bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEDB-20. The outcome of medulloblastoma patients in the 2010-2018 period in Children’s Hospital Zagreb
Authors: Jadrijevic-Cvrlje Filip , Rajacic Nada , Jednacak Hrvoje , Grmoja Tonci , Batos Ana Tripalo , Gjurasin Miroslav , Giljevic Jasminka Stepan 
Published: June 2022

Abstract
This study aims to present the key characteristics of the medulloblastoma patients treated in Children’s Hospital Zagreb and the University Hospital Center Zagreb in Croatia between 2010-2018 period. Croatia has around 145 newly diagnosed pediatric oncology patients annually, including approximately 30 neurooncology patients. We have conducted the retrospective analysis of the hospital records and have collected data on 32 medulloblastoma patients (9 females, 23 males). At the time of diagnosis, the median age was 5,62 (range 0.85-15.86). Before the treatment commencement, we determined conventional risk factors and stratified our patients into standard and high-risk groups (17 standard risk patients, 15 high risk). Qualification for high-risk included metastatic disease, postoperative local residual disease greater than 1.5 cm2, confirmed myc/nmyc amplification in the tumor tissue, and the large cell/anaplastic tumor subtype (p53 positive). The methods of molecular diagnostics were not available at the time. The patients that received solely postoperative chemotherapy were younger than three years. Children younger than five suffering from desmoplastic tumor subtype also received intraventricular methotrexate (Ommaya). High-dosage chemotherapy with autologous stem cell transplantation failed to treat metastatic infant medulloblastoma (2 patients with a lethal outcome). The rest of the patients received craniospinal irradiation, followed by adjuvant chemotherapy. According to the Kaplan-Meier survival analysis, the 5-year overall survival is 65,6 % (40% in the high-risk group and 88% in the standard-risk group). In addition, 5-year event-free survival is 59,4 % (33% in the high-risk group and 82,4% in the standard-risk group). None of the patients developed a secondary malignant disease during the follow-up. Conventional characteristics that determine standard-risk group affiliation are reliable, leading to a satisfactory treatment outcome. The results of the high-risk group treatment are poor necessitating modification treatment approach within clinical trials.
MEDB-21. SOX2+ cells: the perpetrators of medulloblastoma relapse
Authors: Swiderska-Syn Marzena , Mir-Pedrol Julia , Rodriguez-Blanco Jezabel 
Published: June 2022

Abstract
Pediatric brain tumors are the number one cause of cancer-related death in children, with medulloblastoma being the most common type. While survival in patients with medulloblastoma has dramatically improved since chemotherapy was added to standard of care protocols, still 30% of tumors will recur. As recurrent disease in medulloblastoma patients in considered uniformly lethal, it is key to identify the cells allowing tumor relapse, and their targetable regulators. By analyzing single cell transcriptomic data, we uncovered a population of SOX2 labeled astrocyte like cells resistant to SMO inhibitors in clinical trials. Using SOX2-enriched medulloblastoma cultures, we observed that SOX2+ cells rely on non-canonical GLI signaling to propagate medulloblastoma. Therefore, in vivo inhibition of SHH signaling using functionally different GLI inhibitors depleted the SOX2+ cell pool, what led to less aggressive tumors that lacked the ability to further engraft. Stressing the translational relevance of our findings, a clinically relevant GLI inhibitor not only exhausted SOX2+ cells driving tumor relapse, but increased overall survival in mice harboring medulloblastoma. Our results emphasize the importance of using targeted therapies that deplete SOX2+ cells to prevent medulloblastoma recurrence.
MEDB-24. Tumour secreted extracellular matrix predicts survival and influences migration and cell death in SHH medulloblastoma 3D models
Authors: Johnson James , Linke Franziska , Merry Cathy , Coyle Beth 
Published: June 2022

