bluuebunny/crossref_metadata_2025 huggingface dataset:
MDB-63. AN INTERNATIONAL META-ANALYSIS OF SHH MEDULLOBLASTOMA SUBTYPES DEFINES A CLINICALLY SIGNIFICANT HIGH-RISK VARIANT OF SHH-SUBTYPE 3
Authors: Schwalbe Edward C , Sill Martin , Suzuki Hiro , Charron Frederic , Taylor Michael D , Pfister Stefan M , Clifford Steven C
Published: June 2024

BACKGROUND

The distinction of MBSHH into four methylation-dependent subgroups was recognized by the WHO in 2021. However, these subgroups have not previously been defined by international experimental consensus and their clinico-molecular features and behavior have not formally been investigated in large cohorts. We aimed to robustly identify SHH subgroups through analysis of MBSHH with DNA-methylation profiling.

METHODS

A cohort of 683 MBSHH, confidently classified using the Heidelberg classifier v12.5, was assembled for analysis from multiple international studies. To define subgroups, we applied consensus sampling-based clustering approaches to tumor methylomes, including assessment of confidence in class-definition and inter-technique concordance. The clinico-molecular features of consensus subgroups were investigated.

RESULTS

Lowest complexity analysis supported the division of MBSHH into the 4 WHO-subtypes. SHH-1 and SHH-2 were associated with lower age and infrequent mutations of PTCH1/SUFU; SHH-2 was distinguished from SHH-1 by enriched MBEN histology, absence of chromosome 2 gain, less frequent metastasis and more favorable overall-survival. SHH-4 presented in older children and adults (3-57; median 24 years), and was primarily defined by mutations in U1-snRNA (67/72). Consensus analyses supported the division of SHH-subgroup-3 into three. Importantly, the SHH-3C subtype was associated with a coalescence of high-risk features (LCA histology, TP53mut, MYCNamp/GLI2amp) alongside 3p, 10q and 17p loss, and had dismal survival. The remaining SHH-3A/B subtypes were characterized by 9q loss, frequent focal amplifications of TERT and PPM1D, and equivalent better survival.

CONCLUSIONS

This study affirms the distinction of MBSHH into 4 major subgroups. For infant disease, SHH-2 is a favorable-risk marker. For childhood-MBSHH, the SHH-3C subtype provides a molecular definition of high-risk that subsumes other previously-defined high-risk disease markers (LCA, MYCNamp, TP53mut) into a unified high-risk disease group. The other SHH-3 subtypes behave similarly and are favorable-risk. These subtypes have potential to enhance molecularly-guided risk-stratification in routine diagnostics, to improve patient outcomes and quality-of-life.
MDB-64. NOVEL TRANSCRIPTS ASSOCIATE WITH SURVIVAL IN CHILDHOOD MEDULLOBLASTOMA
Authors: Mateos Marion K , Williamson Daniel , Danilenko Marina , Goddard Jack , Crosier Stephen , Fletcher Anya , Schwalbe Edward , Hicks Debbie , Bailey Simon , Clifford Steven C
Published: June 2024

BACKGROUND

Medulloblastoma is the commonest malignant brain tumour in childhood, with progression-free survival (PFS) <65% in high-risk disease. Novel biomarkers, independent of current clinicopathological risk factors, could enhance understanding of biology and support improved treatment approaches.

METHODS

Using high-depth RNA sequencing of 217 patients, we identified novel multi-exonic medulloblastoma transcripts using a de novo analysis. We evaluated these alongside known/curated gene transcripts, including correlative survival analysis for 170 patients (aged 3-16 years and treated with curative intent). Multivariable survival analyses of the overall cohort (n=145) and a MBGroup3/MBGroup4 (Group3/Group4)-specific subcohort (n=95) was undertaken to identify prognostic transcripts, adjusting for current risk criteria and correcting for multiple testing.

RESULTS

From 3,150 novel transcripts identified, expression of 217 varied significantly and were further assessed. One was prognostic for PFS independent of subgroup (located on chromosome 20) while three were independently prognostic within Group3/Group4 (located on chromosome 1, 4 and 21 respectively). Transcript presence was validated by qPCR. From >60,000 known transcripts identified, 9693 were assessed. Four were independently prognostic for PFS in the whole-cohort (MRPS12, SLC25A34, MLYCD and ROGD1). In Group3/Group4, the top upregulated canonical pathways associated with PFS were: polo-like kinase, cyclin/cell cycle regulation, BRCA1/ DNA damage response, and glutamate receptor signalling. MELK and NQO2 were among the top 10 transcripts most highly associated with Group3/Group4 PFS. The prognostic significance of six transcripts (MRPS12, MLYCD, MELK, CDK4, NQO2, ROGD1) was validated in an independent Group3/Group4 dataset (n=470) while ROGD1 was prognostic independent of subgroup. Immunohistochemical validation showed low CDK4 expression, low MLYCD expression and high CHK1 expression were independent prognosticators in Group3/Group4.

