bluuebunny/crossref_metadata_2025 huggingface dataset:
DDEL-07. A Phase I study examining the feasibility of intermittent convection-enhanced delivery (CED) of MTX110 for the treatment of children with newly diagnosed diffuse midline gliomas (DMGs)
Authors: Zacharoulis Stergios , Szalontay Luca , CreveCoeur Travis , Neira Justin , Higgins Dominique , Englander Zachary , Spinazzi Eleonora , Sethi Chankrit , Canoll Peter , Garvin James , Zylber Rebecca , Damment Steve , Zamoryakhin Dmitry , Maddocks Alexis , Feldstein Neil , Bruce Jeffrey
Published: June 2022

Histone deacetylase inhibitors have been found preclinically to be among the most active agents against DMGs, however, they are clinically ineffective with systemic delivery due to blood brain barrier limitations and toxicity. Using a repurposed device (implantable subcutaneous pump connected with a catheter directly implanted into the pons/thalamus) we are performing a phase I, standard 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Midatech Pharma), a water-soluble formulation of panobinostat, via CED. Eligible patents are between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without hemorrhage or cyst in the tumor, and having intact organ function. Following tumor biopsy and device implantation, patients receive two 48-hour-infusion pulses 7 days apart of MTX110 (30, 60, or 90 mM). The infusion pump is prefilled with MTX110 (and gadolinium for co-infusion to serve as a surrogate for drug distribution) and administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. Seven patients (30 mM group, n=3 and 60 mM group, n=4) have been treated with the MTX110 infusate. All but one patient had adequate tumor coverage as measured by co-infused gadolinium on MRI. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) and the infusion (n=3). In a follow up period of 12-22 months from diagnosis, progression free survival ranges from 8 to 20 months. With one objective response, 3 patients remain alive (2 without progression, both at 12 months, and 1 with progressive disease, at 22 months post diagnosis). Three patients are expected to be treated at 90 mM level. Using MTX110, we demonstrated the safety and feasibility of repeated drug infusion by CED in DMG patients.
EPCT-07. Updated report on the pilot study of using MRI-guided laser heat ablation to induce disruption of the peritumoral blood brain barrier to enhance deliver and efficacy of treatment of pediatric brain tumors
Authors: Shatara Margaret , Gauvain Karen , Cantor Evan , Meyer Ashley , Ogle Andrea , McHugh Michele , Beck Mary , Green Tammy , King Allison , Cluster Andrew , Brossier Nicole , Shimony Joshua S , Abdelbaki Mohamed S , Tran David D , Campian Jian , Leuthardt Eric C , Rubin Joshua , Limbrick David
Published: June 2022

BACKGROUND: MRI-guided laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive surgery useful for managing unresectable brain tumors. LITT disrupts the blood brain barrier (BBB) and facilitates chemotherapy delivery. We report the toxicity and outcome for pediatric brain tumors treated on a pilot trial of LITT and chemotherapy. The primary objectives were to quantify peritumoral BBB disruption following LITT and evaluate toxicity and efficacy. METHODS: The trial had two arms, A: patients with newly diagnosed gliomas underwent LITT followed by standard of care management, and B: patients with relapsed malignant brain tumors received 6 weeks of weekly doxorubicin post-LITT followed by maintenance etoposide. RESULTS: Between 2015 – 2018, six patients were enrolled: five on arm A (four with low-grade gliomas, one with high-grade glioma), one on Arm B with progressive anaplastic astrocytoma. All patients tolerated the procedure well; four experienced a transient hemiparesis post-LITT. The Arm B patient progressed and died of disease 2 months and 22 months post-LITT, respectively. The HGG patient received standard therapy and remains without disease progression 44 months post-LITT. One patient with LGG required additional treatment for disease progression 14 months post-LITT. Two patients with LGGs did not require additional therapy, now 51 and 41 months post-LITT. One patient was alive 24 weeks post-LITT and subsequently lost to follow-up. Peritumoral BBB disruption was analyzed in two ways: serum abundance of brain-derived proteins and MRI Dynamic contrast enhancement (DCE). Neuron-specific enolase were measurable in the serum of all patients, using ELISA up to 84 days post-LITT. DCE 2 weeks post-LITT demonstrated increased enhancement and FLAIR signal, consistent with BBB disruption and vasogenic edema. This effect was evident up to 4 months post-procedure. CONCLUSION: LITT is safe in children with brain tumors and can be combined with chemotherapy. DCE and serum brain-derived proteins can measure BBB disruption.
EPEN-10. Elucidating the biological difference between pediatric supratentorial ependymomas using genetically engineered brain tumor organoids.
Authors: Roosen Mieke , Stathi Phylicia , Bunt Jens , Kool Marcel
Published: June 2022

