bluuebunny/crossref_metadata_2025 huggingface dataset:
IMG-33. EXPLORING RARE CASES OF SUBEPENDYMAL GIANT CELL ASTROCYTOMA (SEGA) IN PATIENTS WITH AND WITHOUT TUBEROUS SCLEROSIS COMPLEX (TSC): EXPERIENCE FROM INDONESIA
Authors: Amal Mohamad Yanuar , Rahmartani Ludi Dhyani , Susanto Eka
Published: June 2024

INTRODUCTION

Subependymal giant cell astrocytoma (SEGA) represents a rare type of brain tumor that predominantly manifests in individuals with tuberous sclerosis complex (TSC), a genetic disorder characterized by the growth of benign tumors in various organs. In radiology, SEGA exhibits distinct imaging characteristics in various modalities such as magnetic resonance imaging (MRI) and computed tomography (CT). Radiological features include well-defined intraventricular masses with variable enhancement patterns and associated hydrocephalus. Moreover, SEGA typically demonstrates signal characteristics consistent with glial tumors on MRI, aiding in differentiation from other intraventricular lesions. In TSC patients, SEGA often arises in association with other typical manifestations such as cortical tubers and subependymal nodules, facilitating diagnosis through multimodal imaging approaches. In contrast, SEGA occurring in non-TSC individuals presents challenges in diagnosis due to its rarity and lack of associated clinical features.

CASE PRESENTATION

Two patients with tuberous sclerosis complex exhibit intraventricular masses suggestive of SEGA, confirmed by histopathological results. Another patient, one patient with an intraventricular mass was suspected to have choroid plexus papilloma based on MRI findings; however, additional features correlated with SEGA. Histopathological examination subsequently confirmed the diagnosis of SEGA.

CONCLUSION

Radiological evaluation plays a crucial role in the assessment of SEGA, guiding treatment decisions and prognostic considerations. This abstract provides an overview of the radiological findings of SEGA in the context of TSC and non-TSC populations, highlighting the importance of imaging in managing this uncommon brain tumor.
IMMU-05. TARGETING THE DYSREGULATED DNA METHYLOME DURING CAR T CELL MANUFACTURING IMPROVES THEIR FITNESS IN IMMUNOCOMPETENT BRAIN TUMOR MODELS
Authors: Yi Zhongzhen , VanNoy Elton , Lee Abigail , Chiappinelli katherine , Haydar Dalia
Published: June 2024

BACKGROUND

Epigenetic reprogramming and T-cell exhaustion are key factors impacting the effectiveness of chimeric antigen receptor (CAR) T-cell immunotherapies in brain tumors. These processes are regulated by DNA methylation, an epigenetic modification that is crucial for gene regulation. Here, we investigated whether targeting the dysregulated DNA methylome in engineered immune cells can improve their anti-tumor efficacy.

METHODS

We optimized a transduction protocol that incorporates adding DNA methyltransferase inhibitors (DNMTi) early during the manufacturing process of murine CAR T-cells targeting B7-H3. We then used standard in vitro assays and immunocompetent glioma models to evaluate whether DNMTi treatment improved CAR T-cell effector functions by regulating activation, memory differentiation, and cytokine responses in adoptive T-cells.

RESULTS

In repeated-stimulation assays, CAR T-cells generated in the presence of DNMTi exhibited significantly higher levels of expansion and persistence compared to CAR T-cells without DNMTi exposure. Notably, CAR T-cells manufactured in the presence of DNMTi persisted up to 12 repeat stimulations, in contrast to a maximum of 7 stimulations for CAR T-cells generated without DNMTi treatment. Moreover, DNMTi-treated CAR T-cells expanded up to 55-fold higher than T-cells generated without DNMTi treatment upon repeated-stimulation with B7-H3-positive glioma cells. This was also associated with remarkably enhanced secretion of immune-stimulatory cytokines that persisted across repetitive stimulations. Furthermore, DNMTi-treated CAR T-cells exhibited greater cytotoxicity at lower effector-to-target ratios compared to untreated CAR T-cells, with sustained differential cytotoxicity even after the 4th stimulation. Preliminary in vivo data from immunocompetent glioma models further support the potential of DNMTi pre-treatment, showing improved T-cell persistence and reduced dose requirements. Mechanistic studies suggest that DNMT inhibition enhances B7-H3 CAR T-cell anti-tumor activity by regulating memory differentiation of CAR T-cells early in the production phase.

CONCLUSION

This study proposes that DNMTi pre-treatment may offer a promising approach for optimizing CAR T-cell manufacturing and enhancing performance in brain tumors.
IMMU-09. PHASE 2 TRIAL USING INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH CHILDHOOD BRAIN CANCER: INTERIM ANALYSIS OF THE GCC1949 STUDY (NCT04049669)
Authors: Johnson Theodore S , Pacholczyk Rafal , Ring Eric K , Aguilera Dolly , Castellino Robert C , Fangusaro Jason R , Eaton Bree R , Chi Susan , Yeo Kee Kiat , Hummel Trent R , Berrong Zuzana , Creager Julianne , Ingerski Lisa , Schniederjan Matthew , Huang Chenbin , Satpathy Sarthak , Thomas Beena E , Sadek Ramses F , Kennedy Eugene P , Bhasin Manoj K , MacDonald Tobey J , Munn David H
Published: June 2024

BACKGROUND

Brain tumors are the leading cause of pediatric cancer-related death.

METHODS

We report interim outcome data from an ongoing multi-site phase 2 study (NCT04049669) of indoximod-based chemo-immunotherapy for patients 3-21 years of age with either recurrent brain cancer (ependymoma, medulloblastoma, high-grade glioma) or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Treatment is oral IDO pathway-inhibitor indoximod (38.4 mg/kg/day, divided BID) plus temozolomide (200 mg/m2/day for 5 days) in 28-day cycles. Patients who may benefit from additional irradiation receive indoximod during the radiation regimen and are analyzed separately.

