October 2022, included 3 female patients aged 14, 17, and 9 years, respectively. All had a histological grade 4 tumor, two of which were radiation-induced secondary HGG. Although the first patient with recurrent disease had early progression after enrollment and experienced disease-related adverse events, no serious, treatment-related toxicities or device-related issues were observed. The second patient had a recurrence after six courses, and the third patient remained through the second course. All 3 patients were able to maintain device usage of 75% or more of the time, in alignment with use recommendations, suggesting treatment feasibility.

DISCUSSION

Based on the results presented above, the study was resumed as the current, multicentric study aimed at obtaining approval for the expanded use of NovoTTF-100A for pediatric HGG.
HGG-13. ONCOGENIC STAT3 AND SHP2 ACTIVATION IN ROS1-FUSION DRIVEN INFANT-TYPE HEMISPHERIC GLIOMAS
Authors: Postlmayr Andreas , De Micheli Andrea , Hofmann Nina , Zuckermann Marc , Stücklin Ana Guerreiro
Published: June 2023

Genomic analyzes identified a subgroup of gliomas – infant-type hemispheric gliomas – that are driven by oncogenic fusions of, amongst others, ROS1 receptor tyrosine kinase with a variety of fusion partners. These fusions result in ligand independent constitutively active oncogenic kinases. In the present study we aim to identify the, yet poorly characterized, alterations in cellular signaling driven by ROS1 fusions leading to tumor formation to enhance our understanding of IHG formation and to identify complementary targets for therapy. To answer these questions, we deploy a combination of biochemical characterization of cellular models as well as in vivo experiments and transcriptomic and phosphoproteomic analyzes. Expression of different ROS1-fusions results in robust tumor formation in two different mouse models, proving their tumorigenic potential. The impact of the fusion partner, which dictates subcellular localization, as shown by immunofluorescence microscopy, on differences in tumor formation has not yet been established. Transcriptomic and phosphoproteomic analyses of ROS1-fusion cellular models revealed diverging effects of the fusions on transcriptomic and proteomic alterations. A common denominator, however, is a significant hyper-phosphorylation of the tyrosine phosphatase SHP2, which we established to be a direct substrate of ROS1. ROS1 fusions, irrespective of the fusion partner, drive non-canonical STAT3 signaling, indicated by direct phosphorylation of STAT3 by ROS1 and upregulation of STAT3 target genes. Characterizing the main signaling pathways using immunoblots did not detect alterations in the PI3K/AKT/mTOR or MAPK pathways. STAT3 signaling is a well characterized pathway for promoting pro-survival, proliferation and stemness cues in development and cancer, making it a paramount candidate for ROS1 driven tumorigenesis as well as an excellent target for targeted therapies.
HGG-22. PROGNOSTIC FACTORS FOR PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH NON-DIPG GRADE 4 GLIOMAS: A CONTEMPORARY POOLED INSTITUTIONAL EXPERIENCE
Authors: Matsui Jennifer , Allen Pamela , Perlow Haley , Johnson Jason , Paulino Arnold , McAleer Mary , Fouladi Maryam , Grosshans David , Ghia Amol , Li Jing , Zaky Wafik , Chintagumpala Murali , Palmer Joshua , McGovern Susan
Published: June 2023

BACKGROUND

WHO grade 4 gliomas are rare tumors in the pediatric and AYA (adolescent and young adult) population. In this study, we evaluate prognostic factors, toxicities, and outcomes in the pediatric versus AYA population.

METHODS

This retrospective pooled institutional study included patients < 30 years old with grade 4 gliomas. Overall survival (OS) and progression free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis.

RESULTS

Ninety-seven patients (n=20 < 15y, n=77 ≥ 15y) were identified with a median age 23.9y at diagnosis. Most had biopsy-proven glioblastoma (91%) and the remainder had diffuse midline glioma, H3K27M-altered (9%). All patients received surgery and adjuvant radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection was associated with better PFS in multivariate analysis [HR 2.00 (1.01–3.62), p = 0.023]. Age ≥15y was also associated with improved OS [HR 0.36 (0.16–0.81), p = 0.014] while female gender [HR 2.12 (1.08–4.16), p = 0.03] and K27M altered histology [HR 2.79 (1.11–7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity during radiation. Sixty-two percent of patients experienced tumor progression, 28% local and 34% distant. Analysis of salvage treatment found reirradiation was not associated with improved OS, but second surgery and systemic therapy significantly improved survival from the time of tumor progression.