Ependymomas (EPN) are neuroepithelial tumors of the central nervous system occurring both in adults and children. DNA methylation profiling has identified ten distinct molecular groups. In the supratentorial (ST) compartment, ZFTA-fusion positive and YAP1-fusion positive ST-EPN represent the two main groups in pediatric patients that are histologically very similar but have a completely different clinical behavior. While most ST-EPN-YAP1 patients survive, only 50% of ZFTA positive patients survive longer than 5 years. Improving survival of ZFTA positive patients requires better understanding of the tumor biology. Despite having different oncogenic fusions, it is unclear whether the cellular origin and tumor biology is related or not and why they respond differently to treatment. The development of human stem cell-derived brain organoids provides a novel opportunity to model these ST-EPN in vitro. These organoids mimic embryonal brain development, during which the cells-of-origin of ST-EPN as well as their micro-environment are present. To induce the development of ST-EPN in vitro, we genetically manipulated cerebral organoids to overexpress the group-specific oncogenic fusion proteins. Electroporating constructs expressing the different fusion proteins into organoids early in brain development (day 11), induced ectopic growth after approximately 30 days. Based on immunohistochemistry, we observed a different phenotype using either the ZFTA or YAP1 fusion constructs, as well as (over)expression of group-specific markers in the organoids. Preliminary transcriptomic analyses suggest that these genetically modified brain organoids represent models with features of human ST-EPN tumors. Ongoing single-cell RNA-sequencing and epigenomic analyses during normal organoid and tumor development will further reveal how well these models represent human primary tumors, how they develop in time, and possibly whether they originate from similar cells or different cells within these organoids. Hence, these models will uniquely contribute to the molecular and biological understanding of ependymomas and can be used to identify new targeted therapies.
EPEN-17. Recurrent infratentorial ependymomas in children: a meta-analysis on molecular-based outcomes
Authors: Montgomery Eric , Thirunavu Vineeth , Shlobin Nathan , Lam Sandi , DeCuypere Michael
Published: June 2022

The overall prognosis of infratentorial ependymoma differs based on molecular signature, however the impact of recurrence on prognosis remains poorly defined in the pediatric population. PubMed, Scopus, Embase, and Ovid were searched for publications on recurrent infratentorial ependymomas in patients under 25 years of age. Exclusion criteria were case series of less than 5 patients and studies that did not provide individualized patient data. Our search yielded 472 unique articles, of which 17 were included in the analysis. There was a total of 460 recurrent ependymomas reported, with 52.8% WHO grade II tumors and 47.2% grade III. The overall mortality for recurrent infratentorial ependymoma was 49.1% (226/460). The pooled median survival was 32.39 months after recurrence (95% CI: 23.45-41.33). Gross total resection was achieved in 237 (53.1%) patients at initial presentation. Raw mean survival post-recurrence was 32.9 months (SD: 11.2 months) for those who received GTR for their primary tumor versus 23.7 months (SD: 10.8 months) for those who received subtotal resection (STR) (p < 0.001). There was no difference in survival between those that received GTR (49.3 months, 95% CI: 32.3-66.3) versus STR (41.4 months, 95% CI: 11.6-71.2) of their recurrent tumor (p=0.610). In the studies that provided molecular classification, there were 169 PFA tumors (83.3%) and 34 PFB (16.6%), with 28 that demonstrated 1q gain. PFA-A tumors demonstrated worse post-progression survival (24.7 months, 95% CI: 15.3-34.0) compared to PF-B (48.0 months, 95% CI: 32.8-63.2) (p=0.0073). The average post-recurrence survival for tumors with 1q gain was 5.93 months (SD: 9.15). The overall mortality rate for recurrent infrantentorial ependymomas was found to be 49.8%, with a pooled median survival of 32.39 months. Almost 90% of recurrent infratentorial ependymomas were of the PFA molecular subtype, and those tumors that demonstrated 1q gain had a worse survival than those that did not.
EPEN-19. Impact of molecular classification on prognosis in children and adolescents with spinal ependymoma: Results from the HIT-MED database
Authors: Engertsberger Lara , Benesch Martin , Mynarek Martin , Tonn Svenja , Stickan-Verfürth Martina , Funk Angela , Pajtler Kristian W , Timmermann Beate , Kortmann Rolf-Dieter , Pietsch Torsten , Bison Brigitte , Warmuth-Metz Monika , Rutkowski Stefan , Schüller Ulrich
Published: June 2022

