bluuebunny/crossref_metadata_2025 huggingface dataset:
LGG-15. DEEP LEARNING ENABLES LONGITUDINAL RISK PREDICTION FOR PEDIATRIC LOW-GRADE GLIOMAS AFTER SURGERY
Authors: Tak Divyanshu , Garomsa Biniam Amsalu , Zapaishchykova Anna , Ye Zezhong , Vajapeyam Sridhar , Mahootiha Maryamalsadat , Pardo Juan Carlos Climent , Familiar Ariana , Liu Kevin , Bandopadhayay Pratiti , Nabavizadeh Ali , Mueller Sabine , Aerts Hugo , Haas-Kogan Daphne , Poussaint Tina Young , Kann Benjamin Harris
Published: June 2024

BACKGROUND

Disease progression is challenging to predict following surgery for pediatric low-grade glioma (pLGG), and early progression indicators on MRI surveillance imaging would help guide management. Longitudinal surveillance imaging data may capture subtle temporal tumor changes and patterns that could inform recurrence risk but are difficult to synthesize clinically. We applied deep, self-supervised learning to longitudinal surveillance MRI to predict short-interval event-free-survival (EFS) risk from time-of-scan.

METHODS

We retrospectively collected data from 278 patients (2,174 scans) who underwent surgical resection for pLGG at Dana-Farber Cancer Institute/Boston Children’s Hospital (DFCI/BCH) from 1990-2022. A deep-learning model was pretrained with T2-FLAIR sequences to determine the chronological scan order for each patient (temporal pretraining). The model was fine-tuned to predict 1-year EFS from point-of-scan using a subset of scans from DFCI/BCH and then validated on a hold-out dataset (511 scans, 67 patients). Separately, the model was fine-tuned on an external dataset from the Children’s Brain Tumor Network (CBTN) and validated on a hold-out set (204 scans, 61 patients). Results were compared to a model trained without temporal pretraining.

RESULTS

Median follow-up and interval between scans were 73 and 6.3 months for DFCI/BCH and 20 and 5.8 months for CBTN. Temporal pretraining improved performance for 1-year EFS, for DFCI/BCH (AUC: 0.83 [0.71-0.90] vs. 0.78 [0.62-0.91]; F1-score: 0.80 vs. 0.67), and CBTN hold-out sets (AUC: 0.75 [0.58-0.90] vs. 0.53 [0.35-0.70], p=0.01; F1-score: 0.65 vs. 0.55). Increasing the number of longitudinal scans available to the model incrementally improved performance up to 7 scans/patient for DFCI/BCH and 10 scans/patient for CBTN.

CONCLUSIONS

Deep-learning with temporal pretraining improves the predictive analysis of tumor growth patterns in postoperative pLGG surveillance MRI, enabling accurate short-interval EFS prediction. This model could help inform patients and clinicians regarding surveillance regimen and initiation of adjuvant therapy.
LGG-19. SLIPPED CAPITAL FEMORAL EPIPHYSIS (SCFE): A RARE ADVERSE EVENT ASSOCIATED WITH FGFR TYROSINE KINASE INHIBITOR THERAPY IN A CHILD
Authors: Brizini Meziane , Drimes Tina , Bourne Catherine , Streilein Jessica , Drapeau Annie , Wrogemann Jens , Archer Lori Anne , Bigio Marc Del , Vanan Magimairajan Issai
Published: June 2024

BACKGROUND

FGFR tyrosine kinase inhibitors (FGFR-TKIs) are being increasingly used off-label in children with hard-to-treat tumors harboring specific FGFR alterations. We report a case of Slipped Capital Femoral Epiphysis (SCFE), an on target skeletal toxicity of a pan-FGFR TKI inhibitor, erdafitinib.

METHODS

Data was extracted from chart review of the patient and literature search for the use of FGFR-TKIs in children and their side effects.

RESULTS

A 13-year-old boy was diagnosed to have a optic pathway/ hypothalamic glioma with signs of increased intracranial pressure and obstructive hydrocephalus requiring placement of ventriculo-peritoneal (VP) shunt. Sequencing of the tumor showed FGFR1-Tyrosine kinase domain internal tandem duplication (FGFR1-KD-ITD) and was negative for BRAF mutation/ fusion. Two weeks later, he was treated for a VP shunt infection (surgical revision and 6 weeks antibiotics). He developed hypothalamic obesity with rapid weight gain and BMI >30. After a four-month delay from the initial diagnosis, he was started on erdafitinib a pan-FGFR1-4 inhibitor, through a special access program. At 12 weeks of treatment, he developed persistent knee pain. X-ray of the hips showed slipped capital femoral epiphysis (SCFE) of the right hip. Erdafitinib was discontinued and he underwent surgery with in-situ pinning of the right hip and prophylactic pinning of the left hip. MRI at the time of stopping the medication showed a 30% decrease in the size of the tumor, which has remained stable at 6 months follow up.

