bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-52. MYC-DRIVEN PEDIATRIC BRAIN TUMORS SHARE A COMMON PHOTORECEPTOR IDENTITY
Authors: Zhao Miao , Rosén Gabriela , Sundstrom Anders , Olsen Thale Kristin , Furukawa Takahisa , Gudenas Brian L , Northcott Paul A , Swartling Fredrik J 
Published: June 2024

Abstract
Mouse models serve as invaluable tools for improving the understanding and treatment of pediatric brain tumors. We recently published a highly aggressive MYC-driven brain tumor model (GMYC), which exhibits approximately 70% penetrance. Our transcription profiling indicates that GMYC tumors accurately resemble human Group 3 medulloblastoma (MB-G3). Interestingly, a strong photoreceptor program was activated in the tumor model. This is commonly upregulated in MB-G3 but also in pineoblastoma (PB), another malignant pediatric brain tumor. CRX, a transcription factor critical for pineal cell development is also a master regulator for MB-G3 maintenance. By studying early tumor initiation using Crx-lineage tracing and scRNA-seq, we confirmed that GMYC tumors originate from early pinealocytes. Exome sequencing of GMYC tumors further confirmed mutations of epigenetic regulators commonly reported in either PB or MB. To investigate tumor development from photoreceptor-positive progenitors in the developing brain, we performed Crx-lineage tracing with tamoxifen injections, confirming that Crx-positive cells exist in pineal gland progenitors. However, Crx-traced cells also marked granule neurons in the flocculonodular lobe of the cerebellum, which is the suggested site of MB-G3 origin arising from the developing rhombic lip. To investigate if the Myc oncogene can generate different types of pediatric brain tumors in Crx-positive cells, an XMYCT58A-Tomato mouse model was established by crossing Crx-CreERT2; LSL-MycT58A and Rosa26LSL-tdTomato strains. Here, MycT58A was turned on with tamoxifen injection after birth and tumor development followed using the tdTomato reporter. XMYCT58A-Tomato mice developed brain tumors from both the pineal gland and cerebellum after 2-6 months. Histologically, tumors were non-glial (GFAP-, Olig2-), showed neuronal activity (Neurod1+), and stained positive for photoreceptor identity markers (CRX+, OTX2+) similar to both MB-G3 and PB-MYC. Collectively, our data suggest that both MYC-driven MB-G3 and PB-MYC originate from photoreceptor-positive cells, which has implications for developing novel treatments targeting these devastating childhood malignancies.
MDB-54. GENOMIC VARIANCE OF MATCHED PRIMARY AND RECURRENT HUMAN MEDULLOBLASTOMA
Authors: Su Yu N/A , Liu Hailong N/A , Li Jiankang N/A , Qiu Xiaoguang N/A , Jiang Tao N/A , Tian Yu N/A 
Published: June 2024

Abstract

BACKGROUND
To investigate the difference between matched primary and recurrent human medulloblastoma across four molecular subgroups and to further expand the existing mutational spectrum in the recurrence or dissemination lesions.

METHODS
We analyzed the whole-exome sequencing (WES) data of 56 matched samples from 28 pairs with primary and recurrent/disseminated medulloblastoma. WES was performed using the Illumina HiSeq 2500 system, and the sequencing data were then subjected to variant detection, genome annotation, GO functional enrichment analysis, and GWAS.

RESULTS
All tumor samples were classified as four subgroups, including 4 cases of WNT-MB, 8 cases of SHH-MB, 20 cases of G3-MB and 24 cases of G4-MB. Conical and non-conical chromosomal variations were observed in each subgroup. Recurrent G3-MB cohort exhibited the loss of chr1p and chr22q and gain of the chr16p. The gain of chr2p, 2q, and 9p, as well as the loss of chr9q were found in the recurrent lesions of G4-MB. Recurrence of SHH-MB exhibited the loss of chr19q and chr4p, and loss of chr5p was found in the WNT-MB recurrences. CTNNB1, IDH1, and ARID1A were only observed in recurrent tumors of G3-MB; MYC was only observed in the recurrent tumors of G4-MB; IDH1 and TERT were only observed in recurrent tumors of the SHH-MB. Compared to primary medulloblastoma, recurrent tumor samples obtained a higher level of tumor mutation burden. The mutant gene profiles were mainly enriched in cell adhesion function.