PURPOSE: Ependymomas of the spinal cord are rare among children, and individual risks of disease progression are difficult to predict. This study aims at evaluating the prognostic impact of DNA methylation-based classification in children with spinal ependymoma. METHODS: Eighty-two patients with spinal ependymoma <22 years registered in the HIT-MED database between 1992 and 2021 were included. Clinical, radiological, and histopathological data were collected retrospectively. DNA methylation profiles of 46 tumors were classified according to the Heidelberg Brain Tumor Classifier. RESULTS: Spinal myxopapillary ependymoma (SP-MPE, n=27) was the most common methylation group followed by spinal ependymoma (SP-EPN, n=15). Two cases belonged to MYCN-amplified subgroup, one had no match, and one was re-classified as anaplastic pilocytic astrocytoma (the latter excluded from final analysis). WHO grade I and III ependymomas (according to the WHO 2016 classification) classified predominantly as SP-MPE, whereas grade II ependymomas clustered into SP-MPE and SP-EPN. 6/15 patients with SP-EPN (40%) suffered from Neurofibromatosis type 2. Among patients with SP-MPE, 23 underwent gross-total and four a subtotal resection (GTR/STR). Relapses of SP-MPE were more common following STR (5-year progression-free survival (5y-PFS) [STR] 25.0% [95% confidence interval: 0.0-68.4], [GTR] 75.0% [53.4-96.6], p=0.003). In the SP-EPN group, 2/8 patients relapsed after STR (5y-PFS 64.3% [22,3-100]) and 0/7 after GTR (n.s.). WHO I° ependymoma had significantly inferior PFS than II° and III° ependymoma (5y-PFS [I°] 39.0% [5.8-62.2], [II°] 82.4% [67.8-97.0], [III°] 50.5% [18.9-82.1], p=0.009). However, PFS did not significantly differ between SP-MPE and SP-EPN (5y-PFS 65.9% [44.9-86.9], 76.9% [46.3-100], respectively). CONCLUSION: Spinal ependymomas of WHO grade I go along with relatively poor PFS in our cohort, while DNA methylation profiling does not segregate patients into distinct risk groups. Still, larger cohorts and further investigations of methylation class heterogeneity in pediatric spinal ependymomas are needed to complete the basis for future clinical decision-making.
EPEN-22. Molecularly aggressive ependymomas treated with Image guided pencil beam proton therapy: consecutive patient Indian experience
Authors: Sudarsan Rishan Thimma , Chilukuri Srinivas , Noufal M P , Adhithyan R , Uppuluri Ramya , Panda Pankaj Kumar , Patil Sushma , Sharma Dayananda , Roopesh Kumar V R , Jalali Rakesh
Published: June 2022

AIM: To assess the toxicities and early clinical outcomes in patients of primary and recurrent ependymomas treated with image guided pencil beam scanning proton beam therapy (PBS-PBT). MATERIALS AND METHODS: Between January 2019- December 2021, we analyzed consecutive patients of ependymomas treated with image guided PBS-PBT. They were also analyzed molecularly, and all recurrent/re-irradiated patients were considered for craniospinal irradiation (CSI). Acute toxicities were assessed based on NCI CTC v5.0, local control and radiological response by 3-monthly MRI post therapy. RESULTS: Seventeen consecutive patients with ependymoma (13 Grade III and 4 Grade II) (median age-9 years) were analyzed. 9 patients were primary, 7 were treated at first recurrence and 1 at second recurrence. Majority had posterior fossa (PF) tumors (12) followed by supratentorial (ST) (3) and spine (2). Among PF ependymomas, 10 had global loss of H3K27me3, whereas amongst ST, 1 had YAP1 fusion, 1 had L1CAM positivity and other, negative L1CAM and p65/RELA on immunohistochemistry. Gross/near-total resection was achieved in 87% patients. Primary ependymomas were treated with focal radiotherapy; and among recurrent cases, 7 received CSI followed by primary site boost to a total median dose of 55CGE (50.2-55.8CGE). Grade 2 dermatitis, grade 2 and 3 hematological toxicities (CSI) were noted in 3,2 and 2 patients respectively. Grade 2 fatigue noted in 53% of all and 71% receiving CSI. With a median follow-up of 10 months (2-24 months), local control (LC) and disease-free survival (DFS) was 87.5% (primary-100%, recurrent-75%) and overall survival (OS) was 94% (primary-100%, recurrent-88%). CONCLUSION: Our experience of treating patients of ependymoma with complete resection followed by PBS-PBT including CSI is encouraging with low acute toxicities. Recurrent/molecularly aggressive cases may be considered for CSI.

Keywords: PT, proton beam therapy, ependymomas, primary and recurrent
GCT-12. SIOP CNS GCT II: High Risk (HR) CNS Non-germinomatous Germ Cell Tumours (NGGCT) treated with Dose intensified PEI – final results
Authors: Calaminus Gabriele , Frappaz Didier , Ajithkumar Thankamma , Müller Jans-Enno , Zimmermann Martin , Conter Cecile Faure , Timmermann Beate , Alapetite Claire , Murray Matthew , Garre Maria Luisa , Dieckmann Karin , Peyrl Andreas , Gerber Nicolas U , Kortmann Rolf-Dieter , Nicholson James
Published: June 2022