CONCLUSION

De novo transcripts represent a significant component of the medulloblastoma transcriptome, providing prognostic information, and enhancing biological understanding of Group3/Group4 disease. CHK1 and MELK represent promising validated candidates for further evaluation as prognostic biomarkers in Group3/Group4 medulloblastoma.
MDB-72. BREFELDIN A (BFA) INDUCES CD133 PROTEOLYTIC PROCESSING IN MEDULLOBLASTOMA STEM CELLS (MBSCS)
Authors: Spinello Zaira , Cese Martina , Ronci Maurizio , Giusti Laura , Abballe Luana , Miele Evelina , Ferretti Elisabetta , Catanzaro Giuseppina
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is a malignant brain tumor occurring in children, characterized by elevated resistance to conventional chemotherapy. Medulloblastoma stem cells (MBSCs) represent a fraction of the tumor cell population which has been associated with poor prognosis and refractoriness to conventional therapies. CD133 (Prominin 1, PROM1) is a transmembrane protein serving as a cancer stem cell marker associated with cancer progression. Brefeldin A (BFA) is an antibiotic disrupting the Golgi apparatus, thus triggering Endoplasmic reticulum (ER) stress signaling pathways. BFA cancer-inhibitory properties have been already described in cancer of different tissue origin. However, the effects of BFA on MBCSs have not been investigated yet. Thus, the aim of this study was to characterize the response of MBSCs to BFA and the effects induced by BFA on CD133.

METHODS

Human group 3 MB (G3MB) cell lines were grown in stem selective medium (B27™) and treated with 0.3 uM BFA for 24h before collection. Apoptosis, clonogenicity and CD133 expression were evaluated. CD133 was immunoprecipitated and the corresponding bands were excised and analyzed by nanoLC-MS/MS. Raw data were processed using PEAKS XPro.

RESULTS

Our results show that BFA-treated cells induced the overexpression of a CD133 isoform that was missing the N-terminus region. Moreover, we found a downregulation of CD133 activated intracellular signalling together with a reduced exposition on cell membrane.

CONCLUSIONS

We report here for the first time, a N-terminus proteolytic processing of CD133, potentially associated to the cell trafficking effects induced by BFA. Finally, this study suggests a proof of principle for the design of novel molecules with similar structures and mechanism of action of BFA.
MDB-73. INHIBITING THE B7-H3 CHECKPOINT IN MEDULLOBLASTOMA
Authors: Moziak Kirsten , Pensabene Juliana , Perez Natalia Muñoz , Yazejian Rita , Picarda Elodie , Zhang Xingxing , Martin Allison M
Published: June 2024

INTRODUCTION

Tumors express immune checkpoints to evade detection and clearance by the immune system. Immune checkpoint inhibition (ICI) allows for tumor clearance. Medulloblastoma (MB) has not seen success with ICI and relapsed/refractory tumors remain incurable. B7-H3 is an immune checkpoint that is highly and specifically expressed by many cancers including MB. It is implicated in immune evasion in cancer. We hypothesize inhibiting B7-H3 in MB will enhance the anti-tumorigenic properties of immune cells.

METHODS

Murine MB cells, which mimic aggressive disease, were transduced with a CRISPR/Cas9 lentivirus (courtesy of Zhang lab) to create a B7-H3 knockout (B7-H3–). Unsuccessful iterations of the same CRISPR/Cas9 sgRNA were used as a B7-H3+ control. B7-H3+ and B7-H3– cells were co-cultured for 5 days with splenic, bead isolated, CD4-T cells from C57BL/6J mice. Proliferation of the T cells was measured with Cell Trace Violet via flow cytometry using a Cytek Aurora.

RESULTS

We saw comparable tumor cell inhibition of T cell proliferation when cultured with B7-H3+ and B7-H3– tumor cells, as measured by CTV elution.

CONCLUSIONS

We saw similar amounts of T cell proliferation inhibition from both B7-H3 – and + tumor cells. This could indicate a few possibilities. First, B7-H3 may not be contributing to CD4-T cell inhibition, in which case it is important to explore its role in other immune cells. Another option is that B7-H3 is targeting the function of these cells, rather than the proliferation. To examine this, we could look at markers of effector function. Lastly, B7-H3 could be mediating inhibition of CD4-T cells via other cell(s) in the tumor microenvironment (TME) of MB, which we could test in vivo. If B7-H3 promotes ant-tumorigenic immune responses, it would be a promising approach relapsed/refractory medulloblastoma that presently has no cure, as well as other cancers that highly express it.
MDB-74. SERINE/GLYCINE METABOLISM REPRESENTS A NOVEL TARGETABLE THERAPEUTIC VULNERABILITY IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Adiamah Magretta , Poole Bethany , Lindsey Janet C , Swartz Shanel , Morcavallo Alaide , Gosling Samantha Jepson , Singh Mankaran , Blair Helen J , Kohe Sarah , Zhang Tong , Maddocks Oliver , Peet Andrew , Chesler Louis , Hickson Ian , Maxwell Ross , Hill Rebecca M , Clifford Steven C
Published: June 2024

BACKGROUND

Medulloblastoma is the most frequent malignant brain tumour of childhood. Whilst advances in risk-stratification and upfront multimodal therapy have led to five-year survival rates around 70%, a subset of tumours remain refractory to current therapies. Group 3 medulloblastomas (MBGRP3) are enriched for amplification or overexpression of the proto-oncogene MYC which conveys a dismal prognosis (<10% survival), highlighting the urgent need for novel therapeutic strategies. Recent advances have revealed a role for metabolic reprogramming in MYC-amplified MBGRP3 tumorigenesis, providing novel opportunities for selective therapeutic targeting.

