bluuebunny/crossref_metadata_2025 huggingface dataset:
GCT-61. CORRELATION OF PATTERNS OF DISEASE RECURRENCE WITH RADIOTHERAPY TECHNIQUES AND DOSE IN INTRACRANIAL GERM CELL TUMOURS (icGCT): LESSONS FROM THE UK COHORT OF SIOP GCT96 STUDY
Authors: Ajithkumar Thankamma , Mandeville Henry , Carceller Fernando , Ronghe Milind , Foord Tina , Lowis Stephen , Kwok-Williams Michelle , Calaminus Gabriele , Murray Matthew , Nicholson James
Published: December 2020

BACKGROUND

There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques.

METHODS AND RESULTS

Data from 20 patients with tumour recurrence after treatment within the SIOP GCT96 study in the UK were analysed. Seven (35%) patients had germinoma and 13 (65%) had non-germinoma. Twelve patients had local recurrence, 5 had metastatic and 3 had local and metastatic disease. Radiotherapy details were retrieved in only 8 patients (40%). Six patients had received focal radiotherapy and two craniospinal radiotherapy. Of the patients who received focal radiotherapy, 4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions. Both patients who received CSI recurred within the CSF space. The main reasons for poor retrieval of treatment details were difficulty in retrieving archived information and that the study was conducted during a period before PACS or electronic radiotherapy records.

CONCLUSION

This study highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study, radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy quality assurance measures in future clinical trials.
GCT-65. INCIDENCE AND OUTCOME OF INTRACRANIAL MALIGNANT GERM CELL TUMOURS DIAGNOSED IN WESTERN DENMARK IN THE LAST DECADE
Authors: Lassen-Ramshad Yasmin , Mikkelsen Torben Stamm , Rosthoej Steen , Henriksen Louise Tram , Tuckuvienne Ruta , Kristensen Ines Ackerl , von Oettingen Gorm , Cortnum Soeren , Als Anne-Birgitte , Safwat Akmal , Agerbaek Mads
Published: December 2020

INTRODUCTION

Intracranial malignant germ cell tumours (iGCT) are rare brain tumours mainly diagnosed in children and younger adults.

MATERIAL AND METHODS

A retrospective analysis was performed by chart review of patients treated for iGCT in the northern and central region of Denmark. Teratoma only patients were not included in the study.

RESULTS

20 patients with iGCT were diagnosed from 2008–2019 in Western Denmark. The cumulative incidence was 1.05 per 100.000. The yearly incidence was 0.1 per 100.000. Mean age at diagnosis was 18 years (range 8–36 years), 17 were males and 3 were females. 13 patients presented with germinoma and 7 patients with non germinomateous germ cell tumours (NGGCT). Three patients had disseminated disease, two with germinoma and one with NGGCT. All patients had received radiotherapy and 18 patients were treated with multidrug chemotherapy including platinum and etoposide before irradiation. Two patients experienced recurrent disease, both non disseminated at diagnosis, one patient with germinoma and one patient with NGGCT. Both received salvage treatment including high dose chemotherapy with stem cell transplantation and reirradiation. Two NGGCT patients died, one patient after development of an anaplastic astrocytoma in the radiation field five years after radiotherapy and one patient after intracranial hemorraghe 18 months after salvage treatment for recurrent disease. Overall survival was 90%, 100% for GCT and 71% for NGGCT.

CONCLUSION

The outcome of patients with iGCT in Western Denmark was comparable to the literature. A nationwide study of epidemiology and outcome of iGCT in Denmark is planned.
GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWO CAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM DISORDER
Authors: Toll Stephanie , Gorsi Hamza
Published: December 2020

BACKGROUND

Central nervous system germ cell tumors (CNS-GCT) account for approximately 5% of all pediatric brain tumors. These tumors are pathologically heterogeneous, but have recurrent somatic mutations in KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased tumor development and familial cases have been reported, but no germline tumor syndromes are known. We describe a pair of siblings, both with autism spectrum disorder (ASD) that developed CNS-GCT, which previously has not been described outside of Japan. CASES: We report two siblings with ASD who developed CNS germinomas within two months of each other. The older brother, with basal ganglia and hypothalamic tumors, underwent surgical resection followed by treatment per ACNS0232 with chemotherapy and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required additional chemotherapy and WVI. Both siblings are without evidence of disease 7 years after end of therapy. Genetic testing, including chromosomal microarray, karyotyping, and whole genome sequencing did not elucidate any variant identified as causative at that time.

