Articoli di riviste: "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.

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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.

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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.

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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.

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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.

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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.

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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.

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Akililu, Yemisirach Bizuneh, e Mersha Abebe Woldemariam. "PAEDIATRIC-01 SURGICAL OUTCOME OF MEDULLOBLASTOMA IN ETHIOPIA". Neuro-Oncology Advances 5, Supplement_4 (31 ottobre 2023): iv9. http://dx.doi.org/10.1093/noajnl/vdad121.038.

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Abstract OBJECTIVE Medulloblastoma is one of the commonest CNS[1] tumors in pediatric patients. This study tries to assess surgical treatment outcome and prognostic factors in patients diagnosed with medulloblastoma in Ethiopia, a LIC[2]. MATERIALS AND METHODS Retrospective study involving twenty-seven patients (21 pediatrics & 6 adults) who underwent surgery for medulloblastoma (January 1, 2010-April 30, 2018), at two neurosurgical centers. Structured questionnaire was used to collect patients’ data & surgical treatment outcome variables were assessed by suitable statistical tests. RESULTS 1-year and 6-month survival probability were 29% and 41 % respectively with a median survival of 107 days (95% CI: 49,166). Median survival was 66 days (95% CI: 27,105), with 6 months and one-year survival rate of 24 % (p=0.031) for pediatric patients. Majority (61.90%) of pediatric deaths were in the first two months of surgery. Six months & one-year PFS[3] were around 83% and 44% respectively with median PFS of 9 months (95%CI: 7, 12). Younger age at presentation, postoperative open EVD[4], longer SICU[5] stay, lack of radiation treatment & postoperative complications were negative outcome predictors. CONCLUSION Overall median and PFS of operated patients <15 years old is poor. Patients with negative outcome predictors have higher mortality& poor postoperative functional status. Standardization of treatment with surgery & CSI[6] ± chemotherapy yields longer survival rates in both pediatric and adult patients. [1] Central Nervous System [2] Low Income Country [3] Progression Free Survival [4] External Ventricular Drainage [5] Surgical Intensive Care Unit [6] Craniospinal Irradiation

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Journal, Baghdad Science. "Detection of RAF fusion transcripts in FFPE samples of Medullablastoma and Ependymom in Iraqi children with RT-RQPCR assays". Baghdad Science Journal 11, n. 3 (7 settembre 2014): 1411–19. http://dx.doi.org/10.21123/bsj.11.3.1411-1419.

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Medulloblastomas and ependymomas are the most common malignant brain tumors in children. However genetic abnormalities associated with their development and prognosis remain unclear. Recently two gene fusions, KIAA1549–BRAF and SRGAP3–RAF1 have been detected in a number of brain tumours. We report here our development and validation of RT-RQPCR assays to detect various isoforms of these two fusion genes in formalin fixed paraffin embedded (FFPE) tissues of medulloblastoma and ependymoma. We examined these fusion genes in 44 paediatric brain tumours, 33 medulloblastomas and 11 ependymomas. We detected both fusion transcripts in 8/33, 5/33 SRGAP3 ex10/RAF1 ex10, and 3/33 KIAA1549 ex16/BRAF ex9, meduloblastomas but none in the 11 ependymomas examined. This investigation provided evidence to the value of RT-RQPCR assays for the detection of these fusion genes in large-scale studies on FFPE tissues. The study also reports the first detection of RAF fusion genes in meduloblstomas.

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Obaidy, Luma H. A. Al, Nada A. Al Anssary, Nahi Y. Al Rekabi, Haider L. Mohammed e Khalid A. Tobal. "Detection of RAF fusion transcripts in FFPE samples of Medullablastoma and Ependymom in Iraqi children with RT-RQPCR assays". Baghdad Science Journal 11, n. 3 (7 settembre 2014): 1411–19. http://dx.doi.org/10.21123/bsj.2014.11.3.1411-1419.

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Medulloblastomas and ependymomas are the most common malignant brain tumors in children. However genetic abnormalities associated with their development and prognosis remain unclear. Recently two gene fusions, KIAA1549–BRAF and SRGAP3–RAF1 have been detected in a number of brain tumours. We report here our development and validation of RT-RQPCR assays to detect various isoforms of these two fusion genes in formalin fixed paraffin embedded (FFPE) tissues of medulloblastoma and ependymoma. We examined these fusion genes in 44 paediatric brain tumours, 33 medulloblastomas and 11 ependymomas. We detected both fusion transcripts in 8/33, 5/33 SRGAP3 ex10/RAF1 ex10, and 3/33 KIAA1549 ex16/BRAF ex9, meduloblastomas but none in the 11 ependymomas examined. This investigation provided evidence to the value of RT-RQPCR assays for the detection of these fusion genes in large-scale studies on FFPE tissues. The study also reports the first detection of RAF fusion genes in meduloblstomas.