RESULTS

Planned accrual is 140; 80 patients have been treated to date. Estimated median follow-up time was 23.5 months (range 0.2 - 42.7 months), and indoximod-based therapy has been well tolerated. Estimated median overall survival (OS) was 23.8 months for recurrent ependymoma (n=31); 11.5 months for recurrent medulloblastoma (n=22); 5.7 months for recurrent HGG (n=18, includes diffuse midline glioma except primary DIPG); and 15.0 months for newly diagnosed DIPG (n=9). Single-cell TCR and RNA sequencing of serially collected blood samples was used to identify expanded CD8+ T cell clones with late-effector phenotypes, and their emergence was associated with significantly improved survival. In patients treated with immunotherapy, radiographic measurement of objective response is challenging, owing to the high incidence of mixed responses and pseudoprogression events. In our recently published phase 1 trial of indoximod (NCT02502708, Neuro-Oncology 26:348-361, 2024) we showed that 41% of relapsed patients had MRI evidence of objective response in at least one tumor using RAPNO criteria, and that these “responder” patients had 3-fold better median OS (25.2 months, p=0.007) than non-responders (7.3 months). To date, the phase 2 data is similar.

CONCLUSIONS

The GCC1949 phase 2 study is replicating the published phase 1 results, and we will present updated results from the first 80 patients in the GCC1949 trial.
IMMU-10. DEVELOPING NOVEL CHIMERIC ANTIGEN RECEPTOR THERAPIES FOR PAEDIATRIC HIGH GRADE GLIOMA
Authors: Davenport Alexander J , Lertsumitkul Leesa , Cross Ryan S , Jenkins Misty R
Published: June 2024

Paediatric high-grade gliomas (pHGG), particularly Diffuse Midline Glioma (DMG), present a formidable challenge in oncology. Due to the aggressive biology and location of pHGGs the implementation of adult treatment modalities (surgery, chemotherapy, and radiotherapy) is severely limited resulting in pHGG remaining a terminal disease. Thus, there is a pressing and urgent unmet clinical need for the development of innovative therapeutics. We will demonstrate the identification of cell surface targets using mass spectrometry proteomics. We have developed novel binders and engineered them into second-generation CAR T cells. We will present pre-clinical in vivo intracranial mouse models examining the efficacy of novel CAR T cell therapies. We have recently reported effective CART cell targeting of HER2 in DMG, and presently we will also demonstrate superior efficacy of additional CAR T cell targeting, both in vitro and in vivo in preclinical PDX models of DMG. We will present new data that CAR T cells targeting EphA3 show curative efficacy in pre-clinical models of DMG. Recognising that single targeting CAR T cells are unlikely to provide long-term clinical benefit, we will also present our combination approaches using CAR T cells targeting antigens such as GD2, EGFR, HER2, EphA3, CD276 and CD63. We are expanding our research to other CAR T combination strategies focusing on immune-modulating drugs such as checkpoint inhibitors or co-stimulatory agonists. We are committed to advancing CAR T cell therapies for pHGG patients and their families with an aim to aid in the development of much-needed new therapeutic options.
LGG-05. REPORT ON PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC)-029B, A PROSPECTIVE PHASE 2 CLINICAL TRIAL OF SELUMETINIB IN TREATING YOUNG PATIENTS WITH RECURRENT/PROGRESSIVE LOW-GRADE GLIOMA: NEW RESULTS ON STRATA 2, 5, AND 6 WITH UPDATED LONG-TERM SURVIVAL OUTCOMES ON STRATA 1, 3, AND 4
Authors: Fangusaro Jason , Onar-Thomas Arzu , Poussaint Tina Young , Lensing Shelly , Ligon Azra H , Lindeman Neal , Banerjee Anuradha , Kilburn Lindsay , Lenzen Alicia , Pillay-Smiley Natasha , Pollack Ian F , Robison Nathan , Partap Sonia , Qaddoumi Ibrahim , Landi Daniel , Jones David T W , Stewart Clinton F , Fouladi Maryam , Dunkel Ira J
Published: June 2024

BACKGROUND

PBTC-029B was a phase 2 trial evaluating efficacy of selumetinib (up to 26 courses) in children with recurrent/progressive low-grade glioma. We report new results on strata 2, 5, and 6 as well as update long-term survival outcomes on strata 1, 3, and 4.

METHODS

Stratum 2 enrolled children with pilocytic astrocytoma (PA) whose tumor screened negative for the BRAF-KIAA1549 fusion and the BRAFV600E mutation. Stratum 5 enrolled children with non-PA whose tumor screened positive for one of these two BRAF aberrations. Stratum 6 enrolled children who consented to tissue screening, but there was an assay failure. Responses were based on T2/FLAIR.

RESULTS

Stratum 2: among 14 patients, there was 1 partial response (PR), 7 stable disease (SD) and 6 progressive disease (PD) with overall response rate (ORR) of 7.1%. Two-year progression-free survival (PFS)/overall survival (OS) were 57.1/100%, respectively. Stratum 5: among 23 patients, there was 1 complete response, 4 PR, 12 SD and 6 PD with ORR of 21.7%. Two-year PFS/OS were 74.8%/100%, respectively. Stratum 6: among 26 patients, there were 7 PR, 14 SD and 5 PD with ORR of 26.9%. Two-year PFS/OS were 72.0%/100%, respectively. Long-term outcomes have now been evaluated in strata 1, 3, and 4. Stratum 1 enrolled patients with PA whose tumor screened positive for one of the two BRAF aberrations; stratum 3 enrolled patients with neurofibromatosis type-1 (NF1) associated pLGG; and stratum 4 enrolled non-NF1 optic pathway/hypothalamic tumors. Among strata 1, 3, and 4, the current median follow-up for patients without events are 60.4, 60.4, and 58.1 months, respectively. Five-year PFS/OS are 30.8%/88.9%, 54.2%/100%, and 51.0%/100%, respectively.