CONCLUSIONS

Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. Diffuse midline glioma was associated with worse OS compared to hemispheric glioblastoma; this may be related to lack of effective targeted therapies. Surgery and systemic therapy were effective salvage options that significantly improved outcome. Better understanding of prognostic factors may guide future treatment within this understudied patient population, and prospective studies are warranted.
HGG-27. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASK FORCE
Authors: Negm Logine , Nobre Liana , Bennett Julie , Chung Jiil , Komosa Martin , Fernandez Nick , Ku Michelle , Johnson Monique , Bianchi Vanessa , Aronson Melyssa , Zhang Cindy , Stengs Lucie , Lim-Fat Mary Jane , Keith Julia , Tsang Derek , Gao Andrew , Munoz David G , Nguyen Lananh , Das Sunit , Levine Adrian , Das Anirban , Resnick Adam , Wheeler David , Hawkins Cynthia , Tabori Uri
Published: June 2023

Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond to immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) or Constitutional Mismatch Repair Deficiency (CMMRD). However, the prevalence of MMRD in gliomas of children, adolescents, and young adults (CAYA), and impact of germline inheritance is unknown. We utilized functional genomic tools on population-based and validation cohorts from 3 large databases (Toronto, St-Jude and CBTN) to determine the prevalence, subgroup, and impact of germline mutations on MMRD-gliomas. Ongoing data on 998 pediatric-gliomas from Toronto reveals that MMRD is extremely rare in pediatric low-grade gliomas (PLGG) but common in pediatric high-grade gliomas (PHGG) (9%, p<0.0001). Similarly, data from St-Jude and CBTN (n=374) reveals that MMRD exists only in PHGG (8%). In both cohorts, MMRD-PHGG are enriched for RAS/MAPK, IDH, and TP53 mutations while pediatric-type fusions, BRAF-V600E and histone mutations are absent. In AYA-HGG (n=884), the most common groups include glioblastomas without chromosome-7/10 alterations (9%) and IDH1-astrocytomas, while MMRD is not present in IDH-oligodendrogliomas. All but 1 CAYA-MMRD-gliomas harbored germline MMR mutations. Data from the IRRDC on 174 patients reveal that LS is more common than CMMRD in gliomas, with the median age of onset 11 and 29 years in CMMRD and LS, respectively (p<0.001). Furthermore, CMMRD gliomas are commonly caused by germline PMS2 and MSH6 mutations, enriched for secondary polymerase mutations (60%, p<0.001), and exhibit ultra-hypermutation. In contrast, LS-gliomas are caused by MSH2 and MLH1 mutations, and enriched for IDH1 mutations (32%, p<0.025) with a lower mutational burden. Our data reveals high prevalence of MMRD in CAYA-HGG with alarming impact of germline predisposition. Specifically, unrecognized LS patients with AYA MMRD-HGG. These findings support universal screening for MMRD in HGG to identify patients for immunotherapy and surveillance.
IMG-02. VISUALIZATION OF TIGIT IN THE GLIOMA MICROENVIRONMENT: THE CREATION OF A PET IMAGING TRACER
Authors: Frederico Stephen , Vincze Sarah , Nisnboym Michal , Li Bo , Sneiderman Chaim , Server ReidAnn , Day Kathryn , LaToche Joseph , Nedrow Jessie , Edwards Wilson , Kohanbash Gary
Published: June 2023

Pediatric high-grade gliomas (HGGs) are aggressive tumors and are one of the drivers of pediatric brain tumor mortality. Few effective treatment options exist for pediatric HGGs beyond surgery and chemoradiation. Additionally, some HGGs, such as diffuse midline glioma, are often surgically inaccessible and respond poorly to chemotherapy leaving radiotherapy as the only treatment for this disease. While immune checkpoint inhibitors (ICIs) have seen success in treating cancers outside the CNS, ICIs for gliomas have shown limited efficacy.