CONCLUSIONS
When relapsing, medulloblastoma subgroup generally remains consistent, but exhibits the specific CNV, SNV and mutated gene profiles.
MDB-56. CLINICAL OUTCOME AND SURVIVAL OF INFANT MEDULLOBLASTOMA PATIENTS: THE BAMBINO GESÙ CHILDREN’S HOSPITAL EXPERIENCE
Authors: Baldo Giada Del , Ruscio Valentina Di , Sasso Annalisa Lo , Megaro Giacomina , Cacchione Antonella , Alessi Iside , De Salvo Andrea , Albino Giulia , Cipri Selene , Agolini Emanuele , Miele Evelina , Rossi Sabrina , Giovannoni Isabella , Colafati Giovanna Stefania , Vennarini Sabina , Vinci Maria , Carai Andrea , Mastronuzzi Angela 
Published: June 2024

Abstract
Young children diagnosed with medulloblastoma (MB) pose a significant challenge due to the high susceptibility of the developing brain to neurotoxic agents such as craniospinal irradiation (CSI). Different innovative strategies were developed with the aim to enhance outcomes while either delaying or avoiding CSI. We describe a case series of patients affected by infant MB treated according to the Italian Infants High Risk recommendation. Retrospective data from 42 children with MB younger than 5 years of age at diagnosis treated between 2007 and 2023 at Bambino Gesù Children Hospital were recorded. Demographic, clinical, surgical, radiological, molecular, and histopathological data were collected. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Seventeen patients were excluded for first-line radiotherapy. Conclusively, 25 patients (13 male, 12 female) with a median age of 25.3 months at diagnosis were eligible for the analysis. Eleven patients had metastatic disease at diagnosis. Histotype: 13/25 classic, 6/25 desmoplastic nodular (DNMB), 4/25 extensive nodularity (MBEN) and 2/25 large cell/anaplastic. DNA methylation profile: SHH-subgroup: 12/25, group 3: 8/25 and group 4: 5/25. MYC amplification was detected in 3 cases. In five cases a cancer predisposition syndrome was found. The median duration of follow-up was 48 months. EFS at 12, 24 and 60 months was 80% (95%CI: 58.4-91.1), 72% (95%CI: 50.1-85.5), and 68% (95%CI: 46.1-82.5), respectively. OS at 12, 24 and 60 months was 80% (95%CI: 67.3-96), 80% (95%CI: 58.4-91.1) and 68% (95%CI: 46.1-82.5) respectively. Significant better survival was found for MBEN/DNMB histotype, with no significant difference between molecular subgroups. We reported high EFS and OS in a population of infant MB treated according Italian Infants High Risk recommendation. Our patients presented an average intelligence quotient in the normal range at a median follow-up of 4 years from diagnosis and no long-term toxicity after treatment.
MDB-57. PROTEOMIC ANALYSIS REVEALS AMBRA1 AS A NEW CRL3REN/KCTD11 SUBSTRATE PROMOTING SONIC HEDGEHOG-DEPENDENT MEDULLOBLASTOMA
Authors: Basili Irene , Infante Paola , Conenna Marilisa , Bernardi Flavia , Marsaud Veronique , Cancila Gabriele , Bufalieri Francesca , Severini Ludovica Lospinoso , Yu Hua , Diaz Jacob Torrejon , Re Valentina Lo , Adabbo Gennaro , Guardavaccaro Daniele , Ayrault Olivier , Marcotullio Lucia Di 
Published: June 2024

Abstract

BACKGROUND
Sonic Hedgehog (SHH) signaling pathway is fundamental for a proper embryonic development and its uncontrolled activation is responsible for various cancers. One the most relevant SHH-dependent tumors is medulloblastoma (MB), a highly heterogeneous brain malignancy that predominantly occurs in childhood. Understanding the complex networks that govern SHH aberrant activation represents a dramatic challenge for the development of efficient personalized therapies. Here, we identify a new role of the pro-autophagic protein AMBRA1 as interactor of REN/KCTD11 (here REN), the substrate-receptor subunit of the Cullin3-RING ubiquitin ligase complex (CRL3REN) and tumor suppressor lost in ~30% of human SHH-MBs. We show a novel mechanism of action of AMBRA1 in SHH-MB pathogenesis whereby its highly expression, due to loss of REN, drives the activation of GLI1, the final effector of SHH signaling.