CONCLUSIONS

CNS-GCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline chromosomal disorders associated with increased tumor development, but no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two Caucasian American siblings with ASD and CNS-GCT is novel, refuting that familial CNS-GCT are limited to the Japanese population.
HGG-27. ANTI-CANCER POTENTIAL OF ARGINASE FOR HIGH-GRADE GLIOMA IN VITRO & IN-VIVO
Authors: Fung M K L , Chan S , Sun S , Zhang P D , Leung G K K , Chan G C F
Published: December 2020

BACKGROUND

High-grade glioma is currently incurable. It was reported that glioma may be auxotrophic to arginine due to the lack of urea cycle genes expressions, suggesting arginase may be a potential agent for high grade glioma. AIM: We investigated the efficacy of pegylated arginase I (pegArg-I) or in combination with other anti-cancer drugs for high-grade glioma in vitro and in vivo.

METHODS

4 high-grade glioma cell lines (U87, U373, U138, D54) were treated with pegArg-I in vitro. The molecular mechanism of pegArg-I-induced cytotoxicity was tested in U87. The ultra-morphological changes of pegArg-I-treated U87 was investigated by both scanning and transmission electron microscopy. Orthotopic glioma xenograft model with luciferase-transfected U87 cell line was tested for anti-cancer efficacy of peg-Arg I in vivo.

RESULTS

We showed that pegArg-I induced significant cell death in all 4 cell lines in vitro. Temozolomide, difluoromethyornithine and chloroquine (CQ) were then tested together with pegArg-I in U87 in vitro. We found that only CQ showed additive effect with pegArg-I against glioma in vitro. Such additive cytotoxic effect may be associated with enhanced autophagy and necrosis as shown in transmission electron microscopy and autophagy markers’ expression by Western blotting. PegArg-I prolonged the survival of glioma mice, suggesting its possible anti-glioma efficacy. However, CQ+pegArg-I didn’t show further significant anti-cancer efficacy in vivo.

CONCLUSION

PegArg-I may be useful in slowing the progression of glioma, but additional drug candidate which works synergistically with pegArg-I remains to be explored.
HGG-31. UNIQUE BIOLOGICAL CHARACTERISTICS OF RADIATION-INDUCED GLIOMAS
Authors: Váňová Kateřina , Vícha Aleš , Krsková Lenka , Zámečník Josef , Malinová Běla , Sumerauer David , Mišove Adéla , Libý Petr , Zápotocký Michal
Published: December 2020

Radiation-induced gliomas (RIGs) are the most common secondary solid tumours with very unfavourable prognosis. We aimed to describe different clinical and molecular biological characteristic of RIGs from primary gliomas. We reviewed clinical data of ten patients with RIGs. In patients with available samples, we used the whole genome methylation array and performed targeted sequencing for specific mutations. Between 2000–2018, we diagnosed RIG in 10 patients (M/F 2/8) aged 5–12 years at primary diagnosis of different solid tumours and acute leukaemia. These patients developed RIG with a median 9.5 years (ranging 3–31) after primary diagnosis. Eight patients died within 1 year after diagnosis of RIG and 2 patients are still alive more than 4 years from this diagnosis. According to Heidelberg DNA methylation-based classification, most RIGs belong to the IDH-wild type glioblastoma subclass midline which biologically corresponds to diffuse midline glioma (DMG). However, compared to primary DMGs they do not carry the characteristic H3K27M mutation. One patient developed anaplastic ganglioglioma with BRAF-V600E mutation and methylation profile identical to pleomorphic xanthoastrocytoma (alive for 4 years after diagnosis of RIG). In half of the patients from the group DMGs IDH wild type, examined by methylation array, PDGFRA amplification was found. Our data shows that most RIGs are midline IDH-wild type glioblastomas with poor prognosis that are biologically different from primary DMGs. PDGFRA amplifications are potentially targetable by kinase inhibitors in order to order to prognosis of these patients.
HGG-32. UNCOVERING THERAPEUTIC VULNERABILITIES IN MISMATCH REPAIR-DEFICIENT GLIOMAS
Authors: Boynton Adam , Pal Sangita , Touat Mehdi , Currimjee Naomi , Qian Kenin , Bellamy Charlotte , Ho Patricia , Berstler Jim , Ligon Keith , Beroukhim Rameen , Bandopadhayay Pratiti
Published: December 2020

INTRODUCTION

We have observed that approximately 26% of recurrent gliomas acquire hypermutation following treatment with temozolomide (TMZ). Intriguingly, 91% of these tumors harbor mutations in mismatch repair (MMR) genes. Strategies to target MMR-deficient gliomas thus stand to impact a large number of patients.