METHODS & RESULTS

To investigate MYC-dependent metabolic alterations in MBGRP3, we generated three independent isogenic MBGRP3 cell-based models with regulable MYC expression (iMBGRP3-MYC) using a doxycycline-inducible shRNA system. Using 1H high-resolution magic angle spectroscopy and stable isotope-resolved metabolomics, we identified upregulation of the de novo serine/glycine biosynthesis pathway (SGP), attributable to elevated expression of the rate-limiting enzyme PHGDH, as a novel therapeutic target. Genetic and pharmacological (NCT-503) inhibition of PHGDH induced greater cell death in MYC-expressing cells compared to MYC knockdown cells and increased survival across two independent MYC-amplified MBGRP3 mouse models. The decrease in tumour growth observed was moderate; we therefore hypothesised that a compensatory reliance on exogenous serine/glycine may play a role in sustaining tumour progression under therapy. To explore this, we investigated the impact of exogenous serine/glycine starvation on MBGRP3-MYC tumour development. Starvation resulted in a marked MYC-dependent reduction in cell viability in vitro across independent iMBGRP3-MYC models. Notably, dietary serine/glycine starvation was well-tolerated, delayed tumour progression, and increased survival (by 50%) in an MBGRP3-MYC mouse model (p=0.005), highlighting the metabolic plasticity of MYC-amplified tumours to utilise both de novo and exogenous serine/glycine sources to survive and proliferate.

CONCLUSIONS

These findings identify serine/glycine metabolism as a targetable therapeutic vulnerability within MYC-amplified MBGroup3 and a novel therapeutic strategy to treat this poor-prognosis disease group.
MDB-78. ISOCITRATE DEHYDROGENASE 1 INHIBITION PRIMES GROUP-3 MEDULLOBLASTOMAS FOR CUPROPTOSIS
Authors: Dang Derek , McKolay John , Smith Kyle , Panwalkar Pooja , Sweha Stefan , Natarajan Siva Kumar , Pun Matthew J , Ji Sunjong , Patel Diya , Animasahun Olamide , Achreja Abhinav , Ogrodzinski Martin P , Cotter Jennifer , Hawes Debra , Yang Fusheng , Doherty Robert , Franson Andrea T , Hanaford Allison R , Eberhart Charles G , Raabe Eric H , Chen Brandon , Lyssiotis Costas A , Shah Yatrik , Lunt Sophia Y , Judkins Alexander R , Prensner John , Koschmann Carl J , Waszak Sebastian , Nagrath Deepak , Northcott Paul , Venneti Sriram
Published: June 2024

BACKGROUND

MYC-driven Group-3 medulloblastomas (MB) are deadly and malignant pediatric brain cancers and we sought to define actionable metabolic dependencies in these tumors.

METHODS

To identify uniquely upregulated genes in Group-3 MB, we performed transcriptomic analysis on two previously published medulloblastoma RNA-seq datasets. To elucidate the relationship between c-MYC/IDH1/DLAT and assess impact on tumor metabolism, we performed metabolic and transcriptional profiling of Group-3 MB cell lines that were either untreated or were subjected to shRNA-mediated knockdown of DLAT or treatment with IDH1 inhibitor. We also treated Group-3 MB cell lines containing varying levels of DLAT expression with copper ionophore elesclomol and assessed its ability to induce toxicity. Finally, we established in vivo models of Group-3 MB via orthotopic implantation to assess the effect of DLAT knockdown, IDH1 inhibition, and cuproptosis induction on tumor growth and survival outcomes.

RESULTS

We identified upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of Group-3 MB. DLAT was induced by c-MYC and targeting DLAT lowered TCA-cycle metabolism and glutathione synthesis in Group-3 MB cells. We also noted upregulation of isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Remarkably, genetic and pharmacologic suppression of IDH1 epigenetically reduced c-MYC and downstream DLAT levels. DLAT is a central regulator of cuproptosis, a copper-dependent cell death mechanism induced by the copper ionophore elesclomol. DLAT expression in Group-3 MB cells correlated with increased sensitivity to cuproptosis. Elesclomol was CNS-penetrant and suppressed tumor growth in vivo in Group-3 MB animal models.

CONCLUSIONS

Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill Group-3 MB by cuproptosis.
MDB-88. DUAL TARGETING OF PROCESSIVE TRANSCRIPTION FOR MYC-DRIVEN CIRCUITRY IN MEDULLOBLASTOMA
Authors: Walker Faye M , Madhavan Krishna , Sobral Lays Martin , Donthula Sahiti , Balakrishnan Ilango , Wang Dong , Pierce Angela , Veo Bethany , Karam Sana D , Serkova Natalie J , Foreman Nicholas K , Venkataraman Sujatha , Vibhakar Rajeev , Dahl Nathan A
Published: June 2024

BACKGROUND

The highest-risk medulloblastomas are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB.

METHODS

Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with the dual CDK9/7 inhibitor zotiraciclib to evaluate effect on Myc-driven programs and tumor growth.

RESULTS

Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cell lines are sensitive to CDK9 inhibition at low nanomolar concentrations, and these synergize with CDK7 inhibition. We find that treatment with the dual CDK9/7 inhibitor zotiraciclib depletes Myc binding and transcriptional activity at enhancer elements within the Myc topologically associated domain, largely abrogating transcriptional output from the Myc promoter. This leads to a decrease in Myc binding genome-wide with a concordant downregulation of hallmark Myc-driven transcriptional programs. Clinically relevant CDK9 inhibitors show variable efficacy in vivo, but CNS-penetrant agents achieved a significant prolongation in xenograft survival.