METHODS
Proteomic analysis, co-immunoprecipitation, ubiquitylation and cycloheximide assays have been performed to demonstrate that AMBRA1 is a substrate of ubiquitylation of CRL3REN and to define AMBRA1 mechanism of action in SHH-MB tumorigenesis. Transcriptomic analysis, in vitro and in vivo proliferation assays have been carried out on murine and patient-derived xenograft (PDX) models to examine the effect of AMBRA1 modulation on SHH-MB growth.

RESULTS
We demonstrate that CRL3REN binds and induces polyubiquitylation and proteasome-mediated degradation of AMBRA1. Interestingly, we found that genetic depletion of AMBRA1 strongly reduces SHH-dependent MB growth both in vitro and in vivo, an effect associated with the decrease in the expression of GLI1 and other SHH target genes. We hypothesize that AMBRA1 could impact on the stability of GLI1 by counteracting the activity of E3 ubiquitin ligases regulating GLI proteins. Remarkably, transcriptomic analysis of SHH PDX upon AMBRA1 knockdown revealed an impairment of SHH activity and an upregulation of cerebellum differentiation.

CONCLUSION
Our findings identify AMBRA1 as a novel CRL3REN substrate and promising therapeutic target for SHH-dependent cancer.
MDB-58. REDUCED CRANIOSPINAL DOSE FOR NEWLY DIAGNOSED HIGH-RISK MEDULLOBLASTOMA IN CHILDREN YOUNGER THAN 5 YEARS OLD: RETROSPECTIVE EXPERIENCE FROM SFCE
Authors: Oozeerally Jihann , Dufour Christelle , Faure Cécile , Cardine Aude , De Carli Emilie , Merlin Marie-Sophie , Andry Leslie , André Nicolas , Icher Céline , Klein Sébastien , Pagnier Anne , Puiseux Chloé , Briandet Claire , De Benaze Gwenaelle Duhil , Bolle Stéphanie , Padovani Laetitia , Flumian Clara , Bertozzi Anne-Isabelle 
Published: June 2024

Abstract

BACKGROUND
High Risk medulloblastoma (MB) treatment strategy is based on an intensive multimodal treatment including surgery, chemotherapy and radiotherapy. French adapted PNET HR +5 is based on high-dose chemotherapy and age-stratified (18 Gy &lt; 3 yo, 23 for 3-5 yo, 36 Gy for &gt; 5 yo) craniospinal dose irradiation to reduce long-term side-effects of radiotherapy.

METHODS
To estimate progression-free (PFS) in a national multi-institutional retrospective study, we enrolled children younger than 5 yo with newly diagnosed high-risk MB treated according to adapted PNET HR +5 trial.

RESULTS
Thirty-seven children from 15 French hospitals (median age, 3.4 yo; range, 0.7-4.8) with confirmed high-risk MB were included. 15 patients (39%) were less than 3 years old. 29 patients (81%) had metastatic disease. Group 3 was the most represented molecular subgroup. 5-year PFS and OS was 59 % and 77 %, respectively. According to dose of craniospinal irradiation, PFS for 18 Gy, 23.4 Gy and 36 Gy patient groups were 100 %, 75 % and 45%, respectively. Treatment was well tolerated. One toxic death was declared. Analysis of longitudinal neurocognitive performance is ongoing.