Abstract
Medulloblastoma is the most common malignant paediatric brain tumour. Four molecular sub-groups exist (WNT, Sonic hedgehog (SHH), Group 3 and Group 4), each associated with different patterns of metastasis and chemoresistance. We have shown that within these sub-groups further clinically relevant sub-types exist, characterised by differential expression of extracellular matrix (ECM) proteins. For example, good overall survival in two-thirds of SHH sub-group patients is associated with the expression of specific ECM proteins. Our aim here is to further characterise these ECM components in SHH medulloblastoma and to determine how they confer better overall survival in this sub-group. Using a combination of 3D OrbiSIMs and immunohistochemical staining we have identified, that when grown in 3D hyaluronic acid hydrogels or as spheroids, SHH medulloblastoma cell lines form an ECM shell-like structure composed of laminin, collagen and lumican. In addition, scRNAseq of SHH hydrogel nodules revealed sub-group specific clusters of cells with high levels of ECM interaction and adhesion. We therefore hypothesise that ECM interaction restricts SHH tumour invasion and metastasis through this shell-like structure. To understand how this ECM shell-like structure potentiates better survival in SHH medulloblastoma we have created a CRISPRcas9 laminin knockout SHH medulloblastoma cell line. 3D culture of the laminin knockout cell line demonstrated that laminin is essential for the formation of 3D cell structures as well as migration in SHH medulloblastoma. Furthermore, we have identified that apoptosis is increased in the laminin knockout SHH cell line, suggesting that apoptosis-targeted therapeutics may represent a beneficial treatment option for SHH patients whose tumours exhibit this ECM shell. In summary, tumour-secreted ECM plays a major role in SHH medulloblastoma progression. Expression of laminin, collagen or lumican can be used to classify SHH patients into low and high-risk groups with different therapeutic outcomes and treatment options.
MEDB-32. Reducing treatment-related toxicity for children with WNT-activated medulloblastoma
Authors: Taylor Jessica , Toker Joseph , Masih Katherine , Nathan Erica , Terranova Sabrina , Gilbertson Richard 
Published: June 2022

Abstract
WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care (SOC) surgical resection, radiotherapy, and chemotherapy. Unfortunately, while curative, this treatment is associated with major, long-term, debilitating motor, developmental, and neuroendocrine side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. Similarities have been demonstrated between cancer cell lysosomes and those of patients with Niemann-Pick, a lysosomal storage disease characterised by lysosomal fragility and sphingomyelin accumulation. A class of drugs known as Functional Inhibitors of Acid Sphingomyelinase (FIASMAs), increase lysosomal sphingomyelin and destabilise the cancer cell’s more fragile lysosomal membrane which leads to the induction of cell-death pathways via lysosomal membrane permeabilisation. Loratadine, an antihistamine with high FIASMA activity, consistently induced lysosomal membrane permeabilisation, leading to increased cell-death, in our panel of mouse and human WNT-medulloblastoma lines. Loratadine exhibited no detrimental effect on normal mouse embryonic stem cells from the lower rhombic lip – the putative cell of origin in WNT-medulloblastoma. Luciferase-expressing mouse WNT-medulloblastoma cells were orthotopically implanted into CD1-nude mice and monitored for tumour development via bioluminescent imaging. Upon tumour engraftment, mice were subjected to reduced SOC (radiotherapy and adjuvant vincristine) plus a clinically relevant dose of loratadine. Response and survival were compared to mice treated with full SOC (radiotherapy, vincristine, cisplatin, and etoposide). Mice treated with 2mg/kg/day of loratadine following reduced SOC demonstrated increased survival when compared to those treated with full SOC (p=0.02) along with a significant reduction in weight loss during treatment (p=&lt;0.0001). This work suggests that loratadine, or other FIASMA compounds, may be good alternative adjuvant therapies for WNT-medulloblastoma. Using less toxic adjuvants could improve long-term outcomes through reducing therapeutic related toxicities for children with this devastating disease.
MEDB-36. Clinical and molecular heterogeneity withinMYC andMYCN amplified medulloblastoma
Authors: Schwalbe Edward , Lindsey Janet , Hill Rebecca , Crosier Stephen , Ryan Sarra , Williamson Daniel , Kool Marcel , Milde Till , Pfister Stefan , Bailey Simon , Clifford Steven 
Published: June 2022