METHODS

We ablated the MMR genes MSH2, MSH6, MLH1, and PMS2 using an all-in-one sgRNA-CRISPR/Cas9 expression vector to generate panels of isogenic MMR knockouts in patient-derived glioma cell lines. We have characterized the phenotype of these MMR-deficient glioma cells, and leveraged high-throughput drug screens to identify therapeutic vulnerabilities induced by loss of MMR.

RESULTS

We demonstrate that sgRNA-CRISPR/Cas9 targeting of either MSH2 or MLH1 – the two obligatory components of the MutSα and MutLα complexes, respectively – also results in loss of protein expression of their respective binding partner MSH6 or PMS2. Moreover, we show that loss of each MMR component confers resistance to TMZ while maintaining sensitivity to the alkylating nitrosourea CCNU. Furthermore, we show that long-term TMZ treatment of MSH2 and MSH6 knockouts in an MGMT-methylated line induces hypermutation with enrichment of C > T mutations but not in MMR wild-type controls. Lastly, loss of MSH2 or MLH1 confers differential dependencies to small molecule inhibitors.

CONCLUSIONS

CRISPR/Cas9 knockout of individual MMR pathway members allows us to systematically study the response of MMR-deficient cells to alkylating agents in an isogenic context. MMR deficiencies in glioma confer dependencies to small molecule treatment, which may inform future therapies for MMR-deficient tumors.
HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS
Authors: Fuchs Quentin , Pierrevelcin Marina , Papin Christophe , Dontenwill Monique , Entz-Werlé Natacha
Published: December 2020

Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.
HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Dubois Frank , Shapira Ofer , Greenwald Noah , Zack Travis , Tsai Jessica W , Harutyunyan Ashot S , Kumar Kiran , Sinai Claire , Malkin Hayley , Jones Robert , Ho Patricia , O’Rourke Ryan , Kang Kyung S , Jabado Nada , Kieran Mark W , Ligon Keith , Beroukhim Rameen , Bandopadhayay Pratiti
Published: December 2020

BACKGROUND

Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide.

METHODS

Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq.

RESULTS

The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants.

CONCLUSION

Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.
HGG-42. CLINICAL FEATURES AND TREATMENT OUTCOME OF MALIGNANT GLIOMAS IN CHILDREN AND ADOLESCENTS
Authors: Yonezawa Hajime , Uchida Hiroyuki , Higa Nayuta , Oyoshi Tatsuki , Yoshimoto Koji
Published: December 2020

INTRODUCTION

Malignant gliomas in children and adolescents are rare. They are difficult to treat and are associated with an extremely poor prognosis.

SUBJECTS AND METHODS

The treatment and outcomes of WHO grade IV -gliomas and diffuse intrinsic pontine gliomas (DIPG) in children and adolescents (Age 4–39, median 28) treated at our institute since 2001 were retrospectively reviewed. Thirty-five cases were included in this study. Nine cases were located in their brain stem and 2 of them were diagnosed as DIPG clinically without biopsy. Three (brain stem -2, thalamus- 1) cases were diffuse midline glioma H3 K27 M mutant. Remaining 30 cases were diagnosed histologically as glioblastoma. Expect for 2 cases, all were irradiated. Twenty-four cases were treated with temozolomide (TMZ). Bevacizumab (BEV) was administrated as an initial therapy in 10 cases (concomitant with TMZ in 9 cases) and was administrated at the time of relapse in 9 cases. In summary, 19 cases were treated with BEV.

RESULTS

Median survival time (MST) of all cases was 16.8 (4.4 -152.3) months. In total, BEV did not prolonged overall survival (OS), MST 16.02 vs 14.44, (p=0.498). Among adolescents (age 15–39), patients treated with BEV had a trend of longer OS but did not reached statistical significance, MST 19.64 vs 10.76 (p=0.167). An extent of resection and KPS =>70 at discharge from hospital were beneficial factors associated with prolonged OS.

