bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-47. DEEP LEARNING DECODES NEW SITES OF RNA TRANSLATION IN MEDULLOBLASTOMA
Authors: Clauwaert Jim , Menschaert Gerben , Prensner John 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma, a malignant brain cancer predominantly affecting children, possesses a high propensity for metastasis and is frequently fatal. Through studies on RNA translation, a core biological process, we aim to uncover the disease biology of cancer in order to design therapeutic targets. Yet, the exploration of canonical protein-coding genes has thus far yielded few viable targets in medulloblastoma, where non-canonical open reading frames (ORFs) are increasingly being investigated for their regulatory role.

METHODS
To address the significant challenge in delineating novel translated ORFs in individual cells or tissues, we have designed RIBO-former, a best-of-its-class machine learning model that leverages ribosome profiling data to detect translated open reading frames. Through RIBO-former, we expanded the proteome of healthy prenatal (n=30) and adult (n=42) samples, which are notoriously hard to process due to low read depth and noise, in addition to medulloblastoma cancer tissue (n=8) and cell line (n=15) data.

RESULTS
Across all medulloblastoma cell lines, we determine an initial selection of 3,638 non-canonical ORFs. Unsupervised clustering of the ribosome profiling read counts within these non-canonical ORF regions group samples according to the described subtypes of medulloblastoma cancer, hinting at the significant role these ncORFs play in protein homeostasis. Looking into distinct expression profiles between cell lines with high and low MYC expression, we revealed 201 non-canonical ORFs that are differentially expressed. We evaluate our data through various analyses including testing of which ORFs have a viable sequence context for translation, achieved through another in-house tool (TIS Transformer).

CONCLUSIONS
By taking advantage of advances in machine learning, we were able to uncover new sites of translation in medulloblastoma that can aid the future discovery of therapeutic targets. As such, we were able to find 22 highly promising non-canonical ORFs that show unique expression profiles in relation to MYC in medulloblastoma.
MDB-50. CAR-T CELL-DERIVED EXOSOMES LOADED WITH THERAPEUTIC SIRNA IS A PROMISING TECHNIQUE IN THE TREATMENT OF SUBGROUP 3 MEDULLOBLASTOMA
Authors: Alahdal Murad , Perera Ranjan J 
Published: June 2024

Abstract
Medulloblastoma (MB) is a childhood life-threatening tumor that occurs in the cerebellum. This tumor showed resistance against several types of immunotherapies like anti-PD1, cancer vaccines, monoclonal antibodies (mAbs), and even CAR-T cells. Subgroup 3 MB is the worst threatening subtype that poorly responds to treatment. Interestingly, our data showed that the HLX gene a transcription factor that regulates cell growth is highly expressed in G3-MB and associated with poor prognosis. The siRNA-HLX inhibited tumor growth in vitro and in vivo and promisingly showed long survival in the immunocompetent mouse model. We developed CAR-T-Exosomes that can pass brain-blood barriers (BBB) and deliver therapeutic siRNA to the brain tumor. Further analysis revealed that CAR-T-Exosomes contain T cell cytotoxicity materials that can destroy tumor cells and induce anti-tumor immune response. Promisingly, the expression of HLX was significantly inhibited in the tumor cells and the anti-tumor immune response was enhanced. CAR-T-Exosomes have high safety and can induce anti-tumor response without stimulation of immunotoxicity side effects like cytokine release syndrome (CRS). In this study, we are highlighting anti-EPHA2-CAR-Exosomes as a highly specific type of tumor CAR-T-Exos immunotherapy due to a very low expression of EPHA2 in normal cells and overexpression in medulloblastoma, particularly G3-MB. Therefore, we speculate significant inhibition of tumor growth and activation of CTL effector cells in the tumor microenvironment. This study provides a new biological technique for delivering tumor suppressor RNAs and developing specific anti-tumor immune responses. Indeed, the promising safety of anti-EPHA2-CAR-T cell exosomes compared to cell-based immunotherapy.
MDB-51. PHASE II INTERVENTIONAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF STANDARD AND HIGH-DOSE CHEMOTHERAPY COMBINED WITH CRANIOSPINAL IRRADIATION WITH PROTON THERAPY IN PATIENTS WITH METASTATIC MEDULLOBLASTOMA AND OTHER EMBRYONIC CANCERS: PRELIMINARY RESULTS
Authors: Guidi Milena , Fonte Carla , Tellini Marco , Censullo Marialuigia , Castelli Barbara , Gori Carlotta Gemma , Giunti Laura , Nicola Marco Di , Buccoliero Anna Maria , Caporalini Chiara , Giordano Flavio , Rombi Barbara , Desideri Isacco , Pugi Alessandra , Tortora Katia , Greto Daniela , Genitori Lorenzo , Leo Maria Carmela , Sardi Iacopo 
Published: June 2024

Abstract

BACKGROUND
The high risk medulloblastoma remains a leading cause of cancer-related death in children.

