bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-53. SALVAGE CRANIOSPINAL IRRADIATION FOR RELAPSED WNT-PATHWAY MEDULLOBLASTOMA PATIENTS TREATED WITH UPFRONT FOCAL CONFORMAL RADIOTHERAPY AND CHEMOTHERAPY AT INITIAL DIAGNOSIS: LONG-TERM AND MATURE OUTCOMES FROM A PROSPECTIVE DE-INTENSIFICATION STUDY
Authors: Gupta Tejpal , Chatterjee Abhishek , Dasgupta Archya , Epari Sridhar , Sahay Ayushi , Sahu Arpita , Moiyadi Aliasgar , Prasad Maya , Chinnaswamy Girish 
Published: June 2024

Abstract

BACKGROUND
Excellent long-term outcomes (5-year overall survival &gt;90%) in WNT-pathway medulloblastoma (MB) patients have prompted systematic attempts at de-intensification of therapy to mitigate treatment-related toxicities. Mature outcomes of a prospective study (FOR-WNT) treating low-risk WNT-MB children with focal conformal radiotherapy (RT) and adjuvant systemic chemotherapy omitting upfront craniospinal irradiation (CSI) are being reported herein.

METHODS
Seven children with rigorously-defined low-risk WNT-MB were treated with post-operative focal conformal RT to the index tumor-bed (54Gy/30 fractions) followed by 6-cycles of adjuvant systemic chemotherapy after written informed consent/assent. Survival outcomes were computed using Kaplan-Meier method and reported as point estimate with 95% confidence intervals (CI). The trial was terminated prematurely due to unacceptably high risk of neuraxial failures.

RESULTS
One child succumbed to chemotherapy-related toxicity while 3 of 7 children were detected with leptomeningeal relapse on surveillance neuro-imaging within 2-years of index diagnosis. Full-dose salvage CSI (35Gy/21 fractions) at relapse followed by further chemotherapy led to excellent clinico-radiological response in all 3 children; however, one child developed further local recurrence and leptomeningeal metastases and succumbed to recurrent/progressive disease despite further aggressive salvage therapy. Five of 7 children including the other two treated with salvage CSI and systemic chemotherapy are alive and continue to remain in remission on long-term follow-up. At a median follow up of 61 months, the 5-year Kaplan-Meier estimates of event-free survival, relapse-free survival, and overall survival were 42.9% (95%CI: 18.2-100%), 50.0% (95%CI: 22.5-100%), and 71.4% (44.7-100%) respectively.

CONCLUSIONS
Omission of upfront CSI in low-risk WNT-MB is associated with unacceptably high-risk of neuraxial failure. Although full-dose salvage CSI achieves excellent response, remissions are not durable resulting in sub-optimal long-term overall survival. Judicious de-escalation with upfront low-dose CSI (18Gy) is currently being tested in a successor study (FOR-WNT 2).
MDB-62. SUBGROUP AND SUBTYPE-SPECIFIC OUTCOMES IN METASTATIC INFANT MEDULLOBLASTOMA
Authors: Senapati Akanksha , Lindsay Holly , Gilheeney Stephen , Bale Tejus , Taylor Michael , Khuong-Quang Dong-Anh , Bouffet Eric , Khan Sara , van Veelan Marie-Lise , Kros Johan M , Vasiljevic Alexandre , Pollack Ian , Chambless Lola , Gupta Nalin , Weiss William A , Jabado Nada , Sterba Jaroslav , Zapotocky Michal , Hansford Jordan R , Ramaswamy Vijay 
Published: June 2024

Abstract

BACKGROUND
Metastatic infant medulloblastoma (MB) is a major challenge given the devastating long-term effects of craniospinal irradiation to the developing brain. However large cohorts of metastatic infant medulloblastoma have not been analysed to date.

METHODS
A multicentre molecularly informed international cohort of children &lt;6 years old with metastatic medulloblastoma was assembled and analysed.