CONCLUSIONS

These data demonstrate that selumetinib provides tumor stability and responses among diverse pLGG tumors as well as show that many patients will achieve long-term disease control even several years after stopping treatment.
LGG-06. THREE PRACTICAL CHALLENGES IN IMPLEMENTING RAPNO RESPONSE ASSESSMENT FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Bag Asim Kumar , Robinson Giles W
Published: June 2024

The RAPNO criteria for pediatric low-grade gliomas (pLGGs), designed to improve upon the RANO criteria, are increasingly being employed to assess treatment responses. However, the adoption of the RAPNO guidelines in our clinical trials has revealed some notable challenges that stymie their practical implementation. These challenges should be addressed to render the guidelines more comprehensive and facilitate their widespread adoption. Definition of tumor burden should be modified: The current guidelines define tumor burden as the sum of the products of the longest tumor diameter and its longest perpendicular diameter. While this approach generally works, implementing it in optic pathway gliomas involving the nerve and subtotally resected pLGGs where the longest diameter is often disproportionally larger than the perpendicular diameter creates a challenge. The result is an inaccurate measure of tumor burden as well as poor reproducibility. Progressive disease should be confirmed with follow-up imaging. Unlike response confirmation, guidelines do not recommend confirmation of progression. Since pLGGs grow slowly, the change in diameters between two consecutive scans is often so small that it can be indistinguishable from measurement error. This is particularly problematic in smaller tumors and in diffusely infiltrating tumors, in which minor measurement change can erroneously shift response to progressive disease. Definition of target lesion should be more specific: pLGGs can recur focally without involving the entire previously treated residual tumor. Based on RAPNO guidelines, the target lesion includes both the growing and the stable residual components. This poses a challenge and can result in a serious underestimate of efficacy, particularly with biologic therapy, when the response of the recurrent focal tumor is major or complete but, by the current criteria, only registers as stable disease or minor response. Our discussion will show real-world examples of these challenges and propose recommendations to enhance the practical application of RAPNO criteria.
LGG-11. UNDERSTANDING THE TRANSCRIPTIONAL HETEROGENEITY OF PEDIATRIC LOW-GRADE GLIOMAS AND ITS IMPLICATION FOR TUMOR PATHOPHYSIOLOGY
Authors: Boisvert Michelle , Perera Ashwyn A , Jeang John , Condurat Alexandra L , Tsai Jessica W , Novikov Dana , Collins Jared , Morin Eric , Woods Jared , Zhou Kevin , Chacon Madison , DiGiacomo Jeromy , Kumbhani Rushil , Wang Dayle , Taylor Michael D , Hansford Jordan R , Ludlow Louise E A , Jabado Nada , Ligon Keith L , Beroukhim Rameen , Bandopadhayay Pratiti , Jones David T W
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or radiation therapy, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms.

METHODS

To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (>250,000 cells) of 55 pLGGs across many histological subtypes (pilocytic astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, DNET, ganglioglioma, RGNT, diffuse astrocytoma, SEGA, glioneuronal, oligodendroglioma).

RESULTS

Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we used spatial transcriptomic data to investigate and annotate the cellular architecture of multiple pLGGs with BRAF mutations and draw comparisons to findings from our single-cell and single-nuclei transcriptomic analysis.

CONCLUSIONS

Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.
LGG-17. NATURAL HISTORY AND MANAGEMENT OF INCIDENTALLY DISCOVERED BRAIN LESIONS SUSPECT FOR NEOPLASM IN CHILDREN
Authors: Delhez Celine C A , Kersbergen Karina J , van Meeteren Antoinette Y N Schouten – , van den Bergen Janneke C
Published: June 2024

BACKGROUND

The rise in neuroimaging has resulted in an increase of incidentally discovered brain lesions suspect for a neoplasm (‘incidentaloma’) in children. With the experience in our national hospital, we aim to diversify and broaden the knowledge on the management and natural history of pediatric incidentaloma.

METHODS

A retrospective analysis of all incidentaloma patients in the Princess Maxima Center for Pediatric Oncology from June 2018 until March 2023.

RESULTS

Our research population consists of 23 patients (10M/13F) with an incidentaloma. The lesions were mostly located in the cerebellum (21.7%), thalamus and ventricle (both 17%) and cerebral hemisphere (13%) The average age at diagnosis was 7.9 years (range 0-15 years) and the mean duration of follow-up was 4.6 years (range 0-11 years). The initial management was clinical and radiological follow-up in seventeen (74%), resection in five (22%) and biopsy in one patient (4%). Pathological examination performed in the six neurosurgical patients revealed low grade gliomas (LGGs) in three patients, medulloblastoma in one and plexus papilloma in one patient respectively. The pathological analysis of the patient with biopsy only was indecisive. One patient became symptomatic with clear tumor growth on imaging after 6.8 years of follow-up. Biopsy showed a H3K27M mutant diffuse midline glioma. She died 8.1 years after initial diagnosis. In 11 other patients radiographic changes (mostly tumor progression) were observed with a median of 23 months after diagnosis (range 3-70 months). Two of these underwent complete resection of an LGG.

