bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-90. PRIMARY LEPTOMENINGEAL MEDULLOBLASTOMA: A SINGLE-SITE RETROSPECTIVE STUDY OF 5 CASES
Authors: Wells Olivia , Bhatia Kanika , Campbell Marty , Hansford Jordan R , Sullivan Michael , Williams Molly , Mignone Cristina , D’Arcy Colleen , Eisenstat David D , Khuong-Quang Dong-Anh 
Published: June 2024

Abstract

BACKGROUND
Primary leptomeningeal medulloblastoma without mass is a rare entity with fewer than 10 reported paediatric cases. Establishing an accurate diagnosis is challenging and reported outcomes are very poor.

METHODS
We conducted a retrospective analysis of cases presenting to the Royal Children’s Hospital Melbourne between 2013 and 2023.

RESULTS
Between 2013 and 2023 five patients, all male, were identified, with an average age of 6.6 years [1.9 - 12.2 years]. The presenting history was short in all cases (2-3 weeks) and all had symptoms of raised intracranial pressure. Diagnostic imaging (MRI brain and spine) showed non-specific leptomeningeal thickening and enhancement with no primary posterior fossa mass seen; interestingly only two imaging reports considered malignancy in the differential diagnosis. Surgical biopsy confirmed the diagnosis of medulloblastoma on histology; 3 anaplastic and 2 with classic histology. Subgrouping by IHC, available for 4 patients, showed non-WNT/non-SHH, with one reclassified as SHH by DNA methylation (performed in 2 patients). MYC was amplified in one patient (assessed by FISH in all tumours). Four patients were treated with craniospinal irradiation (36-39.6Gy with 18Gy boost), followed by chemotherapy as per SJMB12 stratum N3 (n=3) or HeadStart III (n=1). One case, an infant, was treated according to COG ACNS0334 with concurrent intraventricular topotecan, followed by maintenance with irinotecan/temozolomide/IVent topotecan. At follow up (average 54 months; 11 – 126 months), four children with residual disease on end of treatment MRI are alive without disease progression. One patient with classical SHH medulloblastoma and MYCN amplification progressed on treatment and died of disease 11 months after diagnosis.

CONCLUSIONS
Contrary to the historical literature, our case series suggests a more favourable outcome if this disease is recognised early. Further studies are warranted to better understand the molecular profile of these tumours.
MDB-93. A TRANSCRIPTOME-BASED APPROACH TO DRUG REPURPOSING FOR AGGRESSIVE GROUP 3 MEDULLOBLASTOMAS
Authors: Doss David , Kanchan Ranjana K , Perumal Naveenkumar , Batra Surinder K , Mahapatra Sidharth 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common malignant brain tumor in children, representing 20% of pediatric brain tumors. International consensus has identified molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4). Current treatments, guided by histologic tumor grade and stage, do not fully harness these subgroups, resulting in varying prognoses. G3MB particularly faces challenges with rapid recurrence and aggressive disease, necessitating focused intervention.

METHODS
We conducted differential expression analysis on MB patient datasets (GSE148389, GSE164677) to generate a G3MB gene expression signature. This gene expression signature was analyzed against the LINCS database, yielding candidate antineoplastic compounds. Candidates were filtered for blood-brain barrier permeability and FDA approval. Functional assays evaluated drug effects on cytotoxicity, clonogenicity, wound healing, cell cycle, and apoptosis in G3MB cell lines (HDMB03 and D425). RNA sequencing of treated cells identified differentially regulated pathways to infer mechanism, followed by in vitro validation. Mitochondrial function and membrane potential were measured by Seahorse and TMRM assays, respectively.

RESULTS
Eighty-one candidates passed filtering. The leading drug class identified was antidepressants. Based on MTT assays, the top four candidates were nortriptyline, simvastatin, fluoxetine, and sertraline. Nortriptyline (NT) emerged as the lead compound, with IC50 values of ~7uM (HDMB03) and ~11uM (D425). Amongst the four drugs, NT induced consistent anti-neoplastic effects on wound healing, colony formation, medullosphere generation, and apoptosis. Mechanistically, NT induced mitochondrial stress, escalated mitochondrial superoxide, and decreased mitochondrial membrane potential. CHRM3, a receptor antagonized by NT and upregulated in G3MB samples was downregulated by NT treatment. Western blotting confirmed the inhibition of CHRM3 downstream effectors.

