bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-16. CLINICAL AND MOLECULAR CHARACTERISTICS OF JAPANESE MEDULLOBLASTOMA, WNT-ACTIVATED
Authors: Go Kohichi , Katsuma Asako , Makino Yasuhide , Yamamoto Etsuko , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Terada Yukinori , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Kodama Yoshinori , Mano Masayuki , Ichimura Koichi , Sasaki Atsushi , Hirato Junko , Inoue Takeshi , Nishikawa Ryo , Date Isao , Nonaka Masahiro , Nagane Motoo , Arakawa Yoshiki , Kanemura Yonehiro 
Published: June 2024

Abstract

BACKGROUND
Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the latest WHO classification, which has become fundamental and indispensable. Medulloblastoma, WNT-activated (WNT-MB) accounts for about 10% of all medulloblastomas, and their prognosis is excellent, and it is desired to ensure that patients with WNT-MBs are diagnosed exactly. In this study, we have summarized results of molecular analysis of Japanese MBs collected by Japanese Pediatric Molecular Neuro-oncology Group (JPMNG) study, and analyzed clinical and molecular characteristics of WNT-MBs.

METHODS
We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study since 2012.Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed using molecular subgrouping, DNA sequencing (CTNNB1), and copy number analysis.

RESULTS
A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. The age at diagnosis was 3 years or older (6-40 years) in all cases, with no cases occurring in infants, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. Histological features were classic (CMB) in the majority of cases and large cell (LCA) type in only 2 cases. The positivity rate of nuclear β-catenin by Immunological staining was 9 out of 12 (75%) of the cases examined. While, CTNNB1mutation was positive in 39 of 39 cases (100%) and monosomy 6 was also positive in 35 of 35 cases (100%), respectively. The 5-year survival rate was 91.9%.

CONCLUSIONS
Clinical characteristics of Japanese WBT-MB were almost similar to those reported in other countries, which showed excellent prognosis, and their molecular genetic status were also identical with results from other ethnics.
MDB-17. A COMPARISON OF MAGNETIC RESONANCE IMAGING AND CEREBROSPINAL FLUID CYTOLOGY FOR DETECTING LEPTOMENINGEAL METASTASIS IN PATIENTS WITH MEDULLOBLASTOMA
Authors: Peeran Zain , Phelps Ryan , Aabedi Alexander , Fisher Edward , Khela Harmon , Rios Jennifer , Shukla Poojan , Reddy Alyssa , Kline Cassie , Aghi Manish K , Gupta Nalin 
Published: June 2024

Abstract

BACKGROUND
For medulloblastoma, CSF cytology and MRI together are considered to be superior to either modality alone in identifying leptomeningeal dissemination (LMD). However, MRI has vastly improved since the initial assessment of this approach.

METHODS
A retrospective medical record review of 130 patients (36.2% female) with medulloblastoma was performed. CSF samples and MR images (6.3% utilized FIESTA) obtained within 1 month of each other from 2000-2023 were analyzed. There were 302 CSF-MRI pairs (range: 1-12 pairs per patient) in total. A 3-tier system (negative, atypical/suspicious, positive) was utilized to account for equivocal findings.

RESULTS
The mean (SD) age at surgery was 13.2 (13.0) years. Mean (SD) postoperative follow-up time was 7.0 (5.2) years. 71.5% underwent gross or near-total resection, 80.8% received radiotherapy, and 93.1% received chemotherapy. The molecular subtypes were: SHH (24.6%), WNT (4.6%), non-WNT/non-SHH (38.5%), unknown (32.3%). MRI had an 89.8% sensitivity and CSF cytology had a 22.7% sensitivity for detecting LMD that was positive on CSF and/or MRI. MRI was positive in 23.1% of CSF negative cases. CSF was positive in 2.2% of MRI negative cases. For all CSF positive-MRI negative pairs, the CSF samples and MR images were obtained within 10 days of surgery. MRI was positive in 38.9% of CSF atypical cases. CSF was positive in 11.9% of MRI suspicious cases. MRI demonstrated greater or equal ability to CSF in 94.7% of pairs. MRI was more likely to exceed CSF at 3T versus 1.5T (51.3% vs. 27.4%; p&lt;0.01). The overall concordance between CSF cytology and MRI was 61.3%, and this differed by subtype (75.4% SHH vs. 80.0% WNT vs. 52.3% NWNS; p&lt;0.01).