CONCLUSIONS

For most incidentalomas, clinical and radiological follow-up is sufficient. As late disease progression can occur as seen in our patient who became symptomatic after 7 years, this follow-up should be long-term. Future studies should focus on identifying (radiological) prognostic factors for tumor progression, so follow-up of incidentaloma can be more personalized.
LGG-21. IMMUNE MICROENVIRONMENT PROFILING OF BRAF-FUSION PILOCYTIC ASTROCYTOMA: DIRECTIONAL PRIORITIZATION OF IMMUNOTHERAPEUTIC TARGETS
Authors: Tripathi Shashwat , Najem Hinda , Heimberger Amy , DeCuypere Michael
Published: June 2024

BACKGROUND

The immune microenvironment of pediatric gliomas is relatively understudied despite being a leading cause of childhood mortality. Pilocytic astrocytomas (PA) are the most common pediatric glioma and surgical resection is often curative. However, PAs are not always amenable to surgery and can have significant long-term morbidity and mortality. The ten-year progression-free survival for PA patients with significant residual tumor is less than 50% and other non-surgical treatment options are frequently necessary.

METHODS

To identify PA patients that may be responsive to immune checkpoint inhibitors and to guide prioritization of available immunotherapeutic treatments, orthogonal immune profiling strategies were used to identify patients that may benefit from the next generation of immune therapeutics. Because the KIAA1549-BRAF fusion is expressed in 70% of PA, we prospectively collected patients to comprehensively characterize the unique immune biology of these tumors using nanostring profiling, scRNASeq, and SeqIF™ multiplex staining.

RESULTS

The tumor microenvironment of BRAF-fusion PA was notable for antigen presentation and the interaction of CD11c+ cells with T cells through Lck+ immunological synapses. PA CD11c+CD206+ dendritic cells localized to vessel walls and were positive for TIM3 expression, an immune checkpoint marker. A unique highly activated microglia subcluster was identified that morphologically resembled T cells expressing TNF and TIM3. Our results are consistent with others that suggest potential benefit in targeting tumors with elevated MAPK activity. Finally, the expression of other immune checkpoints such as Lag-3, PD-1, and TIGIT are minimally co-expressed, suggesting that T cells are not in a state of exhaustion, as seen in adult high-grade gliomas.

CONCLUSIONS

Analysis of BRAF-fusion PA identified a unique highly activated P2RY12+ microglia population dispersed throughout the tumor microenvironment, active antigen presentation between a CD11c+ antigen presenting cells and T cells, and a unique therapeutic opportunity for targeting TIM3.
LGG-24. PEDIATRIC GANGLIOGLIOMA WITH GERMLINE BRCA2 MUTATION
Authors: Gupta Anya , Lechpammer Mirna , Shatara Margaret , Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Cluster Andrew , Abdelbaki Mohamed S , Brossier Nicole M
Published: June 2024

BACKGROUND

BRCA1 and BRCA2 are genes associated with breast and ovarian cancer development in adults. Their influence on brain tumor formation is less understood.

METHODS

Retrospective review

RESULTS

An 11 year-old girl was diagnosed with ganglioglioma after presenting with seizures. Tumor sequencing revealed three mutations: a PDAP1-BRAF fusion, a BRAF-HIP1 non-canonical fusion, and a pathogenic BRCA2 variant D252*fs. Upon further review, a family history of breast cancer in the grandmother and several great-aunts was identified, and genetic testing confirmed this mutation to be germline. We then conducted an institutional review and identified a second pediatric low-grade glioma (pilocytic astrocytoma) patient with a pathogenic mutation in BRCA2 (T3085Fs*26) in addition to a BRAF-KIAA1549 fusion; the family declined germline BRCA2 testing. BRCA1/2 knockout models have demonstrated that both genes play a role in brain development. Concurrent BRCA2 and TP53 loss triggers formation of early onset murine medulloblastoma, a finding not observed with TP53 loss alone. In human patients, heterozygous and biallelic mutations in BRCA2 were identified as risk factors for medulloblastoma development in a recent integrative genomic analysis. Retrospective review

CONCLUSION

We report two cases of BRCA2 mutation in pediatric low-grade gliomas, one of which was confirmed to be germline. While somatic variants of BRCA2 have been reported in both high- and low-grade glioma, their role in these tumors has not been established to date. The BRCA2 tumor predisposition syndrome increases the risk of some types of brain tumors such as medulloblastoma, although the risk remains low compared to the risk of developing breast or ovarian cancer later in life. More evidence is required to determine whether BRCA2 germline mutations can similarly increase the risk of glioma formation.
LGG-32. MALIGNANT TRANSFORMATION OF PEDIATRIC LOW-GRADE GLIOMA TO SECONDARY HIGH-GRADE GLIOMA - REPORT FROM THE GERMAN BRAIN TUMOR STUDIES
Authors: Perwein Thomas , Gielen Gerrit H , Kandels Daniela , Bison Brigitte , Karremann Michael , Kühn Alexander , Sturm Dominik , Spix Claudia , Warmuth-Metz Monika , Stock Annika , van Buiren Miriam , Monoranu Camelia M , Hartmann Christian , Friker Lea L , Eyrich Matthias , von Bueren André O , Driever Pablo Hernáiz , Witt Olaf , Koch Arend , Pietsch Torsten , Benesch Martin , Kramm Christof M , Gnekow Astrid K
Published: June 2024

BACKGROUND

Malignant transformation (MT) of pediatric low-grade glioma (pLGG) to secondary high-grade glioma (sHGG) is a rare but momentous event. We explored its clinical, epidemiologic, and molecular characteristics and risk factors.

METHODS

Forty-eight pediatric patients with histology-based or radiological (n=4) diagnosis of primary LGG (median age 10.2 years [range, 0.7–16.9]) and subsequent sHGG were identified within registries of the HIT-network from 1996-2019. For 29 patients, tumor specimens of both pLGG and corresponding sHGG were available for neuropathological review and studied genetically.