Based on results of SIOP CNS GCT 96, patients enrolled in SIOP CNS GCT II with AFP higher or 1000 ng/ml (serum and/or CSF) and/or age less than 6 years with NGGCTs at diagnosis received two standard cycles of PEI and two higher dose PEI courses followed by radiotherapy according to dissemination (54 Gy local RT or 30 Gy CSI/24 Gy tumour boost). Between 2/2012 and 7/2018, 112 patients with CNS NGGCT were registered, of whom 23 were identified as HR patients; 18/23 had an AFP higher or 1000 ng/ml and were older than 6 years. Five children were < 6 years and showed YST elements in histology. of whom 3 received chemotherapy alone due to age. Primary site was pineal in 15/23, suprasellar in 5/23, bifocal in 3/23 patients; 3/23 patients were metastatic at diagnosis and 9/23 patients relapsed. Three years EFS was 0.60±0.10 with a median observation time of 3.96 years. Two recurrences were local, 4 distant (metastatic) and 3 combined, local and distant. HR CNS NGGCTs appeared to benefit from dose intensified PEI, compared with those treated in SIOP CNS GCT 96 with standard dose PEI. These results support the further exploration of this chemotherapy regimen in future clinical trials in such patient groups, including the consideration of delivering three dose intensified courses after one standard chemotherapy course, as is the practice in some groups treating very high risk extracranial GCTs.
GCT-15. Multi-institutional analysis and literature review of central nervous system germ cell tumors in patients with Down syndrome
Authors: Harris Micah K , Stanek Joseph R , Graham Richard T , Cappellano Andréa M , Margol Ashley S , Michaiel George , Crawford John R , Liu Kevin X , MacDonald Shannon M , Abdelbaki Mohamed S
Published: June 2022

BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.
HGG-01. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes and promotion of the NOTCH pathway
Authors: Abdallah Aalaa , Cardona Herminio , Gadd Samantha , Brat Daniel , Picketts David , Becher Oren , Li Xiao-Nan
Published: June 2022

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are an aggressive CNS tumor which are often characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). A substitution of the Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described in a large cohort of pHGG samples and has been characterized as occurring in anywhere between 5-20% of pHGGs. Attempts to study the mechanisms of H3.3G34R have proven difficult due to the developmental nature of the disease and the requirement of co-occurring mutations for model development. METHODS: We utilized the RCAS system to develop a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the context of ATRX loss and ATRX presence in nestin expressing progenitors. RESULTS: We show that in H3.3G34R expressing mice, ATRX loss significantly increased tumor latency from 90 days to 143 days (p < 0.01, Log rank test) and decreased tumor incidence from 81% to 57% (p < 0.01, Fisher’s exact test). By contrast, H3.3G34R did not significantly impact tumor latency in either our ATRX loss (163 days to 143 days, p = 0.178, Log-rank test) or our ATRX expressing (95 days to 90 days, p = 0.415, Log-rank test) models. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates the PRC2 associated genes Hoxa2, Hoxa3, Hoxa5, and Hoxa7 (p < 0.05, unpaired t-test). GSEA analysis and RT-qPCR data suggest that ATRX loss works synergistically with H3.3G34R to promote NOTCH pathway activation through upregulation of the NOTCH ligand Dll3 (p < 0.01, unpaired t-test). CONCLUSIONS: Our study proposes a model in which ATRX loss is the major contributor to transcriptomic changes in the majority of H3.3G34R pHGGs. Broadly, our work highlights the importance of studying mechanisms of co-occurring genetic events separately and in combination.
HGG-05. Systematic review of diffuse hemispheric glioma, H3 G34-mutant and clinical factors influencing outcomes
Authors: Crowell Cameron , Mata-Mbemba Daddy , Bennett Julie , Matheson Kara , Mackley Michael , Erker Craig
Published: June 2022

BACKGROUND: A comprehensive description of clinical features and factors impacting prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (DHG H3G34) is not easily accessible. Understanding survival data and prognostic features is paramount for clinical advancements and ensuring patients/families are fully informed. METHODS: To summarize clinical, basic histomolecular, and treatment variables and their impacts on survival of DHG H3G34, a systematic review was undertaken. PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012, and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumour with at least one measure of survival or progression. A protocol was prospectively registered in PROSPERO (CRD42021267764) and PRISMA guidelines were followed. RESULTS: 27 studies met criteria for inclusion (13 pediatric-focused, 3 adult-focused, and 11 all ages). 135 unique patients with DHG H3G34 were included (118 G34R, 8 G34V, and 9 determined via methylation alone). Median age at diagnosis was 15.8 years (IQR=13.3-22.0). At presentation, 90% had localized disease. Co-occurring alterations included ATRX mutation 93%, TP53 mutation 88%, PDGFRA mutation 46%, PDGFRA amplification 13%, and MGMT promoter methylation in 70%. 89% of patients reported progressive disease with a median time-to-progression of 10.0 months. At last follow-up, 71% had died. Median time from progression to death was 5.0 months (IQR=3.0-12.0). Median overall survival was 17.3 months (95% CI 13.5-21.1) with a 1-, 2-, 3-, 5-year survival of 75, 39, 24, and 12%, respectively. Factors found to influence survival duration were presence of MGMT promoter methylation (HR=0.48, 95% CI 0.25-0.90) and less than near-total resection upfront (HR=3.59, 95% CI 2.07-6.22). CONCLUSION: This review highlights the poor prognosis, available survival measures, important prognostic features of DHG G34, and serves as a baseline for future clinical trials, though further study to identify prognostic biomarkers is needed.
HGG-12. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana , Serkova Natalie , Foreman Nicholas , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan
Published: June 2022