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Whitby, Alison, Bhoomi Shastri, Dong-Hyun Kim e Madhumita Dandapani. "BIOM-07. DEVELOPING A CEREBROSPINAL FLUID-BASED BIOMARKER FOR MINIMAL RESIDUAL DISEASE AND RELAPSE IN PAEDIATRIC BRAIN TUMOURS USING METABOLOMIC METHODS". Neuro-Oncology 26, Supplement_4 (18 giugno 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.026.

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Abstract BACKGROUND Many paediatric brain tumours have poor outcomes due to relapse (50% in ependymoma and 30% in medulloblastoma) following treatment. Most of these occur within two years, suggesting persistent minimal residual disease (MRD) below the imaging detection threshold. Diagnosing MRD at the end-of-treatment or early relapse using a sensitive, minimally-invasive liquid biopsy could improve outcomes. Extracting metabolites arising from aberrant cancer metabolism, from cerebrospinal fluid (CSF) is promising because of the proximity of tumour to CSF. METHODS Liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) using 25µl CSF extracted with 75µl methanol was shown to differentiate malignant paediatric brain tumours (n=47;day 14 samples) from controls (n=49). RESULTS Ependymomas (n=33) differed from medulloblastomas (n=14). Eighteen metabolites were identified as differentially abundant between tumours and controls with 14 metabolites being increased in abundance in tumours. These included amino acids and derivatives (n=8), metabolites in one carbon metabolism (n=1), carnitine cycle (n=2), aerobic glycolysis (n=2), purine catabolism (n=2), ascorbate degradation (n=1) and creatinine synthesis (n=2). From those, betaine/creatinine ratio gave an area under the curve (AUC) of 0.96 (excellent) in receiver operating curve analysis. Using a cut-off ratio of 0.1775 for discriminating brain tumours from controls, had sensitivity and specificity of 92% and 89%. Medulloblastomas were largely similar to ependymomas; nevertheless, three metabolites could discriminate between them, and met the criteria of corrected p<0.05. A ratio of glutarate semialdehyde/malic acid had AUC of 0.85 (good). With a cut-off ratio of 0.0422, the sensitivity and specificity were 79% and 82%. CONCLUSION This is the first CSF-based metabolomics study in ependymoma and third in medulloblastoma. Ratios of CSF metabolites can be used as biomarkers to detect brain tumours sensitively and specifically. This work will further be developed into a liquid biopsy test for the detection of MRD and early tumour recurrence.

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Singh, Somesh, Amrin Israrahmed, Vikrant Verma e Vivek Singh. "Extra-axial tentorial medulloblastoma: a rare presentation of a common posterior fossa tumour". BMJ Case Reports 14, n. 6 (giugno 2021): e242865. http://dx.doi.org/10.1136/bcr-2021-242865.

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Medulloblastoma is a common paediatric posterior fossa tumour typically presenting as midline intra-axial mass involving the cerebellar vermis and/or roof of fourth ventricle with typical radiological features. These can be extra-axial in extremely rare instances with less than 50 cases reported so far in literature. We present a case of 18-year-old boy presenting with ataxia and headache. MRI showed dural mass (involving the left tentorium cerebellum) with typical imaging features of extra-axial lesion. The patient underwent near total excision of the tumour. Histopathology along with immunohistochemistry revealed the mass to be medulloblastoma. We present this case to highlight rarity of this location for medulloblastoma and the importance of considering this in the differential diagnosis of atypical posterior fossa extra-axial lesions. This can help in performing other relevant preoperative workup similar on the lines of medulloblastoma and planning of relevant management.

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Low, Sharon Y. Y., Derrick W. Q. Lian, Phua Hwee Tang, Eva Loh, Wan Tew Seow e David C. Y. Low. "Concurrent paediatric medulloblastoma and Chiari I malformation with syringomyelia". Child's Nervous System 33, n. 6 (21 aprile 2017): 881–83. http://dx.doi.org/10.1007/s00381-017-3413-2.

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Spreafico, Filippo, Maura Massimino, Lorenza Gandola, Graziella Cefalo, Elena Mazza, Giuseppe Landonio, Emanuele Pignoli et al. "Survival of adults treated for medulloblastoma using paediatric protocols". European Journal of Cancer 41, n. 9 (giugno 2005): 1304–10. http://dx.doi.org/10.1016/j.ejca.2005.02.022.

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Loo, S. W., G. Horan, M. Lenane, J. C. Dean, J. Fairfoul, M. A. Cowen, S. J. Thomas, N. G. Burnet e M. V. Williams. "Craniospinal Irradiation using Helical Tomotherapy for Paediatric Metastatic Medulloblastoma". Clinical Oncology 23, n. 3 (aprile 2011): S44. http://dx.doi.org/10.1016/j.clon.2011.01.449.