METHODS
A total of 18 patients have been enrolled from February 2018 to May 2022.The median age was 7,5 years (range; 12 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months.

RESULTS
At October 2023, the median follow up was 24 months. After the induction phase 14 patients showed CR, 2 PR, 1PD, 1SD. At subsequent re-evaluations two with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. Patient with SD showed an unchanged state of the disease. During the reporting period two patient died for progression of the underlying disease. At 24 months from the start of treatment the PFS was 75,4 % (95% CI: 34.1% - 87.6%) and at 15 months the OS was 86,1% (95% CI: 68.1% - 99.2%). The principal expected side effects of chemotherapy were hematology toxicity and 58% rate of GH deficiency. Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation. We reported only one case of ototoxicity.

CONCLUSIONS
The use of proton therapy combined with intensive chemotherapy and myeloablative chemotherapy only in selected cases and always before irradiation has proven feasible and effective in the treatment of high-risk patients medulloblastomas and other embryonic tumors.
MDB-59. INTEGRATIVE PROTEO-GENOMICS TO DECIPHER MOLECULAR MECHANISMS UNDERLYING SUBGROUP-SPECIFIC HETEROGENEITY IN MEDULLOBLASTOMA
Authors: Li Yiran , Gudenas Brian L , Smith Kyle S , Lin Hong , North Kelsey C , Soliman Taha , Hadley Jennifer , Batts Melissa , Dhanda Sandeep K , Atkinson Natasha , Mercer Kimberly S , High Anthony , Yuan Zuo-Fei , Wang Xusheng , Peng Junmin , Roussel Martine F , Robinson Giles W , Orr Brent A , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma (MB), an aggressive pediatric brain cancer, poses significant treatment challenges due to its complex disease biology, comprising a collection of discrete molecular subtypes that require different treatment. Although the genomics, transcriptomics, and epigenetic landscapes of biologically distinct MB subgroups are well-annotated and have contributed to enhanced diagnostics and risk stratification, the intersection of these molecular layers with the MB proteome remains poorly defined

METHODS
To overcome this knowledge gap, we sought to create a deep proteomics and phospho-proteomics cohort from a large MB clinical trial cohort (SJMB12), comprising 166 primary patient tumors, complemented with matched DNA methylation, whole-exome sequencing (WES), and RNA sequencing (RNA-seq) datasets. Proteomics data were interrogated using unsupervised computational techniques and evaluated for pathway enrichment and kinase activity. To complement these bulk tumor datasets, we investigated the tumor microenvironment focusing on immune and glial cell populations, using single-nuclei RNA and ATAC sequencing (snRNA-seq and snATAC-seq) for validation

RESULTS
Distinct proteomics subgroups were identified, correlating with established MB clinical subgroups and unveiling previously unrecognized proteomics subgroups. The integration of proteomics with mutational data revealed downstream effects of genetic alterations not evident in the transcriptome, implicating novel molecular mechanisms contributing to disease pathogenesis. Protein-protein interaction networks discovered novel signaling hubs and pathways, highlighting the power of proteomics to detect subgroup-specific drivers of disease that may represent attractive therapeutic vulnerabilities

CONCLUSIONS
Our multi-omics approach applied to a large series of primary MB patient tumors revealed novel mechanisms underlying MB subgroup biology that were previously hidden at the genetic, epigenetic, and transcriptional level. These findings offer a comprehensive, systems biology view of MB pathogenesis, fostering provocative insights that serve as a foundation for future discovery and the development of more effective personalized treatment strategies.
MDB-83. OUTCOMES OF INFANTS AND YOUNG CHILDREN WITH NEWLY DIAGNOSED SHH MEDULLOBLASTOMA TREATED ON THE NEXT CONSORTIUM “HEAD START” 4 PROTOCOL
Authors: Dhall Girish , Stanek Joseph , Blue Megan , Patel Parth , Thomas Diana , Pierson CHristopher , Tamrazi Benita , Mahadeo Kris , Fleming Jessica , Bell Erica , MIller Katherine , Grischow Olivia , Liszkay Thomas , Owen Scott , Hastings Caroline , Tsui Karen , Mazewski Claire , Friedman Gregory , Moertel Christopher , Hanson Derek , Koschman Carl , Brock Guy , Asgharzadeh Shahab , Chakravarti Arnab , Wong Kenneth , Nelson Marvin , Boue Daniel , Biegel Jaclyn , Mardis Elaine , Finlay Jonathan 
Published: June 2024