CONCLUSIONS
Our pipeline identified cytotoxic compounds against G3MB, including NT, which we hypothesize induces mitochondrial stress via CHRM3 modulation. This approach offers repurposable FDA-approved candidates for high-risk G3MB, potentially reducing current treatment toxicity and improving outcomes.
MDB-96. CEREBROSPINAL FLUID LEVELS OF THE MIR216B-5P AS A MINIMALLY INVASIVE MONITORING TOOL FOR MEDULLOBLASTOMA
Authors: Koptyra Mateusz P , Coyle Anne , Hollawell Madison , Rathi Komal , Arif Shehbeel , Diamond Maura , Diarra Noni , Naqvi Ammar , Madsen Peter , Storm Phillip B , Foster Jessica B , Resnick Adam C 
Published: June 2024

Abstract

BACKGROUND
Current management of pediatric brain tumor patients relies on imaging as the only non-invasive tool available for monitoring therapeutic response and tumor progression. Results are often inconclusive and unable to capture biologically relevant changes that presage progression on imaging. Circulating miRNA provides an attractive non-invasive biomarker because miRNA has an essential role in regulating gene expression, stability in bio-fluids, selective over-expression in tumors, and is actively released from tumors into the extracellular environment. We aimed to establish the diagnostic and monitoring value of miRNA biomarkers for pediatric brain tumors in cerebrospinal fluid (CSF).

METHODS
We performed HTG EdgeSeq miRNA panel profiling (2100 targets) of CSF (n=33) samples across pediatric brain tumors from 5 histologies (low grade glioma, ependymoma, germ cell tumor, medulloblastoma, high-grade glioma). We utilized unsupervised consensus clustering, differential expression analysis, and machine learning approaches to investigate miRNA biomarkers. Results were validated using qPCR and ddPCR methods.

RESULTS
CSF miRNA signatures revealed a correlation with leptomeningeal disease and higher disease burden (p&lt;0.05). Differentially expressed miRNA revealed histology-specific signatures for low grade glioma, medulloblastoma, and germinoma (p&lt;0.05). miR216 expression was significantly elevated in medulloblastoma patients with active disease, indicating a potential novel biomarker for tumor monitoring. The miR216b-5p expression in CSF was confirmed using qPCR and ddPCR. The analysis of independent tumor tissue-based dataset confirmed miR216b-5p and its coding gene MIR217HG expression upregulated in medulloblastoma. MiR-216b-5p expression was also confirmed in patient-derived medulloblastoma cell lines and detected in cell free-media composition indicating extracellular release of miR216b-5p.

CONCLUSIONS
These results support the use of circulating miRNA in CSF as a potential biomarker for diagnosis and clinical monitoring of medulloblastoma. Further utilization of this approach provides a unique platform to inform liquid biopsy-based management in the clinical setting.
MDB-101. TARGETING CTPS1 AND NUCLEOTIDE BIOSYNTHESIS PATHWAYS AS A NOVEL THERAPEUTIC APPROACH IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Hathaway Matthew , Jagana Hawa , Terrones Isabella , Miyaki Aya , Hemenway John , Meechan Michael , Gadek Kate , Slusher Barbara , II Myron Evans 
Published: June 2024