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Dell’Oro, Mikaela, Michala Short, Puthenparampil Wilson, Chia-Ho Hua, Melissa Gargone, Thomas E. Merchant e Eva Bezak. "Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach". Cancers 12, n. 9 (10 settembre 2020): 2578. http://dx.doi.org/10.3390/cancers12092578.

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Background: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. Methods: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1–3 cm) and position (central and 1–2 cm shifts). Results: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8–12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). Conclusions: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

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Law, Nicole, Mary Lou Smith, Mark Greenberg, Eric Bouffet, Michael D. Taylor, Suzanne Laughlin, David Malkin et al. "Executive function in paediatric medulloblastoma: The role of cerebrocerebellar connections". Journal of Neuropsychology 11, n. 2 (4 agosto 2015): 174–200. http://dx.doi.org/10.1111/jnp.12082.

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Zakrzewska, Magdalena, Sylwia M. Grešner, Krzysztof Zakrzewski, Beata Zalewska-Szewczyk e Pawel P. Liberski. "Novel Gene Expression Model for Outcome Prediction in Paediatric Medulloblastoma". Journal of Molecular Neuroscience 51, n. 2 (7 maggio 2013): 371–79. http://dx.doi.org/10.1007/s12031-013-0016-6.

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Ranade, Manali, Khushi Naik, Prachi Bapat, Mamta Gurav, Omshree Shetty, Aekta Shah, Ayushi Sahay et al. "MDB-55. LYMPHOID ENHANCER-BINDING FACTOR 1 (LEF1): AN IMMUNOHISTOCHEMICAL PREDICTIVE MARKER FOR WNT-ACTIVATED MEDULLOBLASTOMA". Neuro-Oncology 26, Supplement_4 (18 giugno 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.504.

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Abstract AIM To evaluate lymphoid enhancer-binding factor 1 (LEF1) immunohistochemical expression in various molecular subtypes of medulloblastoma. MATERIALS AND METHODS Molecular subtyping of medulloblastomas was based on real-time PCR target 12 gene panel. LEF1 immunohistochemistry was performed and its expression was correlated with histological and molecular subtypes. RESULTS The study cohort included 65 cases; comprising 17 WNT-activated, 20 SHH-activated, and 28 non-WNT/non-SHH [group 3: 11, group 4: 10, non-WNT/non-SHH NOS: 7] medulloblastomas. The age range was 1-40 years (≤18 years=54 [WNTa:15, SHHa:13, non-WNT/non-SHH:26], 19-40 years=11) with a median age of 9, and an interquartile range (IQR) of 5-14.5. Forty-one were males and 24 were females (M:F=1.7:1). LEF1 immunostaining was diffuse (≥50% tumour cells) in 13 cases, focal (5-49% tumour cells) in 11 cases, and negative in 41 cases. All cases with diffuse LEF1 immunostaining (n=13) were WNT-activated with classic histology. Twelve of the 13 cases had CTNNB1 mutation on Sanger sequencing and monosomy 6 by fluorescence in-situ hybridization (FISH) while 1 case was uninterpretable for CTNNB1 Sanger sequencing and chromosome 6 FISH. LEF1 staining intensity was strong in 9 cases while heterogenous in 4 cases. No differential staining pattern was observed for paediatric and adult cases. Diffuse LEF1 immunostaining was significantly associated with the WNT-activated subtype of medulloblastoma (p=<0.01). Of 11 focal LEF1 positive cases, 4 were WNT-activated (all having classic histology and CTNNB1 mutation) and 7 were SHH-activated, TP53-wildtype (classic: 2 and desmoplastic nodular [D/N]: 5). None of the WNT-activated, 12 SHH-activated, TP53-wildtype (6 classic, 6 D/N), 1 SHH-activated, TP53-mutant (large-cell/Anaplastic [LC/A]) and all (n=28) non-WNT/non-SHH (classic: 25, LC/A: 3) were LEF1 negative. CONCLUSION Classic histology with diffuse (≥50% tumor cells; including heterogeneous intensity) LEF1 immunostaining is a good predictive marker for the WNT-activated molecular group of medulloblastoma, however focal staining is not.

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Dixit, Alok, R. Venkatesh, T. T. Pradeep e Pratibha Prabhakar. "EPIDEMIOLOGICAL PATTERNS OF PAEDIATRIC BRAIN TUMORS IN COIMBATORE". International Journal of Advanced Research 9, n. 09 (30 settembre 2021): 891–96. http://dx.doi.org/10.21474/ijar01/13499.