Abstract

BACKGROUND
Infants and young children with SHH medulloblastoma were demonstrated to have a favorable outcome on “Head Start (HS)” III clinical trial utilizing five cycles of induction followed by one myeloablative high-dose chemotherapy (HDCT) cycle. We present the results of “Head Start” 4 (HS-4) trial where SHH subgroup patients received either three or five cycles of induction based on response followed by one HDCT cycle (similar to HS III).

METHODS
Eligibility included children &lt;6 years of age at diagnosis of localized medulloblastoma and &lt;10 years for patients with disseminated disease. Eligible patients with SHH medulloblastoma were considered “low-risk” and non-randomly assigned to receive three cycles (five cycles if &lt;complete response) of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate) followed by consolidation with single HDCT cycle (thiotepa, carboplatin, etoposide) and autologous hematopoietic stem-cell rescue.

RESULTS
Thirty-nine children with SHH medulloblastoma were enrolled on HS-4 with median age of 2.18 years (range: 0.28-6.88 years). Median follow-up for this cohort is 41 months (range: 18-67 months). Patients with localized SHH medulloblastoma (n=28) had significantly better 3-year event-free (EFS) compared to disseminated patients (n=11): 96.4% (95% CI: 90-100%) and 36.4% (95% CI: 16.6-79.5%), respectively (p&lt;0.0001); however, there was no significant difference in 3-year overall survival (OS) between the two groups: 100% and 90.0% (95% CI: 73.2-100%), respectively (p=0.10). The estimated 3-year EFS for localized SHH subtype 1 and 2 patients was 100% and 95%, respectively (p=0.63). None of trial patients received irradiation prior to progression. All patients, except for four, underwent three cycles of induction. Germline variants were detected in 27% of patients tested (8/30).

CONCLUSION
We report excellent results for young children with localized SHH medulloblastoma when treated with only three cycles (reduced) of induction and single HDCT cycle on HS-4 trial without irradiation. Molecular data will be presented.
MDB-97. INVESTIGATING THE IMMUNOMODULATORY ROLE OF V-DOMAIN IG SUPPRESSOR OF T-CELL ACTIVATION IN AN AGGRESSIVE MURINE MODEL OF PEDIATRIC MEDULLOBLASTOMA
Authors: Perez Natalia Andrea Munoz , Pensabene Juliana , Moziak Kirsten , Yazejian Rita , Zang Xingxing , Loeb David M , Martin Allison M 
Published: June 2024

Abstract

BACKGROUND
Efforts to treat relapsed medulloblastoma patients with immune checkpoint inhibitors aim to enhance T-cell recognition and elimination of tumor cells. However, significant barriers to treatment efficacy include low numbers of infiltrating effector T-cells and paucity of PD-L1 expression in the tumor microenvironment. Thus, identifying alternative immune checkpoints on the predominant immune cells that infiltrate tumors represents an attractive therapeutic alternative.

METHODS
Medulloblastoma tumor cells (mCB MYC DNp53) are orthotopically implanted into the right cerebellum of C57/BL6J mice. Once moribund, tumors are harvested and analyzed by flow cytometry. For in vitro studies, tumor cells are co-cultured at increasing concentrations with naïve splenic CD4+ T-cells, CD3/CD28 beads, and rIL-2 for 5 days and then analyzed by flow cytometry.

RESULTS
Flow cytometric analysis of tumors reveals an abundance of CD45highCD11bhigh tumor-associated macrophages (TAMs), CD45intCD11bint tumor-associated microglia, and CD4+FoxP3+Treg cells. Across all three immune populations, we observe high expression of the inhibitory immune checkpoint, V-domain Ig Suppressor of T-cell Activation (VISTA), with the highest MFI observed on Mø-like TAMs (n=9 tumors; p&lt;0.05). Compared to sham controls, infiltration of Mø-like TAMs is specific to the tumor and express higher levels of MHCII than Mg-like cells (n=14 tumors, 6 sham; p &lt;0.05). Additionally, we find that medulloblastoma tumor cells (mCB MYC DNp53) express VISTA’s binding partner, VSIG3. Tumor cells co-cultured with CD4+ T-cells can inhibit T-cell proliferation in vitro. Preliminary results suggest that addition of 2ug/mL of anti-VISTA blocking antibody (13F3) can rescue proliferation.