CONCLUSIONS

CDK9/7 catalytic activity represents a druggable vulnerability underpinning Myc-driven transcriptional programs. The development of CNS-penetrant CDK9/7 inhibitors may open new avenues for rational therapy in these high-risk medulloblastomas.
MDB-89. DETERMINING THE IMMUNOMODULATORY POTENTIAL OF PI3KΓ IN AGGRESSIVE MEDULLOBLASTOMA AND THE TUMOR MICROENVIRONMENT
Authors: Yazejian Rita M , Moziak Kirsten , Perez Natalia Munoz , Pensabene Juliana , Martin Allison
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is the most common pediatric embryonal brain tumor arising in the cerebellum. It has a “cold” tumor microenvironment (TME) characterized by an abundance of immunosuppressive Tumor Associated Macrophages (TAMs) and low T-cell infiltration. TAMs include tissue resident microglia and migrating bone marrow derived macrophages. While microglia play important roles in the central nervous system through their immune surveillance and ability to activate other immune cells, they can be polarized by tumor cells toward an anti-inflammatory state which allows for maintained tumor growth and proliferation. A potential new target to combat the immunosuppressed TME of MB is the class IB isoform PI3Kγ. Inhibiting this isoform has been attributed to controlling a critical switch between immune suppression and immune stimulation in TAMs but has yet to be examined in MB and its TME. We hypothesize that inhibiting PI3Kγ in TAMs and MB tumor cells will induce an anti-tumorigenic immune response within the MB TME and promote tumor clearance.

METHODS

Engineered murine MB cells, mCB DNp53 MYC, are treated with a pan-PI3K or specific PI3Kγ inhibitor for 48 hours before being co-cultured with naïve splenic CD4 T-cells from C57BL/6J mice for 5 days. Proliferation of the T cells is measured using Cell Trace Violet through flow cytometry on a Cytek Aurora.

RESULTS

Pan-PI3K inhibition revealed that tumor cells treated with the inhibitor prior to co-culturing did not suppress T-cell proliferation as drastically when compared to untreated tumor cells. Treatment with a selective inhibitor is on-going.

CONCLUSIONS

These results suggest that inhibition of the PI3K pathway in our MB tumor cells dampens their ability to suppress T cell proliferation. The PI3K pathway may play an active role in tumor cell’s ability to induce immunosuppression. Inhibiting this pathway may be a new avenue for therapeutic intervention for relapsed/refractory MB.
MDB-106. MEDULLOBLASTOMA TUMOR MICROENVIRONMENTS SHOW INTRA- AND INTER-TUMORAL HETEROGENEITY ON SPATIAL TRANSCRIPTOMICS
Authors: Chien Franklin , Michaud Marina , Bakhtiari Mojtaba , Ross James L , Schroff Chanel , Snuderl Matija , MacDonald Tobey , Bhasin Manoj
Published: June 2024

BACKGROUND

Medulloblastoma defines a heterogeneous set of neuroepithelial neoplasms of the posterior fossa. Four groups of medulloblastoma are recognized: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. The tumor microenvironment (TME) influences tumor progression and response to therapy and has emerged as a growing target for the study of novel therapeutic approaches.

METHODS

We show spatial gene expression architecture through 10X Visium Spatial Sequencing on 16 formalin-fixed paraffin-embedded (FFPE) samples representing all molecular groups of medulloblastoma. Spatial transcriptomics data is correlated with clinical parameters, including M-stage at diagnosis, tumor histological classification, and outcomes data including survival and relapse status.

RESULTS

Spatial sequencing demonstrates both intra- and inter-tumoral TME heterogeneity across molecular subgroups. Unsupervised clustering and uniform manifold approximate projection illustrate clusters of distinct spatial gene expression representing cell states from different components of the TME, including tumor-associated astrocytes (TAA), macrophages (TAM), and vascular endothelium. Medulloblastoma cells constitute the majority of cells and express marker genes representing different stages of neuronal differentiation and cell cycle. Pathway analysis reveals the enrichment of pathways associated with cell motility (RHO GTPase, MET, MAPK signaling), heat shock response, growth factor signaling, and adaptive immune response (TLR, MHC-II signaling). In addition, molecular pathways known in medulloblastoma, including NF-kB and TP53 regulatory pathways, were also enriched. Neighborhood-enrichment analysis reveals the co-localization of TAMs and TAAs in close spatial relationship with mitotic progenitor-like medulloblastoma cells. Additionally, these two cell types constitute a greater proportion of the TME in patients at relapse compared to initial diagnosis.

CONCLUSION

Spatial transcriptomics enables new insight into the heterogeneity of the medulloblastoma TME. Notably, our analysis elucidates the spatial association of TAMs and TAAs with proliferating tumor cells and an increased abundance of these cell types following relapse. These initial results support the role of TAMs and TAAs in medulloblastoma progression.
MDB-107. MINNELIDE, A PROMISING COMPOUND FOR THE TREATMENT OF HIGH-RISK MEDULLOBLASTOMA
Authors: Blanco Jezabel Rodriguez , Salvador April , Sahani Pritika , Kliebe Valentin , Peterson Kendell , Turos Maria
Published: June 2024

Despite the overall good outcome of children with medulloblastoma (MB), a subset faces the challenge of highly aggressive metastatic tumors. The poor prognosis for these patients underscores the urgent need for advancing therapeutic approaches. Minnelide, an analog of the natural product triptolide, exhibits potent antitumor activity in preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, Minnelide has not been assessed against MB. Using a bioinformatic dataset integrating cellular drug response and gene expression, we predicted sensitivity of Group 3 (G3) MB, characterized by a poor five-year survival, to triptolide/Minnelide. Subsequent experiments confirmed the ability of both triptolide and Minnelide to reduce the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a crucial driver of G3 MB, as a downstream target of these drugs. We validated the MYC dependency and demonstrated that triptolide affects both MYC transcription and protein stability. Notably, Minnelide acted in vivo on MYC, leading to reduced tumor growth and metastatic spread, resulting in improved survival in mouse and patient-derived G3 MB models. Furthermore, Minnelide enhanced the efficacy of adjuvant chemotherapy, suggesting its potential repurposing for treating MYC-driven G3 MB patients.
NFS-04. GENETIC COUNSELLING IN A MULTI-TUMOR PREDISPOSITION SYNDROME: A NOVEL FOUR-GENERATION TUNISIAN PEDIGREE
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss
Published: June 2024

