bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-14. TREATMENT AND OUTCOMES OF MEDULLOBLASTOMA: FIRST REPORT FROM ARMENIA
Authors: Hoveyan Julieta , Bardakhchyan Samvel , Asatryan Eduard , Papyan Ruzanna , Hovhannisyan Saten , Grigoryan Henrik , Hovsepyan Shushan , Lalazaryan Nara , Sujyan Paylak , Lazaryan Armine , Mkhitharyan Armen , Hakobyan Lusine , Sargsyan Lilit , Sargsyan Samvel , Salman Zeena , Qaddoumi Ibrahim , Tamamyan Gevorg , Amayiri Nisreen , Bailey Simon 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma accounts for approximately 20% of all primary CNS tumors. Although advanced diagnostic tools and risk-adjusted treatment regimens produce a more than 70% five-year overall survival in HICs the data from LMICs is scarce. This study analyzed the outcome of children with medulloblastoma treated in Armenia.

METHODS
Demographic and treatment data was collected from medical records of pediatric and young adult patients (≤ 25 years) treated in four major centers in Armenia from 1995-2023. Event-free survival and overall survival were estimated using Kaplan-Meier method.

RESULTS
During the study period 41 patients with medulloblastoma were registered (20.7% of primary CNS tumors), male-to-female ratio 1.73:1. The median age at diagnosis was 8 years (range: 0.83-25 years). Most common presenting symptoms were nausea and vomiting (82.5%), headache (75%) and ataxia (50%). Metastatic status was evaluated (spinal MRI and CSF cytology) in 48.8% of patients (25% M+ disease). Risk assessment was available for 30 patients (12 standard-risk and 18 high-risk). All patients underwent surgery, gross-total or near-total resection was achieved in 53.7% of cases. Radiation therapy and chemotherapy given to 63.4% and 58.5% of cases, respectively. Of 8 infants included in this study 4 were treated with chemotherapy only, 3 died without further treatment. Median time from surgery to RT/chemotherapy was 6 weeks. Five-year EFS and OS were estimated 58.3% (95% CI 37.5-71%) and 62.5% (95% CI 43.75-77.1%), respectively. Patients with GTR/NTR had a higher OS than patients with STR (83.3% vs 33.3%, p=0.005). No statistically significant difference in EFS/OS was detected based on risk group, metastatic status, or completion of the protocol.

CONCLUSIONS
OS was lower than expected in this study. Accurate risk assessment and risk-stratified treatment were often lacking during the study period. Compliance to the standardized treatment protocols and multidisciplinary care are needed for improving outcomes of medulloblastoma.
MDB-15. INHIBITING THE IRON-SULFUR CLUSTER TRANSPORTER ABCB7 CAN POTENTIATE CISPLATIN RESPONSE IN PEDIATRIC GROUP 3 MEDULLOBLASTOMAS BY TRIGGERING FERROPTOSIS
Authors: Mahapatra Sidharth , Kanchan Ranjana K , Doss David , Khan Parvez , Nasser Mohd Wasim , Batra Surinder K 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with group 3 tumors (G3MB) being the most aggressive. Uniquely, their aggressiveness is inversely proportional to ferroptosis activation. Intracellularly, these tumors activate iron-sulfur (Fe-S) cluster export and upregulate the expression of glutathione peroxidase 4 (GPX4), the central regulator of ferroptosis. Our main objective was to investigate whether ferroptosis evasion was a targetable driver of aggressiveness in G3MBs that can be inhibited to potentiate classical chemotherapy. We hypothesized that inhibiting Fe-S cluster export would trigger ferroptosis and potentiate cisplatin cytotoxicity in G3MBs.

METHODS
We repressed ABCB7 expression (si-/sh-/KO) in classic G3MB cell lines (HDMB03 and D425) and studied its impact on cancer cell growth, ferroptosis activation, mitochondrial function, and cisplatin cytotoxicity. We further investigated the impact of artesunate, an FDA-approved anti-malarial agent capable of inhibiting ABCB7, on cisplatin action and tumor burden. To rescue cells from iron overload and ferroptosis, we used deferoxamine and ferrostatin-1, respectively.