Abstract
MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma. Their overall association with a poor prognosis has supported their adoption as high-risk disease biomarkers in trials. However, emerging evidence suggests that certain patients with MYN/MYCN focally-amplified tumours can achieve long-term survival and therefore may suffer unnecessary late-effects associated with intensified therapies. To investigate this heterogeneity, we characterised the molecular and clinico-pathological features of curated cohorts of MYC (n=64) and MYCN (n=95) amplified tumours, drawn from &gt;1000 diagnostic cases, and assessed their associations with disease outcome. Within the MYCN-amplified cohort, survival was related to molecular group; patients with MYCNGrp3 or MYCNGrp4 tumours with no other clinico-pathological risk factors (subtotal resection (STR), metastatic disease, LCA pathology) were intermediate-risk (n=25;70% 5-year PFS). In contrast, a very-high-risk group was defined by positivity for MYCNSHH, STR and/or LCA (n=64;32% 5-year PFS). 22/35 assessable MYCNSHH harboured TP53 mutations; 9/12 with data were germline. MYCGrp3 represented the majority (46/58; 79%) of molecularly-grouped MYC-amplified tumours. Importantly, while radiotherapy receipt conferred a modest survival advantage, for MYC-amplified tumours with additional clinico-molecular risk factors (LCA, metastasis, STR, Grp3), survival was dismal, irrespective of radiotherapy receipt. A very-high-risk group of MYC-amplified tumours was identified (n=51;10% 5-year PFS), defined by positivity for ≥1 additional risk factors (STR, LCA and/or metastasis). Alternatively, membership of subgroups II/V defined a smaller, very-high-risk patient group (n=28;7% 5-year PFS). Long-term survival was seen in the majority of remaining MYC-amplified tumours negative for these specified features (61% 5-year PFS; high-risk). MYC and MYCN-amplified medulloblastomas are biologically heterogeneous with diverse clinical outcomes. Molecular subgroup assignment and established clinical features are critical for their improved stratification. Patient subgroups identified may be eligible for therapy de-escalation; in contrast, the very-high-risk patient groups are incurable using current therapies and urgently require novel experimental treatment strategies upfront.
MEDB-39. Oncogenic mechanisms underlying GLI2-amplified medulloblastoma
Authors: Murad Najiba , Zhang Jiao , Liu Xiao , Tao Ran , Taylor Michael , Pei Yanxin 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB, and among them, the subtype of GLI2-amplified SHH-MB associated with P53 mutations has the worst prognosis and a poor survival rate; the 5-year survival rate is &lt;30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover, the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting results, we hypothesize that GLI2-driven MB originates from a specific cell population of Math1+ GCPs and in a particular spatiotemporal window during cerebellar development, and targeting MAPK/MEK/ERK pathway may represent a novel effective approach to treating GLI2-amplified MB.
MEDB-40. RUNNING FOR INCLUSION IN SIOPE PNET5 MB
Authors: Massimino Maura , Boschetti Luna , Minasi Simone , Erbetta Alessandra , Chiapparini Luisa , Mastronuzzi Angela , Miele Evelina , Barra Salvina , Scarzello Giovanni , Cavatorta Claudia , Antonelli Manila , Gandola Lorenza , Buttarelli Francesca Romana 
Published: June 2022