CONCLUSIONS
Tumors are highly infiltrated by VISTA+ T-regs and TAMs. These TAMs upregulate MHCII, suggesting that they are presenting antigen in the context of an inhibitory molecule. Furthermore, our in vitro results warrant further investigation into the role of the VISTA/VSIG3 axis in inhibiting T-cells and supports blocking VISTA as a potential strategy to promote T-cell activation and an anti-tumor response.
MDB-98. HISTOPATHOLOGY IS A ROBUST TOOL TO DIFFERENTIATE BETWEEN SHH AND WNT MEDULLOBLASTOMA VERSUS NON-SHH/NON-WNT MEDULLOBLASTOMA: COMPARATIVE ANALYSIS OF HISTOPATHOLOGY, CHROMOSOMAL MICROARRAY, NANOSTRING BASED 22-GENE ASSAY, AND DNA METHYLATION FOR MEDULLOBLASTOMA SUBGROUP ASSIGNMENT ON “HEAD START” 4 CLINICAL TRIAL
Authors: Littrell Mary Elizabeth , Patel Parth , Blue Megan , Biegel Jaclyn , Almira-Suarez Isabel , Hwang Eugene , Miller Katherine , Thomas Diana , Pierson Christopher , Boue Daniel , Mardis Elaine , Finlay Jonathan , Dhall Girish 
Published: June 2024

Abstract

BACKGROUND
“Head Start-4” (HS-4) is a prospective, randomized clinic trial that tailors treatment based on medulloblastoma molecular subgroups (WNT, SHH, Group 3, and Group 4) and response to induction chemotherapy, and compares the efficacy of one versus three (tandem) cycles of myeloablative therapy. Here we compare different methodologies used to distinguish between WNT/SHH medulloblastoma (low-risk arm) and non-SHH/non-WNT medulloblastoma (high-risk arm) during the course of the trial.

METHODS
When HS-4 trial began enrolling patients in 2015, in the absence of a CAP-CLIA certified test for methylation and gene expression profile, we utilized histopathology/immunochemistry (HP/IHC) and chromosomal microarray (CMA) via OncoScanTM (Thermo Fisher) to classify medulloblastoma samples into either WNT, SHH, or non-WNT/non-SHH (Subgroups 3 and 4) at the time of diagnosis. Retrospectively, we performed both NanoString based 22-gene assay and DNA methylation profiling on all patient samples.

RESULTS
We have HP/IHC, CMA, NanoString and methylation profiling for 54 infants and young children with medulloblastoma enrolled on HS-4. While indeterminate result occurred with CMA in three cases and NanoString in two cases, HP/IHC successfully assigned samples to SHH/WNT and non-SHH/non-WNT arms of the study in all 54 cases. We have HP/IHC, CMA and DNA methylation profiling for additional 33 patients. While pathology/IHC was indeterminate in two cases (one WNT and one group 3 MB), remaining cases accurately categorized medulloblastoma methylation subtype as WNT/SHH and non-WNT/non-SHH.

CONCLUSION
Due to the long turnaround time, waiting for medulloblastoma molecular subtype confirmation by DNA methylation array may delay treatment initiation. HS-4 data displays robust prediction of WNT/SHH versus non-WNT/non-SHH molecular subtypes by HP/IHC in comparison to DNA methylation profiling and provides a platform to initiate treatment based on HP/IHC while awaiting molecular information. In addition, these data support relying on histopathology for medulloblastoma subtypes in resource poor countries where methylation profiling is not readily available.
NFS-07. RESPONSE OF A CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMA TO BELZUTIFAN IN A PEDIATRIC PATIENT WITH VON HIPPEL-LINDAU DISEASE (VHL)
Authors: Brandt Cierra M , Zajo Kristin N , Ronsley Rebecca , McAllister Aaron S , Sribnick Eric A , Salloum Ralph 
Published: June 2024

Abstract

BACKGROUND
VHL is a rare cancer predisposition syndrome which affects many organ systems, leading to renal clear cell carcinoma (RCC), pheochromocytoma, retinal angiomas and CNS hemangioblastomas. Surgical resection has traditionally been the mainstay of treatment of VHL-associated tumors. In 2021, belzutifan, a Hypoxia Inducible Factor 2-alpha inhibitor was approved by the Food and Drug Administration for the treatment of VHL-associated RCC based on efficacy in adults. There is a paucity of data in pediatric VHL patients with hemangioblastoma treated with this novel agent. Herein we present such a case.