RESULTS
Silencing ABCB7 resulted in cytoplasmic and mitochondrial iron overload, oxidative stress, and lipid ROS, culminating in ferroptosis and growth retardation. Seahorse studies revealed a switch from oxidative phosphorylation to glycolysis, and TMRM staining revealed loss of mitochondrial membrane potential in ABCB7-silenced cells. Notably, silencing ABCB7 abrogated GPX4 expression and reduced GSH levels. Moreover, ABCB7 silencing reduced the IC50 of cisplatin 2-fold, and ABCB7-silenced cells treated with cisplatin experienced a heightened index of ferroptosis. In vivo, silencing ABCB7 resulted in smaller tumors, dramatically prolonged survival, and potentiated cisplatin action. Artesunate recapitulated ABCB7 silencing by potentiating cisplatin action, reducing tumor burden, and prolonging survival in vivo.

CONCLUSION
The current study illustrates how targeting mitochondrial Fe-S cluster transport can trigger ferroptosis and potentiate cisplatin in G3MBs. Our study also provides evidence for using an FDA-approved drug with the same mechanism of action to treat G3MB tumors.
MDB-18. SYNERGISTIC TARGETING OF CDK8 AND MTOR FOR MYC-DRIVEN MEDULLOBLASTOMA
Authors: Wang Dong , Ritz Caitlin , Luo Yuhuan , Veo Bethany , Pierce Angela , Vibhakar Rajeev 
Published: June 2024

Abstract
MYC-driven medulloblastoma represents a highly aggressive subgroup with poor prognosis and limited treatment options. CRISPR-Cas9 screening across MB cell lines revealed cyclin-dependent kinase 8 (CDK8) as a top dependency for MB growth. Loss of CDK8 significantly decreased both MYC expression and MB growth. Mechanistically, our RNA-Seq analysis demonstrated that CDK8 depletion suppressed ribosome biogenesis and mRNA translation. We found dual role of CDK8 in regulating protein synthesis. Firstly, CDK8-mediated phosphorylation of 4EBP1 was essential for initiating eIF4E-dependent translation and maintaining the typical function of medulloblastoma cells. Secondly, the inhibition of CDK8 led to a reduction in Pol II phosphorylation, resulting in the suppression of gene expression, particularly genes associated with ribosomal function. Targeting CDK8 effectively suppressed cancer stem and progenitor cells characterized by increased ribosome biogenesis activity. We revealed the synergistic effects of the combination inhibition of CDK8 and mTOR in MYC-driven MB cell lines and in xenograft models. Our findings suggest a promising therapeutic approach for MYC-driven MB by targeting CDK8 and mTOR to improve patient outcomes.
MDB-20. TOXICITY PROFILE OF TWO CHEMOTHERAPEUTIC REGIMENS ADOPTED FROM COG A9961 AND ACNS0331 FOR STANDARD-RISK MEDULLOBLASTOMA, A COMPARATIVE STUDY
Authors: Elayadi Moatasem Mohamed Hatem , Elsayed Sarah Magdy , Maher Eslam , sidhom Iman Abdelmokhales , Aboulnaga Sherif Aboulnaga 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is classically treated with surgery, irradiation, and chemotherapy (CTH). Cisplatin-based CTH regimens for standard-risk (SR) MB entail significant toxicities particularly ototoxicity which adversely affect patients’ quality of life. We compared the toxicity profile of two regimens in terms of grade 3 or 4 ototoxicity, hematologic toxicity, hepatotoxicity, nephrotoxicity, and neurotoxicity.

METHODS
SR-MB patients enrolled at Children Cancer Hospital-Egypt (57357) between January 2016 and December 2019 (cohort A) received adjuvant CTH adopted from COG-A9961 protocol (regimen A; 8 cycles of vincristine, cisplatin, and CCNU; cumulative cisplatin dose 600 mg/m2). Starting from January 2020 (cohort B), patients received CTH adopted from ACNS0331 protocol (9 cycles; 2 cycles of vincristine, cisplatin, CCNU followed by 1 cycle of cyclophosphamide and vincristine, for 3 rounds; cumulative cisplatin dose 450 mg/m2). Toxicity grading was done using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

RESULTS
enrolled patients (n=168; cohort A = 112; 67% and cohort B = 56; 33%). Cohort A had significantly higher rate of grade ≥3 ototoxicity at some point during treatment (27% vs 3.6%, p &lt;0.001). Similarly, cohort A had higher grade ≥3 neurotoxicity (26% vs 12%, p =0.046), anaemia and thrombocytopenia (72% vs 56%, p =0.04). Cumulative rate of leukopenia was very high in both cohorts, 98% of all patients, while the rate of febrile neutropenia was much lower in cohort A (38% vs 67%, p &lt;0.001). No toxic deaths were observed in both cohorts. There was no difference in grade ≥3 nephrotoxicity nor hepatotoxicity between the 2 cohorts. The 2-year OS for cohort A and B were 96.4% and 86.6%, respectively, p=0.11. Similarly, the 2-year EFS were 92.9% and 86.8%, p=0.29.