CONCLUSIONS

Based on our experience and literature review of pediatric patients who are treated with pan-FGFR TKIs, we recommend: a) monitoring both rate of weight gain/ BMI for obesity and growth velocity while on therapy and b) update the drug toxicity profile of FGFR TKIs to include skeletal toxicities and inform parents/ patients of these toxicities at the time of consent for therapy.
LGG-29. BEYOND MAPK SIGNALING - GENOME-SCALE CRISPR/CAS9 SCREENS REVEAL NEW TARGETS FOR TREATMENT OF KIAA1549::BRAF-DRIVEN PEDIATRIC LOW-GRADE GLIOMA
Authors: Borgenvik Anna , Misek Sean , Zhang Alexander , Fekade Ruth , Ragnoni Timothy , Fultineer Aaron , Zhou Kevin , Bondeson Daniel , Novikov Dana , Bahadur Sher , Choi Seung (Riley) H , Goodale Amy , Condurat Alexandra L , Cordero Carolina Ortiz , Persky Nicole , Kiessling Laura , Root David , Eck Michael , Boehm Jesse , Jones David , Beroukhim Rameen , Bandopadahayay Pratiti (Mimi)
Published: June 2024

Since the KIAA1549::BRAF fusion was discovered as the most common driver of pediatric low-grade glioma (pLGG), it has been hypothesized that the fusion induces oncogenicity through BRAF activation as a result of KIAA1549 replacing the BRAF negative regulatory N-terminus. This led to the rapid translation of MAPK pathway inhibitors into the clinical setting. Despite most tumors exhibiting promising initial responses, some tumors are not sensitive and about half of responsive tumors grow back after treatment cessation. Therefore, strategies that result in sustained tumor responses are desperately needed. We have recently performed genome-scale CRISPR/Cas9 screens across isogenic neural stem cell models transduced to express pLGG-associated oncogenes (KIAA1549::BRAF, BRAFV600E, and multiple FGFR1 and MYB family alterations) to generate a dependency map of genetic vulnerabilities associated with expression of these oncogenes. We also included normal neural stem cells to allow identification of genetic dependencies specifically induced by the expression of each oncogene. Surprisingly, through these efforts, we have discovered KIAA1549::BRAF expressing cells to harbor striking and specific dependency on multiple members of an enzymatic complex that exerts its activity outside of the MAPK signaling axis*. Interestingly, this enzymatic complex has been described to modify only a few substrates, including KIAA1549, suggesting specificity. We have now validated this dependency across other isogenic models of KIAA1549::BRAF-expressing cells. Finally, our KIAA1549::BRAF-expressing models exhibit preferential sensitivity to a tool compound that targets our novel enzyme, suggesting novel therapeutic potential for KIAA1549::BRAF. These findings highlight a MAPK pathway-independent avenue for therapeutically targeting the most frequent genomic alterations in pediatric brain tumors. Consequently, we also propose that the fusion partner KIAA1549 is instrumental for the aberrant BRAF signaling driving pLGGs. (* we are currently in the process of working with our IP offices to ensure that we can disclose the names of the genes and proteins at the ISPNO meeting)
LGG-30. CLINICAL CHARACTERIZATION OF PEDIATRIC LOW-GRADE GLIOMAS REQUIRING MULTIPLE ANTI-TUMOR TREATMENTS
Authors: Rijsdijk Tiago P J , Lammers Julie A S , Kranendonk Mariëtte E G , Meijer Lisethe
Published: June 2024

BACKGROUND

In pediatric low-grade gliomas (pLGG), central nervous system World Health Organization grade 1-2 tumors, the majority of patients achieve favorable outcomes. However, a significant minority requires multiple anti-tumor treatments. The objective of this study is to identify the clinical characteristics of patients requiring multiple anti-tumor treatments, enabling early detection and the subsequent adjustment of treatment strategies

METHODS

Data was retrieved on tumor location, age at diagnosis, gender, NF1 status, extent of resection, and number and type of anti-tumor treatments of 282 patients from our institution. Patients were categorized into a single (STG) and multi-treatment group (MTG). Multi-treatment was defined as tumor progression after initial anti-tumor treatment requiring additional treatment, including more than a 3-month waiting period between initial surgery and subsequent treatment.

RESULTS

The median follow-up was 3 years. Optic pathway glioma was more prevalent in the MTG vs the STG, 62% vs 22%, respectively. Patients in the MTG were younger at diagnosis vs the STG (4.9 vs 8.5 yrs, P < 0.001). There was no significant difference in NF1 prevalence or gender between both groups. The predominant characteristic of patients in the MTG was carboplatin and vincristine as initial treatment, with a tumor in the optic pathway and a mean age at diagnosis of 4.9 yrs. In addition, the patients in the MTG mostly underwent partial resection (PR) and never gross total resection (GTR).

CONCLUSIONS

Our results indicate that a younger age at diagnosis, a tumor in the optic pathways and not undergoing GTR are prognostic factors for multi-treatment. The goal of anti-tumor treatment is to achieve senescence. Our results show that in the MTG, this is not attainable with the current treatment strategies. Therefore, exploring alternative treatment strategies is essential to diminish morbidity and mortality and enhance the quality of life for these patients.
LGG-45. LOW DOSE CARBOPLATIN – ETOPOSIDE REGIMEN IN PEDIATRIC PATIENTS WITH LOW GRADE GLIOMA
Authors: Tellini Marco , Nicola Marco Di , Fonte Carla , Castelli Barbara , Guidi Milena , Giordano Flavio , D’Incerti Ludovico , Balducci Federico , Censullo Maria Luigia , Scagnet Mirko , Genitori Lorenzo , Buccoliero Anna Maria , Bianchi Benedetta , Sardi Iacopo
Published: June 2024

INTRODUCTION

Chemotherapy remains the cornerstone in case of incompletely resected pedatric Low Grade Glioma (pLGGs) and for recurrent tumors in unfavorable locations. Based on previous cisplatin etoposide regimen (INT Milan strategy), we tried to reduce toxicity and achieve a similar tumor control using a modified regimen composed of CBCDA-etoposide.

METHODS

From August 2012 to December 2023 we treated 79 pLGGS (45 F (57%), 34 M (43%)) with carboplatin (400 mg/m2 day 1) and etoposide (100 mg/2 day 1-3) at 4-6 weeks interval with 10 cycles in one year or until disease progression. Median age at diagnosis is 7 years. Seventeen patients were affected by neurofibromatosis type 1 (21.5%). 28 pLGGS affected visual pathway (35.4%). Treatment was delivered for clinical symptoms and/or radiological evidence of progression.

