bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-27. OUTCOMES FOR CHILDREN TREATED FOR MEDULLOBLASTOMA USING A RADIATION-SPARING APPROACH: A REPORT FROM THE CHILDREN’S BRAIN TUMOR NETWORK
Authors: Ronsley Rebecca , Crotty Erin E , Vitanza Nicholas A , Stevens Jeffrey , Goldstein Hannah , Cole Bonnie , Ermoian Ralph , Leary Sarah E S 
Published: June 2024

Abstract

OBJECTIVE
To describe real-world outcomes in children with medulloblastoma treated with radiation-sparing chemotherapy in the USA.

METHODS
Clinical and molecular data were obtained from the Children’s Brain Tumor Network (CBTN), a multi-institutional collaboration to collect and freely share biological samples and longitudinal clinical data from consented patients. Patients with medulloblastoma treated with radiation-sparing regimens were included. Clinical data included patient demographics, stage, extent of resection, treatment regimen, and survival. Three-year overall survival (OS3) was calculated from diagnosis to death from any cause or last follow-up with log-rank p-value.

RESULTS
Eighty-one patients (56% male, median age 2.51 [range 0-7.44] years) with medulloblastoma (32% metastatic) were included. Molecular group was available for 36 (44%). Patients were treated according to protocols CCG99703 (n=26), ACNS0334 Arm A (n=13), ACNS0334 Arm B (n=30), PBTC026 (n=10), and ACNS1221 (n=2). Only 29 (36%) were enrolled on a therapeutic study. Seventy-two patients had median follow-up of 2.7 years (range 0.3-13 years). OS3 was 79+6; OS3 by molecular group was 90+9 in SHH (n=14), 55+14 in Group 3 (n=16), 56+25 in Group 4 (n=6). OS3 was 92+5 for 55 patients with localized disease versus 53+12 for 26 with metastasis (p=0.001); 86+6 for 55 patients with gross total resection versus 62+11 in 26 with partial resection or biopsy (p=0.03). OS3 was not associated with upfront radiation, 80+7 for 54 patients who received no radiation before relapse versus 78+9 for 27 who received radiation before relapse (21 focal, 6 craniospinal). OS3 was 87+8 for 30 patients on a methotrexate-containing regimen versus 74+7 for 51 without methotrexate (p=0.27). Five patients developed second malignancy.

CONCLUSIONS
CBTN data report real-world survival for young children treated with radiation-sparing approaches, most not enrolled on studies. Ongoing molecular characterization of the CBTN cohort will facilitate additional analysis to improve risk stratification and therapy selection for young children.
MDB-30. ZOLPIDEM, A PROMISING DRUG TO IMPROVE POSTOPERATIVE CEREBELLAR MUTISM SYNDROME (CMS): RETROSPECTIVE STUDY OF 19 PEDIATRIC PATIENTS WITH POSTERIOR FOSSA TUMORS
Authors: Quintero-Garcia Diannet , Añon Juan , Vazquez-Gomez Felisa , Moreno-Carrasco Jose Luis , Perez-Somarriba Marta , Castellano Serafin , Ippolito Hyaissa , Rivero Belen , Arce Begoña , De Caceres-Velasco Carmen , Cartas Susana , Esteso Borja , Galas Sebastian , Alonso-Garcia Isis , Mingarro Roser , Cantarín Veronica , Lassaletta Alvaro 
Published: June 2024

Abstract

INTRODUCTION
Postoperative Cerebellar Mutism Syndrome (CMS) affects up to 25% of patients undergoing surgeries for posterior fossa (PF) tumors. There is no established treatment for CMS, although zolpidem has become widespread after reporting remarkable responses in some cases. However, there is very limited scientific evidence, prompting us to document our experience with zolpidem.

OBJECTIVES
To evaluate the efficacy and safety of zolpidem in patients with postoperative CMS in PF tumors.

METHODS
Observational, descriptive, retrospective study conducted at our institution. Patients &lt;21 years diagnosed with CMS following PF tumor surgery between 2011-2023 and treated with zolpidem were included. Demographic and clinical data, therapies, CMS scales, and outcomes were collected.