RESULTS
Eighty-four patients with a median age of 2.95 (0.66-6.58) years were identified. 48.8% were Group3-MB, 23.8% Group4-MB and 27.4% SHH-MB. 78% of Group3-MB were subtype II (40.4%) and IV (38.1%), 50% of Group 4 were subtype VII, and within SHH, SHHß and SHHγ were 52.2% and 43.5% respectively. 28.5% of all Group3-MB harboured MYC amplification. A multivariable analysis incorporating subgroup, MYC amplification and upfront craniospinal irradiation revealed that survival was superior for SHH patients compared to Group 3 irrespective of MYC status (Group3-veMYCamp: HR 3.05 95%-CI 1.05-8.87 p=0.04, Group3+veMYCamp HR 7.87 95%-CI 2.49-24.87 p=0.00044). Group 4 had a trend to a poor outcome (HR 2.63 95%-CI 0.82-8.39 p=0.1). SHH subjects had a superior outcome with 5-year PFS of 0.657 (95%-CI 0.47-0.92), without a significant difference between SHHß and SHHγ. High-dose chemotherapy regimens portended to a superior outcome for both subtypes of SHH-MB. 5-year PFS for non-radiated SHH-MB was 61% (95%-CI 40.8-91.4), compared to non-radiated Group3-MB (18.5%; 95%-CI 5.4-62.8) and Group4-MB (20%; 95%-CI 3.4-100). SHH-MB patients had more local than metastatic relapses compared to non-SHH-MB (p=0.01).

CONCLUSIONS
In the largest study dedicated to metastatic infant medulloblastoma assembled to date, outcomes for infants with Group 3- and 4-MB with metastatic disease treated with radiation sparing approaches is dismal despite intensified regimens. MYC amplification portends to a near uniformly fatal prognosis with current treatment irrespective of upfront radiotherapy. Novel radiation sparing approaches are urgently needed for this group. Infants with both metastatic SHHß and SHHγ benefit from intensified therapy.
MDB-67. MEDULLOBLASTOMA MOLECULAR SUBGROUPING AND OUTCOMES DATA OF A SINGLE CENTER FROM A LOW-MIDDLE-INCOME COUNTRY
Authors: Mushtaq Naureen , Bashir Farrah , Riaz Quratulain , Zahid Soha , Javed Gohar , Tariq Maria , Qureshi Bilal Mazhar , Hilal Kiran , Ramaswamy Vijay , Hawkins Cynthia , Bouffet Eric , Minhas Khurram 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant childhood brain tumor. The molecular subgrouping of medulloblastoma is a major determinant of management in high-income countries. Subgrouping is still very limited in low- and middle-income countries, and its relevance to management has yet to be evaluated in this setting. We describe molecular findings and their implications in the outcome of a single tertiary care center.

METHODS
Children between 3 and 18 years diagnosed with medulloblastoma between April 2014 and December 2020 at Aga Khan University Hospital were included. Subgrouping was performed by nanostring through a collaboration with the Hospital for Sick Children, Toronto.

RESULTS
Thirty-five children were identified (85.17% male); the median age was 8. Nineteen patients were high-risk, including 9 with metastatic disease. In 28 children, there was a clear molecular subgroup: 4 WNT (11.4%), 7 Sonic Hedgehog (20%), 3 Group 3 (8.6%), and 14 Group 4 (40%) medulloblastomas. Molecular subgrouping was inconclusive for two patients (5.7%) and not done in 5 patients (14.3%). All patients underwent surgery; 91.4% received radiation therapy and chemotherapy. Of 35 children, overall Survival at 5 years was 100%, 57.1%, 66.7%, and 85.7% for WNT, Sonic Hedgehog, Group 3, and Group 4, respectively. WNT and Group 3 had 100% Progression-free survival, whereas Sonic Hedgehog and Group 4 had decreased progression-free survival of 42.9% and 85.7%, respectively. Average-risk patients had an overall survival of 93.8%, whereas high-risk patients exhibited a statistically significant lower overall survival of 63.2% (P=0.014).

CONCLUSION
Our cohort demonstrates excellent outcomes for WNT and Group 4, despite one WNT being metastatic and four Group 4 patients being high-risk. Modern risk stratification is an excellent predictor of survival, suggesting that treatment can be tailored according to subgrouping in the LMIC setting.
MDB-70. SYSTEMATIC TRANSCRIPTOMIC ANALYSIS OF CHILDHOOD MEDULLOBLASTOMA IDENTIFIES M6A-LNCRNA SIGNATURES ASSOCIATED WITH PROGNOSIS, MOLECULAR SUBTYPE, AND IMMUNE CELL INFILTRATION
Authors: Joshi Kandarp , Yuan Menglang , Katsushima Keisuke , Saulnier Olivier , Dean Selah , Amankwah Ernest , Stapleton Stacie , Jallo George , Taylor Michael D , Eberhart Charles G , Perera Ranjan J 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the predominant pediatric brain tumor, subdivided into four molecular subgroups, with group 3 and group 4 tumors posing significant clinical challenges due to poor prognosis and classification. This study investigates the roles of N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) in MB, aiming to develop diagnostic and prognostic tools.