RESULTS

According to RAPNO criteria, on brain magentic resonance imaging (MRI) at the end of treatment 40 patients had stable disease (50.6%), 10 had partial response (12.7%), 7 had major response (8.9%), 5 had minor response (6.3%), 2 presented complete remission (2.5%), 13 patient had disease progression (16.5%). 2 patients are undergoing treatment (2.5%). Acute toxicity was unremarkable. During follow up (median time 59,5 months) 9 children (11,4%) developed audiological alterations but 2 of them also received radiotherapy. 14 patients presented hematological toxicity CTCAE grade 3 or 4 (17,7%). During follow up 30 patients developed a progressive disease (38%) and require further treatments and only one patients died because of progressive disease. Overall survival was 98,7% (78/79).

CONCLUSIONS

The combination of low doses CBCDA-etoposide seems equally effective with a lower hematological and audiological toxicity compared to other regimens.
LGG-47. VINBLASTINE TO PREVENT TUMOUR REBOUND AFTER BEVACIZUMAB/IRINOTECAN IN CHILDREN AND ADOLESCENTS WITH MULTIPLY RELAPSED LOW-GRADE GLIOMAS: THE SOUTH LONDON PAEDIATRIC & TYA NEURO-ONCOLOGY NETWORK EXPERIENCE
Authors: Weiser Annette , Cockle Julia V , Angelini Paola , Szychot Elwira , Srivatsa Kavitha , Mandeville Henry C , Vaidya Sucheta , Marshall Lynley , Carceller Fernando
Published: June 2024

INTRODUCTION

Low-grade gliomas (LGG) present 10-year overall survival rates of 90%. However, many require multiple lines of treatment. Bevacizumab/Irinotecan is the standard third line treatment for recurrent LGG in the UK; with targeted therapies being accessible only as a fourth or subsequent line for most cases. Access to targeted therapies may also be limited by the need for tumour tissue, which isn’t always available for LGG cases. Bevacizumab is effective in LGG, but between 65 and 90% regrow within 5-8 months from treatment discontinuation [Hwang 2013; Green 2023]. In this context and based on preliminary evidence from the group in Marseille (France) [Heng, 2016; Roux 2021], we explored if Vinblastine could extend the progression-free survival (PFS) after Bevacizumab.

METHODS

Institutional review of patients aged 1-25 years with relapsed LGG treated between 2018 and 2022 with Bevacizumab/Irinotecan followed by Vinblastine (24 weekly doses) at the discretion of the treating physician. The primary endpoint was PFS post-Bevacizumab (PFS-pB) measured at 8 months from last dose of Bevacizumab to allow for comparison with the results of a recently published national case series of paediatric LGG treated with Bevacizumab-based regimes [Green 2023].

RESULTS

Ten LGG cases received Bevacizumab/Irinotecan. One progressed on treatment, leaving 9 evaluable (8 completed 12 cycles, 1 discontinued treatment due to toxicity): of which 6 received Vinblastine. The PFS-pB at 8 months was 66% (4/6) with Vinblastine vs 35% in the national UK case series.

CONCLUSIONS

In this limited case series, Vinblastine delayed tumour progression following completion of Bevacizumab-based regimes compared to a national UK case series. Vinblastine could be considered as a holding strategy after Bevacizumab where targeted therapies are not readily available. Further prospective studies are required to validate this hypothesis.
LGG-49. EVALUATING THE EFFECTS OF MIRDAMETINIB IN NF1-MUTANT LOW-GRADE GLIOMAS USING BOTH CULTURED CELLS AND A NOVEL ZEBRAFISH XENOGRAFT MODEL
Authors: Wang Kaixuan , Yuan Ming , Graziano Gianna , Ceisel Anneliese , Krishnan Nimisha , Mumm Jeff S , Eberhart Charles , Raabe Eric
Published: June 2024

BACKGROUND

Pediatric low-grade gliomas (LGGs) with NF1 mutations represent a significant portion of childhood brain tumors. NF1 mutations lead to the dysregulation of the MAPK kinase and mTOR pathways, contributing to tumor growth. However, obtaining cell lines and xenograft animal models for NF1-mutated LGGs remains challenging due to their slow growth and less aggressive nature.

Methods and RESULTS

We examined the therapeutic efficacy of a novel MEK inhibitor mirdametinib in targeting the MAPK pathway within JHH-NF1-PA1 cells, a cell line derived from a low-grade optic pathway glioma originating from a patient with type 1 neurofibromatosis. Mirdametinib decreased p-ERK protein expression levels on western blot within four hours. We confirmed that mirdametinib significantly suppressed tumor cell proliferation by approximately 60% (BrdU staining (P<0.05), CellTiter Blue assay). β-galactosidase staining revealed approximately a 50% induction of cellular senescence in JHH-NF1-PA1 cells following mirdametinib treatment (P<0.05). We confirmed our findings using murine Nf1-null low grade glioma cell lines 1861 and 1491. To establish an in vivo model for drug testing, we utilized zebrafish due to their transparency, rapid reproduction, and short development time. Injecting RFP-labeled JHH-NF1-PA1 cells into the zebrafish at the 1000-cell stage, we monitored tumor growth using TECAN fluorescence detection from the third to eighth days post-injection. The fluorescence signals obtained from TECAN were validated by fluorescence microscopy. Western blot analysis confirmed a decrease in p-ERK levels within the zebrafish following mirdametinib treatment. We are evaluating the effect of mirdametinib on NF1 low grade glioma cell survival, migration and senescence in the zebrafish brain.