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Background: Tumors of the nervous system are the second most common childhood tumors after leukemia,constituting approximately 35% of all childhood malignancies and remain the leading cause of cancer related deaths in children. In India,in the absence of a comprehensive population based national cancer registry,we depend on local hospital based registries for assessing the incidence of pediatric brain tumor.Hence,more and more institutional data are required to assess the actual disease load in India. Objective: The main objective of the present study is to assess the epidemiological patterns of brain tumors in children presenting in CMCH. Materials and Methods: Data regarding age,gender,topography and histopathology of 22 pediatric patients (0-18years)with brain tumors operated inCMCH over a period of 5 years(January 2015 to December 2019)was collected retrospectively and analysed. The results obtained were compared with available Indiandata and western literature. Results: Of 22 cases, males(63.6%) outnumbered females. In the present study, the most common anatomical site for brain tumors was cerebellum(45.5%) followed by cerebral hemispheres(36.2%), ventricles(13.6%) and sellar region(4.5%). The present study showed that Infratentorial tumors were more common (54.5%) as compared to Supratentorial tumors (45.5%).Thepresent study revealed that astrocytoma(36.4%) is the most common brain tumor in childhood. other common tumors include medulloblastoma(27.2%), followed by ependymoma(13.6%), oligodendroglioma(9%),pineal gland tumor(4.5%),craniopharyngioma(4.5%) and meningeal tumor(4.5%). Conclusion: From the present series, we conclude that, the frequencies of major histologic types of brain tumors found in the study do not differ substantially from that found in other developed and developing countries. Medulloblastomas and astrocytomas, which form the major histologic types in pediatric patients need special attention.

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Wade, Philippa, Hannah Jackson, Louisa Taylor, Alistair Hume, Ian Kerr e Beth Coyle. "MEDB-25. Do extracellular vesicles transfer a multidrug resistant phenotype via ABC transporters in medulloblastoma?" Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i110. http://dx.doi.org/10.1093/neuonc/noac079.399.

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Abstract INTRODUCTION: Medulloblastoma is the most common malignant paediatric brain tumour accounting for 20% of all childhood tumours; approximately one-third of patients present with metastatic disease at diagnosis and the outcome for these patients remains very poor. The high frequency of recurrence and metastatic relapse in medulloblastoma supports the idea of intrinsic drug resistance within cells. This work looks at the ATP-binding cassette (ABC) transporters, known to be upregulated in several cancers, and we hypothesise that extracellular vesicles may transfer ABC transporters to surrounding cells, promoting multidrug resistance within tumours. METHODS: The Cavalli dataset, made up of 763 patient samples, was used to assess the gene expression of a number of ABC transporters across medulloblastoma subgroups. ABC transporter gene and protein expression was then further assessed in medulloblastoma cell lines, including drug-tolerant lines, using qPCR and western blot. Cell viability analysis was used to assess changes in drug response. Matched cell and EV protein samples were used for proteomic analysis. RESULTS: Patient gene expression data showed that high expression of two ABC transporters correlated with reduced patient survival in high-risk subgroups. qPCR analysis of medulloblastoma cell lines showed differential subgroup expression patterns. Additionally, qPCR analysis of drug-tolerant cell lines showed significant increases in the expression of specific drug transporters across the subgroups. RNA-seq confirmed the presence of ABC transporter mRNA in exosomes isolated from high-risk medulloblastoma cell lines. Functional studies of EV transference of ABC transporters are ongoing. CONCLUSIONS: Data to date supports the hypothesis that multidrug transporter carrying extracellular vesicles may transfer their multidrug resistant phenotype to surrounding cells in medulloblastoma, promoting drug resistance. Future work will test this hypothesis by knocking down candidate ABC transporters and assessing the effect on transference of drug resistance by extracellular vesicles.

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Johnson, James, Franziska Linke, Cathy Merry e Beth Coyle. "MEDB-24. Tumour secreted extracellular matrix predicts survival and influences migration and cell death in SHH medulloblastoma 3D models". Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i110. http://dx.doi.org/10.1093/neuonc/noac079.398.

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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.

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Entwistle, Susannah, Hannah K. Jackson, Ian Kerr, Beth Coyle e Alistair Hume. "MEDB-64. Are Rab GTPases metastatic drivers in metastatic medulloblastoma?" Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i121. http://dx.doi.org/10.1093/neuonc/noac079.438.

