Letteratura scientifica selezionata sul tema "Medulloblastoma paediatric"
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Articoli di riviste sul tema "Medulloblastoma paediatric":
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Tan, Geok Chin. "Molecular Subtyping of Paediatric Medulloblastoma by Immunohistochemistry". Medicine & Health 15, n. 2 (31 dicembre 2020): 124–39. http://dx.doi.org/10.17576/mh.2020.1502.13.
Abstract (sommario):
Four core molecular subgroups of medulloblastomas have recently been introduced disparate by their transcriptional profile, all of which have different prognostic value. We aimed to determine the histological variants and molecular subtypes of medulloblastomas by immunohistochemistry in our population, and to correlate that with clinicopathological parameters. Seventeen patients aged four-month to 14.3 years diagnosed with medulloblastoma were recruited from year 2002 to 2017. All medulloblastomas were assigned to various histological variants and molecular subgroups by immunohistochemistry surrogate markers (YAP-1 and beta catenin). They were then correlated with clinicopathological parameters and outcomes. Classic histology (76.5%) was the commonest, followed by large cell/anaplastic (LCA) (17.6%) and desmoplastic/nodular (DN) variants (59%). The most frequent molecular subgroup was non-SHH/WNT tumours (64.7%), seconded by SHH tumours (35.3%). Among the SHH tumours, 66.7% was classic histology and the remaining 33.3% was LCA variant. Interestingly, one DN histology demonstrated YAP-1 and beta catenin immunonegativity, denoting non-SHH/WNT molecular subgroup. Majority (88.2%) medulloblastomas were at midline 4th ventricle location, including DN variant. Estimated three-year diseasefree- survival (DFS) and overall-survival (OS) was 60% and 86.7%, respectively. Age <3 years at diagnosis, tumour size >5 cm, LCA histology and high risk group were inversely correlated with DFS, with early relapse. Infant <3-year-old had worse OS. Other factors had no significant impact on DFS and OS. We had demonstrated the feasibility of simple immunohistochemistry-based surrogate markers (YAP-1 and beta catenin) to stratify medulloblastomas into distinct molecular subtypes. Prognostic and predictive values of YAP-1 immunomarker in medulloblastomas however await further investigations.
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Abbas, Zahra, Jessica Buck, Mathew Ancliffe, Clara Andradas Arias, Meegan Howlett, Hilary Hii, Terrance Johns, Siddhartha Mitra, Nicholas Gottardo e Raelene Endersby. "MODL-18. Enhancing anti-CD47 mAb efficacy with radiotherapy for Group 3 paediatric medulloblastoma in preclinical models". Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i172—i173. http://dx.doi.org/10.1093/neuonc/noac079.641.
Abstract (sommario):
Abstract Medulloblastoma is the most common paediatric brain cancer. Standard treatment approaches, including craniospinal irradiation (CSI), can result in severe lifelong side effects and have not changed for decades resulting in a stagnation of survival outcomes for children with aggressive medulloblastoma. Despite successes in other cancers, no immunotherapies have been approved for use in paediatric medulloblastoma. Unlike other solid tumours, medulloblastomas are myeloid dominant, and immunotherapies must be rationally designed with the tumour microenvironment in mind. Anti-CD47 antibody therapy activates macrophages against cancer cells by blocking anti-phagocytic signalling mediated by CD47-SIRPa ligation and has shown preclinical efficacy in brain cancer models. We have developed preclinical CSI protocols that mimic clinical treatment response using a small animal radiotherapy platform. We show that CSI depletes adaptive immune cells in the brain, increasing the proportional abundance of myeloid cells, suggesting an opportunity to combine radiation with myeloid-targeted immunotherapy. We show that anti-CD47 therapy is ineffective as a single agent against a patient-derived xenograft model of Group 3 medulloblastoma (SJ_MB002), and that while the CSI protocol causes temporary tumour regression, the combination of anti-CD47 with CSI results in marked and persistent tumour regression. To enhance our preclinical evaluation of CSI and anti-CD47, we have developed new mouse models that more accurately reflect the developing microenvironment of children and show that immune populations in paediatric brain are distinct from adult mouse brain. Future work will elucidate the mechanisms by which radiotherapy alters the medulloblastoma microenvironment to enhance the anti-tumour activity of myeloid immune cells in the brain. By evaluating this novel combination of immunotherapy with standard medulloblastoma treatments, in age-appropriate models, our research should facilitate the rational selection and rapid translation of optimised treatment combinations for future medulloblastoma clinical trials.
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Lasseini, Ali, Aliyu Muhammad Koko e Ashafa Birnin Gwari Isa. "Demographic and Interventional Pattern of Pediatric Brain Tumors Managed at UDUTH Sokoto: A Decade Review". International Journal of Research and Review 10, n. 10 (21 ottobre 2023): 374–77. http://dx.doi.org/10.52403/ijrr.20231045.