CONCLUSIONS
the French strategy comprising high-dose chemotherapy and age-adapted craniospinal irradiation is promising with a high rate of survival in young children and must be confirmed by a prospective trial.
MDB-75. MOLECULAR PATHOLOGY, TREATMENT AND PROGNOSIS OF INFANT SONIC HEDGEHOG MEDULLOBLASTOMA: A GLOBAL MULTI-COHORT STUDY
Authors: Richardson Stacey , Hicks Debbie , Gough Melissa , Castle Jemma , Crosier Stephen , Garcia-Ariza Miguel , Martín-Guerrero Idoia , LA Plasschaert Sabine , Bourdeaut Franck , Dufour Christelle , Masliah-Planchon Julien , Buttarelli Francesca R , Garre Maria-Luisa , Biassoni Veronica , Massimino Maura , Kanemura Yonehiro , Ramaswamy Vijay , Gajjar Amar , Northcott Paul , Robinson Giles , Korshunov Andrey , Pfister Stefan M , Mynarek Martin , Rutkowski Stefan , Schwalbe Edward C , Bailey Simon , Clifford Steven C 
Published: June 2024

Abstract

BACKGROUND
Clinical studies in infant medulloblastoma (iMB; &lt;5 years) have, to date, focussed on modestly-sized or national trials cohorts and have not directly compared therapeutic approaches or placed these in the context of dedicated biomarker studies, to inform future treatment strategies.

METHODS
We assembled a multi-national cohort of molecularly and clinically-annotated iMBs (&lt;5 years at diagnosis; n=646), the largest to date. We investigated molecular pathology, treatments received, and relationships to outcome within this population.

RESULTS
The SHH group (iMBSHH; n=267, 40%) predominated, encompassing SHH-1 (37.7%, median age 2.0 years), SHH-2 (47.0%, 1.4 years) and SHH-3 (14.4%, 3.0 years) WHO subgroups. MBEN histology was significantly enriched in SHH-2, and SUFU mutation and MYCN amplification in SHH-1 and SHH-3, respectively. Notably, TP53 mutations were identified in all subgroups; in SHH-1 and SHH-2 (each n=3) tumours lacked features typically associated with TP53-mutated SHH-3 (LCA histology and MYCN amplification) and did not have a worse survival. Upfront radiation-sparing treatments were used in 132/267 children and comprised regimens founded on intraventricular methotrexate (IVT-MTX; 54.5%), high-dose (HDCTx; 22.0%) or standard-dose (23.5%) chemotherapy. Across all radio-naive iMBSHH, non-DN/MBEN histology (HR 2.76, CI 1.26-6.01, p=0.011) and SHH-1 (vs SHH-2, HR 2.51, CI 1.25-5.01, p=0.009) conferred worse PFS in univariable analysis; subgroup was the only independently prognostic risk-factor (multivariable analysis; SHH-1 HR 2.65, CI 1.27-5.51, p=0.009). 5-year OS for HDCTx recipients was very favourable in SHH-1 (100%) and SHH-2 (93.3%), and subgroup-dependent for IVT-MTX (SHH-1; 76.4%, SHH-2; 100%, p=0.009). In CSI-treated iMBSHH (n=49), non-DN/MBEN histology (HR 10.23, CI 2.22-47.04, p=0.003) and MYCN amplification (HR 7.35, CI 2.01-26.87, p=0.003) conferred worse PFS.

CONCLUSION
iMBSHH outcomes in this cohort are dependent upon WHO subgroup, histology and therapy received. These findings provide an evidence-based foundation for selection of cohorts and therapies for prospective assessment in forthcoming iMBSHH clinical trials (e.g. SIOP-CONNECT-YC-MB-LR).
MDB-79. THE DEUBIQUITINATING ENZYME USP7 COOPERATES WITH SONIC HEDGEHOG SIGNALING TO PROMOTE MEDULLOBLASTOMA
Authors: Cigna Sara Maria , Basili Irene , Bernardi Flavia , Severini Ludovica Lospinoso , Forget Antoine , Chang Chia-Hsiang , Yu Hua , Cancila Gabriele , Marsaud Veronique , Talbot Julie , Mercier Audrey , Lasgi Charlene , Puget Stéphanie , Beccaria Kevin , Blauwblomme Thomas , Kawauchi Daisuke , Kumar Suresh , Tsai Jin-Wu , Marcotullio Lucia Di , Ayrault Olivier 
Published: June 2024

Abstract

BACKGROUND
Constitutive activation of the Sonic Hedgehog (SHH) signaling pathway during cerebellar development may lead to medulloblastoma (MB), one of the most common malignant pediatric brain tumor. Clinically, SHH-MB with mutations downstream of SMO or TP53-mutated are a real challenge and alternative targeted therapies are sorely needed for this group of patients. In SHH-MB, the transcription factor Atoh1 is constitutively overexpressed and essential for tumor initiation and progression. Previous work demonstrated that proteasomal-mediated degradation of Atoh1 induces tumor regression in vitro and in vivo, therefore deciphering mechanisms controlling Atoh1 stabilization should provide new avenues for drug development in SHH-MB.