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Abstract Medulloblastoma is the most common malignant paediatric brain cancer with poorer prognosis related to the onset of metastasis. It has four molecular subgroups; Wingless (WNT), Sonic Hedgehog (SHH), group 3 and group 4, of which group 3 is the most likely to be metastatic and is therefore associated with the poorest prognosis. Exosomes are small membrane-bound extracellular vesicles of endosomal origin which contain a variety of cargo including RNA and proteins. Increased exosome release is connected with disease progression and metastasis in multiple cancers. Rabs are a family of small GTPases (70 in humans) which regulate vesicle trafficking. Several Rabs are known to regulate exosome biogenesis and secretion and may thereby contribute to cancer progression. The role of Rabs in metastatic medulloblastoma is unclear. We aim to explore whether Rabs contribute to the progression of metastatic medulloblastoma through the exosome biogenesis and secretion pathways. Through analysis of literature, databases such as ExoCarta.org, the R2: Genomics analysis and visualisation platform, and mRNA content of medulloblastoma exosomes, five novel Rab candidates were identified that may contribute to disease progression in group 3 medulloblastoma. Gene expression of these Rabs was then verified across SHH, group 3 and group 4 patient-derived cell lines using RT-qPCR, with candidate Rab expression confirmed in the three subgroups. Presence of Rab mRNA has also been found in exosomes derived from group 3 and group 4 patients, with an enrichment in group 3 exosomes. Current and future work aims to determine the potential roles of Rabs in medulloblastoma pathogenesis, and to determine whether Rabs contribute to increased exosome biogenesis which drives metastasis or are metastatic drivers in medulloblastoma themselves. Therefore, experiments to characterise Rab candidate protein expression within cells and assess their function after knockdown are necessary and timely.

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Ruchiy, Yana, Ioanna Tsea, Bronte Manouk Verhoeven, Indranil Sinha, Efthalia Preka, Thale Kristin Olsen, Shenglin Mei et al. "MDB-04. SINGLE-CELL TRANSCRIPTOMIC ANALYSIS REVEALS DISTINCT GENOMIC LANDSCAPES, CELL TRAJECTORIES, AND TUMOUR-MICROENVIRONMENT INTERACTIONS IN FOUR SUBTYPES OF MEDULLOBLASTOMA". Neuro-Oncology 25, Supplement_1 (1 giugno 2023): i62. http://dx.doi.org/10.1093/neuonc/noad073.237.

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Abstract Medulloblastoma is the most common paediatric high-grade brain tumour, which comprises four different molecular subtypes (SHH, Wnt, Group 3, and Group 4), each defined by different molecular characteristics, genomic aberrations, and prognosis. High levels of inter- and intra-tumoural heterogeneity, together with the detrimental side effects caused by the current medulloblastoma treatments, need to be addressed in order to develop more personalised treatments and improve the quality of life of these patients. In this study, we analysed single-cell RNA sequencing data from 14 medulloblastoma patients, comprising all four molecular subtypes. We found that these tumours exhibit great levels of heterogeneity with regard to their copy number variation (CNV) profiles analysed using Numbat, as well as immune cell infiltration and composition within these tumours. Tumour-infiltrating immune cells represented a heterogeneous population comprised of monocytes, M1- and M2-like macrophages, dendritic cells, and microglia. Our ligand-receptor analysis also identified a subset of immune cells that send EGF signals to the tumour clusters, potentially contributing to the tumour growth. In addition, we showed that the tissue of origin of the immune cells found within the tumour microenvironment and their medulloblastoma subgroup specificity greatly influence their clustering when projected onto a UMAP. We also found that the clustering of tumour cells is influenced by their CNV levels. Finally, we performed RNA velocity analysis and identified subgroup-specific cell trajectories for each medulloblastoma subtype. As predicted, identified cell trajectories demonstrated that cells move in a direction of increasing CNV levels, making it possible to visualise and track the tumour progression and identify genetic markers specific to either earlier or later tumour stages. Overall, our study underlines high levels of inter-tumoural heterogeneity in medulloblastoma. It also provides opportunities for the identification of subgroup-specific biomarkers for the early stages of medulloblastoma, potentially contributing to the discovery of novel drug targets.

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Mabbott, Donald. "INSP-06. Recent advances in improving neuropsychological outcomes for paediatric brain tumour patients - Are we entering a new era?" Neuro-Oncology 24, Supplement_1 (1 giugno 2022): i187. http://dx.doi.org/10.1093/neuonc/noac079.702.

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Abstract Children and youth treated for brain tumours can sustain a brain injury as a consequence of the tumour and curative therapy leaving them with significant cognitive challenges. Advances in treatment for paediatric brain tumours – particularly the delivery of radiotherapy – have been associated with improved neuropsychological outcome in survivors, however. This presentation will first focus on work documenting the impact of changes in cranial radiotherapy delivery and modality on neuropsychological late effects in children treated for medulloblastoma. Outcomes in patients treated on modern protocols are substantially improved relative to prior therapy, however challenges remain. Second, novel approaches for cognitive recovery and brain repair in survivors of paediatric brain tumours will be discussed, with a focus on novel approaches for fostering endogenous neuroplasticity for cognitive recovery and brain repair in children and youth treated for paediatric brain tumours.

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Bacon, S., J. Clinkard e R. E. Taylor. "Paediatric medulloblastoma associated with poor prognosis and short volume doubling time". British Journal of Radiology 78, n. 935 (novembre 2005): 1059–60. http://dx.doi.org/10.1259/bjr/29536247.

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Ahern, V., E.-S. Koh, V. Gebski e Y. Sathiyaseelan. "Paediatric medulloblastoma: Patterns of care and radiotherapy quality assurance in Australia". Australasian Radiology 51, n. 5 (ottobre 2007): 458–64. http://dx.doi.org/10.1111/j.1440-1673.2007.01753.x.