Abstract (sommario):
BACKGROUND: The Epidemiologic pattern of childhood brain tumours during the past ten years in Usmanu Danfodiyo University Teaching Hospital Sokoto was reviewed. OBJECTIVE: The aim of the study is to describe the epidemiological profile, diagnoses and pattern of paediatrics brain tumour. METHODS: This is a retrospective study analyzing the demographic profile, clinical diagnoses and operative interventions of paediatric neurosurgical patients managed at our center over a period of 10years, from January 2007 to December 2016 with Brain Tumour. RESULT: A total of 81 patients had operative interventions during the study period. Forty-three (43) patients were males representing 53.1%, thirty-eight (38) were female with male to female ratio 1.1:1; the majority of them were between 5 and 8 years of age thirty (37%) and most of them are infratentorial forty-eight (48) accounting for 59.3%. Medulloblastoma was the predominant diagnosis accounting for eighteen cases (18) 22.2%. Ventriculo-peritoneal shunt insertion was the commonest procedure performed representing 44.4%. CONCLUSION: Infratentorial tumours are the commonest paediatric tumours seen in our center, with medulloblastoma accounting for the majority of cases. VP shunt is the commonest neurosurgical intervention on paediatric brain tumor patients Keywords: Paediatric; Brain tumor; Medulloblastoma; Infratentorial; Supratentorial; Ventriculoperitoneal shunt
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Tang, Phua Hwee, Sharon Low, Enrica Tan e Kenneth Chang. "IMG-01. DWI RATIO OF HISTOLOGICAL MOLECULAR SUBTYPES OF PAEDIATRIC MEDULLOBLASTOMAS". Neuro-Oncology 22, Supplement_3 (1 dicembre 2020): iii354. http://dx.doi.org/10.1093/neuonc/noaa222.337.
Abstract (sommario):
Abstract AIM To evaluate if diffusion weighted imaging (DWI) ratio on MRI is able to distinguish between the histological molecular subtypes of paediatric medulloblastomas. MATERIALS AND METHODS From 2002 to 2017, 38 cases of medulloblastoma with preoperative MRI available had histological subtyping performed with NanoString nCounter technology. The medulloblastomas were classified into 4 subtypes. There were 3 Sonic Hedgehog (SHH), 9 Wingless (WNT), 12 Group 3 and 14 Group 4 subtypes. Single operator manually outlined solid non-haemorrhagic component of the tumour on DWI images with largest axial tumour cross sectional diameter, correlating with the other MRI images (T1 pre and post contrast, SWI/GRE, FLAIR) to identify areas of haemorrhage. The same operator also drew region of interest to identify normal cerebellar tissue on the same axial images on which the tumour was outlined. All MRI images were obtained from the department’s Radiological Information System Picture Archiving and Communicating System (RIS PACS). DWI ratio for each case was obtained by dividing the values obtained from tumour by normal cerebellar tissue seen on the same axial image. RESULTS DWI ratio of all medullloblastomas is 1.34 +/- 0.18. DWI ratio of SHH subtype is 1.43 +/- 0.07. DWI ratio of WNT subtype is 1.40 +/- 0.07. DWI ratio of Group 3 subtype is 1.31 +/- 0.25. DWI ratio of Group 4 subtype is 1.30 +/- 0.17. There is no significant statistical differences in the DWI ratio between the various subtypes. CONCLUSION DWI ratio of medulloblastoma is unable to distinguish between the 4 medulloblastoma subtypes.
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Grosshans, David R. "Proton therapy for paediatric medulloblastoma". Lancet Oncology 17, n. 3 (marzo 2016): 258–59. http://dx.doi.org/10.1016/s1470-2045(15)00217-x.
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Burki, Talha Khan. "Postoperative radiotherapy for paediatric medulloblastoma". Lancet Oncology 17, n. 9 (settembre 2016): e381. http://dx.doi.org/10.1016/s1470-2045(16)30390-4.
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Padovani, L., G. Horan e T. Ajithkumar. "Radiotherapy Advances in Paediatric Medulloblastoma Treatment". Clinical Oncology 31, n. 3 (marzo 2019): 171–81. http://dx.doi.org/10.1016/j.clon.2019.01.001.
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McLendon, Friedman, Fuchs, Kun e Bigner. "Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study". Histopathology 34, n. 2 (febbraio 1999): 154–62. http://dx.doi.org/10.1046/j.1365-2559.1999.00577.x.
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Wong, Gabriel Chun-Hei, Queenie Junqi Huang, Manix Fung Man Poon, Nellie Yuk-Fei Chung, Queenie Hoi-Wing Wong, Zhen-Yu Zhang, Zhi-Feng Shi et al. "PATH-32. CLINICAL AND MUTATIONAL PROFILES OF ADULT MEDULLOBLASTOMA GROUPS". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii171. http://dx.doi.org/10.1093/neuonc/noaa215.713.
Abstract (sommario):
Abstract INTRODUCTION Adult medulloblastomas are clinically and molecularly understudied due to their rarity. METHODS We studied a cohort of 101 adult medulloblastomas grouped by Nanostring assay. We performed targeted sequencing on exonic regions of 69 genes implicated in medulloblastoma, and Sanger sequencing for TERT promoter hotspot mutations. RESULTS Median age was 27 (range 19-63), and 9.5% were metastatic at diagnosis. SHH accounted for 50% of cases. Unlike previous studies, Group 3 comprised a significant proportion (14%) of adult medulloblastomas, comparable to WNT (19%) and Group 4 (18%). Median follow-up was 51.1 months. Median OS and PFS were 102 and 99 months respectively. In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in adults, for both OS (p=0.956) and PFS (p=0.162). Most frequently mutated genes were TERT (including promoter, mutated in 35% cases), chromatin modifiers KMT2C (32%) and KMT2D (31%), TCF4 (31%), PTCH1 (26%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. 5 WNT cases harboured concurrent CTNNB1 and PTCH1 mutations. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and seldom downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 71% of adult SHH patients, and were restricted to this group. Adult Group 3 patients lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 patients had recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%) in adult medulloblastomas. CONCLUSIONS We identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their treatment and risk stratification. Importantly, molecular groups were not prognostic in adult medulloblastoma, TP53 mutations were enriched in adult WNT, and MYC amplifications were absent in adult Group 3.