CONCLUSIONS
Understanding the ability of CSF cytology and MRI to detect LMD is important. While MRI is superior overall, LMD detection varies by MRI Tesla, medulloblastoma subtype, and time since surgery.
MDB-29. SALL4 IS A CRL3REN/KCTD11 SUBSTRATE THAT DRIVES SONIC HEDGEHOG-DEPENDENT MEDULLOBLASTOMA
Authors: Severini Ludovica Lospinoso , Loricchio Elena , Navacci Shirin , Basili Irene , Alfonsi Romina , Bernardi Flavia , Moretti Marta , Conenna Marilisa , Cucinotta Antonino , Coni Sonia , Petroni Marialaura , De Smaele Enrico , Giannini Giuseppe , Maroder Marella , Canettieri Gianluca , Mastronuzzi Angela , Guardavaccaro Daniele , Ayrault Olivier , Infante Paola , Bufalieri Francesca , Marcotullio Lucia Di 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common malignant pediatric brain tumor arising from alterations in cerebellum development. The Sonic Hedgehog variant (SHH MB) is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Mutations in key components of the SHH pathway and cytogenetic alterations (such as chromosome 17p deletion) lay the pathogenetic foundation for SHH MB subgroup. RENKCTD11 (here REN) is a tumor suppressor and substrate-receptor subunit of the Cullin3 Ring E3 ubiquitin ligase (CRL3) complex mapping on chromosome 17p and frequently deleted in SHH MB. We wished to expand the knowledge of CRL3REN activity to unveil molecular circuitries whose deregulation can contribute to SHH MB onset and to uncover novel therapeutic targets.

METHODS
Affinity purification coupled to mass spectrometry was performed to identify new REN interactors. Co-immunoprecipitation and ubiquitylation assays validated proteomic data. The proliferation of primary murine SHH MB cells and Patient Derived Xenografts (PDXs) models was evaluated in vitro by using the IncuCyte imaging system. Heterotopic and orthotopic allograft in vivo models of SHH MB were established in immunodeficient mice.

RESULTS
Proteomic analysis revealed that the pro-oncogenic stemness Spalt-like transcriptional factor 4 (SALL4) interacts with REN. We found that SALL4 is re-expressed in mouse SHH MB models and its high levels correlate with worse overall survival in SHH MB patients. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppress SHH MB growth both in murine and PDX models.

CONCLUSIONS
Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers.
MDB-65. RESULTS FROM THE SJ-ELIOT PHASE 1 CLINICAL TRIAL EVALUATING PREXASERTIB (LY2606368) IN COMBINATION WITH CYCLOPHOSPHAMIDE OR GEMCITABINE FOR CHILDREN AND ADOLESCENTS WITH REFRACTORY OR RECURRENT MEDULLOBLASTOMA
Authors: Gottardo Nicholas G , Endersby Raelene , Billups Catherine , Orr Brent , Hansford Jordan R , Hassall Tim , Zielgler David S , Stewart Clinton , Onar-Thomas Arzu , Clarke Molly , Roussel Martine F , Gajjar Amar , Robinson Giles W 
Published: June 2024

Abstract

BACKGROUND
SJ-ELIOT (NCT04023669) was a phase 1 trial that explored the combination of the checkpoint kinase inhibitor, prexasertib with the DNA-damaging agents, cyclophosphamide and gemcitabine, in recurrent or refractory medulloblastoma.

METHODS
Participants ≥ 1 year and &lt; 25 years were stratified to one of two treatment strata: stratum A prexasertib and cyclophosphamide and stratum B prexasertib and gemcitabine. Patients with Group 3/4 medulloblastoma were assigned to either stratum A or B, whereas patients with SHH medulloblastoma were assigned to stratum A. A Rolling-6 design was used.