CONCLUSION
adjuvant CTH from ACNS0331 protocol showed a better toxicity profile particularly for ototoxicity compared to A9961 CTH regimen, while maintaining comparable survival.
MDB-22. DECIPHERING MEDULLOBLASTOMA’S MOSAIC: UNVEILING SUBGROUP CLASSIFICATION THROUGH METHYLATION PROFILING
Authors: Ashraf Nader , Kofide Amani Al , Arabi Tarek , Sabbah Belal , Aboian Mariam , Ouban Abderrahman 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma represents the most prevalent malignant brain tumor in children, posing significant treatment challenges despite advances in multimodal therapies. The heterogeneity of medulloblastomas necessitates precise classification to improve therapeutic outcomes. This study explores the utility of genome-wide DNA methylation profiling in categorizing medulloblastomas into molecular subgroups, aiming to refine diagnostic and treatment strategies.

METHODS
This investigation involved the analysis of medulloblastoma samples from pediatric patients at the King Faisal Hospital and Research Centre. We employed the Illumina Infinium 850K EPIC assay to assess the CpG methylation status in six medulloblastoma cases. The methylation data were then compared with immunohistochemical findings to validate the methylation-based subgroup classification.

RESULTS
The Infinium 850K EPIC assay successfully classified all six medulloblastoma cases into the recognized subgroups: WNT, SHH, Group 3, and Group 4. This classification was further supported by immunohistochemical analysis, demonstrating the assay’s robustness in accurately identifying the molecular subtypes. Notably, the assay also distinguished a control case within the cohort, illustrating its potential for widespread clinical application. The study highlights the feasibility of using formalin-fixed, paraffin-embedded (FFPE) tissues, which offers a practical advantage by eliminating the need for fresh tissue samples.

CONCLUSIONS
Genome-wide methylation profiling emerges as a superior method for the classification of pediatric medulloblastomas, facilitating the identification of molecular subgroups with distinct prognostic and therapeutic implications. The ability to utilize FFPE tissues broadens the applicability of this approach, particularly in settings where fresh samples are not readily available. This advancement holds significant promise for enhancing the clinical management of medulloblastoma in pediatric populations.
MDB-28. THE CYTOSKELETON REGULATORS FORMINS CONTROL THE SHH PATHWAY AND ARE INVOLVED IN MEDULLOBLASTOMA TUMORIGENESIS
Authors: Infante Paola , Conenna Marilisa , Adabbo Gennaro , Bufalieri Francesca , Bottero Marta , Severini Ludovica Lospinoso , Bartolini Francesca , Marcotullio Lucia Di 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is a lethal pediatric malignancy of the cerebellum. Among MB’s molecular subgroups, Sonic Hedgehog (SHH) is the most abundant and it is characterized by alterations of key components of the SHH development pathway. However, the molecular mechanisms driving SHH-MB require to further be unveiled to design more effective therapies. Recently, we identified formins, well-known players of cytoskeletal dynamics, as regulators of SHH signaling able to affect SHH-MB growth.

METHODS
Luciferase functional assays, western-blot and RT-qPCR have been performed to analyze the effect of formins on GLI1 (the final effector of SHH signaling) transcriptional activity and expression. Proliferation assays and Brillouin microscopy have been carried out on primary murine SHH-MB cells to test the effect of formins on SHH-MB growth and stiffness.

RESULTS
We demonstrated that formins have a dual role in the regulation of SHH signaling, either positive or negative. The modulation of formins expression in SHH-dependent cell models affect GLI1 transcriptional activity and expression. Moreover, formins show opposite protein expression levels during the development of murine cerebellum, and their modulation impair the proliferation of granule cell progenitors (GCPs), the cells of origin of MB. Interestingly, formins protein levels are highly altered in SHH-MB samples. Notably, the overexpression or the genetic silencing of formins in SHH-MB primary cells from Math1-Cre/Ptc1fl/fl mice significantly impact on the cell proliferation as consequence of modulated GLI1 expression levels and the stiffness of primary SHH-MB cells, thus suggesting that formins could affect tumor cell motility and invasiveness.