RESULTS
Nineteen patients met the criteria, 84% males, median age 8 years (range, 9 months-19 years), and median follow-up time 30 months (range, 2-126). Diagnoses included 58% medulloblastoma, 21% pilocytic astrocytoma, 10.5% ependymoma, 10.5% others. CMS mutism scale was rated mild, moderate and severe in 5%, 21% and 74%, respectively. Median zolpidem administration was 31 days (range, 2-241) and median maximum dose was 0.25 mg/kg/day (range, 0.10-0.90). Mutism scores improved in 37% (7/19), 53% (8/15) and 64% (9/14) of patients that received zolpidem for at least 48h, 7 and 14 days, respectively. Subjective improvement in communication and interaction was observed in 74% (14/19). Only three patients with mild somnolence and one with initial irritability and insomnia were reported.

CONCLUSIONS
To our knowledge, this is the largest study of patients treated with zolpidem for CMS. A considerable proportion of children improved their language abilities within the first 24-48h, but some patients may even benefit from more prolonged treatment. Most children showed an adequate tolerance with very few side effects. Further studies are urgently needed, preferably within a randomized clinical trial, to find the real efficacy, appropriate dosage, and duration of zolpidem.
MDB-37. RAC1 INHIBITION FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Ayad Nagi , Jangde Nitish 
Published: June 2024

Abstract
Despite considerable advances in identifying genetic and epigenetic abnormalities in medulloblastoma, many patients succumb to the disease. In addition, patients who respond to traditional therapy suffer from cognitive and intellectual deficits. Therefore, there is a dire need to identify novel therapies for treating medulloblastoma. Rho family GTPases are targets in multiple cancers including medulloblastoma. Rho, Rac1 and Cdc42 are essential mediators of cell-cell adhesion and cellular motility signaling, which are dysregulated in medulloblastoma. These GTPases are involved in the regulation of the cytoskeleton, cell migration, cellular proliferation, and developmental signaling. The small GTPase Rac1 has recently been reported as a possible therapeutic target in SHH-medulloblastoma due to its regulation of Hedgehog signaling via the GLI1 and GLI2 transcription factors. We have recently reported that GLI1/GLI2 are in a novel complex that contains the epigenetic regulators UHRF1 and DNMT1. Therefore, Rac1 may play a previously unappreciated role in epigenetic regulation of medulloblastoma by controlling the GLI1/GLI2/UHRF1/DNMT1 complex. To test this, we have utilized a novel brain penetrant Rac1 inhibitor termed GYS32661. GYS32661 treatment of medulloblastoma cells inhibits the GLI1-UHRF1 interaction. Importantly this inhibition of the interaction occurs rapidly suggesting that it is disrupting an early event in SHH signaling. GYS32661 also inhibits actin polymerization suggesting that utilizing this compound may provide a dual mechanism of inhibiting Shh signaling and cellular migration concurrently. GYS32661 is not toxic in animal models and is approximately 50% brain penetrant and therefore is an important clinical candidate for the treatment of medulloblastoma. Our studies identify an essential link between Rac1, Shh signaling, epigenetics, and cellular migration in medulloblastoma.
MDB-40. DEFORMATION-HETEROGENEITY RADIOMIC MEASURES TO RISK-STRATIFY PEDIATRIC MEDULLOBLASTOMA PATIENTS: A PRELIMINARY ANALYSIS
Authors: Ismail Marwa , Um Hyemin , Salloum Ralph , de Blank Peter , Tiwari Pallavi 
Published: June 2024

Abstract

BACKGROUND
A significant challenge in medulloblastoma (MB), the most frequent malignant brain tumor in children, is to accurately identify ‘average-risk’ patients who may benefit from therapy de-escalation without affecting treatment outcomes, from ‘high-risk’ patients. Unfortunately, the current clinical risk-assessment approaches (Chang/molecular stratification) are sub-optimal in reliable risk-stratification in MB. This work evaluates the hypothesis that infiltration in aggressive tumors manifests as deformations (shifts) with larger magnitudes and positive orientations (angles) in the surrounding healthy tissue, on MRI scans, compared to average-risk tumors (smaller shift magnitudes and negative orientations). The proposed imaging marker, complementary with current approaches, may allow for more reliable risk-stratification.