CONCLUSION

Our findings show that mirdametinib inhibits cell proliferation and induces senescence in NF1-mutated LGGs. Moreover, our zebrafish model provides a valuable tool for evaluating the efficacy of MEK inhibitors in vivo, particularly in cases where traditional xenograft models are difficult to establish.
LGG-58. A MULTI-CENTER RETROSPECTIVE CASE SERIES OF SURGICAL OUTCOMES FOR INTRAVENTRICULAR JUVENILE PILOCYTIC ASTROCYTOMA
Authors: Woodiwis Timothy , Pingel Wade , Vivanco-Suarez Juan , Li Derek , Gray Gabrielle , Malley Joan , Shimony Joshua , Greenlee Jeremy , Dlouhy Brian , Strahle Jennifer , Brossier Nicole M
Published: June 2024

INTRODUCTION

Juvenile pilocytic astrocytoma (JPA) is a common pediatric grade I astrocytoma. Prognosis is excellent with gross total resection (GTR) and 10-year survival rates of up to 95%. However, undesirable outcomes may occur, such as when tumors are in poorly accessible locations. Intraventricularly tumors present a unique surgical challenge due to their midline location in a fluid filled space with any intraparenchymal invasion involving critical neurologic structures. Here we retrospectively describe the clinical features of intraventricular JPA neoplasms from two centers to highlight the challenges in caring for this uncommon presentation.

METHODS

We retrospectively searched the electronic medical record from 2000-2023 for patients with neurosurgical treatment for intraventricular JPA at two centers. Intraventricular location was verified by a neuroradiologist. Data were collected on demographics, pathology, tumor location, extent of resection, adjuvant therapies, reoccurrence, progression, and neurological deficit.

RESULTS

We identified 28 surgical treated patients with intraventricular JPA. Females were 15/28 (54%) of patients with a mean age of 11.2±6.4 years. Most tumors presented in the 4th ventricle 15/28 (53.5%), followed by 9/28 (32%) in 3rd ventricle locations, and 4/28 (14%) in lateral ventricles. GTR was achieved in 12/28 patients (43%) and STR in 16/28 patients (57%). Progression/recurrence was noted in 8/28 (29%) and the 5-year PFS was 56% (10/18). Adjuvant treatment was used in 11/28 (39%) patients and repeat surgery was required in 4/28 patients (14%). Chemotherapy in 8/28 (29%) patients and radiation in 4/28 (14%) patients. A pre/post-operative neurological deficit was noted in 10/28 (36%) patients. A BRAF protein fusion was noted in 7 patients and 1 patient demonstrated a v600E mutation (some molecular data not available). Average follow up was 92 months with no deaths.

CONCLUSION

We observed that intraventricular JPA tumors commonly undergo subtotal resection with frequent progression/recurrence. Subsequently, recurrent surgeries and adjuvant therapies can be necessary.
LGG-60. DISTRIBUTION AND CLINICAL SIGNIFICANCE OF FGFR ALTERATIONS IN PEDIATRIC AND AYA GLIOMAS
Authors: Nobre Liana , Farouk Sameer , Larsen Alexandra , Bennett Julie , Ho I-Chen , Siddaway Robert , Mellinghoff Ingo , Perreault Sebastien , Magimairajan Vanan , Larouche Valerie , Renzi Samuele , Thacker Nirav , Zelcer Shayna , Ellison David , Santi Mariarita , MacLean Nasrallah , Stone Sara , Bale Tejus , Karajannis Matthias , Tabori Uri , Hawkins Cynthia
Published: June 2024

Fibroblast growth factor receptor (FGFR) alterations are prevalent in human cancers. In a large Canadian population-based cohort, encompassing over 1,300 pediatric and Adolescent and young adult (AYA) gliomas, FGFR mutations occurred in 10% of pediatric low-grade gliomas (LGG) and 20% of IDH-WT AYA LGGs. Here we assembled a large multi-institutional cohort including more than 300 mutated gliomas, aged 6 months to 87 years, 53% of which were LGG. High-grade gliomas were more common with increasing age; over 90% of pediatric cases were LGGs, compared to 30% in the AYA group. Fusions, predominantly seen in the pediatric group (70% of LGGs), contrast with FGFR3-TACC3 fusions frequent found in adult high-grade gliomas. Interestingly, FGFR mutations sometimes existed as sole drivers or co-occurred with other alterations (~30%), it is unclear how this alters tumor behavior, although gain of additional alterations could be implied in malignant transformation and poor prognosis. Despite higher incidence of high-grade gliomas in AYAs, their progression-free survival was significantly better than that of pediatric LGGs (p=0.007), largely due to the prevalence of hemispheric tumors amenable to gross total resection. Approximately 30% of our LGG cohort underwent adjuvant therapy; with available data for 28 patients, objective responses were noted in 2/12 to chemotherapy, 2/9 to MEK inhibitors, and 3/7 to FGFR inhibitors, respectively. With the increasing promise of precision targeted therapy, molecular profiling and assessment for FGFR alterations is essential. Although encouraging, further studies are needed to assess the benefit of FGFR inhibition in these patients.
MDB-07. A SUICIDE GENE THERAPY TARGETING SOX9-POSITIVE THERAPY-RESISTANT MEDULLOBLASTOMA CELLS
Authors: Lin Tong , Hutter Sonja , Vikström Elin , Zhao Miao , Holmberg Karl O , Rosén Gabriela , Bergström Tobias , Giraud Geraldine , Swartling Fredrik J
Published: June 2024