CONCLUSIONS
Our findings identify formins as regulators of SHH signaling and illuminate on the role of cytoskeleton in SHH-MB for the design of innovative interventions.
MDB-34. LITHIUM AND RADIATION REDUCE TUMOUR GROWTH IN GROUP 3 MEDULLOBLASTOMA
Authors: Ruchiy Yana , Nunes Daniela , Salinas Casandra , Kanatani Shigeaki , Rosen Gabriela , Zhao Miao , Swartling Fredrik J , Rodrigues Carlos F D , Blomgren Klas , Carlson Lena-Maria 
Published: June 2024

Abstract
Medulloblastoma (MB) is the most common high-grade paediatric brain tumour, accounting for ~20 % of all childhood CNS tumours. It is comprised of 4 distinct molecular subtypes, with Group 3 MB having the worst prognosis with an overall survival of around 50 %. Additionally, current treatments, especially radiotherapy (RT), come at a very high cost for the developing brain and result in permanent complications, including lower IQ, slower processing speed, as well as social problems and lifelong dependency. Lithium has been shown to protect neurogenesis and cognitive functions from the negative effects of RT on the juvenile brain in vivo and can therefore be hypothesised as a preventive treatment strategy to ameliorate these side effects. However, the effects and mechanisms of action of lithium on MB tumours remain largely unknown. In this study, we used GMYC GFP Group 3 MB cells (Mainwaring et al., 2023) to study the effects of lithium and RT in vitro, as well as creating a syngeneic model of Group 3 MB to study those effects in vivo. By using a whole brain immunostaining technique (iDISCO+) and light sheet microscopy, we created a 3D model of every tumour and quantified the tumour volume under different treatment conditions. Our results show that lithium – alone and in combination with radiation – significantly decreases Group 3 MB tumour growth both in vitro and in vivo. Additionally, we studied the transcriptomic changes induced by lithium, validating them through protein analysis that identified Klf4 as a potential effector of its underlying mechanism of action.
MDB-36. 22-HDOHE, A PREDICTIVE MARKER IN CSF OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA TREATED WITH MEMMAT
Authors: Peyrl Andreas , Hagn Gerhard , Stepien Natalia , Senfter Daniel , Madlener Sibylle , Sterba Jaroslav , Lassaletta Alvaro , Leblond Pierre , Nysom Karsten , Haberler Christine , Bileck Andrea , Azizi Amedeo A , Mayr Lisa , Gojo Johannes , Slavc Irene , Gerner Christopher 
Published: June 2024

Abstract

BACKGROUND
With the antiangiogenic metronomic MEMMAT combinatorial regimen, we could achieve sustained responses in a quarter of the patients with previously irradiated recurrent medulloblastoma. There are currently no molecular biomarkers predicting response to MEMMAT treatment for recurrent medulloblastoma. Lipid mediators, including classical arachidonic acid-derived eicosanoids and docosanoids, are locally acting bioactive signaling lipids that regulate a diverse set of homeostatic and inflammatory processes. Before initiation of MEMMAT treatment for relapsed medulloblastoma, we examined the bioactive lipid mediator profile in the cerebrospinal fluid (CSF) of patients and compared it with samples from patients with different neurological disorders, but without cancer.

METHODS
We analyzed CSF samples from 23 patients with relapsed MBL before initiation of MEMMAT treatment and from 12 controls. Lipid mediators were enriched via solid phase extraction and analyzed using liquid chromatography coupled to a high resolution orbitrap Exploris 480 mass spectrometer.

RESULTS
Mass spectrometry-based untargeted oxylipin analysis led to the identification of 98 lipid mediators. Several molecules were downregulated in medulloblastoma samples versus control, such as lipoxin A4 and 14(15)-DiHETE. Non-responders had lower levels of these molecules than responders. Glycodeoxycholic acid and deoxycholic acid were up-regulated in medulloblastoma patients, again with higher levels in non-responders. Remarkably, the docosahexaenoic acid (DHA)-derived 22-HDoHE was specifically identified in the CSF samples of medulloblastoma patients but not in control samples.

CONCLUSION
An oxylipin pattern in CSF might serve as a predictive biomarker signature for response in patients with recurrent medulloblastoma treated with the antiangiogenic metronomic MEMMAT regimen. Our findings advocate for the prospective assessment of CSF-derived lipid markers in future trials for recurrent medulloblastoma.
MDB-42. RADIOMIC TEXTURAL AND MORPHOLOGICAL-BASED FEATURES TO RISK-STRATIFY PEDIATRIC MEDULLOBLASTOMA PATIENTS
Authors: Ismail Marwa , Um Hyemin , Salloum Ralph , de Blank Peter , Tiwari Pallavi 
Published: June 2024

Abstract

BACKGROUND
One key determinate in the treatment pathway for pediatric medulloblastoma (MB), the most frequent malignant brain tumor in children, is accurate risk-stratification. MB tumors are classified as standard- or high-risk based on current approaches (Chang’s/molecular stratification). However, there is still a need for additional attributes towards reliable risk-stratification. This work presents a radiomic-based approach that combines textural- and morphological-based attributes to risk-stratify MB patients. Our rationale is that coupling texture and morphology attributes from the intra-tumoral regions that quantify the heterogeneity and disorderly nature of aggressive tumors can transcend the current clinical approaches in accurately stratifying tumors into high- and standard-risk.