RESULTS
Fifteen patients were enrolled on stratum A and six patients on stratum B. The study was closed early due to drug supply issues. In stratum A, three patients were escalated to dose level (DL) 3 and none had dose limiting toxicity (DLT). For stratum B, of the first three patients enrolled on DL1, two had DLTs (grade 3 hypotension) related to drug reactions. Consequently, stratum B was amended to add hydrocortisone prophylaxis. A further three patients were enrolled. One patient had a grade 3 DLT (ALT increase). The remaining two patients electively stopped therapy within the first two courses. One patient on stratum A, with SHH TP53 mutant, MYCN amplified medulloblastoma, achieved a complete sustained response, received 12 cycles, and electively stopped treatment after 408 days. They progressed nine months later. The remaining 14 patients on stratum A progressed. There were no objective responses on stratum B. Median PFS were 1.9 and 2.1 months for stratum A and B respectively.

CONCLUSIONS
The MTD/RP2D was not established for either arm. In stratum A, DL3 was tolerated, whereas DL1 for Stratum B was not tolerated. Despite robust preclinical data, no efficacy signal was observed. Intriguingly, one patient with a highly aggressive tumor (SHH TP53 mutant, MYCN amplified) appeared to derive a sustained benefit from the combination of prexasertib and cyclophosphamide.
MDB-68. DISCOVERING DRUG SENSITIVITIES IN MEDULLOBLASTOMA USING PATIENT- AND PDX-DERIVED TUMOROIDS
Authors: Meulenbroeks Chris , Stathi Phylicia , van de Wetering Marc , Villarejo Chio Carranza , Mack Norman , Schwalm Benjamin , Geisemeyer Neal , Schueler Julia , Kolodziejczak Anna S , Milde Till , LA Plasschaert Sabine , Kranendonk Mariëtte E G , Hoving Eelco W , Northcott Paul A , Roussel Martine F , Pfister Stefan M , Bunt Jens , Kool Marcel 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor types and is subdivided into four major types: WNT, SHH, Group 3 and Group 4. Treatment, including resection, cranio-spinal radiotherapy, and chemotherapy, often leads to undesirable long-term side effects. MB prognosis depends on type, subtype, and genetic alterations, reflecting the high level of heterogeneity observed in these tumors and indicating that specific patient populations with particularly poor prognosis require alternative treatment approaches. Therefore, preclinical models are essential for recapitulating MB heterogeneity and developing subtype-specific treatments.

METHODS
Long-term in vitro MB tumoroid models were developed from patient and PDX tumors and molecularly characterized using DNA methylation and transcriptomic analyses. High-throughput single drug screening (225 compounds) and combination screening were performed to identify (subtype-specific) drug sensitivities.

RESULTS
Fifteen tumoroid lines were established from TP53-mutated SHH (n=6), Group 3 (G3) MYC-amplified (n=4) and non-amplified (n=5) patient (n=6) and PDX (n=9) tumors. DNA methylation analyses confirmed the maintenance of molecular identity in these tumoroids after long-term culture (&gt;5 passages). Transcriptome analyses reveal a more proliferative, progenitor-like phenotype in these tumoroids compared to patient/PDX tumors. Hight-throughput drug screens identified both common and type-specific drug sensitivities within MB. Notably, drugs targeting CDK7, CDK12, CHECK1, BCL2L, and HDAC demonstrated efficacy in both G3 and TP53-mutated SHH-MB, while TOP1/2 and MDM2 inhibitors were specific for G3-MB. Currently, these drugs are being further investigated to select the most effective synergistic drug combinations for in vivo validation in PDX models.

CONCLUSIONS
Thus far, we have established already fifteen MB tumoroid models representing SHH-MB and G3-MB and identified several drug targets, including cell cycle kinases and HDACs. Tumoroids closely resemble patient tumors, based on methylome and transcriptome, enhancing their relevance for drug discovery applications in a high-throughput fashion and for prioritizing new treatment strategies for MB patients in clinical trials.
MDB-81. THE ROLE OF SURVEILLANCE IMAGING IN DETECTING RECURRENCE OF MEDULLOBLASTOMA
Authors: Dasgupta Archya , Dhele Rudrani , Sahu Arpita , Chatterjee Abhishek , Chinnaswamy Girish , Prasad Maya , Choudhary Amit , Bhattacharya Kajari , Epari Sridhar , Sahay Ayushi , Shah Aekta , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Menon Nandini , Gupta Tejpal 
Published: June 2024

Abstract

BACKGROUND
In patients with medulloblastoma, imaging with magnetic resonance imaging (MRI) of the brain and spine plays an integral role in surveillance following treatment completion. The primary objective of imaging surveillance is to detect early recurrences, possibly leading to better salvage treatment. However, there is a lack of data to demonstrate the utility of imaging with possible demerits associated with increased resource utilization, scan-related anxiety, and lead or length time bias.