The transcription factor SOX9 is a stem cell factor and a glial fate marker in the developing brain. SOX9 levels correlate with worse prognosis and relapse in Group 3 medulloblastoma, a malignant pediatric brain tumor with poor survival. SOX9 activation promotes epidermal to mesenchymal transition and leptomeningeal spread. It is also upregulated by and facilitates cisplatin resistance in medulloblastoma cells. Direct SOX9 inhibition has proven difficult and few targeted substances have emerged from drug screening efforts. SOX9 acts as a selective and potent activator of a minimal collagen type II alpha 1 enhancer element. We here show that cells with SOX9 activity can be efficiently and specifically labeled when this SOX9 response element is coupled to a minimal promoter (S9RE-minP) driving GFP or luciferase. We further show that S9RE-minP construct can be used to drive herpes simplex virus thymidine kinase (TK) in a suicide gene construct that can convert ganciclovir to a cytotoxic drug in mitotic SOX9-positive cells. The gene therapy worked efficiently together with cisplatin to eradicate SOX9-positive medulloblastoma cells in vitro and could be safely combined and synergize with fractionated radiation in vivo. We suggest that this could be an attractive approach to target therapy-resistant cells in malignant pediatric brain tumors.
MDB-21. MYC-DRIVEN RECURRENT MEDULLOBLASTOMA AND CD74: TARGETING THE NEXUS FOR EFFECTIVE TREATMENT
Authors: Draper Benjamin , Thompson Dean , Morcavallo Alaide , Chesler Louis , Clifford Steve , Huang Lei F , Donovan Laura K
Published: June 2024

BACKGROUND

One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration.

METHODS/RESULTS

Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB.

CONCLUSIONS

Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.
MDB-23. MULTICENTRE EVALUATION OF THE MANAGEMENT OF CHILDREN WITH HIGH RISK MEDULLOBLASTOMA: REAL WORLD PERFORMANCE OF THE SJMB03 AND COG99701 PROTOCOLS
Authors: Apps John R , Sahmoud Shaimaa , Green Katherine , Hedge Kriti , Keeling Claire , Cherungonath Anoop , Srikumar Banuja , Lumb Blanche , Whitby Jennifer , Hayden James , Pizer Barry , Clifford Steve , Kilday John-Paul , Jorgensen Mette , Carceller Fernando , Adamski Jenny
Published: June 2024

BACKGROUND

Several treatment protocols are used in the treatment of patients with high risk medulloblastoma (HRMB). In 2015 the UK Children’s Cancer and Leukaemia Group issued interim guidance recommending treatment as per the SJMB03 protocol, whilst also recognising that the COG99701 protocol may be used. Patients were defined as high risk, if metastatic at presentation, large cell anaplastic histology, MYC amplification, significant residual disease or MYCN amplification, the latter two, more recently only if other adverse features present.

METHODS

We present a retrospective multi-centre service evaluation of treatment of patients with HRMB at 5 tertiary paediatric oncology centres in the UK. Patients were included if treated for HRMB with SJMB03, COG-99701. Patients were excluded if treated for HRMB on other protocols, including the SIOP HRMB trial, or if initially treated for standard risk medulloblastoma and subsequently treated with these protocols due to upstaging or disease progression. Event free, and overall (EFS and OS) survival analyses were calculated from date of primary resection.

RESULTS

59 patients were included (median age 8 years, range 3-19): 26 treated as per SJMB03, 33 as per COG-99701. 5-year OS was 83% (95% Confidence Interval, 73-94%) and 5-year EFS was 66% (54-80%). For patients treated as per SJMB03 5-year OS and EFS was 79% (65-97%) and 70% (55-92%)respectively. and for patients treated as per COG99701, 5-year OS and EFS was 86% (73-99%) and 60% (44-83%). There was a higher incidence of grade 3 & 4 ototoxicity (44% vs 6%) and a higher rate of admission to paediatric intensive care (36% vs 6%) in patients treated as per SJMB03 compared to those treated with COG97701 (p<0.05).

CONCLUSIONS

These real-world outcomes of patients treated in the UK for HRMB are consistent with the published literature for their outcomes for high risk medulloblastoma.
MDB-24. SHH MEDULLOBLASTOMA WITH SMO MUTATION BEFORE THE AGE OF 5YEARS OLD
Authors: de Bénazé Gwenaelle Duhil , Planchon Julien Masliah , Espariat Arnault Tauziede , Cardoen Liesbeth , Rousseau Léa Guerrini , Ayrault Olivier , Blouin Pascale , Dufour Christelle , Entz-Werle Natacha , Yvert Marion , Bourdeaut Franck
Published: June 2024

BACKGROUND

SHH medulloblastomas represent around 30% of MB’s and occur mostly in infants and adults with an intermediate prognosis. The driving mutations concern mostly PTCH1(43%), SUFU(10%) or SMO(9%). SMO activating mutations have been described almost exclusively in adults, and is extremely rare in infants. The features and outcome of SMO mutated infant MB are not known so far.

PATIENTS AND METHODS

We did a national retrospective analysis of children under 5 years with a SHH medulloblastoma and a somatic SMO mutation. We collected clinical, radiological and biological data (centralised reviews) with addition of methyloma, aiming to depict the clinico-molecular features and the outcome of these rare MB.

RESULTS

We identified 6 patients from 2014 to 2020. The median age at diagnosis was 3.2years. No evidence of metastatic disease was found for 5/6 patients and one had a positive CSF cytology. All patients underwent a complete removal. All had an extensive nodularity histologic subtype, no specific alterations in CGH apart from gains of all chromosomes 2,7 and,15. Methyloma classified 4/6 in subgroup SHH-1 and 2 in subgroup SHH-2. One patient had a second cerebellar lesion with a different radiological aspect; histological analysis and methylation profiling revealed a subependymoma, sharing the same SMO mutation than the MB ((c.1604G>T/p.(Trp535Leu)), suggesting a mosaicism. Another patient presented a polymalformative disorder diagnosed as a Curry-Jones syndrome, in agreement with the finding of mosaic SMO variant (c.1234C>T(p.Leu412Phe)). All patients received several cycles of chemotherapy, and no radiotherapy. With a median follow-up of 3.9 years, all patients were alive in complete remission with no relapse.