METHODS
T1-weighted MRI scans of 119 MB patients (2–18 years) were collected from Cincinnati Children’s Hospital Medical Center (Site1-n=42), Children’s Hospital Los Angeles (Site2-n=47), and Children’s Hospital of Philadelphia (Site3-n=30), used interchangeably for training and testing. Following preprocessing and performing annotations for the enhancing lesion and edema sub-compartments, 232 textural and morphological features were extracted from each sub-compartment. Namely, 214 textural (gradient, Haralick, intensity, Gabor, Laws, entropy) as well as 34 morphological (4 surface-based (e.g., curvedness and sharpness), 18 global (e.g., roundness, elongation, compactness, flatness)) features were extracted. Features were then fed into Elastic-Net regression models for survival analysis.

RESULTS
Our analysis revealed that texture and morphology features, combined, yielded Concordance index (CI) and p-value of 0.52, 0.0001, respectively, for the enhancing lesion, using Sites1,3 for training, and CI=0.61, p=0.0065 using Site3 for testing. Additionally, for edema, CI and p-value of 0.514, 0.0001 were obtained when employing Sites2,3 for training and CI=0.61, p=0.00096 using Site1 for testing. Results were not significant when using Chang’s or molecular stratification alone for survival analysis.

CONCLUSIONS
Our study shows that radiomic-based morphological and textural features show promise towards reliable MB risk-stratification.
MDB-61. STARVING TUMORS OF POLYAMINES: A NOVEL APPROACH IN TREATING AGGRESSIVE PEDIATRIC MEDULLOBLASTOMA
Authors: Khan Aaminah , Gopalakrishnan Anjana , Liu Jie , Burns Mark R , Tsoli Maria , Ziegler David S 
Published: June 2024

Abstract

BACKGROUND
Polyamines, essential intracellular polycations, govern fundamental cell processes and drive oncogenesis. Our research unveiled the dependency of pediatric Diffuse Midline Gliomas (DMG) on the polyamine pathway (Khan et al.,2021). Disruption of this pathway with the synthesis inhibitor DFMO, and the transport inhibitor AMXT1501, potently inhibited DMG tumors, yielding unprecedented survival in-vivo. We hypothesized that dual polyamine pathway targeting could similarly suppress growth in other aggressive pediatric brain tumors.

METHODS/RESULTS
We analyzed the expression of polyamine pathway regulators in high-risk pediatric brain cancers ZERO precision medicine platform and found elevated expression in medulloblastoma. ODC1, a polyamine synthesis driver, was found to have significant correlation in high-grade gliomas with four key functional tumor states—stemness, cell cycle, hypoxia, and angiogenesis. Medulloblastoma cells were sensitive to treatment with DFMO but showed a compensatory increase in polyamine transporter expression. Conversely, treatment with AMXT1501 increased ODC1 expression. Dual targeting of the polyamine pathway potently and synergistically inhibited cell proliferation and clonogenic potential in Group-3 medulloblastoma cells. Flow cytometric analysis of Annexin V-stained cells showed that treatment with DFMO and AMXT1501 in combination led to induction of apoptosis. Critically, dual polyamine inhibition potently sensitized medulloblastoma cells to the topoisomerase-I inhibitor, SN-38, leading to complete eradication of medulloblastoma cell proliferation and colony formation at nanomolar chemotherapeutic concentrations, with the effect most pronounced in Group-3 medulloblastoma. In triple combination-treated cells, over-representation analysis revealed heightened mitotic DNA damage, macroautophagy, and apoptosis, coupled with diminished neuron/synapse development, glycosylation, and cellular signaling pathways. We are currently testing this treatment strategy in aggressive orthotopic medulloblastoma models.

CONCLUSION
These findings suggest targeting the polyamine pathway as a promising strategy to sensitize aggressive pediatric medulloblastoma tumors to chemotherapy. DFMO/AMXT1501 is in Phase I evaluation for adults (NCT05500508) and advancing to a Phase I/II trial for children through the CONNECT consortium.