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Allen, Joseph, Susannah Entwistle, Beth Coyle e Alistair N. Hume. "MDB-46. ARE RAB40 SMALL GTPASES DRIVERS OF MEDULLOBLASTOMA PATHOGENESIS?" Neuro-Oncology 26, Supplement_4 (18 giugno 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.495.
Abstract (sommario):
Abstract BACKGROUND Medulloblastoma is the most common solid paediatric neoplasm and is among the leading causes of cancer-related deaths in children. Patients associated with high-risk molecular subgroups convey poor outcomes due to frequent relapse and metastasis, with two thirds of survivors experiencing life-changing developmental deficits. Poor patient outcomes and significant co-morbidities highlight an urgent need for specific, molecularly targeted therapies. The RAB40 subfamily of atypical small GTPases regulate cytoskeletal structure and cell adhesion via their ubiquitin ligase activity. Although previous studies have linked the RAB40 subfamily with cell invasiveness, their role in paediatric brain cancer remains undefined. METHODS Patient methylation and survival data from Cavalli et. al (2017) was analysed via the R2 Genomics Analysis and Visualisation Platform. RAB40 gene and protein expression were determined in eight in vitro models of medulloblastoma via qRT-PCR and western blotting. Cells were transfected with EGFP-Cas9 mRNA and RAB40-targeted CRISPR sgRNA and seeded singly using fluorescence-activated cell sorting. RAB40 knockout clones were identified via western blot and Sanger sequencing. RESULTS Patient data demonstrated that higher RAB40 gene expression correlates with worse outcomes in group 3 and 4 medulloblastoma. RAB40 genes were also significantly more highly expressed in high-risk groups 3 and 4 compared to low-risk WNT group medulloblastoma. RAB40 mRNA was enriched in cell lines derived from high-risk group 3 and 4 medulloblastoma relative to SHH controls. RAB40 knockout models were subsequently generated in HD-MB03, an in vitro model of metastatic Group 3 medulloblastoma using CRISPR/Cas9. CONCLUSIONS Our data supports the hypothesis that RAB40 small GTPases are enriched in high-risk medulloblastoma subgroups, and that their expression correlates with worse patient outcomes. We have generated knockout models which will be used to characterise the impact of RAB40 GTPases on cell growth, adhesion, invasiveness, and chemotherapeutic tolerance.
Tesi sul tema "Medulloblastoma paediatric":
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Nasir, Aishah. "An investigation of metastatic markers in models of paediatric medulloblastoma". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/42405/.
Abstract (sommario):
Introduction: Medulloblastoma is an aggressive malignant neuro-ectodermal tumour of the cerebellum which accounts for 15-20% of childhood central nervous system tumours and frequently disseminates to the leptomeningeal spaces of the brain and spinal cord. Patients with disseminated disease respond poorly to post-surgical multimodal treatment which is thought to be explained by the intrinsic drug-resistant nature of these tumours. Here, we hypothesized that cells gain migratory and invasive capabilities by undergoing an Epithelial-Mesenchymal Transition (EMT)-like process whereby cells alter phenotypically and acquire stem cell-like properties during tumour dissemination. In this study, metastatic genes were identified and tested using 3D in vitro model systems which incorporated important components of the extracellular matrix. Using these markers, evidence for an EMT-like process and the role of the multi-drug transporter, ABCB1, was investigated in metastatic medulloblastomas. Small molecule inhibitors were also used to investigate whether metastatic processes could be targeted and drug resistance mechanisms could be circumvented in both in vitro and/or in vivo settings. Materials and Methods: Growth, morphology and biological processes (e.g. cell migration) were assessed in a panel of non-metastatic and metastatic medulloblastoma cell lines, as well as in non-tumourigenic neural stem cells cultured in a 3D basement membrane extract (BME) using the alamar blue assay (measure of metabolic activity) and time-lapse imaging. Putative metastatic markers were identified through literature review analysis of gene expression datasets or immunohistochemistry of tissue micro-arrays (TMA). These markers were then assessed in samples obtained from medulloblastoma cell lines cultured as 2D monolayers and grown in BME (for 3 and 6 days) by QRT-PCR analysis. Protein expression of selected markers were also assessed in mouse orthotopic xenograft samples by immunohistochemistry or in cell lines using immunofluorescence analysis. Finally, small molecule inhibitors (WIP1 and ABCB1 inhibitors) were used in 3D culture systems (3D spheroid and 3D BME assays) and in an orthotopic metastatic mouse model. Results: Medulloblastoma cell lines demonstrated different growth patterns in 3D. Metastatic cell lines formed metabolically active aggregates which sustained continual cell migration for at least 6 days; whilst non-metastatic and non-tumourigenic cells showed low metabolic activity and rapidly differentiated. Metastatic cell lines which were sustained longest in BME (D283 Med and MED1) demonstrated upregulation of the EMT transcription factor, TWIST1, along with several other EMT and TWIST1-related factors. Further analysis included overexpressing TWIST1 in a non-metastatic cell line (MED6 TWIST1) which induced a dispersed phenotype in 2D and cell aggregation in the 3D BME model which phenotypically resembled metastatic cell lines. TWIST1 and ABCB1 expression correlated with metastasis in patients and was upregulated in the invasive edge of primary tumours and in spinal metastases in an orthotopic metastatic mouse model. Small molecule inhibitors targeting WIP1 (a published metastatic marker) and ABCB1 inhibited cell migration of metastatic cell lines grown in 3D including the MED6 TWIST1 cell line. ABCB1 inhibition also increased sensitivity to etoposide treatment in 3D spheroid models and an orthotopic metastatic in vivo model. Conclusion: The 3D BME model utilised in this study can be used to distinguish metastatic capacity and transcriptional changes of medulloblastoma cell lines. Furthermore, data from this study supports a role for a TWIST1 driven EMT-like process in metastatic medulloblastoma and supports the use of ABCB1 inhibition to overcome chemoresistance.