BACKGROUND: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. DESIGN/METHOD: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. RESULTS: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. CONCLUSION: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
HGG-17. Novel Fusion in Congenital Brainstem Diffuse High-Grade Glioma
Authors: Norris Gregory , Donson Andrew , Milgrom Sarah , Gaskell Alisa , Willard Nicholas , Foreman Nicholas , Gilani Ahmed , Dahl Nathan
Published: June 2022

BACKGROUND: Infant-type hemispheric glioma, previously termed infantile glioblastoma multiforme, is a rare infantile neoplasm with improved survival and distinct molecular features when compared to other pediatric and adult-type high-grade glioma. Infant-type high-grade gliomas are typically located in the cerebral hemispheres and are characterized by ALK, ROS1, MET, and NTRK fusions. Typical brainstem gliomas (diffuse midline glioma, H3 K27-altered or diffuse intrinsic pontine glioma) are comparatively rare in this age group. As a result, the biology of brainstem congenital high-grade gliomas is poorly described. RESULTS: A 3 month old female who initially presented with failure to thrive had an apneic event and was found to have an infiltrative mass in the medulla with expansion into the pons and cervical spine on magnetic resonance imaging. She underwent surgical biopsy with pathology revealing diffuse high-grade glioma, WHO grade 4. Next generation sequencing showed no alterations to H3F3A, IDH, or fusions involving BRAF, ALK, ROS1, MET, or NTRK. Whole-transcriptome sequencing revealed a novel fusion of PDGFRB:APOBEC3C. She received chemotherapy with 2 cycles of carboplatin/etoposide and 2 cycles of carboplatin/etoposide/imatinib before having disease progression. She then underwent palliative radiation (35 Gy in 10 fractions) with near complete regression of her disease. Surprisingly, our patient has not had any progression of disease or new lesions now two years from her last therapy. CONCLUSION: Congenital high-grade glioma is a rare, unique entity that greatly differs from its adult and childhood counterparts. Here, we discuss a previously-unreported fusion of PDGFB:APOBEC3C in a patient with congenital brainstem diffuse high-grade glioma with a favorable clinical course. This highlights the importance of routine molecular characterization, both to better understand the complex biology of this rare disease and to guide prognosis and clinical decision making for individual patients and families.
HGG-24. NTRK-rearranged infantile gliomas of suprasellar/ optic pathway origin
Authors: Lazow Margot A , Mathew Mariam , Salloum Ralph , Rodriguez Diana P , Leonard Jeffrey , Chi Susan , Thomas Diana , Cottrell Catherine , Fouladi Maryam , Boué Daniel R
Published: June 2022

BACKGROUND: Oncogenic fusions involving neurotrophic tyrosine receptor kinase (NTRK) have been identified across cancer types and represent potential therapeutic targets given availability of TRK inhibitors. Gliomas harboring NTRK fusions have been described most commonly in infants with high-grade histology and hemispheric tumor location, though there is emerging evidence suggesting clinical, histopathologic, and molecular heterogeneity. Herein, we present two cases of NTRK-rearranged suprasellar/ optic pathway gliomas. CASE DESCRIPTIONS: The first patient was diagnosed at 6 months old with an extensive suprasellar/ optic pathway tumor, treated with carboplatin/ vincristine, which initially responded but subsequently progressed. A biopsy was then performed, with pathology consistent with infiltrating piloid astrocytoma with anaplastic features (elevated mitoses and Ki-67 index); a BCAN-NTRK1 fusion was identified by RT-PCR and confirmed by Sanger sequencing. After further disease progression on vinblastine monotherapy, this patient began treatment with entrectinib (NCT02650401), with favorable clinical and radiographic responses thus far. The second patient was diagnosed with a large suprasellar/ optic pathway tumor at 3 years old, and underwent upfront partial resection, revealing similar infiltrating piloid/pilocytic astrocytoma with anaplastic features (elevated mitoses and Ki-67 index). A diagnosis of “midline” infantile high-grade glioma (HGG) was also considered, as with the former case. Sequencing demonstrated a SOX10-NTRK3 rearrangement, resulting in an integrated diagnosis of NTRK-fused infantile HGG, for which the patient recently started treatment with larotrectinib (NCT04655404). Both patients’ fusions retain the entire kinase domain of respective NTRK partners, supporting oncogenicity, and neither tumor harbored additional somatic pathogenic variants (both lacked BRAF alterations). Methylation profiling did not confidently classify either tumor. CONCLUSIONS: NTRK-rearranged gliomas may present with primary suprasellar/ optic pathway involvement in infants. Given the potential to offer targeted therapy, testing for the presence of NTRK fusions should be strongly considered for infantile gliomas in any location, including midline, and across the histologic spectrum.
HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
Authors: Abou-Antoun Tamara , Kfoury Najla , Yang Lihua , Warrington Nicole , Chen Xuhua , Reiss India , Wilkinson Michael , Mitra Robi , Rubin Josh
Published: June 2022

Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformation of the astrocytes with male cells being significantly more tumorigenic and therapeutically resistant compared to female cells. In our current work, we aimed to delineate the molecular mechanisms driving this sex-biased tumorigenic phenotype in order to deliver therapies that are more effective to patients with GBM. We examined the inhibition of KLF5 on tumorigenic phenotypes using cellular bio-functional assays. We used barcoded transposon calling cards to determine the genomic localization of KLF5 and the differentially induced gene expression in male versus female GBM cells. Chemical inhibition or shRNA knock-down of KLF5 significantly reduced proliferation, migration, clonogenic stem-cell frequency and survival, but increase apoptosis in male and female GBM cells. Interestingly, male, but not female, GBM cells exhibited an increased migratory phenotype after radiation that inhibition of KLF5 significantly reduced. Moreover, KLF5 inhibition significantly reduced the protein expression of tumorigenic PDGFRB, AKT, ERK and the stem marker Sox-2. Transposon calling cards mapped unique KLF5 genomic localization in male versus female GBM cells with significantly differential gene expression profiles between the two. The top genes induced by KLF5 in male cells were primarily affiliated with poorer prognosis and reduced survival, whereas in female cells they were affiliated with better prognosis and improved survival in patients with cancer. Our findings provide a promising exploratory avenue for KLF5 as a therapeutic target in GBM and warrants further investigation in order to delineate the precise molecular mechanisms driving this antitumor response so that targeted therapy would be more effective taking into consideration the sex-differences in patients with GBM.
HGG-32. Durable response to mTOR inhibitor after failing Checkpoint inhibitors in Ultra-Hypermutated High grade glioma in context of CMMRD
Authors: Hegde Kriti , Dahl Christine , Depani Sarita , Hargrave Darren , Oostveen Minou , Aguirregomezcorta Fernando , Jeelani Owase , Aquilina Kristian , Gains Jenny , Ching Yen , Jacues Thomas , Merve Ashirwad , Chalker Jane , Addy Dilys , Ahmed Saira W , Yasin Shireen , Mankad Kshitij , Carney Olivia , Sudhakar Sniya , D'Arco Felice , Loebel Ulrike , Jorgensen Mette
Published: June 2022

BACKGROUND: Paediatric High Grade Gliomas (HGG) have poor outcomes with conventional treatment. HGG in association with constitutional DNA mismatch repair deficiency (CMMRD) are hypermutated and have shown dramatic response to checkpoint inhibitors. Salvage following progression or failure to respond to check point inhibitors has rarely been reported. We describe a successful alternative therapeutic approach targeting the activated pathway (mTOR) in a hypermutated HGG. CASE SUMMARY: A 6-year-old girl presenting with seizures was diagnosed with left frontal lobe HGG with concurrent neck mass (Pilomatrixoma). Presence of synchronous tumours raised the possibility of cancer predisposition; the HGG was hypermutated with germline PMS2 mutation confirming diagnosis of CMMRD. Near total resection was undertaken followed by focal radiotherapy 54 Gy, with 1 cycle of concomitant CCNU. MRI post radiotherapy showed tumour progression. Anti-PDl inhibitor Nivolumab was commenced. CTLA-4 antibody, Ipilimumab was added after 4 cycles of Nivolumab due to poor response. Tumour response was seen, but dual therapy had to be discontinued due to toxicity. The tumour progressed following further single agent Nivolumab. In view of multiple mutations in the mTOR pathway (NF1, PIK3/PTEN, TSC1, TSC2), a mTOR inhibitor, Everolimus was commenced. There was 25% tumour reduction after 4 weeks treatment and further reduction after 6 months. Resection of residual tumour showed necrotic tissue only. There continues to be a sustained response to Everolimus for over 12 months. DISCUSSION: Approximately a third of CMMRD HGG respond to checkpoint inhibitors. For those that don’t, these hypermutated tumours offers the possibility of targeting specific molecular pathways. Response to Everolimus in HGG harbouring mTOR aberrations have been described. To our knowledge this is the first report of successful use of mTOR inhibitor in CMMRD HGG. CONCLUSION: Targeted molecular treatment for patients with CMMRD hypermutated brain tumours should be considered according to the mutated pathways.
HGG-36. Elucidating the role of long non-coding RNAs in pediatric high grade gliomas
Authors: Tsai Jessica W , Dubois Frank P B , Wang Dayle K , Crane Alexander , Condurat Alexandra L , Krug Brian , Brown Adam , Doench John G , Jabado Nada , Bandopadhayay Pratiti
Published: June 2022