CONCLUSION

As well as in elderly cases, multidisciplinary treatment including resection, radiation and chemotherapy including BEV improves outcomes.
HGG-43. CONGENITAL GLIOBLASTOMA MULTIFORME: A CASE REPORT OF A RARE PEDIATRIC BRAIN TUMOR, MOLECULAR ANALYSIS, AND REVIEW OF THE LITERATURE
Authors: Amend Christina , Stadler James , Salamat Shahriar , Dedekam Erik , Waanders Angela , Wadhwani Nitin
Published: December 2020

Congenital brain tumors are rare, accounting for less than 4% of all pediatric brain tumors. Congenital glioblastoma multiforme (GBM) is rarer still, accounting for 3–15% of congenital brain tumors. There is literature to suggest that these tumors differ from pediatric and adult GBM clinically and molecularly, and as such should be treated as their own distinct entity. Our case is a 4 week old male who initially presented to his pediatrician for enlarging head circumference and upward gaze palsy. An MRI was obtained revealing a right parietal mass. He underwent gross total resection the following day with pathology revealing glioblastoma, WHO grade IV. Further analysis revealed ATRX retained, p53 immunoreactivity in 15–20% of nuclei, IDH1 and IDH2 wildtype, MGMT promoter not methylated, H3K27M wildtype, no 1p and/or 19q deletion/codeletion. Interestingly, RNA analysis of his tumor detected the PPP1CB-ALK fusion transcript as well as amplification of the ALK gene. Co-occurrence of these mutations has been reported in a small number of pediatric glioblastoma patients and PPP1CB-ALK fusions are one of the most common receptor tyrosine kinase fusions in infantile gliomas. ALK rearrangements and amplifications suggest a potential therapeutic target with tyrosine kinase inhibitors in glioblastoma. This patient serves as an example of a rare congenital glioblastoma with unique molecular features that may suggest novel treatment opportunities. We present his clinical course along with a pertinent review of the literature.
HGG-44. DEFECTS OF MISMATCH REPAIR PROTEINS IN PEDIATRIC HIGH GRADE GLIOMAS
Authors: Haberler Christine , Muller Philippe , Müllauer Leonhard , Peyrl Andreas , Czech Thomas , Wimmer Katharina , Slavc Irene
Published: December 2020

Hetero- and homozygous germline mutations of the mismatch repair genes MLH1, PMS2, MSH2 and MSH6 cause Lynch and constitutional mismatch repair (CMMRD) cancer predisposition syndrome, respectively. Affected CMMRD individuals are at risk to develop a variety of neoplasms including CNS tumors, particularly high grade gliomas (HGG), during childhood. Currently, few data exist on the prevalence of CMMRD in children with pediatric HGG. We screened a consecutive series of 79 supratentorial HGGs. Tumor tissue was available in 42 patients, 5 were reclassified as non-HGGs. Immunohistochemistry with antibodies against MLH1, PMS2, MSH2 and MSH6 was performed in 37 tumors. Four patients (3 families) with known CMMRD were included. The evaluation of the slides was performed blinded to the CMMRD status. All four patients with known CMMRD (3 patients with PMS2, one with MSH6 mutation) were identified, showing loss of PMS2 and MSH2/MSH6, respectively. Additionally, we identified 6 patients with loss of MSH2/MSH6 staining in tumor cells, but retained staining in preexisting cells, indicating a pattern like in Lynch syndrome. NGS sequencing of these tumor tissues revealed in 2 patients MSH2 mutations and in one patient a hypermutator phenotype with MSH2 and MSH6 mutations. In 3/6 patients no mutations in the MMR genes were detectable. In summary, we found a low prevalence of CMMRD among HGGs, but identified also 2 patients with probable Lynch syndrome. Immunhistochemistry is an effective tool to screen for patients with MMR defects and should be performed in HGGs to optimize treatment and offer affected families genetic counseling.
IMG-03. RESPONSE ASSESSMENT IN PEDIATRIC LOW-GRADE GLIOMA: RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY (RAPNO) WORKING GROUP
Authors: Fangusaro Jason , Witt Olas , Driever Pablo Hernaiz , Bag Asim , de Blank Peter , Kadom Nadja , Kilburn Lindsay , Lober Robert , Robison Nathan , Fisher Michael , Packer Roger , Poussaint Tina Young , Papusha Ludmila , Avula Shivaram , Brandes Alba , Bouffet Eric , Bowers Daniel , Artemov Anton , Chintagumpala Murali , Zurakowski David , van den Bent Martin , Bison Brigitte , Yeom Kristen , Taal Walter , Warren Katherine
Published: December 2020