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Mather, Rebecca Louise. "Deacetylation of GD3A as a potential therapeutic strategy for paediatric medulloblastoma". Thesis, University of Portsmouth, 2016. https://researchportal.port.ac.uk/portal/en/theses/deacetylation-of-gd3a-as-a-potential-therapeutic-strategy-for-paediatric-medulloblastoma(d5e04f18-7985-48ff-807a-0962e6037835).html.
Abstract (sommario):
Medulloblastoma survivors frequently suffer from low quality of life as a result of aggressive treatment. New treatments are urgently needed to reduce down-stream sequelae. GD3, an oncofoetal ganglioside, has roles in embryonic brain development and is commonly modified to 9-O-acetyl GD3 (GD3A). GD3A plays a role in protecting cells from pro-apoptotic GD3 during brain development, after which GD3 accumulates above a threshold to collapse the mitochondrial membrane potentials of supernumary progenitor cells. GD3 and GD3A then become minor ganglioside species of the postpartum brain. In medulloblastoma however, GD3 and GD3A are re-expressed as shown here by the medulloblastoma cell lines RES256, UW402 and CHLA-01-Med where expression of GD3 is seen in 56.7%, 61.3% and 45.1% of the cell populations respectively. GD3A is expressed by 84.5%, 74.4% and 79.4% of the populations respectively. By bioinformatic analysis we also show that the human endogenous deacetylation enzyme of GD3A, Sialate-O-acetylesterase (SIAE), is significantly down-regulated in medulloblastoma patient tissue (p<0.001). This enzyme is thought to restore GD3 levels by cleaving the acetyl groups from GD3A. In order to evaluate this pathway as a potential therapeutic target we used an inducible SIAE overexpression approach in RES256 cells, the highest intracellular GD3A expresser. This transfection resulted in two SIAE wild-type expressing clones. Upon over-expression of SIAE (in clone 2) we show a significant increase in GD3 expression (p<0.05), and in preliminary experiments a significant increase in depolarisation of the mitochondrial membrane potential was seen in SIAE expressing clone 1 (p<0.05). These changes were not seen on induction of expression of a catalytic mutant SIAE-S127A or vector controls. We also demonstrate that wild-type SIAE expressing clones do not secrete the enzyme, however the catalytic mutant SIAE-S127A protein is secreted. We hypothesise that possible cleavage of caspase 1 could be responsible for this secretion. The expression of SIAE and SIAE-S127Ain cell lysates were confirmed by Western blot and demonstrated a possible cleavage product. We hypothesise that this possible cleavage may result in different abilities for these clones to secrete the enzyme. Furthermore, we show that induction of SIAE overexpression in combination with etoposide treatment resulted in a significant reduction inIC50 in SIAE overexpressing clones after 72 hours of treatment (p<0.001; clone 2). Changes in IC50 for empty vector controls and SIAE-S127A were not significant.
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Nair, Omesan. "Profiling medulloblastoma and juvenile pilocytic astrocytoma brain tumours in a South African paediatric cohort". Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/26896.
Abstract (sommario):
Brain tumours in children are one of the most challenging diseases to treat, and so outcomes are variable and often lacking. There are currently no reliable data of presentation of disease, the spectrum of tumours treated, how these are treated, and what the outcomes are for children in South Africa, and certainly no molecular biology data. In this respect, this thesis investigated the two commonest types of childhood brain tumour, the highly malignant Medulloblastoma (MB) and the generally less aggressive Juvenile Pilocytic Astrocytoma (JPA) with relation to their molecular biology and their clinical correlates to begin to address this gap and build capacity for further molecular-based studies in an African context. The study design in this thesis takes a systematic approach and is structured into MB and JPA biochemical characterisation followed by 4 studies of their respective proteomic profiles. The study design involved creating appropriate patient cohorts and determining sample characteristics for interpretation of results. The statistical power achieved in this thesis showed a minimum of 2-fold difference for a power greater than 0.8 in each case. Proteomic clustering was used to validate or delineate any discrepancies in subtype assignments for MB. Molecular profiles together with proteomic data of MB and JPA cases in this thesis provide evidence for some novel molecular pathways, proteins and peptides associated with pathogenesis. This work therefore provides extensive data that is hypothesis generating for further studies that could build upon molecular understanding in a South African and larger African context.