BACKGROUND

Cancer predisposition syndromes associated with an increased risk of CNS tumors and colorectal polyposis are heterogeneous inherited disorders associated with multiples genes. The delineation of the inheritance pattern and the management of the genetic testing are recommended for optimal care of patients and their families. Our aim was to report a cancer predisposition brain tumor-polyposis syndrome in a four-generation Tunisian consanguineous pedigree characterized by uncommon tumors localizations.

METHODS

The index case was a 43-year-old infertile woman presented to our genetic counselling because of a suspected familial cancer predisposition syndrome. She consulted for digestive symptoms with epigastralgia. Six adenomatous polyposis of the colon were confirmed histologically. Her sister died of colon cancer at the age of 50. She developed a malignant mesenteric recurrence after surgical resection of a moderately differentiated adenocarcinoma infiltrating the meso fat with lymph node metastases. Their three sisters and brother did not have any cancer. From the same third generation, only one cousin died of a brain cancer identified as a glioblastoma at the age of 43. Their maternal grandmother and her two brothers died of respectively breast, laryngeal and urothelial cancers. The second generation and fourth generation involved healthy members.

RESULTS

Analysis of the pedigree of this family indicated an autosomal recessive mode of inheritance of the brain tumor-polyposis syndrome. Clinically, there was uncommon association with breast, laryngeal and urothelial cancers in the first generation and brain/colon cancers in the third generation.

CONCLUSIONS

A recessive multi-tumor predisposition syndrome related to high microsatellite instability resulting in a mismatch repair deficiency seems to be the most reliable diagnosis in this family. Familial NTHL1 tumor and MUTYH associated polyposis syndromes were also suspected. NGS-based testing, from whole exome sequencing to multigene panel testing, is suggested as the most accurate genetic testing in such heterogeneous multi-tumor predisposition syndromes.
NFS-08. CLINICAL AND MOLECULAR FEATURES OF HIGH-GRADE GLIOMA IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1: A PRELIMINARY ANALYSIS
Authors: Kotch Chelsea , Solomon David A , Wallace Keri , de Blank Peter M , Li Yimei , Mbonglou Franziska , Reddy Alyssa T , Gutmann David H , Piotrowski Anna F , Fisher Michael J
Published: June 2024

BACKGROUND

Individuals with neurofibromatosis type 1 (NF1) are at increased risk for developing high-grade glioma (HGG) relative to the general population. Despite the elevated incidence in NF1, adequately powered studies of HGG have not been performed to date, limiting understanding of the clinical course, prevalent treatment approaches, recurrent molecular features, and outcomes.

METHODS

Patients with NF1 and pathologic or molecularly confirmed high grade glioma and high-grade astrocytoma with piloid features at Children’s Hospital of Philadelphia, University of California San Francisco, Washington University, and Cincinnati Children’s Hospital Medical Center diagnosed between 2005 to 2021 were included. Retrospective clinical, molecular, treatment, and imaging data were collated and analyzed.

RESULTS

Thirty-four patients met eligibility criteria, 13 (38%) were female. The median age at diagnosis was 22.7 years; 10 were pediatric (children <18 years of age). The most common diagnoses included high-grade astrocytoma (7), anaplastic astrocytoma (8), glioblastoma multiforme (5), and high-grade astrocytoma with piloid features (5). Fifteen (44%) of tumors underwent biopsy only and 4 (12%) were gross totally resected. Nine tumors (26%) were considered to have transformed from a pre-existing low-grade lesion. In the 22 cases with molecular testing, the most prevalent genetic variants involved the NF1, CDKN2A/B, ATRX, TP53, and SUZ12 genes. Frontline treatment approach varied; however, 26 individuals (76%) received radiation as part of their initial therapy. Overall survival at 2 years was 52% (95% CI 33-67) across all ages and 70% (95% CI 33-89) in children. There was no significant difference in overall survival at 2 years by extent of tumor resection at diagnosis.

CONCLUSIONS

High grade glioma in individuals with NF1 demonstrate a high prevalence of alterations in the CDKN2A/B and ATRX genes, with a poor overall survival despite radiation-inclusive treatment regimens. Collection of additional patient data from collaborating institutions is ongoing to support further analyses.
NFS-11. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS
Authors: Garcia Mekka R , Hagiwara Mari , Yaffe Anna , Mitchell Carole , Akshintala Srivandana , Nicolaides Theodore , Phadnis Sheetal S , Yohay Kaleb , Feng Yang , Goldberg Judith D , Allen Jeffrey C , Karajannis Matthias A
Published: June 2024

BACKGROUND

Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS).

METHODS

Eligible participants were age >5 years with a clinical diagnosis of neurofibromatosis type 2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL).

RESULTS

Twelve participants were enrolled and eight completed 12 cycles, including two pediatric patients. Two patients were non-evaluable due to coming off study prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for non-compliance. Due to slowing accrual, the study closed prior to meeting planned enrollment of 17 evaluable patients. Ten patients were evaluable for the primary endpoint, defined as ≥20% decrease in VS volume, with two volumetric responses observed; both were reached after three cycles and sustained during treatment. Best volumetric response was −53.9% after nine cycles. Hearing response was evaluable in nine participants, with three hearing responses observed, one of which was sustained during treatment. All participants experienced drug-related toxicities, the most common were diarrhea, hematuria and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment in all participants.