Abstract
Enrolling medulloblastoma(MB) patients in the PNET5 protocol is a daily problem in Italy; since June 2015, 59 cases have been enrolled in 13 centres. So far, 44 of the 103 patients claiming for eligibility did not enter the protocol: 13 metastases, 5 for residual, 20 having exclusion criteria, 4 insufficient frozen material, 2 failure to comply with the correct procedures. No case was lost due to delayed centralization, which is respected even with committing weekends; review of the radiation plan was performed on Saturday for 2 cases, and radiotherapy began on the same day. We made some procedural changes to meet expected deadlines; each local centre notifies the national coordinator of a possible case's existence at MRI diagnosis, of the expected surgery date as well as its realization. MRI imaging is reviewed within 2 days after centralization. Paediatricians notify the national coordinator and pathology/biology reference centre of the MB diagnosis; the shipment of frozen tissue, blood and FFPE is booked. A slot is reserved to priority perform the central pathology review, as well as central molecular diagnosis of genetically defined subgroup (WHO classification) upon receipt of the frozen material. Upon receipt of the FFPE and frozen material, the national reference centre undertakes a double-check with the national coordinator and the local treatment centre to validate the eligibility. Within the 7th day from the receipt of the material: IHC, MYC/MYCN, Monosomy 6, beta-catenin mutation and methylation array are performed. Priority execution of somatic (blood control) sequencing of the PTCH, SUFU, and TP53 genes is also triggered for SHH-activated MB, with the deadline on the 15th day. So far we have had 99% agreement between molecular subgrouping and methylation array. CONCLUSIONS: PNET5 requirements are multiple and changing over time; difficulties may and must be overcome by mutual fast collaboration.
MEDB-41. Identifying a subgroup of patients with early childhood sonic hedgehog-activated medulloblastoma with unfavorable prognosis after treatment with radiation-sparing regimens including intraventricular methotrexate
Authors: Tonn Svenja , Obrecht Denise , Sill Martin , Spohn Michael , Milde Till , Pietsch Torsten , Bison Brigitte , Juhnke Björn-Ole , Struve Nina , Friedrich Carsten , von Bueren André O , Gerber Nicolas U , Benesch Martin , Jäger Natalie , Kool Marcel , Korshunov Andrey , Schüller Ulrich , Pfister Stefan M , Rutkowski Stefan , Mynarek Martin 
Published: June 2022

Abstract
PURPOSE/METHODS: Clinical and molecular risk factors in 142 patients &lt;5 years with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were investigated. Patients were diagnosed between 1992 and 2020 and treated with radiation-sparing approaches, 131 with intraventricular methotrexate. 14 patients with metastatic disease received high-dose chemotherapy. DNA methylation profiles of 77 sonic hedgehog (SHH)-activated medulloblastoma were reclassified according to the Heidelberg Brain Tumor Classifier Version 12.3. RESULTS: While metastatic disease or incomplete resection did not impact progression-free survival (PFS) and overall survival (OS), patients with MBEN had superior outcomes to DMB (5-year PFS 93% vs 71%, p=0.004; 5-year OS 100% vs 90%, p=0.026). Older patients had less favorable PFS (5-year PFS [&gt;3 years] 47% vs 85% [&lt;1 year] vs 84% [1-3 years], p&lt;0.001). No TP53 mutations were detected (n=47). DNA methylation classification identified three subgroups: SHH-1v12.3 (n=39), SHH-2v12.3 (n=19), and SHH-3v12.3 (n=19), with distinct cytogenetic profiles (chromosome 2 gains in SHH-1v12.3, very few alterations in SHH-2v12.3, and chromosome 9q losses in SHH-3v12.3), age profiles (median age [years] SHH-1v12.3: 1.7, SHH-2v12.3: 0.9, SHH-3v12.3: 3.0, p&lt;0.001), and histological distribution (SHH-2v12.3: 74% MBEN, SHH-1v12.3/SHH-3v12.3: 77%/79% DMB, p&lt;0.001). PFS was more unfavorable in patients with SHH-3v12.3-medulloblastoma (5-year PFS 53% vs 86% [SHH-1v12.3] vs 95% [SHH-2v12.3], p=0.002), which remained the only risk factor on multivariable Cox regression for PFS. OS was comparable (5-year OS 94% [SHH-3v12.3] vs 97% [SHH-1v12.3] vs 100% [SHH-2v12.3], p=0.6). 8/9 patients with SHH-3v12.3-medulloblastoma received radiotherapy at relapse (6 craniospinal, 2 local [1 Gorlin syndrome, 1 BRCA2 germline mutation], 1 no radiotherapy [Gorlin syndrome]). CONCLUSION: We identify patients with an increased risk of relapse when treated with radiation-sparing approaches among children with early childhood SHH-medulloblastoma. If these tumors differ from SHH-3-medulloblastoma typically described in older children remains to be verified. Treatment recommendations need to consider cancer predisposition syndromes.
MEDB-47. CD4+ T cells restrict medulloblastoma growth and dissemination
Authors: Eisemann Tanja , Wechsler-Reya Robert 
Published: June 2022