METHODS
T1-weighted MRI scans of MB patients (2–18 years) were collected from Cincinnati Children’s Hospital Medical Center (Site1-training) (n=42) and Children’s Hospital Los Angeles (Site2-testing) (n=45). Preprocessing and annotations for the edema sub-compartment were performed. Scans were mapped to age-specific atlases using diffeomorphic registration and inverse transformations were employed to obtain the deformations. Deformation magnitudes (DefMag) were extracted within equidistant bands outside the edema by calculating the Euclidean norm of deformations, generating a magnitude statistics vector (median, skewness, kurtosis, mean, standard-deviation). Angles/Orientations (Defθ) were computed between deformation vectors and vectors connecting each voxel to the tumor’s centroid, then quantized to 6 intervals, creating an orientation vector per band. Deformation magnitudes and angles (DefMag+θ) were employed with Chang and molecular stratification within regression models for risk-stratification.

RESULTS
Our analysis demonstrated that deformation features, complementing molecular and Chang’s stratification, yielded best results for risk-stratification. Employing DefMag+θ+Chang+molecular on training yielded Concordance-index (CI) of 0.56, p=0.0014 (CI=0.6,p=0.03 testing). DefMag+θ+Chang’s yielded CI=0.64, p&lt;0.0001 on training (CI=0.54,p=0.04 testing). Results were not significant when employing Chang’s or molecular classification alone.

CONCLUSIONS
Our results suggest that radiomic deformation features, complementing clinical and molecular approaches, may enable reliable risk-stratification in pediatric MB.
MDB-41. TARGETING PBK IN GROUP 3 MEDULLOBLASTOMA
Authors: Shahab Shubin W , Kenney Anna M , MacDonald Tobey J 
Published: June 2024

Abstract

BACKGROUND
Group 3 medulloblastoma (MB) remains a challenging diagnosis especially due to a tendency for higher prevalence in infants and to develop frequent relapse. Targeted therapy remains elusive for these patients due to a lack of targetable alterations as well as poor understanding of driver mutations. PBK/TOPK has previously been identified as a hub gene in medulloblastoma and we have recently demonstrated that the LIN28B-PBK axis may be playing a crucial role in Group 3 MB development.

METHODS
Here we utilize transcriptomic profiling to identify pathways regulated by PBK in Group 3 MB to help identify potential vulnerabilities, immunofluorescence and cell viability analysis to calculate drug synergy.

RESULTS
Our analysis demonstrates that PBK knockdown leads to significant down regulation of cell cycle pathway genes. We also demonstrate that combining PBK inhibitor HI-TOPK-032 with the CDK 4/6 inhibitor palbociclib is synergistic in Group 3 MB cells.

CONCLUSION
Our investigations suggest PBK inhibition alone or in combination with other targeted agents may be a useful addition to existing therapy for these hard to treat cancers.
MDB-71. IDENTIFICATION AND DESCRIPTION OF A NOVEL TYPE OF MEDULLOBLASTOMA
Authors: Eckhardt Alicia , Meulenbroeks Chris , Geisemeyer Neal , Bockmayr Michael , Hack Karoline , Sönksen Marthe F , Thomas Christian , Schoof Melanie , Koch Arend , Green Sage , Doss David , Guney Ekin , Perry Arie , Frank Stephan , Kuzman Peter , Ratliff Miriam , Suwala Abigail , Rutkowski Stefan , Hasselblatt Martin , Taylor Michael D , Jones David , Kool Marcel , Schüller Ulrich 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is one of the most frequent high-grade brain tumor types of childhood and adolescence. Based on biology, histology, and its clinical course, MB is a heterogeneous disease with four different molecular types (WNT, SHH, Group 3, and Group 4), which are most reliably distinguishable by their global DNA methylation pattern.

METHODS
We analyzed DNA methylation (n=47), copy number variants, transcriptomic data (n=7) and histology (n=28) of a previously unrecognized type of MB.