CONCLUSIONS

Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. The convenience of oral administration appears to be offset, however, by increased toxicity and lower response rates compared to VEGF-A targeted therapy with bevacizumab.
NFS-26.RB1-ALTERED SUBTYPE (GROUP A) PINEOBLASTOMA AS A PART OF «TRILATERAL RETINOBLASTOMA» PHENOMENON: NEURO-ONCOLOGICAL AND OPHTHALMIC-ONCOLOGICAL VIEW
Authors: Levashov Andrey Sergeevich , Serov Yuriy Alexandrovich , Ushakova Tatyana Leonidovna , Stroganova Anna Mikhailovna , Ryzhova Marina Vladimirovna , Gorelyshev Sergey Kirillovich , Kadirov Shavkat Umidovich , Terentyeva Alexandra Igorevna , Grigoryeva Marina Vladimirovna , Polyakov Vladimir Georgievich , Gorovtsova Olga Valeryevna , Grigorenko Vasiliy Andreevich
Published: June 2024

BACKGROUND

RB1-altered subtype (Group A) pineoblastoma as a part of «Trilateral retinoblastoma» is an extremely rare phenomenon. But over the past 10 years, the incidence of this disease has been increasing. Optimal therapeutic strategy is unknown. The aim of this study was to estimate the incidence of this phenomenon among patients with retinoblastoma, age at onset of retinoblastoma/RB1-altered pineoblastoma and genetic, gender, age predisposition.

DESIGN/METHODS

From 2019 to 2023 years 256 pediatric patients with de novo retinoblastoma were treated in the FSBI «N.N.Blokhin National Medical Research Center of Oncology». RB1-altered pineoblastoma was revealed in 9 cases (3,5% of all patients, 9,5% among patients with bilateral retinoblastoma, 6,6% for patient with the onset of retinoblastoma under the age of 12 months). Diagnosis was determined according to familial history, retinal camera and MRI data, histology, immunohistochemistry and Illumina Infinium methylation EPIC Bead Chip method (FFPE tumor samples), NGS and MLPA methods for detection of RB1 germline mutation status (blood samples). Therapeutic options for patients with RB1-altered subtype pineoblastoma were presented as like–COGARET0321, like–HIT–MED2017/2020, selective intra-arterial chemotherapy, intravitreal chemotherapy, transpupillary thermotherapy, brachytherapy.

RESULTS

Gender ratio was 1:2 (3 male and 6 female). In all cases, intraocular retinoblastoma was bilateral. Family history was revealed in two cases. Age at onset of retinoblastoma: less than 6 months in 8 cases, all cases less 2 years, median 3±1,9 months [1,5-20,5]. Median age at onset of RB1-altered subtype pineoblastoma was 20,5±7,3 months [1,5-57,5]. A synchronous variant of the disease was identified in 5 cases, metachronous in 4. Pineoblastoma of pineal region was detected in 7 cases, suprasellar region in 2. Six out of 9 patients are alive, median follow-up 16,5±5,1 months [1,5-43,0].

CONCLUSION

It is necessary to expand both regional and international interdisciplinary cooperation to develop an optimal algorithm for the diagnosis and treatment of this disease.
QOL-01. FEASIBILITY AND EFFICACY OF DIETARY AND LIFESTYLE INTERVENTIONS FOR HYPOTHALAMIC OBESITY DURING CHILDHOOD: A SYSTEMATIC REVIEW
Authors: van Roessel Ichelle , van den Brink M , Dekker J , van Essen B G Ruitenburg- , Tissing W J E , van Santen H M
Published: June 2024

BACKGROUND

Hypothalamic obesity may be encountered in children with genetic or syndromal disease or after (treatment of) a suprasellar tumor. There is currently no effective treatment for hypothalamic obesity, and dietary and lifestyle interventions are the cornerstone of obesity treatment. The obesity in patients with HD is the consequence of decreased satiety feelings (hyperphagia), in combination with a decreased resting energy expenditure and increased fat storage due to hyperinsulinemia. We searched the literature for evidence on feasibility and efficacy of dietary and lifestyle interventions for childhood hypothalamic obesity.

METHODS

A systematic search was conducted in Pubmed, EMBASE, Cochrane and CINAHL. Studies assessing the feasibility, safety or efficacy of any dietary or lifestyle intervention in children with hypothalamic overweight or obesity, were included. Risk of bias was assessed with an adapted Cochrane Risk of Bias Tool.

RESULTS

In total, twelve studies were included, with a total number of 118 patients (age 1 – 19 years) of whom one with craniopharyngioma, one with ROHHAD-NET syndrome, 50 with monogenic obesity and 66 with Prader-Willi syndrome. Four studies reported on feasibility: all diets were judged to be feasible. Seven studies reported on the effect of a dietary intervention; a well-balanced restrictive caloric diet (30% fat, 45% carbohydrates and 25% protein) and various hypocaloric diets (8-10 kcal/cm/day) were effective in terms of weight stabilization or decrease. No negative effect on linear growth was reported. Four studies reported on specific lifestyle interventions. Combined dietary and lifestyle intervention resulted in decreased BMI, however BMI returned to baseline values in the long-term.