INTRODUCTION

Pediatric low-grade gliomas (pLGG) show clinical and biological features that are distinct from their adult counterparts. Consequently, additional considerations are needed for response assessment in children compared to the established adult Response Assessment in Neuro-Oncology (RANO) criteria. Standardized response criteria in pediatric clinical trials are lacking, complicating comparisons of responses across studies. We therefore established an international committee of the Radiologic Assessment in Pediatric Neuro-Oncology (RAPNO) working group to develop consensus recommendations for response assessment in pLGG.

METHODS

The committee consisted of 25 international experts in the areas of Pediatric Neuro-Oncology, Neuroradiology and Neurosurgery. The committee first developed a set of agreed upon topics they deemed necessary to understand the controversies of imaging utilization and assessment in pLGG. These topics were divided up among the committee members who presented all available literature to the entire RAPNO committee via web teleconference. Once presented, the group discussed these data and developed consensus statements and recommendations based on available literature, committee expertise and clinical experience. Each topic was discussed until a consensus was reached.

RESULTS

Final consensus included recommendations about the following topics: specific imaging sequences, advanced imaging techniques, NF1-associated pLGG, molecular and histologic classification, assessment of cysts, vision and other functional outcomes as well as overall radiologic response assessment.

CONCLUSIONS

The RAPNO pLGG consensus establishes systemic recommendations that represent an initial effort to uniformly collect and assess response in pLGG. These recommendations should now be evaluated internationally and prospectively in an effort to assess clinical utility, validate and modify as appropriate.
IMG-06. PREDICTING SURVIVAL FROM PERFUSION AND DIFFUSION MRI BY MACHINE LEARNING
Authors: Grist James T , Withey Stephanie , Bennett Christopher , Rose Heather , MacPherson Lesley , Oates Adam , Powell Stephen , Novak Jan , Abernethy Laurence , Pizer Barry , Bailey Simon , Mitra Dipayan , Arvanitis Theodoros N , Auer Dorothee P , Avula Shivaram , Grundy Richard , Peet Andrew C
Published: December 2020

INTRODUCTION

Magnetic Resonance Imaging (MRI) is routinely used in the assessment of children’s brain tumours. Reduced diffusion and increased perfusion on MRI are commonly associated with higher grade but there is a lack of quantitative data linking these parameters to survival. Machine learning is increasingly being used to develop diagnostic tools but its use in survival analysis is rare. In this study we combine quantitative parameters from diffusion and perfusion MRI with machine learning to develop a model of survival for paediatric brain tumours. METHOD: 69 children from 4 centres (Birmingham, Liverpool, Nottingham, Newcastle) underwent MRI with diffusion and perfusion (dynamic susceptibility contrast) at diagnosis. Images were processed to form ADC, cerebral blood volume (CBV) and vessel leakage correction (K2) parameter maps. Parameter mean, standard deviation and heterogeneity measures (skewness and kurtosis) were calculated from tumour and whole brain and used in iterative Bayesian survival analysis. The features selected were used for k-means clustering and differences in survival between clusters assessed by Kaplan-Meier and Cox-regression.

RESULTS

Bayesian analysis revealed the 5 top features determining survival to be tumour volume, ADC kurtosis, CBV mean, K2 mean and whole brain CBV mean. K-means clustering using these features showed two distinct clusters (high- and low-risk) which bore significantly different survival characteristics (Hazard Ratio = 5.6).

DISCUSSION AND CONCLUSION

Diffusion and perfusion MRI can be used to aid the prediction of survival in children’s brain tumours. Tumour perfusion played a particularly important role in predicting survival despite being less routinely measured than diffusion.
IMG-07. GADOLINIUM IS NOT NECESSARY FOR SURVEILLANCE MR IMAGING IN CHILDREN WITH CHIASMATIC-HYPOTHALAMIC LOW GRADE GLIOMA
Authors: Malbari Fatema , Chintagumpala Murali , Su Jack , Okcu Mehmet , Lin Frank , Lindsay Holly , Rednam Surya , Baxter Patricia , Aldave Guillermo , Whitehead William , Dauser Robert , Kralik Stephen
Published: December 2020

BACKGROUND

Patients with chiasmatic-hypothalamic low grade glioma (CHLGG) have frequent MRIs with gadolinium based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in children is a potential concern. The purpose of this research is to establish whether MRI with GBCA is necessary for determining tumor progression in children with CHLGG.