TIGIT is an IC receptor that is expressed on activated T-cells and has a critical role in suppressing T-cell and NK cell function. Prior work by our group has shown TIGIT to be a promising target for adult gliomas. These studies included analysis of transcriptomic data, and preclinical studies in glioma-bearing mice. We therefore assessed pediatric glioma transcriptomic datasets and identified via optimal cutoff analysis that at a specific mRNA threshold, TIGIT expression is associated with worsened survival. As TIGIT expression may be both prognostic and a biomarker for anti-TIGIT ICI therapy, we created a radiolabeled immunoPET tracer capable of binding TIGIT antigen that could be visualized via PET imaging.

Referred to as “89Zr-DFO-TIGIT”, we found this tracer bound TIGIT with moderate immunoreactivity (57.7% ± 3.5%) as determined by bead-based immunoreactivity assays. As proof of feasibility, we injected glioma-bearing mice (GL261 cell line) with 89Zr-DFO-TIGIT which enabled the visualization of TIGIT in the tumor microenvironment via PET imaging. Thereafter, we performed biodistribution studies which found there to be significantly increased 89Zr-DFO-TIGIT in mouse tumor-bearing hemispheres as compared to non-tumor-bearing hemispheres. PET imaging also showed tracer-to-tumor uptake increased from day one to day eight.

Our findings demonstrate the capability of 89Zr-DFO-TIGIT to visualize and quantify TIGIT in the glioma microenvironment, highlighting how this tracer may be of value in pediatric brain tumor immunotherapy studies.
IMG-07. MOLECULAR PROCESSES GIVE RISE TO EMERGENCE OF RADIO-PHENOTYPES ON MRI SCANS OF PEDIATRIC LOW-GRADE GLIOMA
Authors: Kazerooni Anahita Fathi , Kraya Adam , Kim Meen Chul , Haldar Debanjan , Rathi Komal , Mahtabfar Aria , Familiar Ariana , Khalili Nastaran , Naqvi Ammar , Koptyra Mateusz , Bagheri Sina , Anderson Hannah , Ware Jeffrey B , Storm Phillip B , Vossough Arastoo , Resnick Adam C , Davatzikos Christos , Nabavizadeh Ali
Published: June 2023

There is mounting evidence that tumor microenvironmental pressure selects for somatic genetic alterations that contribute to the formation of distinct morphological characteristics, captured on radiology scans as radio-phenotypes. Such phenotypic variations are a source of heterogeneity in clinical manifestation of tumors of the same histology across the patients, and in part, their heterogeneous responses to therapies. Deeper understanding of the associations between genotype and radio-phenotype in pediatric low-grade glioma (pLGG), the most histologically diverse childhood brain tumor, may facilitate precision diagnostic and therapeutic approaches. Here, we categorize pLGGs into distinct and relatively homogeneous imaging subtypes based on radiomic features and further explore the associations of these imaging subtypes with genotype. From multiparametric MRI scans of 167 pLGGs from the Children’s Brain Tumor Network (CBTN), 881 radiomic features and clinical variables (tumor location, age, and gender) were extracted. After dimensionality reduction using principal component analysis (PCA), K-Means clustering was applied on 19 principal components to group the patients into three imaging subtypes. Using whole transcriptomic data from OpenTargets, differential expression and co-expression of network- and pathway-level and immune-related signaling were compared among these three imaging subtypes. Gene Set Enrichment Analysis (GSEA) revealed differentially higher expression of cell cycle regulatory, extracellular matrix (ECM) remodeling, and cell migratory pathways in imaging subtype1 than subtypes 2 and 3, and upregulation of ECM and immune-related pathways in subtypes 1 and 2 compared to subtype3. Based on Gene Sets Net Correlations Analysis (GSNCA), subtype1 exhibited differential co-regulation of TNF/TNFR1 signaling compared to subtype2, and differential co-regulation of RHOG GTPase and TGFB1pathways when compared against subtype3. Subtype2 showed differential co-regulation in NOTCH1 signaling and transcriptional regulatory pathways. Our proposed multi-disciplinary radiomic-genomic analysis approach elucidates the molecular and biological processes in the genotype of the tumors that are associated with emergence of distinct imaging subtypes in pLGG.
IMG-09. DETERMINING OPTIMAL IMAGING SCHEDULE FOR PLGG AND PHGG PATIENTS OFF-THERAPY
Authors: Patel Krupesh , Moshe Maua , Amankwah Ernest , Holloway Leah , Stapleton Stacie
Published: June 2023