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George, Courtney M. "Medulloblastoma: New animal models, preclinical drug testing, and characterising immune infiltrates". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2575.
Abstract (sommario):
Medulloblastoma is the most common malignant brain tumour in children. The current treatment for medulloblastoma consists of surgery, radiation, and chemotherapy. Although these therapies have their merits, the outcome for some patients, particularly those with MYC amplified tumours, is poor, and the damaging nature of these therapies results in morbidities that significantly impact on a patient’s quality of life. To improve outcome and reduce adverse side effects, several strategies have been employed, including expanding the repertoire of accurate disease models, the development of novel therapies and the initiation of clinical trials, and an improvement in the understanding of the disease pathogenesis. The purpose of this thesis was to contribute to the repertoire of animal models, assist in identifying novel therapeutic approaches to treatment, and to advance the knowledge of the medulloblastoma immune microenvironment. We did so by aiming to (1) develop more accurate, immune-competent animal models of MYC- or NMYC-amplified medulloblastoma, (2) testing a novel treatment that combines conventional chemotherapies with a cell cycle checkpoint kinase inhibitor, and (3) investigating the effects of clinically used chemotherapies on immune cell populations in the brains of medulloblastoma-bearing mice.
Currently, the limited availability of preclinical mouse models that accurately represent subgroup-specific medulloblastoma has hindered the development of therapies that succeed in the clinical setting. In addition, the distinct lack of immunologically competent models has prevented the advancement of immunotherapy drugs in treating medulloblastoma. The models of medulloblastoma developed here were designed to aid in preclinical studies, and to contribute specifically to the repertoire of immune competent mouse models for studies to clarify the role of the immune system in medulloblastoma. Here, we utilised mutated human variants of CMYC, NMYC, and P53, to transform mouse neural stem cells into tumour forming cells. Tumours were established in C57Bl/6 mice and characterised by histology and RNAseq analysis. Whilst these animal models could not be confirmed to accurately represent Group 3 or Group 4 medulloblastomas, this study demonstrated that mouse neural stem cells could be transformed using human genes and could generate brain tumours within immune competent hosts. As we were unable to conclusively define the exact nature of the tumours that were produced here, existing mouse models were used for subsequent chapters in this thesis.
Prior to implementing new therapeutic agents into clinical trial, these are evaluated in a pre-clinical setting. The data presented in chapter two contributed to a larger scale pre-clinical testing pipeline that led to the identification and evaluation of multiple kinase inhibitors for the treatment of medulloblastoma. Here, I examined the combination of the cytotoxic agent gemcitabine (GEM) with the cell cycle checkpoint kinase inhibitor (LY2606368, prexasertib) as a novel approach in the treatment of Group 3 medulloblastoma. Combination GEM/LY2606368 treatment improved the survival of mice with aggressive medulloblastoma. Using immunoblotting and flow cytometry I showed that mechanistically LY2606368 enhanced GEM-induced cytotoxicity by impairing DNA damage response pathway activity, which promoted the accumulation of DNA damage leading to increased apoptosis. Together, these data formed part of the preclinical evidence that supported the establishment of the SJ-ELiOT clinical trial, targeted towards improving outcomes for patients who experience recurrent or relapsed disease following standard-of-care therapy.
There is evidence to suggest that inhibiting the DNA damage response pathway can stimulate the immune system, and aid in tumour elimination. This provides strong rationale for implementing immunotherapies for patients who are predicted to have a poor response to conventional treatments. Unfortunately, to date all clinical trials investigating current popular immune-based therapies have failed in medulloblastoma, likely due to a poor understanding of the immune microenvironment in this disease. This presented an opportunity to improve our understanding of the effects of treatment on the immune system in brain. Here I characterised the immune cell populations in the brains of mice with Group 3 medulloblastoma treated with vehicle or two clinically-used chemotherapies – cyclophosphamide (CPA) and GEM. I revealed that CPA and GEM differentially alter immune cells within the brain in a manner similar to that observed outside of the central nervous system. I also demonstrate that the lack of an adaptive immune system (using mice deficient in Rag1) does not influence the anti-cancer effects of these drugs. This information provides a rationale for exploring alternative avenues when considering the use of cancer-targeting immunotherapies in combination with conventional medulloblastoma treatments.
Collectively, these studies demonstrate the complicated nature of modelling high-risk medulloblastoma in the lab. I have improved upon current preclinical tools for medulloblastoma by the development of accurate immune competent models and advanced our knowledge of disease pathogenesis by elucidating the way medulloblastomas interact with the immune system in the brain. Furthermore, I highlight the translational value of preclinical models in the evaluation of new drug combinations ahead of clinical trial. Improving on the current tools available and accurately evaluating new therapies will ideally lead to improved clinical outcomes for patients with medulloblastoma.
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Okiro, Patricia Opon. "Morphological classification of childhood medulloblastomas with β-catenin immunohistochemistry and mycn fluorescent in situ hybridization". Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15733.