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Smulders, B., M. Aznar, I. Richter Vogelius, J. P. Bangsgaard e M. Jørgensen. "PO-0876: Clinical considerations for introduction of VMAT for paediatric medulloblastoma". Radiotherapy and Oncology 115 (aprile 2015): S448. http://dx.doi.org/10.1016/s0167-8140(15)40868-0.

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Ho, S. Q. E., L. M. Mullaney e S. A. Barrett. "EP-1381: Treatment outcomes of proton craniospinal irradiation for paediatric medulloblastoma". Radiotherapy and Oncology 123 (maggio 2017): S740. http://dx.doi.org/10.1016/s0167-8140(17)31816-9.

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López, G. Y., G. A. Grant, H. E. Fuchs, L. G. Leithe, S. Gururangan, D. D. Bigner, H. Yan, R. E. McLendon e Y. He. "Clinico-pathological description of three paediatric medulloblastoma cases withMLL2/3gene mutations". Neuropathology and Applied Neurobiology 40, n. 2 (21 gennaio 2014): 217–20. http://dx.doi.org/10.1111/nan.12060.

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Abbas, Z., M. Howlett, J. Buck, H. Hii, M. Kuchibhotla, M. Ancliffe, J. Whitehouse et al. "JS04.5.A Enhancing the activity of anti-CD47 antibody therapy with radiotherapy in preclinical models of medulloblastoma". Neuro-Oncology 24, Supplement_2 (1 settembre 2022): ii7. http://dx.doi.org/10.1093/neuonc/noac174.020.

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Abstract Background Brain cancers are the most common solid cancer in children and the leading cause of cancer-related deaths in children. Medulloblastoma is the most common paediatric brain tumour. Treatment for medulloblastoma involves surgery, craniospinal irradiation (CSI) and chemotherapy. These therapies are extremely damaging to the developing brain and have not changed in decades, resulting in stagnation in the survival outcomes for children with medulloblastoma, and poor quality of life for children who survive their treatment. Immunotherapy has become a focus of novel treatment development. While there are multiple clinical trials aiming to increase immune recognition of medulloblastoma, none have been successful to date. Anti-CD47 is an immune-modulating therapeutic antibody which blocks the anti-phagocytic signal, CD47, expressed by brain cancer cells. Anti-CD47 has shown promising preliminary efficacy in brain cancer models. Material and Methods Using a small animal radiotherapy platform, we have developed a preclinical CSI protocol which mimics clinical radiotherapy. Using an orthotopic xenograft model of medulloblastoma, mice were treated with either anti-CD47 antibody therapy, CSI, or the combination of both anti-CD47 and CSI. Results CSI was found to deplete adaptive immune cells in the brain, while myeloid cells remained the dominant populations. Anti-CD47 antibody therapy was ineffective as a single agent against a patient derived xenograft model of Group 3 medulloblastoma, and CSI as a monotherapy resulted in temporary tumour regression. We found that the combination of anti-CD47 with CSI resulted in marked and persistent tumour regression. Conclusion This preclinical work has shown promising efficacy of anti-CD47 in combination with CSI, which we are currently testing in additional models. Our work is currently employing a range of techniques such as high dimensional flow cytometry and single cell sequencing to elucidate the mechanisms by which radiotherapy enhances the anti-tumour activity of myeloid cells. This work will enable the rational design and translation of optimal combination therapies for medulloblastoma clinical trials.

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Faiza Urooj, Mohammad Hamza Bajwa, Muhammad Usman Khalid, Mashal Murad Shah, Ahsan Ali Khan, Ummey Hani, Altaf Ali Laghari et al. "A national overview of paediatric and adolescent and young adult surgical neuro-oncology in Pakistan". Journal of the Pakistan Medical Association 72, n. 11 (15 dicembre 2022): S85—S92. http://dx.doi.org/10.47391/jpma.11-s4-akub14.

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Objective: To build a comprehensive brain tumour database that will allow us to analyse in detail the prevalence, demographics, and outcomes of the disease in paediatric, adolescent, and young adult age groups. Method: A national cross-sectional study was conducted at 32 centres, and data regarding patient demographics and brain tumours were collected. This data was then stratified based on age groups, healthcare sectors, socioeconomic status, tumour types, and surgical outcomes. Result: Most of the patients who were diagnosed with brain tumours belonged to a lower socioeconomic background and went to public sector hospitals. More males were diagnosed with and treated for brain tumours in the paediatric, adolescent, and young adult populations. The most common tumour in the paediatric population was medulloblastoma (23.7%) and the most common tumour in the adolescent (27.8%) and young adult population (34.7%) was glioma. Significant improvement in KPS scores were seen for: craniopharyngioma (p = 0.001), meningioma (p < 0.0005) and pituitary adenoma (p < 0.0005) Conclusion: This study shows that in all three age groups, there was a greater prevalence in males. Most of the patients belonged to a lower-middle-income class background and most patients presented to public sector hospitals. Greater knowledge of these parameters unique to each age group is the key to understanding and alleviating the burden of disease. Cancer registries, specifically brain tumour registries that keep up-to-date records of these patients, are essential to identify and keep track of these unique parameters to advance medical research and treatment strategies, ultimately lowering the disease burden. Keywords: Pediatric, Neuro-oncology, Adolescent and young adult, AYA, Medulloblastoma, Craniopharyngioma, Epidemiology.