Abstract
Although leukemia is the leading pediatric oncology diagnosis, brain tumors are the leading cause of pediatric cancer-related death. Medulloblastoma (MB) is the most common pediatric brain tumor, representing approximately 20% of all diagnoses. MYC-amplified Group 3 medulloblastoma (G3 MB) tumors are the deadliest, with a &lt; 50% 5-year overall survival rate. High risk patients receive large doses of chemo- and radio- therapy (CT/RT) with most survivors experiencing debilitating neurological and cognitive sequelae making the identification of novel targets of the utmost importance. Utilizing whole-genome CRISPR screening, we identified the enzyme CTPS1 as a strong G3 MB-specific vulnerability. Further analysis revealed dependencies on other enzymes in the de novo pyrimidine synthesis pathway, which is corroborated by recent metabolic studies. Targeted knockdown of CTPS1 restricts sphere formation and reduces proliferation of G3 MB tumor lines. Treatment with a specific CTPS1 inhibitor reduced proliferation but did not induce cell death, suggesting a cytostatic mechanism. Previous work has shown that triggering an imbalance in pyrimidine and purine levels leads to replication stress and activation of the ATR/CHK1 pathway. Both genetic and pharmacologic inhibition of CTPS1 leads to CHK phosphorylation, allowing for cell survival despite lack of dNTPs. Previously, the CHK1 inhibitor, prexasertib, demonstrated robust brain accumulation and targeting of G3 MB in pre-clinical models. Dual inhibition of CHK1 and CTPS1 synergizes to significantly reduce cell viability in vitro and tumor growth in vivo. We further demonstrated robust synergy of CHK1 inhibition with either glutamine antagonists or other inhibitors of the de novo pyrimidine synthesis pathway, prolonging in vivo survival in an orthotopic xenograft G3 MB model. The results of this investigation confirm CTPS1 as a novel target in G3 MB, pinpoint a dependency on de novo pyrimidine rather than purine biosynthesis, and identifies a novel rational combination for treatment in MYC-amplified MB patients.
MDB-110. A NOVEL TRANSGENIC MOUSE MODEL FOR GLI2-AMPLIFIED MEDULLOBLASTOMA
Authors: Murad Najiba , Xu Zhenhua , Liu Xiao , Rivero-Hinojosa Samuel , Ramawickrama Prathibhani Gamachchige , Pei Yanxin 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is one of the most common malignant childhood brain tumors. The sonic hedgehog (SHH) subgroup represents 30% of MBs and can arise from granule neuron progenitors (GNPs). SHH-MB is a diverse subgroup of tumors which often exhibit loss-of function mutations in PTCH1 or SUFU, activating mutations in the receptor SMO and amplification of the transcription factor GLI2. Of note, SHH-MBs harboring GLI2-amplification and associated with P53 mutations have extremely poor prognosis with a 5-year survival rate less than 30%. These tumors are non-responsive to SMO inhibitors, which are the only targeted treatment currently available for SHH-MB. Therefore, the development of novel effective therapies for this disease is urgent. Although GLI2 amplification is detected in SHH-MBs, it is not yet known if GLI2 can drive oncogenic activity in this disease.

METHOD
To elucidate the mechanisms underlying tumorigenesis, our group has developed a novel transgenic model of GLI2-driven MB by expressing a constitutively active form of GLI2 (GLI2A) in Atoh1+ cells in the developing mouse cerebellum to form tumors. To accomplish this, we crossed R26;Gli2A mice with Atoh1-Cre.

RESULTS
The resulting tumors faithfully recapitulate human GLI2-amplified MB at the cellular and molecular levels. Inactivation of GLI2A resulted in tumor regression, indicating that GLI2 is not only critical for tumorigenesis, but also required for tumor maintenance, suggesting that targeting GLI2 itself or its downstream targets may be effective to inhibit growth of GLI2-driven MB. Interestingly, activation of GLI2A expression in the neonatal cerebellum was not sufficient to drive tumorigenesis, indicating that GLI2-driven MB arises from more primitive cells in the developing cerebellum.

CONCLUSION
Taken together, our studies demonstrate for the first time the role of GLI2 as an oncogenic driver of MB and introduce a novel mouse model which can be used to develop targeted therapies for this disease.
NFS-10. ROLE OF CDKN2A CO-DELETION IN DRIVING TUMOR INVASIVENESS IN NF1 MUTANT GLIOMA
Authors: Chong Wai Chin , Subramaniam Bavani , Tomasso Federica , Roy Debasish , Yadavilli Sridevi , Bornhorst Miriam , Packer Roger , Nazarian Javad 
Published: June 2024

Abstract

BACKGROUND
Neurofibromatosis type 1, caused by mutations in the NF1 gene, is a common autosomal dominant genetic disorder associated with an increased risk of glioma tumor development. A high occurrence of CDKN2a codeletion in NF1-mutant high-grade gliomas (HGG) compared to low-grade gliomas (LGG) implies a potential role of CDKN2a loss in the transformation of NF1-mutant LGG to HGG. In our study, we aimed to elucidate the role of NF1 and CDKN2a in tumor transformation using a panel of glioma cell line models with varying NF1 and CDKN2a expression.

METHOD
A diverse panel of glioma cell lines, encompassing LGG (1667-ON, RES259, RES186, JHH-NF1-PA1) and HGG (GBM511, GBM110, SF8628, U87-MG, TM-31, 7316-2189, 7316-3058, 7316-4917), was cultured. Their growth rates and invasiveness were further evaluated using cell proliferation and Boyden chamber invasiveness assays.

RESULTS
LGG cell lines exhibited relatively lower growth rates and invasiveness compared to their high-grade counterparts. Intriguingly, RES259, a LGG cell line harboring both NF1 and CDKN2a variants, demonstrated the highest growth rate and invasiveness among LGG cell lines, surpassing even those with intact NF1 and CDKN2a, such as JHH-NF1-PA1 and RES186. To further elucidate the roles of NF1 and CDKN2a, CRISPR-Cas9 technology was employed to knockout these genes individually and in various combinations in RES186. Our findings unveiled that sole NF1 knockout had negligible impact on RES186. Conversely, CDKN2a knockout increased both growth rate and invasiveness. Strikingly, the codeletion of NF1 and CDKN2a in RES186 significantly exacerbated its growth rate and invasiveness. These results underscore the intricate interplay of NF1 and CDKN2a in governing the growth and invasiveness dynamics of glioma cells.