METHODS
We analyzed transcriptome from 1236 samples to identify m6A-associated lncRNA signature (M6LSig). A multivariate-cox analysis identified a gene signature significantly associated with overall survival (OS) of patients. Risk score was calculated based on the sum of weighted gene expression of these genes. Nomograms were calculated for predicting OS and PFS probability. We did feature selection with Boruta to identify minimum gene signature for subgroup classification. We performed correlation analysis of gene signature and risk score with immune-cell abundance. We depleted METTL3 and METTL14 in G3-MB cell-line (D425) to measure impact on cell proliferation and dysregulation of M6LSig genes as a result of loss of m6A.

RESULTS
Nomogram was constructed using risk score derived from 24 M6LSig significantly associated with OS and PFS of the patients. A 171 gene signature was identified that can accurately classify samples into one of four major subgroups of MB with more than 90% accuracy including between Grp3/Grp4 samples. M6LSig genes and risk score showed significant correlation with immune cell type abundance in MB tumors. Expression of CD155 and 4-1BB was significantly different between high and low risk samples. m6A writer genes knockdown in D425 cells resulted in decreased cell proliferation and upregulation of many M6LSig genes.

CONCLUSION
M6LSig based risk can accurately predict OS and PFS and 171 genes signature can classify patients into subgroups with more than 90% accuracy. Risk score can also be used for determining high risk versus low-risk patient and design tailor made immune-therapy for better survival.
MDB-80. PREVIOUS MANAGEMENT OF MEDULLOBLASTOMA IN A MIDDLE-INCOME COUNTRY: IDENTIFYING AREAS FOR IMPROVEMENT
Authors: Sánchez Mauricio , Gamboa Yessika , Delgado Mario , Garita Karla , Esquivel Jessica , Rodríguez Carlos , Caceres Adrian , Leis Amanda , Acuña Maria José , Nuñez Monica 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma stands as the most prevalent malignant brain tumor among the pediatric population. Diagnosis, staging, and treatment protocols are well-established in high-income countries. However, in low- to middle-income countries, management practices often deviate and frequently prove inadequate, potentially impacting final outcomes significantly. In Costa Rica, a middle-income country, a study was conducted to document the prevailing management approaches for patients at the Hospital Nacional de Niños.

METHODS
Data from 31 children under the age of 13, treated between 2009 and 2015, were retrospectively analyzed. All patients were included in the study. Demographic details, initial symptoms, staging procedures, surgical interventions, histologic subtypes, treatment modalities, and survival outcomes were scrutinized. Risk stratification relied on age, CSF analysis (when available), and the extent of resection as per the neurosurgeon’s assessment. Due to incomplete staging, all patients received high-risk chemo - radiotherapy protocol.

RESULTS
The study identified 31 patients. Median age of 6.1 years (range, 0 -12), 51.1% being male. The most prevalent symptoms included headache, vomiting, and ataxia, manifesting in 93% of cases. Histological subtype was unspecified in 45.2% of patients. High-risk status was assigned to 11 patients (35.5%), with 8 of them aged under 3 years, while 20 patients (64.5%) were categorized as low risk, yielding a 5-year overall survival (OS) of 27% and 80%, respectively. Complete resection achieved in 21 cases, resulting in a 5-year OS of 71.5%, compared to 25% for 4 patients with incomplete resection. The overall 5-year OS rate was 61.3%.

CONCLUSIONS
This study underscores suboptimal practices in the diagnosis, staging, and management of medulloblastoma at the time of assessment. While outcomes for patients classified as standard are acceptable, they received intensified chemo/radiotherapy, potentially leading to heightened long-term adverse effects. Importantly, identified deficiencies have since been addressed. The impact of these interventions will be evaluated in future studies.
MDB-87. REAL-LIFE EXPERIENCE WITH A “MEMMAT-LIKE” METRONOMIC REGIMEN FOR RELAPSED/REFRACTORY MEDULLOBLASTOMA
Authors: Cacchione Antonella , D’Antonio Federica , Ruscio Valentina Di , Megaro Giacomina , Baldo Giada Del , Liguoro Ilaria , Tornesello Assunta , Cocciolo Alessandro , Vennarini Sabina , Chiesa Silvia , Carai Andrea , Colafati Giovanna Stefania , Mastronuzzi Angela 
Published: June 2024

Abstract

BACKGROUND
Standard salvage regimen for medulloblastoma’s relapse is currently lacking. An evolving alternative approach is metronomic chemotherapy, which aims to interfere with tumor angiogenesis. We report our experience on a modified combinatorial metronomic chemotherapic/antiangiogenic approach, the Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial (MEMMAT) regimen. Our study aimed to test efficacy and tolerance of that approach in pediatric patients with relapsed/refractory medulloblastoma treated in outpatient unit.