METHODS

Children with progressive CHLGG were identified from Texas Children’s Cancer Center between 2005–2019. Pre- and post-contrast MRI sequences were separately reviewed by one neuroradiologist who was blinded to the clinical course. Three dimensional measurements and tumor characteristics were collected. Radiographic progression was defined as a 25% increase in size (product of two largest dimensions) compared to baseline or best response after initiation of therapy.

RESULTS

A total of 28 patients with progressive CHLGG including 683 MRIs with GBCA (mean 24 MRIs/patient; range: 10–43 MRIs) were reviewed. No patients had a diagnosis of NF1. Progression was observed 92 times, 91 (98.9%) on noncontrast and 90 (97.8%) on contrast imaging. Sixty-seven radiographic and/or clinical progressions necessitating management changes were identified in all (100%) noncontrast sequences and 66 (98.5%) contrast sequences. Tumor growth >2 mm in any dimension was identified in 184/187(98.4%) on noncontrast and 181/187(96.8%) with contrast imaging. Non primary metastatic disease was seen in seven patients (25%), which were better visualized on contrast imaging in 4 (57%).

CONCLUSION

MRI without GBCA effectively identifies patients with progressive disease. One should consider eliminating contrast in imaging of children with CHLGG with GBCA reserved for monitoring those with metastatic disease.
IMG-10. MRI-BASED RADIOMIC PROGNOSTIC MARKERS OF DIFFUSE MIDLINE GLIOMA
Authors: Tam Lydia , Han Michelle , Wright Jason , Toescu Sebastien , Campion Andrew , Shpanskaya Katie , Mankad Kshitij , Ho Chang , Lober Robert , Cheshier Samuel , Hargrave Darren , Jacques Tom , Aquilina Kristian , Monje Michelle , Grant Gerald , Mattonen Sarah , Vitanza Nick , Yeom Kristen
Published: December 2020

BACKGROUND

Diffuse midline gliomas (DMG) are lethal pediatric brain tumors with dismal prognoses. Presently, MRI is the mainstay of disease diagnosis and surveillance. We aimed to identify prognostic image-based radiomics markers of DMG and compare its performance to clinical variables at presentation.

METHODS

104 treatment-naïve DMG MRIs from five centers were used (median age=6.5yrs; 18 males, median OS=11mos). We isolated tumor volumes of T1-post-contrast (T1gad) and T2-weighted (T2) MRI for PyRadiomics high-dimensional feature extraction. 900 features were extracted on each image, including first order statistics, 2D/3D Shape, Gray Level Co-occurrence Matrix, Gray Level Run Length Matrix, Gray Level Size Zone Matrix, Neighboring Gray tone Difference Matrix, and Gray Level Dependence Matrix, as defined by Imaging Biomarker Standardization Initiative. Overall survival (OS) served as outcome. 10-fold cross-validation of LASSO Cox regression was used to predict OS. We analyzed model performance using clinical variable (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variable. Concordance metric was used to assess the Cox model.

RESULTS

Nine radiomic features were selected from T1gad (2 texture wavelet) and T2 (5 first-order features (1 original, 4 wavelet), 2 texture features (1 wavelet, 1 log-sigma). This model demonstrated significantly higher performance than a clinical model alone (C: 0.68 vs 0.59, p<0.001). Adding clinical features to radiomic features slightly improved prediction, but was not significant (C=0.70, p=0.06).

CONCLUSION

Our pilot study shows a potential role for MRI-based radiomics and machine learning for DMG risk stratification and as image-based biomarkers for clinical therapy trials.
IMG-14. DEVELOPING A PREDICTIVE GRADING MODEL FOR CHILDREN WITH GLIOMAS BASED ON DIFFUSION KURTOSIS IMAGING METRICS: ACCURACY AND CLINICAL CORRELATIONS WITH SURVIVAL
Authors: Voicu Ioan Paul , Napolitano Antonio , Carboni Alessia , Lattavo Lorenzo , Carai Andrea , Vinci Maria , Diomedi-Camassei Francesca , Cacchione Antonella , Del Baldo Giada , Tomà Paolo , Mastronuzzi Angela , Colafati Giovanna Stefania
Published: December 2020

PURPOSE

To develop a predictive grading model based on diffusion kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the model via correlations with overall survival and progression-free survival.