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Jahan, Fauzia, Mohammed Kamal e Shamsunnahar Sultana. "Pattern of Paediatric Brain Tumours Evaluated in BSMMU, Dhaka, Bangladesh". Bangladesh Journal of Child Health 37, n. 3 (18 aprile 2014): 154–57. http://dx.doi.org/10.3329/bjch.v37i3.18619.

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Background: In children Central Nervous System (CNS) is the second most common site for primary tumours superseded only by leukaemias. Paediatric brain tumours differ from adult one by their type, location and outcome. Objectives: To study the frequency and histomorphological spectrum of CNS tumours in Children and to correlate with age, sex and distribution of tumours. Methodology: This study was carried out at the Department of Pathology, Bangabandhu Shiekh Mujib Medical University (BSMMU) Dhaka during the period of July 2006 to June 2007. Samples from all Paediatric age and both sexes were included in this study. Results: We studied 55 cases of Paediatric CNS tumours. The patients age ranged between 2 months to 15 years. The mean age at diagnosis was 10.12±4.18 years. Regarding location 59% was infratentorial and 41% were supratentorial. Most common tumour was medulloblastoma (23%). Twenty Seven (27%) of the tumours were high grade. DOI: http://dx.doi.org/10.3329/bjch.v37i3.18619 Bangladesh J Child Health 2013; Vol.37(3): 154-157

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Porter, Harry, Phoebe McCrorie, Cara Moloney, Pamela Collier, Nicola Croxall, David Onion, Anna Kotowska et al. "IN VITRO MODELLING OF CROSSTALK BETWEEN PAEDIATRIC CEREBELLAR TUMOURS AND HEALTHY BRAIN TISSUE IN THE POST-SURGICAL MICROENVIRONMENT". Neuro-Oncology 25, Supplement_3 (16 settembre 2023): iii18. http://dx.doi.org/10.1093/neuonc/noad147.075.

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Abstract AIMS Atypical Teratoid Rhabdoid Tumours (ATRT) and Medulloblastoma are embryonal brain tumours arising in the cerebellum. Many in vitro models of paediatric brain tumours fail to recapitulate key pathophysiological characteristics. We aim to address this gap by developing a bespoke model incorporating cellular and acellular aspects of the TME. METHOD Cerebellar tissue from a healthy human autopsy donor brain was decellularized to form cerebellar ECM and incorporated into a “blank slate” hydrogel. Spheroid-forming multi-well plates were coated with the hydrogel and used to culture patient-derived Medulloblastoma and ATRT cells in co-culture with primary human cerebellar astrocytes. RESULTS Tissue decellularization and retention of ECM components was demonstrated using colorimetric assays and Orbitrap Secondary Ion Mass Spectrometry. Biocompatibility of the ECM hydrogel was shown in 2D and 3D culture conditions using the CellTiter-Glo® 3D cell viability assay. Furthermore, the size and morphology of spheroids grown on the hydrogel was characterised using a high-throughput imaging and analysis methodology. Cell lines were labelled to facilitate discrimination between tumour cells and astrocytes. Optical sections of co-culture spheroids generated using confocal microscopy showed cell-cell contact between tumour cells and astrocytes. Finally, co-culture spheroids were separated by fluorescence activated cell sorting to facilitate downstream analyses on individual cell types. CONCLUSIONS This work presents a highly characterised model of medulloblastoma and ATRT interactions with healthy brain tissue, mimicking the immediate post-surgical microenvironment. Future work will utilise transcriptomics to assess the tumour-astrocyte crosstalk modelled using this system.

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Gatto, Francesca, Giacomo Milletti, Andrea Carai, Angela Mastronuzzi e Francesca Nazio. "Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours". Diagnostics 11, n. 3 (9 marzo 2021): 481. http://dx.doi.org/10.3390/diagnostics11030481.

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Autophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor—by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response—or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours.

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Hussein, Raad Ahmed, Muhammed Hameed Faeadh Al-Jumaily, Rana Hani Mohammed Ali Al-Shaikh Hamed e Asaad F. Albayati. "Paediatric desmoplastic medulloblastoma – Surgical treatment, adjuvant therapy, outcome survival (case series study)". Romanian Journal of Neurology 19, n. 1 (31 marzo 2020): 46–53. http://dx.doi.org/10.37897/rjn.2020.1.7.