METHODS
The study was conducted from January 2017 to December 2022 at Bambino Gesù Children’s Hospital in Rome. MEMMAT-like regimen consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by intravenous bevacizumab and intrathecal topotecan.

RESULTS
Fourteen patients met the eligibility criteria. At diagnosis, six patients (43%) presented a localized disease, the other eight patients (57%) metastatic one; eight patients had the first recurrence and six had multiple recurrences at the start of MEMMAT-like therapy. At relapse, all the recurrences had a metastatic pattern. Methylation profiling classification showed three subgroups 3, six subgroups 4, three with SHH subgroup, and two WNT. The median overall survival after the recurrence that prompted to the use of MEMMAT like regimen, for the whole group, was 17,9 months (range, 8-32 months), with 79% (60%,100%) at 12 months and 19% (5,7%-64%) at 24 months; the mean progression-free survival (PFS) at 12 and 24 months was 57% (36%-90%) and 26% (10%-66%). When the one-year PFS rate was evaluated according to the MEMMAT-like number of treatment lines (after the first relapse or third and beyond), we found respectively 62% (37%-100%) and 50% (22%100%).

CONCLUSIONS
The metronomic outpatient MEMMAT-like combination is feasible, well tolerated, and can lead to sustained control of relapse in medulloblastoma. The best setting seems to be after the first relapse to achieve a higher PFS.
MDB-103. THE SIGNIFICANCE OF CEREBROSPINAL FLUID CYTOLOGY IN SURVEILLANCE FOR RECURRENT MEDULLOBLASTOMA
Authors: Arja Mohammad Hatim Mohammad Abu , Okcu Fatih , Su Jack , Aldave Guillermo , Mohila Carrie , Blessing Melissa , Chintagumpala Murali M 
Published: June 2024

Abstract

BACKGROUND
Surveillance of patients with medulloblastoma includes magnetic resonance imaging of the brain and spine and cerebrospinal fluid (CSF) cytology evaluation. Certain protocols require frequent CSF cytology evaluations off-therapy while others perform CSF cytology only at the time of radiographic relapse. We wanted to determine the incidence of isolated CSF positivity at the time of recurrence and the outcome of these patients.

METHODS
We performed a retrospective analysis of patients with relapsed medulloblastoma treated at Texas Children’s Hospital between 1997 and 2023.

RESULTS
Out of 223 patients with medulloblastoma, 45 patients developed recurrences. Twenty-five (55.5%) patients underwent lumbar puncture for CSF cytology at the time of relapse. The radiographic distribution of recurrences was focal (n=7), focal and disseminated (n=6), disseminated (n=11), and negative imaging (n=1). Seven out of the 25 (28%) patients had positive CSF cytology for malignant cells at initial relapse. All seven patients succumbed secondary to disease progression. Among 18 patients who had negative CSF cytology at recurrence, three infant patients at initial diagnosis were disease-free following craniospinal radiation at recurrence. Only one among 25 patients had positive CSF cytology without radiographic evidence of relapse. Among ten patients with focal disease at the time of relapse, seven had negative CSF cytology for malignant cells, and three did not have CSF cytology evaluated at the time of relapse.

DISCUSSION
Frequent evaluation of CSF cytology to detect recurrence may not be necessary in addition to imaging studies. In our study, it did not influence the outcome of patients with recurrence. Prospective studies are necessary to support periodic CSF surveillance to detect ctDNA, which may allow for early interventions that may influence outcomes in patients with recurrent medulloblastoma who have poor outcomes.
MDB-109. CHARACTERIZING DISTINCT SIGNATURES OF RNA TRANSLATIONAL REGULATION UPON MYC OVEREXPRESSION IN H9 NEURAL STEM CELLS
Authors: Dasgupta Anwesha , Yanuzzi Ian , Ruiz-Orera Jorge , Prensner John R 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB), a childhood brain tumor, emerges typically between 6-8 years, originating from cerebellar neuronal stem cells. Recurrent genetic alterations, notably MYC amplifications, are associated with poor therapy response. Subgrouped as WNT-MB, SHH-MB, Group 3 MB, and Group 4 MB, Group 3 MB is characterized by high-level MYC amplification in approximately 17% of cases. Patients with Group 3 MB and MYC activation present distinct transcriptional and proteomic signatures, including elevated levels of ribosomal proteins and ribosome assembly proteins.