CONCLUSION

This data suggests that an underlying mosaicism must be sought in these very rare patients, and that the outcome seems overall similar to other infants with SHH medulloblastoma and more classical SUFU or PTCH1 mutations.
MDB-45. THE PTBP2 SPLICING FACTOR IS ESSENTIAL IN GROUP 3/4 MEDULLOBLASTOMA
Authors: Caisova Veronika , Rivero-Hinojosa Samuel , Tardito Samuele , Zhang Huizhen , Lu I-An , Chintala Navya , Mochizuki Aaron , Pei Yanxin , Murad Najiba , Sneiderman Chaim , Kohanbash Gary , Yang Jianhua , Rood Brian
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is a common malignant pediatric brain tumor with significant heterogeneity among its four molecular subgroups: WNT, SHH, groups 3 and 4. There is a significant rate of disease recurrence with group 3/4 MB indicating a need for novel therapeutic targets. Since transcriptomic profiling of MB has not identified novel targets, we focused on a proteomic approach. We selected 157 proteins significantly over-expressed in Group 3/4 MB and performed a targeted loss-of-function CRISPR-Cas9 screen in four MB cell lines. We identified 17 essential genes shared by at least 2 of the cell lines. The PTBP2 splicing factor was essential for all cell lines. PTBP2 is an RNA-binding protein involved in splicing regulation that plays an important role during neuronal maturation. We hypothesize that persistent expression of PTBP2 results in a differentiation arrest and preservation of proliferative potential.

METHODS

We stably knocked-out PTBP2 expression in D556 and MB002 MB cells. We performed bulk RNA-seq and quantitative proteomics of these KO clones along with CLIP-seq to map PTBP2 targeted transcripts. We also performed phenotype assays, qPCR array and single-cell RNA-seq in KO clones to validate proliferation and neuronal differentiation.

RESULTS

RNA-seq in PTBP2 KO MB cells revealed 2,213 differentially expressed genes predominantly involved in neuronal differentiation. These genes were cross-referenced with quantitative proteomic and eCLIP data. Using RNAseq from clinical samples, splice inclusion analysis based upon PTBP2 bound transcripts neatly segregated Group 3/4 MB from SHH and WNT. PTBP2 KO cells exhibited reduced proliferation and, upon stimulation, increased differentiated morphology compared to controls. This latter observation was further supported by qPCR array and single-cell RNA-seq.

CONCLUSIONS

The results suggests that the loss of PTBP2 expression stimulates MB differentiation with a subsequent reduction of proliferation activity and nominates PTBP2 and its downstream effectors as potential therapeutic targets in group 3/4 MB.
MDB-49. OUTCOMES OF SONIC HEDGEHOG (SHH) MEDULLOBLASTOMA (MB) IN CHILDREN AND ADULTS TREATED WITH RISK-ADAPTED THERAPY ON A PROSPECTIVE INTERNATIONAL PROTOCOL (SJMB12)
Authors: Gajjar Amar J , Orr Brent , Ellison David , Lafay-Cousin Lucie , Minturn Jane , Fisher Michael , Bendel Anne , Hwang Eugene , Murray Jeffrey , Landi Daniel , Smith Amy , Gottardo Nicholas , Valvi Santhosh , Hassal Tim , Elster Jennifer , Perrault Sebastian , Ramaswamy Vijay , Partap Sonia , Laughton Stephen , Cohn Richard , Chintagumpala Murali , McCowage Geoffrey , Hansford Jordan , Sullivan Michael , Sayour Elias , Bowers Daniel , Marks Asher , Huang Jie , Lucas John , Tinkle Christopher , Pinto Soniya , Bag Asim , Sabin Noah , Northcott Paul , Klimo Paul , Merchant Thomas E , Onar-Thomas Arzu , Robinson Giles W
Published: June 2024

BACKGROUND

SJMB12 (NCT01878617) was among the first protocols to treat newly diagnosed MB incorporating molecular subgrouping.

METHODS

Tumors were subtyped and TP53 mutation assessed via immunohistochemistry. SHH patients were grouped into 2 strata: S1 (GTR/NTR; M0) and S2 (residual > 1.5 cm2; MYC/MYCN amplification; M+). Treatment consisted of maximal surgical resection followed by risk adapted craniospinal irradiation (CSI) (S1 = 23.4 Gy CSI; S2= 36); 54 Gy primary site. Patients then received 4 cycles of chemotherapy consisting of Vincristine 1 mg/m2 on Day 1 and Day 8; Cisplatin 75 mg/m2 on Day 1 and Cyclophosphamide 1.5 gm/m2 on Day 2 and 3 with Mesna and IV fluid support. PEG Filgrastim was administered on Day 4. Skeletally mature pts (males with bone age ≥ 17 yrs.; females with bone age ≥ 15 yrs.) were also treated with the smoothened inhibitor Vismodegib for 12 months.

RESULTS

Of the 660 patients accrued from 2013-2022, 110 were SHH (107 evaluable, 62 in S1 and 45 in S2). Median age was 12.2 yrs. (3.1-39.7) and 67 were males. 98 patients had GTR/NTR, 31 had M+ disease and 63 had nodular desmoplastic histology. TP53 mutation was detected in 7 (11.5%) S1 and 18 (40%) S2 pts. 5-year EFS for S1 and S2 were 84.5 ± 6.4% and 61 ± 11.5%, respectively. Five-year EFS of the S1 was 91.7 ± 5.4% and 28.6 ± 13.9% for TP53 wildtype and TP53 mutant cases, respectively, and 84.2 ± 10.1% and 25.0 ± 21.7% in the S2 cohort.