CASE
A 15-year-old male, diagnosed with VHL caused by a de novo germline mutation at the age of 12, was found to have a left craniocervical junction lesion consistent with a hemangioblastoma on surveillance MRI. The lesion demonstrated growth upon serial imaging but remained asymptomatic. Due to location, the patient was started on medical treatment using once daily oral belzutifan (120mg) continuously, sperm banking was performed prior to initiation of therapy. Hematologic and metabolic laboratory values were monitored, in addition to regular physical examinations including blood oxygen saturation recordings. The first MRI on therapy (3 months after treatment started) demonstrated a major radiologic response using RANO criteria. Treatment has been overall very well tolerated with few treatment-related toxicities limited to CTCAE v5 grade 1 fatigue and grade 2 anemia. No dose reductions or interruptions were required. The patient remains on therapy and has completed 11 months of treatment with further reduction in the size of this target lesion.

CONCLUSION
Hemangioblastomas are preponderantly characterized by their highly vascular nature making surgical resection in some cases arduous depending on location. This unique pediatric case adds to the growing evidence that therapy with belzutifan may be a safe and efficacious option for VHL-associated CNS Hemangioblastomas. Prospective studies in children are needed.
NFS-12. CHOROID PLEXUS CARCINOMA IN PEDIATRIC PATIENTS WITH LI FRAUMENI SYNDROME (LFS) – CLINICAL COURSE AND THERAPEUTIC STRATEGIES
Authors: Perwein Thomas , Nussbaumer Gunther , Filipek Iwona , Piccolo Gianluca , Garrè Maria Luisa , Castellano Serafin , Lassaletta Alvaro , Salvador Hector , Baroni Lorena , Valera Elvis Terci , Scrideli Carlos , Jónsson Ólafur G , Scheinemann Katrin , Kilday John-Paul , Thomas Christian , Hasselblatt Martin , Kordes Uwe R , Adamski Jenny , Benesch Martin , Obrecht-Sturm Denise 
Published: June 2024

Abstract

BACKGROUND
Choroid plexus carcinoma (CPC) is a rare pediatric brain tumor occuring predominantly in infancy. It is commonly associated with the cancer predisposition Li-Fraumeni syndrome (LFS). Management of CPC patients with LFS is challenging and there is no accepted standard treatment. This multinational retrospective analysis aimed to describe the clinical characteristics and outcome of pediatric patients with LFS-associated CPC.

METHODS
We identified 32 patients (male, n=24; median age at diagnosis 2.1 years [range, 0.3-13.2]) with CPC (CNS WHO grade 3), and LFS confirmed by the presence of (likely) pathogenic TP53 germline variants. In 29 patients, LFS was diagnosed after CPC. Seventeen patients (53%) had a positive family history of LFS. CPC arose from the lateral ventricles in 30 patients, 14 had metastases at diagnosis.

RESULTS
Gross total resection was achieved in 21 patients during first-line treatment, as was subtotal resection in 9 and partial resection/biopsy in 2 patients. Thirty-one patients received first-line chemotherapy, with carboplatin/etoposide/vincristine most commonly used (n=9). Eight patients received upfront irradiation (CSI, n=5). Complete remission (CR) and partial remission (PR)/stable disease (SD) was achieved in 20 and 5 patients, respectively. Six patients did not respond to first-line treatment and one patient died during initial surgery. Nineteen patients experienced relapse or progressive disease (PD) with a median progression-free survival of 2.2±1.0 years and with metastases in 79%. At a median follow-up of 1.9 (0.1-17.7) years, fourteen patients were alive in CR (n=10), SD (n=1) or PD (n=3) and eighteen patients died (CPC-related, n=14; other malignancies, n=4). Progression-free and overall survival at 2 and 5 years were 52.2±9.1%/32.8±8.9% and 65.6±8.9%/51.8±10%, respectively.

CONCLUSIONS
LFS-related CPC carries a poor prognosis but should not be considered incurable. Outcomes are not dissimilar to non-LFS-related TP53-mutated CPC. International collaboration is the prerequisite for treatment standardization.