CONCLUSIONS

Hypocaloric diet or restrictive macronutrient diet with lower percentage of carbohydrates seems feasible and effective for childhood hypothalamic obesity. Lifestyle interventions only resulted in BMI decrease in short-term, indicating that additional guidance is needed to successfully implement lifestyle interventions in this group of patients.
QOL-04.IN VIVO MODELLING RECAPITULATES RADIOTHERAPY DELIVERY AND LATE-EFFECT PROFILE FOR CHILDHOOD MEDULLOBLASTOMA
Authors: Castle Jemma , Shaw Gary , Weller Dominic , Fielder Edward , Egnuni Teklu , Singh Mankaran , Skinner Roderick , von Zglinicki Thomas , Clifford Steven C , Short Susan , Miwa Satomi , Hicks Debbie
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is the most common malignant paediatric brain tumour, with 5-year survival rates >70%. Survivors frequently suffer a wide-range of late-effects due to their tumour and its treatment. Cranial radiotherapy (CRT) to the whole-brain, with posterior fossa boost (PFB), underpins treatment for non-infants, however, radiotherapeutic insult to normal brain tissue has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Unfortunately, approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.

METHODS

We have developed a clinically-relevant in vivo model system that recapitulates the radiotherapy dose, delivery and late-effect profile of childhood medulloblastoma, at an equivalent developmental stage. Consistent with human regimens, age-equivalent (postnatal days 28-37) C57Bl/6J mice received targeted, CT image-guided, CRT (human-equivalent 38 Gy, n=12) or CRT with PFB (human-equivalent 49 Gy, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for over a year. Late-effects were compared to a sham-irradiated group (n=12).

RESULTS

CRT was well tolerated, independent of PFB receipt, and no mice suffered severe acute toxicity. Mice were significantly more frail following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod and grip strength were significantly lower (rotarod; p=0.026 and grip strength; p=0.006, respectively). Neurocognitive deficits were consistent with those observed in childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile.

CONCLUSION

We conclude that our in vivo model of childhood MB radiotherapy recapitulates the late-effect profile of MB survivors. Our clinically-relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late-effects and the development of novel interventions for their amelioration.
QOL-05. MEMANTINE FOR PREVENTION OF COGNITIVE LATE EFFECTS IN CHILDREN RECEIVING CRANIAL RADIATION THERAPY FOR FOCAL BRAIN TUMORS: A PILOT STUDY
Authors: Conklin Heather M , Khan Raja B , Ashford Jason M , Owens Christina , Simmons Andrea , Bosley Christina , Hsu Chia-Wei , Pan Haitao , Gajjar Amar , Merchant Thomas E
Published: June 2024

BACKGROUND

Childhood brain tumor survivors treated with cranial irradiation are at significant risk for cognitive late effects that negatively impact quality of life. Memantine (an NMDA receptor antagonist), taken during radiotherapy for brain metastases in adults, resulted in reduced cognitive declines. This is the first investigation of feasibility, acceptability, and preliminary efficacy of memantine for reducing cognitive late effects in children undergoing radiation therapy.

METHODS

In a randomized, double-blind, controlled trial (MEMCRT; NCT03194906) children took memantine (20 mg/d) or placebo for 12 weeks. During the medication phase, participants received weekly phone calls to assess adherence using pill counts and monitor side effects using the SAFTEE structured interview. At baseline, 6 weeks (end of radiation therapy), and 12 weeks (end of medication), participants completed a brief battery of cognitive measures.

RESULTS

30 patients (age at irradiation=11.93±2.87; 47% male) were included; memantine (n=16) and placebo (n=14) groups did not differ in age, sex, race, socioeconomic status or baseline IQ (ps>.26). Study participation (71% of those approached) and medication adherence (88% completed 12 weeks, with 97% of medication taken) were high. Side effects were minimal (only one CTCAE≥ 3; headache in the placebo group) with no difference between groups in change in side effect severity from baseline to any medication week, across any symptom inquiry (ps>.23). At 12 weeks, Cohen’s d effect sizes (ES) indicate the memantine group had better performance on measures of processing speed (Cogstate Identification ES=.61), academic fluency (Woodcock Johnson-IV Reading Fluency ES=.45; Math Fluency ES=.81), and fatigue (PedsQL Multidimensional Fatigue Scale ES=.72).

CONCLUSIONS

Study findings indicate memantine used as a neuroprotectant during radiation therapy for children with focal brain tumors is feasible and acceptable, with preliminary evidence for better cognitive outcomes that require validation in a larger, definitive trial.
QOL-08. THE LONG-TERM UTILITY OF METHYLPHENIDATE FOR THE PRESERVATION OF INTELLECTUAL DEVELOPMENT IN CHILDHOOD SURVIVORS OF BRAIN TUMOUR
Authors: Hagan Alexander J , Verity Sarah J
Published: June 2024

BACKGROUND

Enduring neurocognitive late effects are a common consequence of childhood brain tumour survivorship. Conceptual modelling of intelligence suggests initial deficits to processing speed and attention lead to the subsequent plateauing of intellectual and academic development. The utility of methylphenidate in improving attentional and processing speed deficits within the early phase of recovery has been previously reported. The longer-term contribution of methylphenidate in preserving intellectual ability through ameliorating these early deficits is yet to be evaluated.

METHODS

Twenty-nine childhood survivors were matched retrospectively with a no-treatment synthetic control. Intellectual assessments were conducted prior to starting methylphenidate and a minimum of 12 months thereafter. For the no-treatment control group, intellectual data were collected retrospectively from archival records, employing a similar assessment period. Linear Mixed Models were used to assess the influence of methylphenidate on intellectual trajectories between groups and fatigue scores over time.