METHODS
Patients with histopathological confirmation of medulloblastoma treated in our institute between 2005 and 2022 were screened to identify patients with image-detected recurrences and corresponding documentation of symptoms and imaging intent (surveillance or directed by symptoms).

RESULTS
From a cohort of 545 patients treated during the period, 212 had disease recurrence, of which 153 had known symptomatology during the first recurrence. A total of 114 patients (75%) were having recurrence detected prompted by symptoms. Group 4 medulloblastomas were commonly seen to have recurrence detected on surveillance imaging (35%) compared to the SHH subgroup (25%) and group 3 (12%). During the final analysis, 141 of 153 patients had died. The median survival of patients detected to have asymptomatic relapse was 14 months compared to 5 months for symptomatic recurrences (p=0.03). The overall survival (calculated from index diagnosis) was not statistically significant between the two groups, with a 3-year survival of 53% (asymptomatic) vs 46% (symptomatic) (p=0.51).

CONCLUSION
In most patients, recurrences were detected by unplanned imaging ahead of scheduled surveillance imaging prompted by symptoms. Although the survival after recurrence is better in patients diagnosed on surveillance imaging, the overall survival was not different between the two groups, suggesting the possibility of lead time bias. Prospective studies are warranted to determine the role and appropriate frequency of surveillance imaging in patients with medulloblastoma.
MDB-84. IDENTIFICATION AND CHARACTERIZATION OF NOVEL TRANSCRIBED ULTRA-CONSERVED REGIONS AS LONG NON-CODING RNAS IN MEDULLOBLASTOMA
Authors: Hudson Kadie , Vernon Ashley , Zhang Myron K Gibert Jr Ying , Saha Shekhar , Dube Collin , Sun Yunan 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant pediatric brain tumor. While medulloblastoma survival has improved with molecular subgrouping, children who undergo standard of care treatments frequently experience permanent neurological deficits and many still face poor prognoses. This work investigates the role of “Transcribed Ultra-Conserved Regions” (TUCRs) in medulloblastoma about which there is no published literature. TUCRs represent a distinct group of 481 putative lncRNAs that are 100% conserved across human, mouse, and rat genomes. These elements change 20 times slower than the average genomic region and are therefore under intense negative selection. Since their discovery, TUCRs have remained exceedingly underexamined within cancer research. We hypothesize that TUCRs play critical roles in the molecular basis of medulloblastoma which will lead to the development of targeted therapies for medulloblastoma of which there are none approved.

METHODS
We used RNA-sequencing and differential gene expression analysis of medulloblastoma tumors as compared to normal cerebellum samples to investigate TUCR dysregulation followed by Kaplan-Meier correlation to survival analysis. We generated a multifaceted scoring and prioritization system to rank TUCRs in medulloblastoma. Top ranked TUCRs were then investigated using in vitro functional experimentation in medulloblastoma cell lines.

RESULTS
Bioinformatics analysis of medulloblastoma tumors revealed significant TUCR dysregulation and identified numerous TUCRs whose expression correlated with overall survival. Application of the computational scoring system determined the top ten intergenic TUCRs in medulloblastoma. Analysis of medulloblastoma cell lines indicated significant dysregulation of these TUCRs and functional assays showed that uc.403 promoted cell proliferation.