CONCLUSION
In conclusion, our preliminary study suggests that the concurrent loss of NF1 and CDKN2a promotes enhanced growth and invasiveness in gliomas, shedding light on the collaborative role of these genetic alterations in tumor transformation.
NFS-19. ATYPICAL PRESENTATION OF GLIOMAS IN ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1): A CASE SERIES
Authors: Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Cluster Andrew , Shatara Margaret , Abdelbaki Mohamed S , Brossier Nicole M 
Published: June 2024

Abstract

BACKGROUND
Patients with NF1 are at risk for developing gliomas, usually low-grade in childhood but may be high-grade in adults. In children, the most common sites of disease are the optic pathway and brainstem; tumors in these regions often arise in young children and display histological features characteristic of pilocytic astrocytoma (PA) when biopsied. Typical MRI findings include T2 hyperintense, T1 hypointense lesions with minimal contrast enhancement and no diffusion restriction. Due to the well-established pattern of low-grade tumor formation in children with NF1, as well as the surgically challenging areas in which these tumors develop, low-grade glioma (LGG) therapy is often initiated without histologic confirmation of the diagnosis in classic cases. In cases with atypical disease location, older age at presentation or imaging appearance, a biopsy may be considered to exclude higher-grade lesions.

METHODS
Retrospective chart review, case series

RESULTS
Four adolescent patients with NF1 presented with atypical suspected gliomas. All four patients underwent surgical biopsy/resection. Case 1 was a left temporal lesion in the previous radiation field for optic pathway glioma; biopsy confirmed LGG with MAP2K1 mutation and increased focal proliferation index (28%), but methylation did not match with any established classification. The patient progressed through multiple rounds of therapy and succumbed to her tumor. Case 2 was a left occipital lesion; biopsy confirmed PA with CDKN2A deletion. The tumor displayed rapid regrowth, but subsequently stabilized. Case 3 was a right frontal lesion; confirmed PA. The tumor demonstrated some regrowth but then stabilized. Case 4 was a basal ganglia lesion; confirmed PA. The patient has demonstrated stable MRI findings and has not required further intervention.

CONCLUSIONS
Biopsy yielded helpful prognostic information (additional mutations, proliferation rate) in half of these atypical cases. Biopsy should be carefully considered for NF1 patients with atypical presentation or a history of radiation.
NFS-28. CLINICAL CHARACTERISTICS AND THERAPEUTIC INTERVENTIONS IN A CASE SERIES OF PEDIATRIC PATIENTS WITH VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2
Authors: Stitzlein Lea M , Sun Yusha Y , Munir Faryal , McCutcheon Ian E , Slopis John M , Zaky Wafik 
Published: June 2024

Abstract

BACKGROUND
Pediatric neurofibromatosis type 2 (NF2) is an understudied genetic disorder with high incidence of tumors including vestibular schwannomas (VS) and meningiomas. Although predominately recognized as an adult disease, there is a shortage of comprehensive studies in pediatric NF2. This case series describes a large cohort of pediatric NF2 patients with VS and their disease management.

METHODS
Our study included 24 patients with initial symptoms of NF2 before age 19. The patients were treated at the Neurofibromatosis Clinic of The University of Texas MD Anderson Cancer Center between 1/1/2005-12/31/2023. Our analysis incorporated data from clinic notes, surgical reports, audiology reports, electromyography reports, pathology reports, and imaging studies.

RESULTS
Patients presented with NF2 at an age range from 18 months to 18 years (mean age 8.1 ± 5.2 years). Among the patients, 67% underwent surgical interventions, including auditory brainstem implants, cochlear implants, ventriculoperitoneal shunts, and/or craniotomies for tumor resection. Additionally, treatment in 21% of cases involved radiotherapy, employing stereotactic radiosurgery, intensity-modulated radiotherapy, and proton beam irradiation. Targeted therapies, including bevacizumab, lapatinib, everolimus, temsirolimus, brigatinib, or a combination thereof, were administered to eleven patients. The best exhibited response by most patients was stable disease for a median duration of 10 months, and clinical improvement/stabilization of the hearing loss. Most reported toxicities related to bevacizumab or temsirolimus. Overall, limited clinical improvement was observed within this cohort after interventions.