RESULTS
As a result of integrating DNA methylation data of &gt;2,600 MB and screening of &gt;140,000 data sets uploaded to the DKFZ brain tumor classifier (www.molecularneuropathology.org), we identified a small group of MB that displayed a homogeneous DNA methylation pattern, which was clearly distinct from previously known MB types. Tumors within this group have also been recognized as a separate methylation class by latest versions of the classifier, which has provisionally been named medullomyoblastoma (MB_MYO). Transcriptomic data were similarly distinct from other MB types. Comparison of these data to various cell types of the developing hindbrain revealed transcriptional similarities to precursor cells of the rhombic lip with signatures of WNT signaling and myogenic differentiation. In line with the latter findings, 2/11 cases with DNA sequencing data harbored hotspot CTNNB1 mutations and 5/28 cases showed a myogenic differentiation based on histology. MYC amplifications were present in 11/47 cases, corresponding to a higher fraction of MYC-amplified tumors compared to all known MB types. Median age at diagnosis in this cohort was 16 years, and five-year overall survival was ~75 %.

CONCLUSIONS
In summary, we describe a novel type of MB identified by DNA methylation profiling that likely needs to be addressed separately during the retrospective analyses of MB patient cohorts, for the design of future clinical trials, and when evaluating targeted therapies.
MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331
Authors: Wright Erin N , Billups Catherine , Li Yimei , Rush Sarah , Salloum Ralph , de Blank Peter 
Published: June 2024

Abstract

BACKGROUND
Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival.

METHODS
We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (&gt;75% or &lt;75% of planned dose) for each agent.

RESULTS
274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received &lt;75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup.

CONCLUSIONS
Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.
MDB-102. CDK8 IS A DEPENDENCY IN GROUP 3 MEDULLOBLASTOMA AND COMBINES WITH BET BROMODOMAIN INHIBITION
Authors: Terrones Isabella , Jagana Hawa , Hathaway Matthew , Hemenway John , Rajendran Ashmitha , Conrad Jay , Evans Myron 
Published: June 2024

Abstract
Medulloblastoma (MB) is the most common pediatric CNS malignancy with varying prognoses depending on subgroup diagnosis. Group 3 MB displays the poorest overall prognosis, specifically in cases characterized by MYC hyperactivation. Current standard treatment can cause lifelong debilitating side effects, therefore the identification of targeted therapeutic agents will be critical in enhancing patient survival and bypassing therapy-induced aftereffects. We utilized the Pediatric Cancer Dependency Map to identify CDK8 as the most striking dependency in MB compared to all other pediatric malignancies. Further analysis revealed dependencies on its cognate cyclin, Cyclin C, and other members of the CDK8 kinase module (CKM). The CKM functions as a transcriptional regulator, phosphorylating RNAPol2 and other transcription factors. Interestingly, CDK8 dependency correlates with MYC amplification status in cell lines suggesting it to be a strong dependency in G3 MB. CDK8 expression, both RNA and protein, is highest in G3 tumors. We depleted CDK8 both genetically and pharmacologically and demonstrated downregulation of MYC expression in tumor cells and decreased cell survival. We next tested the efficacy of a CDK8 kinase inhibitor currently in clinical trials. Treatment with SEL-120 reduced cell proliferation and viability in vitro and inhibited tumor growth in vivo. This effect was limited to G3 models, as SEL120 showed little efficacy in SHH MB. Analysis of gene expression revealed that targeting CDK8 did not affect MYC-dependent gene expression but led to de-repression of differentiation genes regulated by PRC2. We further observed a global de-repression of H3K27me3 in cells treated with CDK8i. Finally, we tested the first ever blood-brain barrier penetrant CDK8i which mimics the activity of SEL-120 and potently synergizes with BETi, which antagonizes MYC signaling. In summary, we have identified and validated CDK8 as a novel target in G3 MB and identified a possible synergistic combination to move forward in clinical trials.
MDB-105. CONSTRUCTION OF AN INTERACTIVE MEDULLOBLASTOMA VISUALIZATION PORTAL FROM MOLECULAR AND CLINICAL DATA DERIVED FROM THREE MULTI-INSTITUTIONAL PROTOCOLS (ACNS0331, SJMB03, ACNS0332) TO COMPARE, CONTRAST, AND INVESTIGATE COHORTS AS A MEANS TO REFINE THERAPY
Authors: Robinson Giles W , Dhanda Sandeep K , Lu Congyu , Sioson Edgar , Gangwani Karishma , Peraza Airen Zaldivar , Li Qian , Smith Kyle S , Billups Catherine , Onar-Thomas Arzu , Northcott Paul A , Zhou Xin 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) patients display a heterogeneous mix of molecular and clinical characteristics that influence tumor behavior and survival. We hypothesized that if these multiple characteristics could be incorporated into an organized, searchable, and interactive dataset, this would advance our understanding and improve treatment of this disease. Consequently, we organized multifaceted datasets into an interactive portal equipped with cutting-edge visualization tools.