METHODS
We conducted a comprehensive analysis of RNA-seq and Ribo-seq in human neural stem cells (H9 NSCs) with amplified MYC expression. H9-NSCs were cultured in tumor stem media and transduced with lentivirus for either GFP control or MYC cDNA. RNA and ribosome-protected fragments were isolated from cell lysates for RNA-seq and Ribo-seq in biological triplicates. Ribo-seq data was analyzed using ORFquant for coding sequence quantification and deltaTE for translational efficiency.

RESULTS
Overexpressing MYC in H9-NSCs led to significant differential expression of 4194 genes (p adj &lt; 0.05) using RNA-seq and 2860 genes (p adj &lt; 0.05) using Ribo-seq. While RNA-seq and Ribo-seq exhibited high correlation for most genes, we identified 364 differentially translated genes (p adj &lt; 0.05) upon MYC overexpression. Genes regulated solely at the translational level were enriched for functions in cytoplasmic translation initiation, viral translation, and response to interleukin-4. Key genes highly regulated at the Ribo-seq level included CCND3, YBX1, and EEF2. Validating with proteomics data from the CPTAC medulloblastoma tissue set confirmed protein-specific upregulation of these targets in MYC-driven Group 3 medulloblastomas.

CONCLUSIONS
MYC overexpression revealed distinct behaviors in differentially expressed genes, either regulated at the level of translation alone, correlated with transcription, or independent of transcription. We anticipate that our findings will contribute to a refined understanding of the molecular landscape of MB, particularly in the context of Group 3 MB.
NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1
Authors: Yelak Alexander , Hamdani Gilad , Dagan Amit , Michaeli Orli , Toledano Helen 
Published: June 2024

Abstract

BACKGROUND
Low grade gliomas (LGG), both sporadic & Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1.

METHODS
Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy & bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients.

RESULTS
16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA.

CONCLUSIONS
Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.
NFS-09.NF1 MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS LEADS TO PRENEOPLASTIC LESION FORMATION IN THE BRAIN
Authors: Pan Yuan , Hysinger Jared , Yalçın Belgin , Lennon James , Byun Youkyeong Gloria , Raghavan Preethi , Schindler Nicole , Anastasaki Corina , Chatterjee Jit , Ni Lijun , Xu Haojun , Malacon Karen , Jahan Samin , Ivec Alexis , Aghoghovwia Benjamin , Mount Christopher , Nagaraja Surya , Scheaffer Suzanne , Attardi Laura , Gutmann David , Monje Michelle 
Published: June 2024

Abstract
Oligodendrocyte precursor cells (OPCs) are progenitor cells that give rise to central nervous system oligodendrocytes throughout life. Transcriptomic and lineage tracing studies suggest that OPCs may be the putative cell of origin for many glioma histologic subtypes. While children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to low-grade gliomas following bi-allelic NF1 loss, the cellular and molecular etiologies underlying tumorigenesis remain incompletely elucidated. Using a unique collection of genetically engineered Nf1 mouse strains, we identified discrete hyperdense lesions composed of OPCs. The OPCs within the lesions display a transient increase in proliferation and hypercellularity (hyperplasia). This phenotype was not observed following heterozygous mutation in other tumor suppressors (Trp53, Pten, or Rb1). OPC-specific heterozygous Nf1-mutant mice harbored similar lesions, suggesting an OPC-intrinsic phenotype. OPC-specific Nf1 loss resulted in increased OPC density throughout the entire brain, suggesting that the lesions in heterozygous Nf1-mutant mice represent spontaneous OPC Nf1 loss-of-heterozygosity events. Mechanistically, monoallelic KRAS hyperactivation phenocopies OPC hyperdensities in the brain of Nf1+/- mice; however, KRAS hyperactivity is not necessary for lesion formation or expansion. When the brains of mice engineered with heterozygous NF1 patient-derived Nf1 mutations were examined, the development of hyperdense OPC lesions reflected RAS-independent dysregulated PI3K-AKT signaling. Collectively, our study reveals a potential mechanism driving the development of preneoplastic lesions in the brains of individuals with NF1.