METHODS
Using a proteomic approach, we identified the deubiquitinating enzyme Usp7 as a positive regulator of Atoh1 in MB cells. We then applied a SILAC-based quantitative ubiquitinomics to investigate the Usp7 target landscape in SHH-MB. We also employed several biochemical approaches to demonstrate the functional interaction between Atoh1 and Usp7 in SHH-MB. In parallel, we validated the impact of Usp7 depletion in vitro and in vivo using relevant SHH-MB models. Last, we investigated large transcriptomic and proteomic datasets to unveil the prognostic value of Usp7 in SHH-MB human tumors.

RESULTS
We demonstrate that Usp7 binds and accumulates Atoh1 protein by counteracting its ubiquitylation. Post-natal electroporation in vivo directly into the developing cerebella also indicates that overexpression of Usp7 promotes proliferation, whereas in the absence of Atoh1 Usp7 was no longer able to spread cell growth, demonstrating a functional link between the Usp7-Atoh1 axis. In vivo, disruption of Usp7 expression in SHH-MB blocks tumor proliferation. Pharmacological inhibition of Usp7 triggers tumor growth in a syngeneic SHH MB mouse model. Lastly, SHH-MB cells with either TP53 or SMO downstream mutations are sensitive to Usp7 inhibition.

CONCLUSIONS
Overall, our data pinpoint Usp7 as a promising target against Atoh1, a master regulator of SHH-MB.
MDB-82. TRANSFUSION-RELATED IRON OVERLOAD MIMICKING METASTATIC DISEASE IN A PEDIATRIC PATIENT WITH MEDULLOBLASTOMA ON A RADIATION-DELAYING CHEMOTHERAPY REGIMEN
Authors: Pytel Nicholas , Glanz Hannah 
Published: June 2024

Abstract

BACKGROUND
Transfusion-related iron overload (TRIO) is a known complication of administering numerous packed red blood cell (pRBC) transfusions in pediatric oncology patients undergoing myelosuppressive therapy. Infant medulloblastoma regimens attempt to avoid or delay radiation and its adverse effects in this population, with intensive myelosuppressive chemotherapy. We report a case of TRIO first suspected as hepatic metastatic disease at time of CNS recurrence in a young patient with medulloblastoma after completion of a high-dose chemotherapy protocol.

METHODS
Case Report

RESULTS
A five-year-old male presented with four months of headaches, dizziness, imbalance, and emesis. MRI revealed a posterior fossa mass with near total resection of the mass confirming classic medulloblastoma, non-WNT, non-SHH. The patient received five cycles of induction chemotherapy. This was followed by a single cycle of high-dose chemotherapy (HDCSCR) with autologous stem cell rescue. During therapy, he received 26 pRBC transfusions to correct severe anemia. CNS recurrence occurred 19 months after therapy. Abdominal imaging revealed enlarging hepatic lesions concerning for metastases. Ferritin was 1,268 ng/mL (normal: 7-142 ng/mL) and MRI of liver revealed severe iron load with LIC of 11 mg Fe/g dry weight (dw) (normal: 0.4-2.2 mg Fe/g dw). Ultimately, hepatic lesions were thought to be non-cancerous, and he proceeded with craniospinal irradiation. He was diagnosed with TRIO. He underwent phlebotomy for 33 months with ferritin and MRI liver LIC within normal limits.