METHODS
Clinical and molecular data from the ACNS0331, SJMB03, and ACNS0332 protocols were collated and harmonized. A data dictionary was built to capture demographics, treatment, histology, methylation classification, mutations, chromosomal copy number variations and outcomes. To display the data, a software framework was applied. Five visualization methods were implemented (summary plots, sample view, scatter plots, sample matrix, and survival plots) in an interconnected manner such that these “cross-talk” with each other.

RESULTS
Data from 898 patients with MB were incorporated: 131 WNT, 151 SHH, 220 G3, 396 G4. The portal features enabled the creation of custom cohorts that could be instantly queried by any of the dictionary terms. For example, cohorts could be customized to include only cases with a mutation of the user’s choice and analyzed by molecular group, gender, age at diagnosis, or treatment given. Survival of patients with SHH-MB harboring TP53 mutations could be compared to patients with WNT-MB harboring TP53 mutations. Moreover, the influence of MB subtype (e.g. G34_I-VIII), focal amplifications (MYC, MYCN) and whole chromosome aberration phenotype on survival could be queried across treatment regimens accounting for metastatic status and/or additional variables of the user’s choice.

CONCLUSION
The integration of molecular and clinical data from multiple trials into an interactive visualization data portal presents an unprecedented resource for research and clinical practice. This portal facilitates answering highly specific questions about mutational frequency and patient outcome by molecular and clinical risk factors.
MDB-108. MRI-GUIDED FOCUSED ULTRASOUND BLOOD BRAIN/TUMOR BARRIER DISRUPTION FOR AUGMENTATION OF ANTIBODY DELIVERY TO HIGH-RISK MEDULLOBLASTOMAS
Authors: Maslova Stefanyda , Demir Zehra , Sherlock Thomas , Ak Beyzanur , Yaacoub Serge , Haydar Dalia , Sheybani Natasha 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common pediatric brain cancer, and among its four molecular subgroups, group 3 (G3MB) harbors the worst prognosis (5-year survival rate &lt;50%). Effective treatment of G3MB remains difficult due to disease complexity, its challenging niche within the immunologically- and pharmacologically-privileged central nervous system, and significant risk of long-term developmental deficits due to treatment toxicities. MRI-guided focused ultrasound (MRgFUS) holds the potential to revolutionize care as a non-invasive, non-ionizing approach for spatially precise intervention in G3MBs. Given that the utility of FUS in MBs remains unknown, we implemented FUS-mediated blood brain/tumor barrier disruption (BBB/BTB-D) in a high-fidelity model of G3MB and evaluated its impact on localized antibody delivery – with an eye toward future applications in immuno-oncology.

METHODS
An orthotopic syngeneic model was established via stereotactic implantation of G3MB cells (Gfi1/c-MYC driven) into the cerebellum. G3MB growth kinetics were validated via serial MRI. Multiple protocols for naive cerebellum or G3MB BBB/BTB-D were established with a 1.15 MHz FUS system under 9.4T MRI guidance. Across both settings, mice were sonicated with concomitant intravenous administration of microbubbles and fluorescently-labeled IgG. Safety was confirmed by acoustic emissions monitoring, susceptibility-weighted imaging, histology, and acute activity monitoring. Antibody delivery was evaluated via ex vivo epifluorescence imaging.

RESULTS
Post-contrast T1w-MRI depicted clear evidence of localized BBB/BTB-D in naive and G3MB mice. No damage was noted by imaging or histopathologic analysis, and mice displayed normal cardiorespiratory and motor functions following FUS. FUS conferred significantly increased epifluorescence signal in targeted cerebellum (1.3x) and G3MBs (1.5x) relative to controls, indicating improved antibody access.

CONCLUSIONS
Our findings support the safety and feasibility of FUS BBB/BTB-D in naive and G3MB-bearing cerebellum. We demonstrate that FUS markedly improves antibody penetrance within G3MBs. Ongoing studies are evaluating FUS in combination with novel immunotherapeutic antibodies for G3MB therapy.