CONCLUSION

Patients with low-risk SHH MB lacking TP53 mutation have excellent survival and may be considered for therapy reduction. TP53 mutation, with or without M+ disease, leads to a dismal outcome that needs novel therapy for cure.
MDB-53. SALVAGE CRANIOSPINAL IRRADIATION FOR RELAPSED WNT-PATHWAY MEDULLOBLASTOMA PATIENTS TREATED WITH UPFRONT FOCAL CONFORMAL RADIOTHERAPY AND CHEMOTHERAPY AT INITIAL DIAGNOSIS: LONG-TERM AND MATURE OUTCOMES FROM A PROSPECTIVE DE-INTENSIFICATION STUDY
Authors: Gupta Tejpal , Chatterjee Abhishek , Dasgupta Archya , Epari Sridhar , Sahay Ayushi , Sahu Arpita , Moiyadi Aliasgar , Prasad Maya , Chinnaswamy Girish
Published: June 2024

BACKGROUND

Excellent long-term outcomes (5-year overall survival >90%) in WNT-pathway medulloblastoma (MB) patients have prompted systematic attempts at de-intensification of therapy to mitigate treatment-related toxicities. Mature outcomes of a prospective study (FOR-WNT) treating low-risk WNT-MB children with focal conformal radiotherapy (RT) and adjuvant systemic chemotherapy omitting upfront craniospinal irradiation (CSI) are being reported herein.

METHODS

Seven children with rigorously-defined low-risk WNT-MB were treated with post-operative focal conformal RT to the index tumor-bed (54Gy/30 fractions) followed by 6-cycles of adjuvant systemic chemotherapy after written informed consent/assent. Survival outcomes were computed using Kaplan-Meier method and reported as point estimate with 95% confidence intervals (CI). The trial was terminated prematurely due to unacceptably high risk of neuraxial failures.

RESULTS

One child succumbed to chemotherapy-related toxicity while 3 of 7 children were detected with leptomeningeal relapse on surveillance neuro-imaging within 2-years of index diagnosis. Full-dose salvage CSI (35Gy/21 fractions) at relapse followed by further chemotherapy led to excellent clinico-radiological response in all 3 children; however, one child developed further local recurrence and leptomeningeal metastases and succumbed to recurrent/progressive disease despite further aggressive salvage therapy. Five of 7 children including the other two treated with salvage CSI and systemic chemotherapy are alive and continue to remain in remission on long-term follow-up. At a median follow up of 61 months, the 5-year Kaplan-Meier estimates of event-free survival, relapse-free survival, and overall survival were 42.9% (95%CI: 18.2-100%), 50.0% (95%CI: 22.5-100%), and 71.4% (44.7-100%) respectively.

CONCLUSIONS

Omission of upfront CSI in low-risk WNT-MB is associated with unacceptably high-risk of neuraxial failure. Although full-dose salvage CSI achieves excellent response, remissions are not durable resulting in sub-optimal long-term overall survival. Judicious de-escalation with upfront low-dose CSI (18Gy) is currently being tested in a successor study (FOR-WNT 2).
MDB-62. SUBGROUP AND SUBTYPE-SPECIFIC OUTCOMES IN METASTATIC INFANT MEDULLOBLASTOMA
Authors: Senapati Akanksha , Lindsay Holly , Gilheeney Stephen , Bale Tejus , Taylor Michael , Khuong-Quang Dong-Anh , Bouffet Eric , Khan Sara , van Veelan Marie-Lise , Kros Johan M , Vasiljevic Alexandre , Pollack Ian , Chambless Lola , Gupta Nalin , Weiss William A , Jabado Nada , Sterba Jaroslav , Zapotocky Michal , Hansford Jordan R , Ramaswamy Vijay
Published: June 2024

BACKGROUND

Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of metastatic infant medulloblastoma have not been analysed to date.

METHODS

A multicentre molecularly informed international cohort of children <6 years old with metastatic medulloblastoma was assembled and analysed.

RESULTS

Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01).

CONCLUSIONS

In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.
MDB-67. MEDULLOBLASTOMA MOLECULAR SUBGROUPING AND OUTCOMES DATA OF A SINGLE CENTER FROM A LOW-MIDDLE-INCOME COUNTRY
Authors: Mushtaq Naureen , Bashir Farrah , Riaz Quratulain , Zahid Soha , Javed Gohar , Tariq Maria , Qureshi Bilal Mazhar , Hilal Kiran , Ramaswamy Vijay , Hawkins Cynthia , Bouffet Eric , Minhas Khurram
Published: June 2024

BACKGROUND

Medulloblastoma is the most common malignant childhood brain tumor. The molecular subgrouping of medulloblastoma is a major determinant of management in high-income countries. Subgrouping is still very limited in low- and middle-income countries, and its relevance to management has yet to be evaluated in this setting. We describe molecular findings and their implications in the outcome of a single tertiary care center.

METHODS

Children between 3 and 18 years diagnosed with medulloblastoma between April 2014 and December 2020 at Aga Khan University Hospital were included. Subgrouping was performed by nanostring through a collaboration with the Hospital for Sick Children, Toronto.