MATERIALS AND METHODS

We retrospectively studied 59 children (33M, 26F, median age 7.2 years) affected by gliomas on a 3T magnet. Patients with tumor locations other than infratentorial midline were included. Conventional and DKI sequences were obtained. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps were obtained. Whole tumor volumes (VOIs) were segmented semiautomatically. Mean DKI values were calculated for each metric. The quantitative values from DKI-derived metrics were used to develop a predictive grading model with penalized logistic regression (glmnet package, R). Elasticnet regularization was used to avoid model overfitting. Fitted model coefficients from each metric were used to develop a probability prediction of a high-grade glioma (HGG). Grading accuracy of the resulting probabilities was tested with ROC analysis. Finally, model predictions were correlated to progression-free survival (PFS) with a Kaplan-Meier analysis.

RESULTS

The cohort included 46 patients with low-grade gliomas (LGG) and 13 patients with HGG. The developed model predictions yielded an AUC of 0.946 (95%CI: 0.890–1). Model predictions were significantly correlated with PFS (23.1 months for HGG vs 34.7 months for LGG, p<0.004).

CONCLUSION

In our cohort, a DKI-based predictive model was highly accurate for pediatric glioma grading. DKI-based model predictions were significantly correlated with progression-free survival.
IMG-18. ASSESSMENT OF SUSPECTED DISEASE PROGRESSION USING MULTIPARAMETRIC 18F-CHOLINE PET/MRI IN CHILDHOOD AND TEENAGE-YOUNG ADULT GLIOMAS
Authors: Ferrazzoli Valentina , Shankar Ananth , Cockle Julia , Tang Christine , Al-khayfawee Ahmed , Thomas Benjamin , Barnes Anna , Bomanji Jamshed , Fraioli Francesco , Hyare Harpreet
Published: December 2020

OBJECTIVES

Evaluation of post-treatment glioma burden remains a significant challenge in children, teenagers and young adults (TYA). The aim of this study was to evaluate the utility of ChoPET/MRI for evaluation of suspected disease progression in childhood and TYA gliomas.

METHODS

27 patients (mean age 14 years, range 6–21 years) with suspected glioma disease progression were evaluated with ChoPET/MRI (n=59). Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne, SUVwm). 2 blinded radiologists scored tumour probability (1 = unlikely; 5 = definitely). Sensitivity and specificity calculated with gold standard histopathology or clinical follow-up.

RESULTS

Accuracy for the detection of residual/recurrent tumour on conventional MRI was 96.3% (91.7% ≤14 years, 100% ≥15 years) and ChoPET was 73.1% (66.7% ≤14 years, 80.0% ≥15 years). Lack of agreement was observed in 9/27 patients, with ChoPET superior to MRI in 1 case of a posterior fossa tumour. Tumour component analysis demonstrated significantly higher SUVenh and SUVne than SUVwm (SUVenh: p<0.001; SUVne: p=0.004, equivalent to results were observed for ADV and rCBV (ADCenh, ADCne: p<0.001 vs ADCwm; rCBVenh, rCBVne: p<0.001 vs rCBVwm).

CONCLUSIONS

MRI is more sensitive than ChoPET in the evaluation of suspected disease progression in TYA gliomas. However, quanititative ChoPET is able to detect enhancing and non-enhancing tumour and may be helpful in evaluating posterior fossa disease where MRI is equivocal.
IMG-20. RADIOMIC FEATURES IMPROVE PROGNOSTICATION OVER CONVENTIONAL MR DERIVED QUALITATIVE DESCRIPTORS IN PEDIATRIC SUPRATENTORIAL HIGH GRADE GLIOMA: COMPARISON OF MACHINE LEARNING TECHNIQUES
Authors: Lucas John , Hsu Chih-Yang , Becksfort Jared , Hwang Scott , Lu Zhaohua , Wang Yichuan , Chiang Jason , Tinkle Christopher , Gajjar Amar , Merchant Thomas , Patay Zoltan
Published: December 2020

PURPOSE/OBJECTIVES

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

METHODS

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

RESULTS

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

CONCLUSION

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

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

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

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

BACKGROUND

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

METHODS

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

RESULTS

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

DISCUSSION

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSION

Our novel immuno-monitoring approach offers insight into how vaccine-induced immune responses impact clinical outcomes.