To this point there is no standard imaging schedule across all institutions in the surveillance of pediatric low-grade gliomas (pLGG) and pediatric high-grade gliomas (pHGG) after therapy completion. We at our institution use the Children’s Oncology Group (COG) protocols ACNS1831/ACNS1833 to guide our surveillance of pLGG. The MRI schedule is every 3 months for year 1 (after therapy), every 6 months for years 2 and 3, and annually for years 4 and 5. For pHGG we do MRI imaging every 3 months for year 1, every 4 months for year 2, every 6 months for years 3-5, and annually for years 6-10. It is uncertain if this imaging schedule is optimal in terms of tracking tumor evolution post-treatment. pLGG are a diverse group of tumors but generally tend have a slower progression rate when compared to pHGG. Studies have shown a 5-year progression-free survival (PFS) of 45% to 65% for residual tumor of any size for pLGG. 3-year PFS for pHGG at best is 18%. When possible, spacing imaging, decreasing sedations, and decreasing gadolinium-based contrast agents that can deposit in the body are key drivers in imaging schedules. Through retrospective analysis we are establishing if imaging schedules should be adjusted based on disease progression or recurrence.
IMMU-05. TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS
Authors: Mahdi Jasia , Dietrich Jorg , Straathof Karin , Roddie Claire , Scott Brian , Davidson Tom Belle , Prolo Laura , Batchelor Tracy , Campen Cynthia , Davis Kara , Gust Juliane , Lim Michael , Majzner Robbie , Park Julie , Partap Sonia , Ramakrishna Sneha , Richards Rebecca , Schultz Liora , Vitanza Nicholas , Wang Leo , Mackall Crystal , Monje Michelle
Published: June 2023

Immunotherapies have transformed the therapeutic landscape for various cancer indications; currently several preclinical and clinical studies are exploring immune-based therapies for the treatment of central nervous system (CNS) tumors. The recognition of toxicity syndromes and establishment of toxicity grading scales for cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) have improved the administration and management of chimeric antigen receptor (CAR)-based therapies for B cell malignancies. We have observed a localized neurotoxicity syndrome, distinct from CRS and ICANS, in patients treated with immunotherapies for CNS tumors, which we term tumor inflammation-associated neurotoxicity (TIAN). TIAN arises secondary to localized inflammation at the tumor site causing local neuronal dysfunction and/or local inflammation-induced edema leading to tissue shifts and increased intracranial pressure (ICP). Although TIAN can be associated with inflammation-induced tumoral edema and may share similarities with “pseudoprogression,” TIAN can also occur in the absence of edema due to neural-immune interactions causing primary local neural dysfunction. We distinguish two types of TIAN:1) type 1 TIAN occurs when tumor inflammation-induced edema leads to mechanical space constraints and results in increased ICP, hydrocephalus, and if unmanaged, may cause a herniation syndrome 2) type 2 TIAN reflects inflammation-induced local neural electrophysiological dysfunction resulting in transient worsening/development of new neurological symptoms. In order to facilitate the safe administration of immunotherapies for CNS tumors and standardize reporting and clinical management, we have proposed a TIAN grading scale that encompasses both types of TIAN. Even though type 1 TIAN typically consists of higher-grade toxicities than type 2 TIAN, high-grade toxicities can also be seen in type 2 TIAN when tumor inflammation affects critical cardiopulmonary functions. As the promise of immunotherapies for the treatment of CNS tumors materializes, recognizing TIAN as a distinct, local neurotoxicity syndrome will be essential for patient safety and clinical management.
IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT
Authors: Najem Hinda , Tripathi Shashwat , McCortney Kathleen , Horak Victoria Jane , Leonard Kaethe , Steffens Alicia , Walshon Jordain , Horbinski Craig M , Wadhwani Nitin R , James Charles David , Lam Sandi , Lesniak Maciej S , Burks Jared K , Heimberger Amy B , DeCuypere Michael G
Published: June 2023

PURPOSE

To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG).