RESULTS

MT occurred after median 4 years (range, 0.5-14) following LGG diagnosis. Its 15-year cumulative incidence was 1.6±0.4% (23/1586 SIOP-LGG-2004 patients), but 11.7±4.1% (9/100) for diffuse pLGG WHO-grade 2 (DG2). Clinical risk factors for MT were spinal location and prior dissemination. MT was accompanied by an increment of nuclear p53 accumulation (20/29 tumors), cytogenetic and molecular alterations. CDKN2A/B homozygous deletions (7/12 tumors), 1p/1q alterations (4/12) and ATRX loss (3/12) were the most common acquired alterations detected in sHGG. 8/16 tumors were unclassifiable by methylation profiling. DG2s (n=19), harboring IDH-1 mutation in 3/9 cases, progressed to diffuse WHO-grade 3 (n=8) or grade 4 HGG (n=9), two developed gliomatosis cerebri. Circumscribed LGG (PA, n=13; GG, n=7; PXA, n=4; DNET, n=1) typically harbored MAPK/ERK pathway alterations (BRAF-/NTRK-/FGFR-fusions, n=5/9; BRAFV600E mutation, n=4/12) and transformed to non-diffuse HGG (n=14), but also to diffuse grade 4 HGG. H3 K27M-/BRAFV600E co-mutation in two of these patients eventually resulted in MT to fatal diffuse midline glioma. Thirty-five sHGG patients received radio-chemotherapy. Overall survival at 5 and 10 years following MT was 49±8% and 31±8%.

CONCLUSIONS

Our findings underline the importance of careful long-term follow-up of patients with pLGG. Repeated resection/biopsy of recurrent/progressing or “atypical” tumors should be pursued and include molecular typing to identify patients at risk for MT and initiate appropriate treatment.
LGG-34. THE LANDSCAPE OF GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS REVEALS INSIGHTS ON GLIOMAGENESIS: A CANADIAN ADOLESCENTS AND YOUNG ADULTS NEURO-ONCOLOGY NETWORK (CANON) STUDY
Authors: Bennett Julie , Levine Adrian , Nobre Liana , Negm Logine , Chung Jiil , Fang Karen , Johnson Monique , Komosa Martin , Krumholtz Stacey , Nunes Nuno Miguel , Rana Mansuba , Ryall Scott , Sheth Javal , Siddaway Robert , Bale Tejus A , Bouffet Eric , Cusimano Michael , Das Sunit , Detsky Jay , Dirks Peter , Karajannis Matthias , Kongkham Paul , Giantini-Larsen Alexandra , Li Bryan Kincheon , Lim-Fat Mary Jane , Lin Andrew , Mason Warren , Miller Alexandra , Perry James , Sahgal Arjun , Sait Sameer Farouk , Tsang Derek S , Zadeh Gelareh , Laperriere Normand , Nguyen Lananh , Gao Andrew , Keith Julia , Munoz David G , Tabori Uri , Hawkins Cynthia
Published: June 2024

BACKGROUND

Gliomas are a heterogenous and common cancer in children, adolescents and young adults (CAYA, ages 0-39 years). Little is known about the biologic and clinical implications of gliomas in AYA limiting our ability to appropriately manage these patients.

METHODS

We compiled a population-based cohort of patients with glioma aged 0-39 years diagnosed between 2000-2020, performed molecular characterization of the tumors and collected clinical data including therapy and long-term outcome.

RESULTS

A total of 1456 patients, including 873 AYA patients were included. A pathogenic molecular alteration was found in 98% of AYA samples available. Strikingly, pediatric-type mutations were found in 31% of AYA glioma of which 37% were BRAF V600E and 23% FGFR alterations. Important differences were observed between gliomas in children versus AYAs. First, hemispheric tumors were enriched in AYAs compared to midline tumors in children, especially for RAS/MAPK alterations. Second, increased incidence of high grade tumors in AYA compared to children were observed for BRAF V600E and FGFR mutations (p<0.0001). In contrast, if these alterations were identified in AYA and the tumor was low grade, outcome was improved for BRAF V600E and FGFR mutant tumors in AYAs compared to pediatrics (for BRAF V600E 5 year PFS 55.6% <10 years, 78.1% for 10-20 years and 87.1% for 10-20 years of age, p=0.0002). Third, a specific time window for transformation was observed for each alteration (BRAF, FGFR, IDH). This correlated with different methylation profiles and transcriptional patterns between early midline and late hemispheric tumors. Increased senescence signatures were observed in older patients with low grade RAS/MAPK driven tumors with superior outcome.

CONCLUSIONS

Different cell of origin and secondary mutations shape tumor behavior and lead to either transformation or senescence during gliomagenesis in CAYA. These can affect early interventions and tailored approaches for gliomas by age and molecular alteration.
LGG-37. A PHASE III STUDY COMPARING TWO CARBOPLATIN CONTAINING REGIMENS FOR CHILDREN AND YOUNG ADULTS WITH PREVIOUSLY UNTREATED LOW-GRADE GLIOMA
Authors: Lenen Alicia , Waanders Angela J , Bazzi Latifa , Zhang Hui , Lai Jin-Shei , Plant-Fox Ashley S , Cluster Andrew , Crawford John , Cohen Ken , Dickens David , Dole Mukund , Goodman Jessica , Hoffman Lindsey , Koschmann Carl , Lazow Margot , Marks Asher , Puccetti Diane , Skrypek Mary M , Tanaka Ryuma , Weintraub Lauren , Wright Karen , Rush Sarah Zieber , Fangusaro Jason , Lulla Rishi , Goldman Stewart , Pillay-Smiley Natasha
Published: June 2024

BACKGROUND

Low-grade glioma (LGG) is the most common childhood central nervous system tumor. Carboplatin/vincristine (CV) is a standard of care regimen used for incompletely resected tumors. Monthly carboplatin is an alternative regimen that has not been prospectively compared to CV previously in untreated patients.