Abstract (sommario):
Medulloblastoma is the most frequently occurring childhood malignant brain tumour, affecting 1 of 5 children presenting with a brain tumour, between the ages of 0 and 9 years. The basic prognostic stratification that relies on clinical and histological findings alone has proven unsatisfactory as an outcome predictor. Distinct molecular genetic profiles have been described, with four molecular variants of medulloblastoma with specific demographic and prognostic features. These are the WNT subgroup, SHH subgroup, Group 3 and Group 4 tumours. The aim of this study was to describe the expression status of β-catenin, and MYCN, using IHC and FISH respectively, and to correlate these findings with clinico-pathological and demographic characteristics and clinical outcome. Materials and Methods This study was a nested retrospective analytical study, reviewing 54 cases of childhood medulloblastoma diagnosed between 1988 and 2014. Results Classic histology accounted for 40.7% of cases, LCA 37%, ND 16.7% and 5.6% MBEN). Based on β-catenin IHC, the WNT subgroup accounted for 16.7% of cases. This group had no mortalities or recurrences. Seven patients showed amplification of MYCN gene. The SHH group, defined by ND/MBEN histology and/or MYCN amplification, accounted for 27.7% of patients. Non-WNT/non-SHH tumours 30 patients (55.6%) showed a male predilection, and accounted for 37.5% recurrences and 50%. mortalities also falling in this group. Conclusions Nuclear β-catenin identifies WNT tumours. Nodular desmoplastic morphology is useful in identifying some, but not all cases of SHH group medulloblastomas. MYCN positive tumours also showed classical, and LCA morphology.. Patients of all the beta-catenin positive cases were free of recurrence and alive at last follow up. Patients with MYCN amplification and non-ND histology (LC/A or classic) had poorer outcomes than patients with ND histology. One patient showed both MYCN amplification and nuclear β-catenin translocation, and had good clinical outcome. This finding requires validation with other molecular techniques.
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Penco-Campillo, Manon. "Le VEGFC et les récepteurs CXCR1/2 : des cibles pertinentes pour le traitement des médulloblastomes pédiatriques". Electronic Thesis or Diss., Université Côte d'Azur, 2022. http://www.theses.fr/2022COAZ6025.
Abstract (sommario):
Le médulloblastome (MB) est la tumeur pédiatrique cérébrale la plus fréquente et la plus agressive. Malgré un traitement multimodal agressif, entraînant des effets secondaires importants, 30% des patients développent une résistance et rechutent suite à l'apparition de métastases dans les 5 ans. Les récidives ne peuvent être contrôlées par des traitements conventionnels (radio et chimiothérapie) ou ciblés (anti-angiogénique, anti-inflammatoire, anti-point de contrôle immunitaire). L'objectif de ma thèse est donc de découvrir de nouvelles cibles et stratégies thérapeutiques pertinentes pour ces patients au diagnostic ou après une rechute.Les MB sont des tumeurs très vascularisées. Le phénomène de résistance est, en partie, lié au développement de vaisseaux sanguins (angiogenèse) et lymphatiques (lymphangiogenèse) dans la tumeur, qui constituent les principales voies de dissémination métastatique. Le facteur de croissance des vaisseaux lymphatiques, le VEGFC, et ses récepteurs/co-récepteurs sont les acteurs majeurs de la lymphangiogenèse. Dans la première partie de ma thèse, j'ai montré que le VEGFC est inversement corrélé à la croissance et l'agressivité cellulaire du MB. En effet, le VEGFC diminue de manière autocrine la prolifération et la migration des cellules MB, ainsi que leur capacité à former des pseudo-vaisseaux in vitro. Les cellules résistantes à la radiothérapie présentent des niveaux élevés de VEGFC et perdent leur capacité à migrer et à former des pseudo-vaisseaux. L'irradiation réduit l'agressivité des cellules de MB par un processus dépendant du VEGFC. Les cellules surexprimant le VEGFC et les cellules résistantes à l'irradiation forment des tumeurs expérimentales plus petites chez la souris Nude. Le VEGC semble être un régulateur négatif de la croissance des MB. Ces résultats ouvrent la voie au développement de thérapies pro-VEGFC dans ces cancers.Dans la seconde partie de ma thèse, j'ai corrélé l'expression de la voie de signalisation pro-angiogénique et pro-inflammatoire ELR+CXCL/CXCR1-2 à une survie plus courte chez des patients atteints de MB. J'ai montré qu'un nouvel inhibiteur pharmacologique (C29) des récepteurs CXCR1-2 inhibe la prolifération, la migration dépendante de CXCL8/CXCR1/2, l'invasion et la formation de pseudo-vaisseaux par des cellules de MB sensibles ou résistantes à la radiothérapie. C29 réduit la croissance de MB expérimentaux dans un modèle de souris organotypique ex vivo et traverse la barrière hémato-encéphalique. Ainsi, le ciblage de CXCR1-2 représente une stratégie prometteuse pour le traitement des MB pédiatriques, en première ligne ou à la suite de rechutes.Mots-clés : médulloblastome pédiatrique, VEGFC/VEGFR, CXCR1-2, cytokines ELR+CXCL, thérapie ciblée, lymphangiogenèse, angiogenèseMedulloblastoma (MB) is the most common and aggressive pediatric brain tumor. Despite aggressive multimodal treatment, resulting in significant side effects, 30% of patients develop resistance and relapse following the