CONCLUSION
This case illustrates an occurrence of TRIO presenting as hepatic lesions concerning for metastatic disease during CNS recurrence in a patient who underwent an infant medulloblastoma regimen with HDCSCR. Our patient required phlebotomy for nearly 3 years to return ferritin and LIC to normal limits. Further investigation on the prevalence of TRIO in medulloblastoma survivors treated with radiation delaying/sparing protocols is necessary to improve outcomes and avoid end organ damage due to iron overload.
MDB-85. THE MIGRATORY ROLE OF BAIAP2 IN MEDULLOBLASTOMA
Authors: Ruiz Luz C , Jangde Nitish , Suter Robert , Jermacowikz Anna , Ayad Nagi 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant brain tumor in adolescents. There is still a dire need for a more effective treatment despite advances in technology. One challenge in treating medulloblastoma is its migratory and invasive properties. The underlying mechanisms that lead to these characteristics are still not understood.

METHODS
We sought to identify targets related to invasion and migration in medulloblastoma, first by mining single-cell RNA sequencing and microarray data.

RESULTS
We determined that BAIAP2 is differentially expressed in medulloblastoma compared to non-tumor brain cells and other brain cancers. In addition, there is a significant increase in BAIAP2 in metastatic medulloblastoma compared to non-metastatic. We found that CDC42 and RAC1, small GTPases, are protein-protein interactors with BAIAP2. In three medulloblastoma cell lines, we have demonstrated that these genes modulate each other’s expression. Furthermore, we show that the knockdown of BAIAP2, CDC42, and RAC1 decreases medulloblastoma cell migration and filopodia length. Using surface plasmon resonance, we identified compounds that target BAIAP2 protein. After characterizing these compounds, we have identified potential compound candidates that target these genes and impede their roles in migration and invasion in medulloblastoma.

CONCLUSIONS
These findings demonstrate a migratory role for BAIAP2 in medulloblastoma through the modulation of CDC42 and RAC1. We also demonstrate that BAIAP2 is a therapeutic target and have identified novel compounds that target it.
MDB-86. ISOTRETINOIN HAS NO EFFECT ON EVENT FREE SURVIVAL ACROSS HIGH-RISK MEDULLOBLASTOMA MOLECULAR SUBGROUPS WHEN ADDED TO MAINTENANCE CHEMOTHERAPY: A SECONDARY ANALYSIS OF THE CHILDREN’S ONCOLOGY GROUP ACNS0332 DATA
Authors: Raskin Scott I , de Blank Peter M K , Billups Catherine A , Li Yimei , Olson James M , Leary Sarah E S 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma has been redefined into four molecular subgroups (WNT, SHH, Group 3, and Group 4), with distinct prognoses and responses to treatment. The ACNS0332 trial investigated the impact of carboplatin and isotretinoin in high-risk medulloblastoma finding a differential effect of carboplatin by molecular subgroup. An interim futility analysis showed no benefit from isotretinoin, but did not evaluate results by molecular subgroup in the primary analysis. We performed a secondary analysis to examine whether the effect of isotretinoin on event-free survival (EFS) differed by molecular subgroup.

METHODS
Evaluable patients with known molecular subgroups were analyzed. Molecular subgroup analysis was conducted retrospectively in 231 patients at a central laboratory by methylation array. Kaplan-Meier survival analysis compared EFS (time from enrollment to disease progression or recurrence, second malignancy, death from any cause, or to date of last follow-up for patients without events).

RESULTS
Based on data from the 2014 interim analysis, 164 patients were eligible for secondary analyses. Group 3 (n=56, 34.1%) and Group 4 (n=75, 45.7%) were the most common groups. SHH (n=22, 13.4%) and WNT (n=11, 6.7%) groups were less common. There was no difference in isotretinoin (p=0.87) or carboplatin (p=0.49) randomization by subgroup. Race was well-balanced with expected differences in age (p=0.017) and sex (p=0.016) among molecular subgroups. Based on the interim analysis, there was no evidence of a difference in EFS by isotretinoin randomization (p=0.34; one-sided log-rank test stratified by carboplatin randomization). Based on secondary analysis data, there was no difference in EFS between patients receiving isotretinoin or no additional therapy in any molecular subgroup: Group 3 (p=0.68), Group 4 (p=0.55), SHH (p=0.68), WNT (p=1) based on two-sided log-rank tests.

CONCLUSIONS
Despite differential efficacy of carboplatin among molecular subgroups, no difference was found in EFS between patients receiving isotretinoin and those who did not, regardless of molecular subgroup.