METHODS

Patients ≤ 21 years with LGG and no treatment besides surgery were eligible. Patients were stratified according to NF1 status and randomized to Arm A (carboplatin/vincristine) or Arm B (carboplatin monthly). The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoint analysis is underway and includes quality of life, tumor response rates, toxicity and association of molecular alterations on outcomes. Analyses included log-rank test and descriptive statistics.

RESULTS

There were 95 evaluable patients with a median age of 5 (range 0-18) years; 67 non-NF1 subjects (32 Arm A, 35 Arm B) and 28 NF1 subjects (14 Arm A, 14 Arm B). Three-year PFS was superior for patients without NF1 treated on Arm A (58%; 95% CI: 38%, 74%) versus Arm B (33%; 95% CI: 18%, 49%) (p=0.04). In patients with NF1, there was no statistical difference in PFS between those treated on Arm A (71%; 95% CI: 41%, 88%) and Arm B (93%; 95% CI: 59%, 99%) (p=0.08). Grade 3/4 toxicity neutropenia was more commonly seen in Arm A patients compared to Arm B for both NF and non-NF1 patients. Peripheral neuropathy was also more commonly seen in non-NF1 patients (Grade 1-4; 32%) compared to NF1 patients (7%) for patients treated on Arm A. There were 15 carboplatin reactions (Grade 1-4); 7 non-NF1 on Arm A, 3 non-NF1 on Arm B, and 5 NF1 on Arm A.

CONCLUSIONS

Non-NF1 patients treated with carboplatin and vincristine show statistically significant improved PFS compared to monthly carboplatin. Patients with NF1 are statistically underpowered due to low accrual.
LGG-42. TWENTY YEARS OF PROGRESS IN MANAGING LOW GRADE GLIOMA: THE EXPERIENCE OF THE UNIVERSITY OF CAPE TOWN’S COMBINED PAEDIATRIC NEURO-ONCOLOGY SERVICE FROM 2001 TO 2022
Authors: Davidson Alan , Figaji Anthony , Pillay Komala , Hendricks Marc , Naiker Thuran , Parkes Jeannette
Published: June 2024

BACKGROUND

This study aimed to review the management of childhood low grade gliomas (WHO I and II) by the University of Cape Town’s combined neuro-oncology service at Red Cross War Memorial Children’s and Groote Schuur Hospitals.

METHODS

All patients diagnosed with low grade glioma between 2001 and 2022 were included in this retrospective study. Real time decision-making during the study period was achieved via a weekly neuroimaging meeting, and surveillance by a combined monthly clinic attended by paediatric endocrinology and educational psychology. Despite state of the art surgical and radiotherapy facilities, molecular diagnostics, monoclonal antibodies and small molecules were only available to selected patients.

RESULTS

Among 129 children, aged 0.38 to 14.58 years [median 5.36], six had Tuberous Sclerosis and 11 had Neurofibromatosis-1. The commonest sites were cerebellum (26%), hypothalamus (17%) and optic pathway (16%), and 12 patients (9%) had metastatic disease, mostly grade I supratentorial tumours. Twenty-three patients were diagnosed on imaging without histology, six of whom were biopsied subsequently, yielding a total of 96 grade I and 16 grade II tumours. Initial management was expectant in 16% (including 8 of the 11 Nf-1 tumours), surgery in the form of debulking or total resection in 53%, chemotherapy in 24% and radiotherapy in 8%. Ultimately 36% received chemotherapy and 29% radiotherapy (almost all of them focal RT), and only 16% of those treated with radiotherapy progressed. Estimated 5-year Overall Survival (OS) and Progression Free Survival (PFS) was 90.5% and 52.6% for the whole group. Patients treated with chemotherapy had an OS of 87.2% and a PFS of 39.2%. PFS and OS were inferior for metastatic disease but not for grade II tumours.

CONCLUSIONS

Low grade glioma can be managed effectively in a middle-income country setting. Multidisciplinary team management is crucial to achieving positive outcomes regardless of context.
LGG-43. LASER-ASSISTED ENDOSCOPIC RESECTION OF TECTAL GLIOMA IN A 3-YEAR-OLD CHILD
Authors: Tuniz Francesco , Fabbro Sara , Piccolo Daniele , Vindigni Marco , Liguoro Ilaria , Pilotto Chiara , Toniutti Maristella , D’Agostini Serena , De Colle Maria Cristina , Pegolo Enrico , Cogo Paola , Skrap Miran
Published: June 2024

BACKGROUND

Pediatric tectal gliomas generally have a benign clinical course. However, some patients may present with non-communicating hydrocephalus needing endoscopic procedures. Historically, lasers have been used in neurosurgical procedures including neuroendoscopy, but their adoption was limited by a significant rate of complication due to their inappropriate wavelength and uncontrollable tissue interaction. Recently, a 2-micron near-infrared laser with adequate wavelength and minimal tissue penetration became available.

CASE-REPORT

We describe the case of a 3-year-old child who presented with gait ataxia, papilloedema and headache. Magnetic Resonance (MR) was performed and he was diagnosed with obstructive hydrocephalus due to tectal glioma. Endoscopic third ventriculostomy (ETV) and simultaneous endoscopic biopsy were performed during the same surgery using a single burr hole with a rigid endoscope, a 2-micron continuous-wave thulium laser and the aid of neuronavigation. After tumoral sample removal, the laser was used for hemostasis and to evaporate tissue near the tumour without mechanical stress to the brain tissue. The final histological analysis identified a non-otherwise specified (NOS) low-grade glioma. The hospitalization was uneventful and the boy was discharged home after 4 days. No new cognitive impairment was reported secondary to this procedure and the symptoms present in the preoperative period completely improved. At 1-year follow-up, neurological examination findings were unremarkable, and there was no radiographic evidence of tumour progression.