appearance of metastases within 5 years. Recurrences cannot be controlled by conventional (radio- and chemotherapy) or targeted (anti-angiogenic, anti-inflammatory, anti-immune checkpoint) treatments. The objective of my thesis is therefore to discover new targets and relevant therapeutic strategies for these patients at diagnosis or after a relapse.MBs are highly vascularized tumors. The phenomenon of resistance is, in part, linked to the development of blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels in the tumor, which constitute the main routes of metastatic dissemination. The lymphatic growth factor, VEGFC, and its receptors/co-receptors are the major players in lymphangiogenesis. In the first part of my thesis, I showed that VEGFC is inversely correlated to MB cell growth and aggressiveness. Indeed, VEGFC decreases the proliferation and migration of MB cells, as well as their ability to form pseudo-vessels in vitro, by an autocrine signalization. Cells resistant to radiotherapy show elevated levels of VEGFC and lose their ability to migrate and form pseudo-vessels. Irradiation reduces the aggressiveness of MB cells by a VEGFC-dependent process. VEGFC-overexpressing cells and radiation-resistant cells form smaller experimental tumors in nude mice. Thus, VEGC appears to be a negative regulator of MB growth. These results pave the way for the development of pro-VEGFC therapies in these cancers.In the second part of my thesis, I correlated the expression of the ELR+CXCL/CXCR1-2 pro-angiogenic and pro-inflammatory signaling pathway to shorter survival in patients with MB. I showed that a novel pharmacological inhibitor (C29) of CXCR1-2 receptors inhibits proliferation, CXCL8/CXCR1-2-dependent migration, invasion and pseudo-vessel formation by susceptible or resistant MB cells to radiotherapy. C29 reduces the growth of experimental MBs in an ex vivo organotypic mouse model and crosses the blood-brain barrier. Thus, targeting CXCR1-2 represents a promising strategy for the treatment of pediatric MB, at first line or at relapse.Key words: pediatric medulloblastoma, VEGFC/VEGFR, CXCR1-2, ELR+CXCL cytokines, targeted therapy, lymphangiogenesis, angiogenesis
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Sorensen, James. "Therapeutic Efficacy of a Co-Q10 Analogue in Combating Cachexia and Mortality Induced by Gold-Standard Paediatric Chemotherapy Regimens". Thesis, 2020. https://vuir.vu.edu.au/41826/.
Abstract (sommario):
Chemotherapy is an effective first-line treatment against cancer; however, it induces a myriad of serious sequalae, including skeletal muscle dysfunction and wasting (SMDW) and fatigue, which we hypothesise is underpinned by mitochondrial dysfunction. When chemotherapy-induced (CI) SMDW is instigated in childhood, it often endures and manifests over the lifespan resulting in exacerbated morbidity and, in some cases, mortality. Despite much research having investigated individual chemotherapeutic agents and their effect on the skeletal muscle in mice (including our own), these models failed to evaluate the potential interactions between agents in a poly-pharmaceutical regimen, or, the effects of long-term and multi-staged chemotherapy regimens like that used in hospitals world-wide. Therefore, this thesis investigated the impact that gold-standard chemotherapy regimens used to combat the three common childhood cancers: acute lymphoblastic leukaemia (ALL), non- Hodgkin’s Burkitt lymphoma (NHBL) and medulloblastoma, on the skeletal muscle system in healthy juvenile mice and monitored the effects of treatment endured over the lifespan.
After establishing pre-clinical animal models for three gold-standard chemotherapy regimens, we showed that, regardless of regimen, eight weeks of treatment to four-week-old mice induced considerable skeletal muscle dysfunction which was characterised by significant muscle weakness, fatigability and, in 2 of the 3 regimens, lean mass loss. Although the age of onset of these sequalae were variable (varying between eight-weeks and 30-weeks of life), mitochondrial dysfunction was evident, identifying a point for therapeutic intervention. As such, we investigated the efficacy of daily Idebenone treatment (a powerful antioxidant and mitochondrial Co-Q10 analogue) against mitochondrial dysfunction and thus CI-SMDW. Idebenone co-therapy greatly improved mitochondrial performance in chemotherapy- treated mice, as well as protecting against lean mass loss and improving overall strength in the more aggressive chemotherapy regimen used against NHBL. Moreover, Idebenone co- therapy was shown to completely abate chemotherapy-induced mortality in the NHBL regimen, reducing mortality from 77% to zero.
This thesis shows that childhood chemotherapy, regardless of the aggressiveness of the regimen or the classes of drugs used, induces life-long SMDW which is likely contributed to by mitochondrial dysfunction. The mitochondrial targeting therapeutic, Idebenone, shows promising potential for clinical application against the SMDW sequalae and mortality induced by some regimens, with the potential to improve childhood chemotherapy patient outcomes and survivability.
Libri sul tema "Medulloblastoma paediatric":
1
Taylor, Roger E., Barry L. Pizer, Nancy Tarbell, Alba A. Brandes e Stephen Lowis. Embryonal and pineal tumours. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0009.