METHODS

Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and characterize the tumor microenvironment (TME) of 13 newly diagnosed WHO grade 1 pilocytic astrocytomas (PA), 6 pediatric HGG, and 3 normal brain (NB) samples.

RESULTS

Relative to NB, HGGs were enriched with T cells, cancer-associated fibroblasts (CAF), CD11c+ antigen-presenting cells, and CD163+ macrophages. In contrast, PA showed more CD11c+P2RY12+ microglia and CD11c+CD205+ dendritic cells (DCs). TMEM119+ microglia were present in NB and brain adjacent to PA but were rare within the TME of all gliomas regardless of histology. PA uniquely contained naïve CD45RO-FoxP3-PD-1-TIM-3-LAG-3- T cells forming immunological synapses, as visualized by Lck+ expression at the membrane interfaces, during interaction with either microglia or DCs. This finding was not encountered in HGG. TIM-3 was the most frequently expressed immune modulatory target on all the myeloid populations, regardless of tumor histology. PD-L1 expression, especially on microglia, was more frequent in PA than in HGG. NanoString analysis revealed the pro-inflammatory and enabler of diapedesis IL-1 pathway genes (IL1RAP, TICAM2, and IRAK4) were upregulated in PA relative to the matched adjacent brain using unsupervised hierarchical clustering.

CONCLUSIONS

Based on multiple orthogonal analysis strategies, PAs display a more pro-inflammatory phenotype, in comparison to HGG, suggesting immunological surveillance that may be driven by IL-1, as a baseline feature at presentation.
IMMU-18. TARGETING GD2 IN THALAMIC DIFFUSE MIDLINE GLIOMA WITH TRANSIENT MRNA CAR T CELLS
Authors: Foster Jessica , Madsen Peter , Harvey Kyra , Patterson Luke , Griffin Crystal , Stern Allison , Storm Phillip , Resnick Adam
Published: June 2023

Chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 have shown promise as a therapeutic for diffuse midline glioma (DMG). However, thalamic tumors have been excluded from clinical trials due to prior studies showing neurotoxicity and fatality when using virally transduced CAR T cells. We hypothesized repeated dosing of transient GD2-directed mRNA CAR T cells could be employed for safe and effective treatment of thalamic DMG. GD2-directed CAR T cells were created using mRNA and first tested against the murine thalamic DMG xenograft 7316-6349 via locoregional delivery with an indwelling catheter for repeated dosing. The previously reported fatal neurotoxicity observed in mice using lentiviral CAR T cells could be recapitulated with aggressive dosing. Four doses of 5x106 mRNA CAR T cells delivered intratumorally twice a week resulted in median overall survival of 9 days for GD2-treated mice compared to >30 days for CD19-treated controls (p<0.01). This toxicity could be avoided by decreasing the dose and timing of infusions to 2x106 mRNA CAR T cells delivered once weekly. Bioluminescent imaging showed regression of tumor in GD2-treated mice compared to CD19-treated controls (radiance fold change -3x106 versus +20x106 p/sec/cm2/sr, p<0.01). To assess survival before the onset of graft-versus-host disease, we utilized the aggressive hypermutant thalamic DMG model 7316-3058, treating with 2x106 CAR T cells intratumorally once weekly. Overall survival was significantly prolonged for 7316-3058 mice treated with GD2-directed mRNA CAR T cells compared to CD19-directed controls (median OS 48 days versus 33 days, p=0.03). Notably, non-tumor bearing mice treated with GD2-directed CAR T cells developed fatal neurotoxicity within 14 days, suggesting a very narrow therapeutic window in the brain. These data highlight the utility of titratable mRNA-based CAR T cell therapy for CNS tumors and establish GD2-directed mRNA CAR T cells as a safe and effective method for treating thalamic DMG.