bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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&lt;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&lt;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

Abstract

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

Abstract
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

Abstract
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

Abstract

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

Abstract

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&lt;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

Abstract

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&gt;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&gt;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

Abstract

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

Abstract

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 &gt; 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.