Abstract (sommario):
Embryonal tumours account for 20% of paediatric central nervous system (CNS) tumours. Medulloblastoma (MB), the most frequent, arises in the cerebellum. Clinical strategies have been based on series of multi-institutional trials since the 1970s. Recent understanding of the influence of molecular/biological factors has led to subdivision into four distinct subtypes with differing clinical and prognostic profiles, on which stratification is now based. Management of MB in adults is largely based on principles of managing children, modified according to differing clinical and toxicity profiles. Molecular analysis has led to the understanding that what was previously referred to as CNS-PNET comprise a heterogeneous group of tumours with a significant proportion representing other histologies. Atypical teratoid/rhabdoid tumour (AT/RT) carries mutations in the gene hSNF5/INI1 in most cases, with many now associated with an improved prospect of long-term survival. Pineal tumours have similar clinical presentations, comprising a heterogeneous mix of histologies from pineocytoma through to pineoblastoma.
Capitoli di libri sul tema "Medulloblastoma paediatric":
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Janzen, Laura, e Ute Bartels. "Paediatric Neuro-Oncology: Medulloblastoma". In Physician's Field Guide to Neuropsychology, 133–46. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-8722-1_8.
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Bellapukonda, Snigdha, e Praneeth Suvvari. "Paediatric Case of Medulloblastoma for Whole Brain Radiotherapy". In Problem Based Learning Discussions in Onco-Anesthesia and Onco-Critical Care, 203–12. Singapore: Springer Nature Singapore, 2024. http://dx.doi.org/10.1007/978-981-99-6339-3_19.
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Shahi, Mehdi Hayat. "Mitogen-activated protein (MAP) kinase Roles in Paediatric Brain Tumor “Medulloblastoma”". In Role of Signaling Pathways in Brain Tumorigenesis, 209–18. Singapore: Springer Nature Singapore, 2023. http://dx.doi.org/10.1007/978-981-15-8473-2_18.
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Nelson, M., C. Diebler e W. St C. Forbes. "Paediatric medulloblastoma: atypical CT features at presentation in the SIOP II trial". In Proceedings of the XIV Symposium Neuroradiologicum, 516–17. Berlin, Heidelberg: Springer Berlin Heidelberg, 1991. http://dx.doi.org/10.1007/978-3-642-49329-4_191.
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Talamonti, Cinzia, Stefano Piffer, Daniela Greto, Monica Mangoni, Antonio Ciccarone, Paolo Dicarolo, Maria Evelina Fantacci et al. "Radiomic and Dosiomic Profiling of Paediatric Medulloblastoma Tumours Treated with Intensity Modulated Radiation Therapy". In Computer Analysis of Images and Patterns, 56–64. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-29930-9_6.
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Young, A. "Craniotomy for medulloblastoma". In Paediatric Anaesthesia, 81–85. CRC Press, 2004. http://dx.doi.org/10.3109/9780203413012-15.
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Massimino, Maura, Eric Bouffet e Vijay Ramaswamy. "Embryonal Tumours". In Oxford Textbook of Cancer in Children, 188–97. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198797210.003.0023.
Abstract (sommario):
Paediatric embryonal tumours are highly heterogeneous entities which account for 15–20% of all childhood tumours of the central nervous system (CNS). Although historically considered one entity, integrated genomic analysis has unveiled this is no longer the case, and in fact CNS-PNET (primitive neuroectodermal tumour) has been removed from the World Health Organization (WHO) classification of CNS tumours. Patients are risk-stratified based on residual disease after surgery, metastatic dissemination, and, with the medulloblastoma subgroup, specific molecular features. In patients with medulloblastoma, 60–70% of patients over three years old are classified as standard-risk cases, while high-risk patients include those with disseminated and/or residual disease, large-cell and/or anaplastic histotypes, and MYC gene amplification in some protocols. Atypical teratoid rhabdoid tumours (ATRTs) are risk-stratified in a similar manner; however, recently integrated genomics has revealed the presence of three distinct molecular variants which seem to have distinct clinical features and outcomes. Clinical trials already underway or currently being planned will (1) examine the feasibility of reducing the dose of craniospinal irradiation and the volume of posterior fossa radiotherapy (RT) for patients generally considered at low biological risk (i.e. those with the WNT subgroup of medulloblastomas; (2) ascertain whether intensifying chemotherapy or RT can improve outcomes in high-risk patients; and (3) seek therapeutic targets that will enable tailored therapies, especially for relapsing patients and those at higher biological risk.
Atti di convegni sul tema "Medulloblastoma paediatric":
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Lyman, Stephanie. "730 An exploration of existing and potential novel biomarkers in paediatric medulloblastoma". In Royal College of Paediatrics and Child Health, Abstracts of the RCPCH Conference, Liverpool, 28–30 June 2022. BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health, 2022. http://dx.doi.org/10.1136/archdischild-2022-rcpch.495.
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Shoji Hayashi, Daniel, Ana Luiza Ongaro Seidinger Conte, Isadora Olenscki Gilli, Gabriel Lopes Centoducatte e José Andrés Yunes. "Identification of genetic profile associated with response to treatment with protein Smoothened (SMO) inhibitors in paediatric medulloblastoma patients". In XXV Congresso de Iniciação Cientifica da Unicamp. Campinas - SP, Brazil: Galoa, 2017. http://dx.doi.org/10.19146/pibic-2017-78106.