CONCLUSIONS

The use of the neuroendoscopic laser permits cutting and coagulating simultaneously, avoiding multiple instruments’ use (forceps and coagulation). It therefore makes neuroendoscopic procedures more straightforward with a minimum need to change tools, and particularly suitable also in a pediatric setting.
LGG-48. CLINICAL CHARACTERIZATION OF FGFR-ALTERED, PEDIATRIC LOW-GRADE GLIOMAS
Authors: Posorske Benjamin , Tiwari Nishant , Keller Lisa , Dorris Kathleen , Goldman Stewart , Hoffman Lindsey M , Mangum Ross
Published: June 2024

BACKGROUND

Pediatric low-grade glioma (pLGG) is the most common central nervous system tumor of childhood. Most pLGGs are driven by BRAF alterations, but a subset harbor activating mutations or fusions of FGFR1/2/3. Significantly less is known about the biologic activity, clinical course, and response to targeted inhibition of these FGFR-altered gliomas (FGFR pLGG). We sought to define the epidemiologic characteristics, molecular signature, prognostic markers, and clinical course of patients with FGFR pLGG.

METHODS

We performed a multi-institution, retrospective chart review of pediatric neuro-oncology patients treated at two large, academic cancer centers from 2012 – 2023 with tumor molecular profiling demonstrating any FGFR alteration.

RESULTS

Sixteen eligible patients were identified; 9 (56%) were female and median age was 12 years of age (range 6 - 18 years). Reported histologies included pilocytic astrocytoma (4), rosette-forming glioneuronal tumor (3), low grade glial/glioneuronal tumor (3), low grade glioma NOS (2), intermediate grade astrocytoma (1), dysembryoblastic neuroepithelial tumor (2), and pilomyxoid astrocytoma (1). FGFR point mutations were seen in 10/16 (62.5%) patients followed by FGFR-TACC1 fusions in 4/16 (25%) patients and two patients with FGFR1 tandem duplication. Metastatic disease was noted at diagnosis in two patients and upfront gross total resection was achieved in four patients. The most common systemic therapy for the remaining patients was Vincristine and/or Carboplatin. All sixteen patients are alive at median follow up of 52 months (range 6 - 198 months).

CONCLUSIONS

FGFR pLGG represent a distinct subset of tumors with unique biologic properties and clinical activity. Additional studies are needed to investigate this unique patient population to appropriately adapt our therapeutic approach and improve patient outcomes.
LGG-50. POOR RESPONSE TO MEKI RE-INITIATION IN PEDIATRIC LOW-GRADE GLIOMA AFTER TREATMENT DISCONTINUATION. A PLGG TASKFORCE STUDY
Authors: Bajin Inci Yaman , Siddaway Robert , Levine Adrian , McKeown Tara , Nobre Liana , Das Anirban , Bennett Julie , Ramaswamy Vijay , Huang Annie , Bouffet Eric , Lafay-Cousin Lucie , Quang Dong Anh Khuong , Hansford Jordan , Rajagopal Revathi , Gottardo Nicholas G , Rowe Rachel , Dutton Jordann , Li Amanda , McThenia Sheila , Fangusaro Jason , Perreault Sébastien , Hawkins Cynthia , Tabori Uri
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (pLGG) exhibit dramatic objective response to treatment with MEKi (Mitogen-Activated Protein Kinase inhibitors). Although the initial response to MEKi is promising, it is unknown whether it is safe to stop MEKi therapy and if the response to re-initiating MEKi would have the same impact. The study objective was to compare the first and second response to MEKi in patients with pLGG who stopped therapy and had further tumor progression.

METHODS

PLGG identified at neurooncology centers in Canada, Australia, and US, which were treated twice with MEKi were included. Second therapy was defined as MEKi upon progression for tumors where treatment was stopped. Response to MEKi between 2 treatments (MEKi1, MEKi2) were analyzed by using RANO criteria.

RESULTS

Mature data on 19 patients reveals a median patient age of 13 years (range 7–24), and the most common tumor location is hypothalamic/chiasmatic (89%). PLGG alterations include KIAA1549:BRAF fusion in 69%, NF1 in 21%, and other alterations in 10%. The overall response (minor and partial) to MEKi1 was 63% compared to 26% in MEKi2 (p=0.04). Furthermore, upon restarting MEKi2, 11% had further growth on therapy in contrast to none at MEKi1. MEKi1 resulted in average of 37% size decrease (range, 3%-98%), including 6 PLGG with over 50% response. In contrast, the average decrease to MEKi2 was 10% (range, 6%-40%, p=0.005), and none had >50% size reduction. Comparing each patient MEKi1 to MEKi2 revealed that initial response was superior to the second one in all PLGG.

CONCLUSION

These data suggest that the second response to MEKi is inferior when compared to initial therapy. Expansion of this cohort and biomarker correlates are ongoing. Biological insights are required for this observation, and careful consideration should be made for stopping MEKi, especially in strategic locations such as the optic pathway.
LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Robinson Giles W , Vinitsky Anna , Bag Asim K , Chiang Jason , Li QIan , Lin Tong , Hoehn Mary Ellen , Edwards Angela , Storment Diana , Singh Anjali , Larkin Jennifer , Freeman Jana , Pranica Johanna , Bertrand Kelsey , Bagchi Aditi , Baughman Todd , Hoang Thuy , Shearer Todd , Moreira Daniel
Published: June 2024

BACKGROUND

Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy.

METHODS

Phase 1 required patients to be >2 and <25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort planned to evaluate the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy.

RESULTS

Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), MYB (n=1;4%). The median time of follow-up was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on therapy; 4 (17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D.