CONCLUSION
This study discusses the clinical presentation of pediatric NF2 with VS and highlights the need for effective therapeutic options to manage tumors and symptoms in this patient population. A notable research gap exists in pediatric NF2, compounded by the lack of preclinical models to study the disease. The absence of approved drugs underscores the necessity for more comprehensive studies to guide therapeutic strategies. Combination therapies may advance treatment approaches and achieve improved outcomes.
QOL-03. BONE HEALTH IN CHILDREN WITH SUPRASELLAR AND THALAMIC LOW GRADE GLIOMA; AN UNDERSTUDIED PROBLEM
Authors: van Roessel IMAA , Gorter J E , Bakker B , van den Heuvel-Eibrink M M , Lequin M H , van der Lugt J , Meijer L , van Meeteren A Y N Schouten- , van Santen H M 
Published: June 2024

Abstract

BACKGROUND
Children with a supratentorial midline Low Grade Glioma (LGG) may be at risk for impaired bone health due to hypothalamic-pituitary dysfunction, obesity, exposure to multiple treatment modalities, and/or decreased mobility. The presence of impaired bone health and/or its severity in this population has been understudied. We aimed to identify the prevalence and risk factors for bone problems in children with supratentorial midline LGG.

METHODS
A retrospective study was performed in children with supratentorial midline (suprasellar or thalamic) LGG between 1-1-2003 and 1-1-2022, visiting the Princess Máxima Center for Pediatric Oncology. Impaired bone health was defined as presence of vertebral fractures or collapse, any fractures not related to (the intensity of) trauma, treatment with bisphosphonates, and/or very low bone mineral density (BMD).

RESULTS
In total, 161 children were included, with a median age at tumor diagnosis of 4.7 years (range 0.1 – 17.9) and a median follow-up of 6.1 years (range 0.1 – 19.9). ‘Any’ bone problem occurred in 22.4% (36/161) and nontraumatic fractures in 3.7%. Impaired visual capacity was associated with bone problems in multivariate analysis (OR 3.56 95% CI 1.30 – 9.76, p = 0.014).

CONCLUSIONS
In this retrospective evaluation, bone problems and decreased BMD were prevalent in 36.1% of children with supratentorial midline LGG. Risk to develop bone problems appears to be multifactorial, but visual capacity seems highly relevant. Surveillance of bone health must be an aspect for awareness in the care and follow-up of children with a supratentorial midline LGG.
QOL-06. RECURRENCE PATTERNS AND SURVEILLANCE IMAGING IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Cacciotti Chantel , Lenzen Alicia , Self Chelsea , Pillay-Smiley Natasha 
Published: June 2024

Abstract

BACKGROUND
Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in pediatric central nervous system (CNS) tumors. Frequency of neuroimaging varies with no standardized approach.

METHODS
A single institution retrospective cohort study evaluated frequency and pattern of recurrences. Pediatric patients (birth to age 21 years) diagnosed with a primary CNS tumor between 1988 and 2011 treated at Lurie Children’s Hospital were included.

RESULTS
This study included 476 patients; the majority diagnosed with a low-grade glioma (LGG) (n=138; 29%), high grade glioma (HGG) (n=77; 16%), ependymoma (n=70; 15%) or medulloblastoma (n=61; 13%). LGG, HGG and ependymoma patients more commonly had multiply recurrent disease (p=0.08), with ependymoma patients demonstrating ≥2 relapses in 47% of cases. Recurrent disease was identified by imaging more often than clinical symptoms (65% vs 32%; p=&lt;0.01). Treatment at relapse included surgical managment more often than non-surgical approach (59% vs. 41%; p=0.0016) in patients, leading to pathology confirmation of recurrence. Mean time to first relapse for the entire cohort was 2.5 years (range 1 day-24.8 years). Patients diagnosed with meningioma demonstrated the longest mean time to first relapse (74.7 months) whereas those with Atypical Teratoid Rhabdoid Tumor and Choroid plexus carcinoma tended to have the shortest time to relapse (8.9 months and 9 months, respectively). Overall, 22 patients sustained first relapse &gt;10 years from initial diagnosis, including those diagnosed with LGG, medulloblastoma, pineoblastoma, craniopharyngioma, GCT, and meningioma.

CONCLUSION
With a higher percentage of tumor recurrence/progression seen on neuroimaging before development of symptoms, surveillance imaging is necessary in routine follow up of pediatric CNS tumor survivors. While the study is limited since we did not look at overall survival, earlier detection of recurrence would lead to earlier initiation of treatment and implementation of salvage treatment regimens which can impact survival and quality of life.