BACKGROUND: Genomic and transcriptomic studies have elucidated new insights into the landscape of diffuse intrinsic pontine glioma (DIPG). However, the role of long non-coding RNAs (lncRNAs) has not been explored at depth in these tumors, and there have not been studies focused on how lncRNAs interact with the K27M histone mutation. In a recent analysis of nearly 200 DIPGs and pediatric high-grade gliomas (pHGG), we previously detected a novel, recurring structural variant in the lncRNA CCDC26. This rearrangement occurs in nearly 10% of all DIPGs, and we have furthermore identified alterations in more than 100 lncRNAs in DIPG. METHODS: To identify lncRNAs required for proliferation of patient-derived DIPG cancer cells, we designed two custom genome-scale lncRNA libraries. We generated a genome-scale lncRNA CRISPR-Cas9 knockout pooled library, consisting of 45,766 single guide RNAs (sgRNAs). Additionally, we generated a genome-wide CRISPR interference pooled library consisting of 45,608 sgRNAs, targeting lncRNA transcription start sites (TSS). RESULTS: We utilized in vitro histone-mutant pHGG models as well as edited clones of these models with the K27M mutant corrected in order to compare lncRNA dependencies in these two contexts. We have successfully performed genome-scale CRISPR-Cas9 knockout and CRISPR interference screens targeting lncRNAs in these cell lines, revealing lncRNA dependencies. Candidate dependencies in our CRISPR-Cas9 knockout screen include LOC100507412, LOC105379524, and LINC02193. CONCLUSION: Genome-wide lncRNA CRISPR knock-out and CRISPR interference screens are a novel approach for the unbiased identification of lncRNAs that are required for pediatric high-grade glioma proliferation. Further validation of specific lncRNAs is required, and these lncRNA dependencies represent potential novel therapeutic targets.
HGG-58. SIOPE HGG Working Group approach to obtain consensus on management of paediatric high grade glioma across Europe
Authors: Giraud Géraldine , Szychot Elwira , Kramm Christof , Hargrave Darren , van Vuurden Dannis G ,   SIOPE HGG working group
Published: June 2022

BACKGROUND: There is currently no European standard clinical practice on the management of paediatric HGG (pHGG). AIMS: To develop approved clinical recommendations for the management of pHGG reflecting current best practice, with the ultimate aim of improved outcomes. METHODS: An open questions survey was performed to establish the status quo regarding standards of care in pHGG across Europe. National coordinators from 33 countries were invited to participate in the process. RESULTS: 32 out of 33 countries completed the survey. Substantial areas of agreement were reached. All 32 countries agreed that hemispheric pHGG should be treated with radiotherapy and adjuvant chemotherapy after surgical resection. 30/32 (94%) countries proposed initial radiotherapy with concomitant temozolomide where 23/32 (72%) countries recommended a complementary adjuvant chemotherapy (Lomustine, Valproic acid, or Nivolumab). 32 countries agreed H3K27M diffuse midline glioma DMG, including DMG of the pons (DIPG), should be treated with radiotherapy. 10/32 (31%) countries proposed radiotherapy alone at diagnosis. There was no consensus on the role of adjuvant chemotherapy; temozolomide was recommended in 9/32 (28%), while mTOR inhibitor in 7/32 (22%) countries. A biopsy of DIPG was routinely offered in 18/32 (56%) countries, while in 4 countries was considered on an individual basis. Six countries never performed a biopsy. Re-irradiation at the relapse was consensual in 26/32 (81%) countries. Certain areas of divergence were identified. A Delphi method is being employed to reach a general consensus on those areas. CONCLUSION: This two-step approach will help us to set up the European guidelines on the management of pHGG based on the current best standard of care. This approach will also identify areas, which should be the focus of future collaborative studies. Such efforts will ultimately translate into improved patient outcomes.
HGG-59. Pediatric high-grade gliomas and the WHO classification on CNS Tumors - Different perspectives of pediatric neuro-oncologists and neuropathologists in the light of recent updates
Authors: Gielen Gerrit , Baugh Joshua , van Vuurden Dannis , van Zanten Sophie Veldhuijzen , Hargrave Darren , Massimino Maura , Biassoni Veronica , la Madrid Andres Morales , Karremann Michael , Wiese Maria , Thomale Ulrich , Janssens Geert , von Bueren André , Niehusmann Pitt , Gessi Marco , Kwiecien Robert , Bailey Simon , Pietsch Torsten , Andreiuolo Felipe
Published: June 2022