CONCLUSIONS
We are continuing to investigate the functional effects and mechanisms of action of these select intergenic TUCRs in medulloblastoma. Altogether, our work investigates the oncogenic and tumor suppressive nature of TUCRs. It represents the first study of TUCRs in medulloblastoma that will significantly advance our basic understanding of this highly understudied class of molecules.
MDB-91. MEDULLOBLASTOMA – MOLECULAR CHARACTERISTICS AND RADIOLOGICAL ASPECTS OF A BRAZILIAN COHORT FROM A SINGLE CENTER
Authors: Martins Flávia Delgado , de Lima Benicio Oton , Arrais Bruna , da Silva Emanoelle Cristina , Marcelino Marcio Ferreira , Pinto Pedro Henrique , de Bispo Diogenes Diego Carvalho 
Published: June 2024

Abstract

BACKGROUND
Four molecular subgroups of medulloblastoma are distinguished by their genomic, epidemiological, and prognostic characteristics: Wingless (WNT), Sonic hedgehog (SHH), Group 3 and Group 4. Genotypic classification permits individualized therapeutic planning based on risk stratification, thereby improving patient outcome. This study aims to characterize the epidemiological and molecular data of a cohort treated at a single Brazilian center, as well as to correlate the heterogeneous aspects of magnetic resonance imaging (MRI) with the molecular characteristics of this tumor.

METHODS
The study analyzed 47 medulloblastoma cases, treated at the children’s oncology reference institution of a middle-income country between 2011 and 2021. The medical records, radiological findings and the histological and molecular classification are reviewed. The images were evaluated by an experienced neuroradiologist, blinded to clinical and molecular information.

RESULTS
Thirty-two out 47 patients met the eligibility criteria and were analyzed. The frequency of molecular groups found was 6.25% Non-SHH/ Non-WNT, 12.50% WNT, 34.38% SHH, 3% Group 3 and 44 % Group 4. The analysis revealed tumor location, presence of hemorrhage/calcification, limits and enhancement patterns are significant for molecular group prediction. SHH shows a significant prevalence in the cerebellar hemisphere, lower presence of hemorrhage/calcification and an ill-defined tumor margins when compared with other subgroups. Group 4 showed significantly less enhancement.

CONCLUSIONS
In accordance with the frequency observed in studies on childhood medulloblastoma, our series found a significant prevalence of Group 4 and a lack of representativeness of Group 3. Despite the limitations, it was possible to identify radiological tumor characteristics that may predict the molecular subgroup and contribute to a more effective therapeutic approach, thereby reducing the incidence of post-surgical complications.
MDB-94. RADIOMICS-BASED DECISION SUPPORT FOR PEDIATRIC MEDULLOBLASTOMA RISK STRATIFICATION ON MULTI-PARAMETRIC MRI
Authors: Reddy Kartik , Midya Abhishek , Hajibonabi Farid , Halicek Martin , Damaraju Eswar , Goldman-Yassen Adam , McThenia Sheila , Castellino Robert C , Mazewski Claire , Madabhushi Anant 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common pediatric brain malignancy. Accurate risk stratification is crucial for prescribing appropriate therapy. However, current risk stratification into standard or high-risk groups is limited in scope and does not accurately address the unique biological behavior of each specific tumor, with approximately 30% of children diagnosed with MB suffering from treatment failure. We developed a radiomic tool to more accurately risk stratify children with MB.

METHODS
We collected 1.5T/3T MRI (Siemens, Philips, or GE scanners) and clinical data from 80 patients with MB treated at Children’s Healthcare of Atlanta. Radiomic features that quantify textural heterogeneity including first and second order statistics, Haralick’s features from Gray Level Co-occurrence Matrices, and CoLIAge were extracted from tumor volumes segmented by a board-certified radiologist from multi-parametric MRI data including Apparent Diffusion Coefficient (ADC), T2, and post-contrast T1 sequences. Continuous survival models were built using the Cox proportional hazard method with 70% of the data for progression free survival (PFS) and overall survival (OS) using the 5 most predictive features obtained by univariate analysis after removing correlated features within the training data.

RESULTS
We developed three models with T1, T2, and ADC separately to evaluate predictive power of radiomic signatures. Three models for predicting MB OS delivered Harrel’s concordance indices (C-index) of 0.72 and 0.61 (T1); 0.70 and 0.65 (T2); and 0.80 and 0.76 (ADC) for training and test, respectively. C-indices for PFS were 0.70 and 0.69 (T1); 0.73 and 0.67 (T2); and 0.63 and 0.61 (ADC).

CONCLUSIONS
Our preliminary results show the feasibility and efficacy of our approach for predicting MB OS and PFS. Future studies will build an integrated model combining T1,T2, ADC, and other clinical information for predicting MB OS and PFS using a large multi-center validation cohort.