CONCLUSIONS

Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior exposure to MEKi.
LGG-57. BH3 MIMETICS IMPROVE RESPONSE TO AUTOPHAGY INHIBITION IN BRAFV600E GLIOMAS
Authors: Crespo Michele , Zahedi Shadi , Morin Andrew , Wodetzski Darya , Groat Madeline , Bratbak Emil , Jones Kendra , Griesinger Andrea , Caino Cecilia , Levy Jean Mulcahy
Published: June 2024

BACKGROUND

Autophagy inhibition improves the effectiveness of RAF pathway inhibition (RAFi) and overcomes resistance mechanisms. Mechanistic links between autophagy and apoptotic cell death may explain this ability. BH3 mimetics with autophagy and RAFi further improves this response.

METHODS

RAFi sensitive (MAF 794, AM38) and resistant (MAF 794R, MAF 905-3, AM38R, B76) BRAFV600E tumor cell lines were analyzed at baseline, following RAFi (vemurafenib), autophagy inhibition (chloroquine or shRNAs), BH3 protein inhibition (navitoclax or shRNAs), and combination therapy. Growth assays and caspase activation were monitored by Incucyte Zoom. qRT-PCR evaluated key pro-apoptotic BH3-only members of the BCL-2 family. BH3 profiling was completed using the Letai JC-1 plate-based protocol. Western blot analysis assessed protein levels. Cell Titer Glo determined cell viability.

RESULTS

Combination therapy increased key pro-apoptotic BH3-only proteins including PUMA. shRNAs targeting ATG5 and ATG7 (proteins required for autophagosome formation) also increased PUMA protein and mRNA levels following RAFi. This suggests autophagy-mediated regulation of BH3 proteins helps determine cellular apoptotic thresholds. Combined autophagy and RAFi increased caspase activation and cell death compared to single drug treatment. BH3 profiling demonstrated BCL-2 dependence to inhibit apoptosis. Inhibition of pro-survival BCL-2 family members BCL-2 and BCL-XL (pharmacologically and genetically) with RAFi, MEKi, and autophagy inhibition further increased caspase activation and reduced cell viability.

CONCLUSIONS

BH3 mimetics competitively bind pro-survival BCL-2 family members, increasing apoptosis. Autophagy inhibition improves treatment response by overcoming the apoptotic threshold in RAFi resistant cells and magnifying the apoptotic response in sensitive cells. BH3 profiling reveals CNS BRAFV600E are BCL-2 and BCL-XL dependent, making them good candidates for additional treatment with BH3 mimetics. The addition of navitoclax increased caspase activation and reduced cell viability. Autophagy inhibition can magnify this response even more. This presents an attractive treatment for MAPK activated CNS tumors by enhancing apoptotic cell death by targeting the MAPK pathway, autophagy and BH3.
MDB-04. LONG-TERM OUTCOME OF THE MILANO STRATEGY FOR HIGH-RISK MEDULLOBLASTOMA, INCLUDING THE IMPACT OF MOLECULAR SUBTYPE
Authors: Massimino Maura , Dossena Chiara , Minasi Francesco , Barretta Francesco , Buttarelli Francesca Romana , Biassoni Veronica , Oriani Matilde , Schiavello Elisabetta , Ficorilli Marica , Nigro Olga , Pollo Bianca , Antonelli Manila , Donofrio Vittoria , Maggioni Marco , Kool Marcel , Pecori Emilia , Vennarini Sabina , Gianno Francesca , nigro olga , Erbetta Alessandra , Chiapparini Luisa , Luksch Roberto , Barzanò Elena , Meazza Cristina , Podda Marta , Spreafico Filippo , Terenziani Monica , Bergamaschi Luca , Ferrari Andrea , Casanova Michela , Chiaravalli Stefano , Gattuso Giovanna , Bailey Simon , Modena Piergiorgio , De Cecco Loris
Published: June 2024

BACKGROUND

Since 2008 we have been using the same strategy as for M+ medulloblastoma for all other high-risk subgroups(LC/A histology,TP53 mutations,and/or MYC/MYCN amplification).

METHODS

After surgery,patients >3-year-old received staging/histo-biological revision and sequential HD-methotrexate,HD-VP16,HD-Cyclo,HD-Carbo.HART-CSI,in two daily 1.3 Gy-fractions/5-days-a-week, reached doses tailored to age and pre-radiation response to chemotherapy:31.2 Gy under 10 years-old if CR+PR or no metastases,39 Gy in other/older patients.Boosts to posterior fossa/residual M+ deposits were given reaching total doses of 59.7–60 Gy and 9 Gy,respectively and avoided if metastatic nodules very big or patients very young.Two courses of high-dose thiotepa were delivered in case of not-optimal response after pre-RT phase and in all M0 patients either in pre/post-RT phase.Subgrouping was obtained through IHC and methylation EPICv2.0 in rescued samples.

RESULTS

Patients were 89,median age 8.8 years,64 males,median fup 136 months. OS/PFS/EFS at 5/15-years were 75.9/66.5%,71.1/69.8%,68.2/65.3%,respectively; 6/28 fatal events were not correlated to medulloblastoma relapse(four 2nd tumors).Sex,age below 10/over 15 years, post-sugical residues,histological subtype(#24 LC/A,#57 classic,#7 nodular-desmoplastic),MYC amplification(#17),CSI dose reduction(#31),absence of boosts(#16),use of myeloablative courses(#45),presence/absence of metastases(#77 M+) did not impact prognosis.Patients progressing after pre-HART chemotherapy(#14) and SD+PD after HART(# 10) did significantly worse(P<0.001)with 1/0 survivors, respectively.Subgrouping done in 44/89 patients so far,showed significant worse PFS/EFS for patients with SHH-tumors(#11, 2 with constitutional Tp53-mutations) vs. groups3 and 4(11 and 22 patients, respectively).Patients younger than 10 had worse response to CT and less boosts (P=0.03 in both) but could receive lower CSI-doses if stratified according to CT-response.

CONCLUSIONS

This strategy, partly adopted in the ongoing SIOPE protocol, confirmed satisfying results in all high-risk categories; SHH tumors appeared the most aggressive in this context.