RESULTS

Methylphenidate was associated with raw score improvements across all intellectual indices compared to no-treatment controls. Linear Mixed Modelling reported a borderline significant improvement in Processing Speed (t = 1.98, p =.05) for the methylphenidate group. In comparison, a borderline significant (p =.05) within-group decrease in Working Memory scores was reported for the no-treatment group. There was a significant within-group decrease in pooled PedsQL MFS scores between assessments for the treatment group (t = -4.01, p <.01), with the most notable decrease observed in Sleep/Rest Fatigue (t = -10.17, p <.01).

CONCLUSIONS

Methylphenidate may pose a valuable long-term rehabilitative strategy in preserving Processing Speed in childhood survivors of brain tumour. Whilst our sample size is small, there is tentative evidence for the utility of methylphenidate in alleviating fatigue experienced by childhood survivors.
QOL-10. PHYSICAL ACTIVITY LEVELS AND PATTERNS IN SURVIVORS OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMOURS
Authors: Keating Rachael , Curry Sarah , Hussey Juliette
Published: June 2024

BACKGROUND

Engaging in regular physical activity (PA) has multiple positive health benefits and for survivors of childhood cancer can additionally result in reduced severity of late-effects. There is a lack of objectively measured PA data in survivors of childhood central nervous system (CNS) tumours. The aims of this study were to objectively measure PA levels and patterns in survivors of childhood CNS tumours and to determine whether survivors were meeting the World Health Organisation (WHO) recommended PA guidelines of 60 minutes of moderate to vigorous intensity physical activity (MVPA) daily.

METHODS

Survivors of childhood CNS tumours aged between 6-17 years, between 3 months and 5 years post treatment, were provided with Actigraph GT3X accelerometers to assess their PA patterns over a seven day recording period.

RESULTS

Twenty-six participants were recruited with a mean age of 12.75 (SD 3.29) years. Participants met the WHO PA guidelines for a mean of 3.18 (SD 2.56) days during the assessment week. Participants spent a mean daily time of 591.77 (SD 146.91) minutes in sedentary behaviour and 129.45 (SD 54.14) minutes in light intensity PA. A significant association was found between PA and age (p<0.001, CI[-8.48, -3.05]), child participants engaged in significantly less sedentary time and significantly more MVPA daily than adolescent participants. No significant differences in PA patterns were identified between participants in early survivorship versus those in late survivorship (≥ 2 years post treatment), (p=0.095 – p=0.513).

CONCLUSIONS

The majority of survivors of childhood CNS tumours do not meet the WHO recommended daily PA guidelines and lead significantly sedentary lives. PA patterns differed significantly between child and adolescent participants. Further research is required on interventions to support engagement in PA particularly for adolescent survivors of CNS tumours, with a focus on how this can be implemented into clinical practice.
QOL-11. LATE MORBIDITY AND MORTALITY IN SURVIVORS OF CHILDHOOD EPENDYMOMA: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)
Authors: Lange Katharine R , deBlank Peter , Xing Mengqi , Mirzaei Sedigheh , Srivastava Deo Kumar , Oeffinger Kevin , Neglia Joseph , Krull Kevin , Nathan Paul , Howell Rebecca , Ness Kirsten K , Turcotte Lucie , Leisenring Wendy , Armstrong Gregory T , Brinkman Tara , Bowers Daniel C , Okcu M Fatih
Published: June 2024

BACKGROUND

Between the 1970s and 1990s, therapy for childhood ependymoma evolved to include chemotherapy and focal rather than whole-brain radiation. The impact of these changes on health outcomes is unknown.

METHODS

404 five-year survivors of ependymoma (52.5% male, median 6 [range 0-20] years old at diagnosis, 22 [5-49] years from diagnosis) were evaluated for cumulative incidence of late mortality, subsequent neoplasms, and chronic health conditions (CHC). Outcomes were analyzed by diagnosis decade and brain radiation and chemotherapy exposures. Fine-Gray’s test compared cumulative incidence curves. Relative Risks (RRs) with 95% CIs estimated outcomes using multivariable piecewise exponential models.

RESULTS

Throughout the three decades whole brain radiation exposure decreased (32.7% to 2.3%) while focal brain radiation increased (16.4% to 59.2%), and chemotherapy use increased (23.6% to 47.9%). Fifteen-year all-cause late mortality (incidence, 95% CI) estimates were similar across treatment eras: 1970s (9.3%, 3.4-18.8%), 1980s (14.7%, 9.4-21.2%), 1990s (10.3%, 6.7-14.9%), (p=0.9). Mortality was higher with whole brain radiation (22.5%, 11.2-36.5%) compared to focal radiation (11.4%, 7.5-16.1%) or no brain radiation (3.5%, 0.9-9.1%), (p <0.001). Mortality was also higher with chemotherapy (14.4%, 9.6-20.0%) compared to no chemotherapy (6.8%, 3.8-11.0%) (p=0.004). Differences in mortality were due to recurrence/progression of the primary cancer and health-related causes. Compared to no brain radiation, there were increased risks (RR, 95% CI) of any grade 3-4 CHCs for focal (2.6, 1.3-5.4) and whole brain radiation (3.5, 1.5-8.1) and >1 Grade 3-4 CHCs for whole brain radiation (6.5, 1.3-31.6). There were no differences in CHCs or subsequent neoplasms by chemotherapy exposure.

CONCLUSIONS

Despite the treatment changes over the 1970s to 1990s, late morbidity and mortality in pediatric ependymoma remained unchanged. Whole and focal brain radiation were associated with increased risk of grade 3-4 CHCs compared to no radiation. Future therapies for childhood ependymoma should target reductions in late morbidity and mortality.