BACKGROUND: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring following rapid advances in brain tumor genomics and epigenomics. The most significant changes resulted from the introduction of molecularly defined diagnostic criteria in 2016 (revised 4th edition). In 2021 (5th edition), further essential molecular criteria were incorporated. In the present study, we sought to investigate potential differences between specialists in perception of these newly defined molecular subtypes of pediatric high-grade gliomas (pedHGG). METHODS: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to capture the spectrum of viewpoints and possible differences among neuro-oncologists and neuropathologists. RESULTS: 465 participants from 53 countries responded, of which 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%) and 118 experts in other related fields (neurosurgeons, radiotherapists, neuroradiologists and others; 26%). Neuro-oncologists reported having issues with the introduction of new molecular entities, such as the abolishment and renaming of established tumor entities. Neuropathologists did not define these problems to the same extent. However, both groups felt that in the 2016 version, less relevant or insufficient diagnostic definitions were available for pedHGG. Within the 2021 WHO classification, a substantial improvement was perceived regarding the definition of pedHGG entities. However, some issues of high clinical relevance, like the definition of clinical phenotypes such as diffuse intrinsic pontine glioma (DIPG) and gliomatosis cerebri, are yet to be addressed. CONCLUSIONS: Within the WHO classification of pediatric brain tumors, such as high-grade gliomas, rapid changes in nomenclature have been introduced because of substantial improvement in molecular characterization. This study highlights that ongoing cross-talk between advancing classification of pedHGG subtypes and its biological relevance and clinical impact is essential.
IMG-16. Non-invasive metabolic imaging of response to therapy in diffuse midline gliomas
Authors: Batsios Georgios , Taglang Celine , Tran Meryssa , Gillespie Anne Marie , Nazarian Javad , Mueller Sabine , Viswanath Pavithra
Published: June 2022

Diffuse midline gliomas (DMGs) are universally lethal pediatric tumors that are defined by the presence of histone H3K27 alterations. The infiltrative nature and anatomical location of these tumors prohibit surgical resection. Radiotherapy, which is standard of care, does not significantly enhance long-term outcome. Novel therapies are sorely needed for DMG patients. Imipridone drugs ONC201 and ONC206 have demonstrated anti-tumor activity in preclinical cancer models, including DMGs and have shown promise in pilot studies in DMG patients. Successful clinical deployment of imipridones requires the identification of companion imaging biomarkers that report on response to therapy. Magnetic resonance spectroscopy (MRS) is a safe, non-radioactive, non-invasive method of imaging metabolism in vivo. 1H-MRS assesses steady-state metabolite levels and is used in clinics. 2H-MRS following administration of 2H-labeled substrates is a novel, clinically translatable method of imaging metabolic pathway activity. Our results indicate that treatment of SF7761 DMG cells with ONC206 causes a significant reduction in 1H-MRS-detectable lactate, glutamate, glutathione and phosphocholine, pointing to inhibition of glycolysis, oxidative phosphorylation, redox and phosphatidylcholine biosynthesis respectively. Examination of [6,6’-2H]-glucose metabolism using 2H-MRS indicates that lactate production from [6,6’-2H]-glucose is significantly reduced in ONC206-treated SF7761 cells relative to controls. We then investigated the effect of ONC206 on mice bearing orthotopic SF8628 DMG tumors. At day 7 following the treatment onset, at a timepoint when no change in tumor volume can be observed by anatomical imaging, in vivo1H-MRS-detectable lactate and total choline are reduced relative to day 0. Collectively, our studies indicate that imipridones induce alterations in DMG metabolism that can be leveraged for non-invasive 1H- and 2H-MRS-based imaging of response to therapy. By providing clinicians with an early readout of treatment response prior to anatomical changes, our biomarkers will enable early assessment of treatment response and, thereby, clinical translation of these promising therapeutics.
LGG-01. Children with Supratentorial Midline Pilocytic Astrocytomas Exhibit Multiple Progressions and Acquisition of Neurologic Deficits over Time
Authors: Brossier Nicole , Strahle Jennnifer , Cler Samuel , Wallendorf Michael , Gutmann David
Published: June 2022

Pilocytic astrocytomas are the most common solid tumor of childhood and can arise anywhere in the central nervous system, including the posterior fossa (pf-PA), supratentorial midline (sm-PA; including optic pathway, hypothalamus, thalamus), and brainstem (bs-PA). Location (sm, bs) has been previously proposed as a prognostic factor for PA, but is difficult to separate from resection status on multivariate analysis. To overcome this limitation, we assembled a large cohort of children (n = 251) with biopsy-proved PA treated at St. Louis Children’s Hospital from 2003 – 2021 and analyzed outcomes only in patients with subtotal resection (STR; n = 81). We excluded patients with NF1, as NF1-associated gliomas often display a more indolent clinical course than their counterparts. We identified that children with STR sm-PA had a higher likelihood of multiple progressions compared to children with STR bs-PA and pf-PA. This was associated with worsening neurologic deficits over time, consistent with the sm location as a poor prognostic factor. Furthermore, the only children in our cohort with leptomeningeal dissemination or death harbored sm-PAs. Tumors in this location were also associated with an increased likelihood of non-BRAF-fusion genetic alterations and multiple oncogenic mutations. Overall, these data support location as an independent prognostic factor for PA in cases in which a gross-total resection cannot be achieved. Treating neuro-oncologists may thus wish to consider early intervention rather than watch-and-wait strategies at first progression of STR sm-PA. These patients may also benefit from earlier consideration of molecularly targeted therapy.