Abstract
The immune system serves as a powerful defense not only against pathogens and parasites but also against neoplastic cells. Emerging immunotherapies that boost the activity of tumor-reactive immune cells or counteract immune suppressive mechanisms have shown promising effects in certain cancer types. However, the success of immunotherapy for brain tumors has been limited, highlighting the need for a better understanding of the immune microenvironment. Our preliminary studies have shown that T cells critically affect tumor growth in mouse models of the pediatric brain tumor medulloblastoma. In particular, depletion of CD4+ T cells results in more aggressive growth of medulloblastoma cells and allows these cells to metastasize to the spinal cord. To test whether CD4+ T cells can recognize and attack tumor cells directly, we generated MHC class II knockout tumors. Surprisingly, depletion of CD4+ cells still enhanced tumor growth and metastasis. These results suggest that CD4+ T cells regulate medulloblastoma growth independently of MHC II on tumor cells. We hypothesized that CD4+ T cell may not directly kill tumor cells but recruit and activate another effector immune cell type that eliminates tumor cells. As CD4+ T cells have a well-studied helper function for CD8+ T cells, we examined whether their anti-tumoral function relies on the activation of cytotoxic CD8+ T cells. The depletion of CD4+ T cells still resulted in advanced growth of MHC class I-deficient, and thus CD8+ T cell resistant, tumor cells indicating that CD4+ T cells counteract tumor growth in a CD8+ T cell-independent manner. Ongoing studies are aimed at elucidating the mechanisms by which CD4+ T cells regulate medulloblastoma growth, including the antigen-presenting cells that activate them and the effector cells responsible for killing tumor cells. These studies will advance our understanding of the immune microenvironment in medulloblastoma and allow us to design more effective therapies.
MEDB-52. Organoids as preclinical models to improve and personalize disease outcome for sonic hedgehog medulloblastoma
Authors: Odé Zelda , Maas Joris , Roosen Mieke , Stathi Phylicia , Federico Aniello , Mack Norman , Schwalm Benjamin , Bunt Jens , Kool Marcel 
Published: June 2022

Abstract
Four main medulloblastoma (MB) molecular subgroups are known, including the sonic hedgehog (SHH) subgroup, which represents ~25% of MB cases. The 5-year overall survival of SHH-MB is ~80%. However, survival between patients is highly diverse and dependent on the driver mutation(s) of the tumor. Patients with TP53 mutated tumors (often accompanied with MYCN and/or GLI2 amplifications) don’t respond well to current therapies and have a 10-year overall survival below 20%. Therefore, there is a need for new and more tailored therapies for these patients. In this study we aim to screen patient-derived organoid models of TP53-mutated SHH MB with a library of ~200 different compounds. We have optimized the cultures of two PDX-derived and one patient-derived organoid line in vitro. The lines will be screened in a high-throughput manner and the best hits and combinations will be validated in corresponding in vivo PDX models. To further assess the role of specific mutations in therapy outcome of TP53-mutated SHH MB, cerebellar organoids generated from human iPSCs were genetically modified with overexpression of dominant-negative P53 (DNP53) alone or in combination with MYCN and/or GLI2. Introduction of DNP53 and MYCN overexpression in cerebellar organoids at day 28/35 leads to the outgrowth of a Ki67-positive proliferating mass after three weeks, indicating tumor growth. Further analyses are ongoing to see how they match SHH-MB patient tumors. These genetically engineered organoid models may elucidate the role of specific mutations in therapy response and/or resistance. In addition, as tumors in these genetically engineered cerebellar organoids arise in a microenvironment of normal cerebellar cell types, initial safety of drugs on cerebellar cells can be assessed. In conclusion, different organoid models of TP53-mutated SHH MB will enable us to find more effective treatments and to better understand how to treat patients with different mutation combinations.