RESULTS

Thirty-five children were identified (85.17% male); the median age was 8. Nineteen patients were high-risk, including 9 with metastatic disease. In 28 children, there was a clear molecular subgroup: 4 WNT (11.4%), 7 Sonic Hedgehog (20%), 3 Group 3 (8.6%), and 14 Group 4 (40%) medulloblastomas. Molecular subgrouping was inconclusive for two patients (5.7%) and not done in 5 patients (14.3%). All patients underwent surgery; 91.4% received radiation therapy and chemotherapy. Of 35 children, overall Survival at 5 years was 100%, 57.1%, 66.7%, and 85.7% for WNT, Sonic Hedgehog, Group 3, and Group 4, respectively. WNT and Group 3 had 100% Progression-free survival, whereas Sonic Hedgehog and Group 4 had decreased progression-free survival of 42.9% and 85.7%, respectively. Average-risk patients had an overall survival of 93.8%, whereas high-risk patients exhibited a statistically significant lower overall survival of 63.2% (P=0.014).

CONCLUSION

Our cohort demonstrates excellent outcomes for WNT and Group 4, despite one WNT being metastatic and four Group 4 patients being high-risk. Modern risk stratification is an excellent predictor of survival, suggesting that treatment can be tailored according to subgrouping in the LMIC setting.
MDB-70. SYSTEMATIC TRANSCRIPTOMIC ANALYSIS OF CHILDHOOD MEDULLOBLASTOMA IDENTIFIES M6A-LNCRNA SIGNATURES ASSOCIATED WITH PROGNOSIS, MOLECULAR SUBTYPE, AND IMMUNE CELL INFILTRATION
Authors: Joshi Kandarp , Yuan Menglang , Katsushima Keisuke , Saulnier Olivier , Dean Selah , Amankwah Ernest , Stapleton Stacie , Jallo George , Taylor Michael D , Eberhart Charles G , Perera Ranjan J
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is the predominant pediatric brain tumor, subdivided into four molecular subgroups, with group 3 and group 4 tumors posing significant clinical challenges due to poor prognosis and classification. This study investigates the roles of N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) in MB, aiming to develop diagnostic and prognostic tools.

METHODS

We analyzed transcriptome from 1236 samples to identify m6A-associated lncRNA signature (M6LSig). A multivariate-cox analysis identified a gene signature significantly associated with overall survival (OS) of patients. Risk score was calculated based on the sum of weighted gene expression of these genes. Nomograms were calculated for predicting OS and PFS probability. We did feature selection with Boruta to identify minimum gene signature for subgroup classification. We performed correlation analysis of gene signature and risk score with immune-cell abundance. We depleted METTL3 and METTL14 in G3-MB cell-line (D425) to measure impact on cell proliferation and dysregulation of M6LSig genes as a result of loss of m6A.

RESULTS

Nomogram was constructed using risk score derived from 24 M6LSig significantly associated with OS and PFS of the patients. A 171 gene signature was identified that can accurately classify samples into one of four major subgroups of MB with more than 90% accuracy including between Grp3/Grp4 samples. M6LSig genes and risk score showed significant correlation with immune cell type abundance in MB tumors. Expression of CD155 and 4-1BB was significantly different between high and low risk samples. m6A writer genes knockdown in D425 cells resulted in decreased cell proliferation and upregulation of many M6LSig genes.

CONCLUSION

M6LSig based risk can accurately predict OS and PFS and 171 genes signature can classify patients into subgroups with more than 90% accuracy. Risk score can also be used for determining high risk versus low-risk patient and design tailor made immune-therapy for better survival.
MDB-80. PREVIOUS MANAGEMENT OF MEDULLOBLASTOMA IN A MIDDLE-INCOME COUNTRY: IDENTIFYING AREAS FOR IMPROVEMENT
Authors: Sánchez Mauricio , Gamboa Yessika , Delgado Mario , Garita Karla , Esquivel Jessica , Rodríguez Carlos , Caceres Adrian , Leis Amanda , Acuña Maria José , Nuñez Monica
Published: June 2024

BACKGROUND

Medulloblastoma stands as the most prevalent malignant brain tumor among the pediatric population. Diagnosis, staging, and treatment protocols are well-established in high-income countries. However, in low- to middle-income countries, management practices often deviate and frequently prove inadequate, potentially impacting final outcomes significantly. In Costa Rica, a middle-income country, a study was conducted to document the prevailing management approaches for patients at the Hospital Nacional de Niños.

METHODS

Data from 31 children under the age of 13, treated between 2009 and 2015, were retrospectively analyzed. All patients were included in the study. Demographic details, initial symptoms, staging procedures, surgical interventions, histologic subtypes, treatment modalities, and survival outcomes were scrutinized. Risk stratification relied on age, CSF analysis (when available), and the extent of resection as per the neurosurgeon’s assessment. Due to incomplete staging, all patients received high-risk chemo - radiotherapy protocol.

RESULTS

The study identified 31 patients. Median age of 6.1 years (range, 0 -12), 51.1% being male. The most prevalent symptoms included headache, vomiting, and ataxia, manifesting in 93% of cases. Histological subtype was unspecified in 45.2% of patients. High-risk status was assigned to 11 patients (35.5%), with 8 of them aged under 3 years, while 20 patients (64.5%) were categorized as low risk, yielding a 5-year overall survival (OS) of 27% and 80%, respectively. Complete resection achieved in 21 cases, resulting in a 5-year OS of 71.5%, compared to 25% for 4 patients with incomplete resection. The overall 5-year OS rate was 61.3%.

CONCLUSIONS

This study underscores suboptimal practices in the diagnosis, staging, and management of medulloblastoma at the time of assessment. While outcomes for patients classified as standard are acceptable, they received intensified chemo/radiotherapy, potentially leading to heightened long-term adverse effects. Importantly, identified deficiencies have since been addressed. The impact of these interventions will be evaluated in future studies.