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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". Neuroradiology 33, n. 2 (1991): 140–42. http://dx.doi.org/10.1007/bf00588252.

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Urbach, Stacey L., Normand Laperriere e Ute Bartels. "Endocrine Complications in Children Treated for Medulloblastoma or Ependymoma using Radiation Therapy – Outcomes in the Computed Tomography Planning Era". European Oncology & Haematology 07, n. 01 (2011): 48. http://dx.doi.org/10.17925/eoh.2011.07.01.48.

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Radiation therapy is an integral part of the treatment of paediatric patients with medulloblastoma and ependymoma. With newer surgical techniques and adjuvant chemotherapy regimens, recurrence-free survival rates have improved dramatically. Unfortunately, improved survival has come at the cost of significant late effects, including endocrine dysfunction. Prior to the 1990s, radiation fields were planned using 2D X-rays, exposing large volumes of healthy tissue to harmful radiation. Over the past two decades, radiation oncologists have increasingly applied 3D computed tomography scans to radiation therapy planning. By shaping target fields more precisely, higher doses of radiation may be delivered directly to the tumour while limiting exposure to healthy tissues and reducing side effects. The objective of this article is to review recent evidence about late endocrine effects among survivors of childhood medulloblastoma and ependymoma who received radiation therapy and to assess whether the introduction of 3D radiation planning techniques has affected the prevalence of these effects. Patients treated for medulloblastoma with current doses of craniospinal radiation continue to be at high risk of growth hormone deficiency and primary hypothyroidism, even when conformal radiation is used to deliver posterior fossa radiation. Patients with ependymoma who are treated with focal radiation alone, however, demonstrate fewer late endocrine effects.

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Cotton, Kian, e Maria Victoria Niklison-Chirou. "INVESTIGATING THE ROLE OF LIPID DROPLETS IN MEDULLOBLASTOMA TUMOURS". Neuro-Oncology 25, Supplement_3 (16 settembre 2023): iii15. http://dx.doi.org/10.1093/neuonc/noad147.062.

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Abstract AIMS Medulloblastomas (MBs) are the most common paediatric brain tumour which originates in the cerebellum. It is classified into four subgroups named: sonic hedgehog, wingless, Group 3 and Group 4. Current treatment for MBs includes surgery, followed by high levels of chemotherapy and radiotherapy. This treatment regime is highly aggressive for the developing brain and produces several significant side effects. Therefore, research into new treatments or improving those already available is crucial to improving patients of life. METHOD It is well-documented that cancer cells have the ability to reprogram their metabolism to support rapid proliferation. These metabolic adaptations will provide the cells with the ability to use alternative sources of energy such as glutamine or lipids. Lipid Droplets (LDs) are highly dynamic cytoplasmic organelles that, under homeostatic conditions, are key in the storage of excess lipids within the cell to provide a buffer against lipotoxicity. Recent research has also begun to describe LDs as more than simple storage molecules but instead as function- ally active organelles. Increases in LD formation have been reported in several cancers such as Glioblastoma RESULTS In this study, we observed that aggressive MB cells have significantly more LDs when compared to non- aggressive MB cells. Further, oleic acid stimulation induced LD formation in MB cells. Finally, in silico gene expression analysis was performed to evaluate the expression of multiple components of the de novo lipid synthesis pathway in medulloblastoma. CONCLUSIONS Our work demonstrates that aggressive MB cells overexpress LDs and therefore identifies them as a possible novel target for MB treatment.

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Bailey, Simon, Nicolas André, Lorenza Gandola, Maura Massimino, Stefan Rutkowski e Steven C. Clifford. "Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial". Cancers 14, n. 2 (13 gennaio 2022): 374. http://dx.doi.org/10.3390/cancers14020374.

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Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

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Dury, Richard, Rob Dineen, Anbarasu Lourdusamy e Richard Grundy. "Semi-automated medulloblastoma segmentation and influence of molecular subgroup on segmentation quality". Neuro-Oncology 21, Supplement_4 (ottobre 2019): iv14. http://dx.doi.org/10.1093/neuonc/noz167.060.

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Abstract Medulloblastoma is the most common malignant brain tumour in children. Segmenting the tumour itself from the surrounding tissue on MRI scans has shown to be useful for neuro-surgical planning, by allowing a better understanding of the tumour margin with 3D visualisation. However, manual segmentation of medulloblastoma is time consuming, prone to bias and inter-observer discrepancies. Here we propose a semi-automatic patient based segmentation pipeline with little sensitivity to tumour location and minimal user input. Using SPM12 “Segment” as a base, an additional tissue component describing the medulloblastoma is included in the algorithm. The user is required to define the centre of mass and a single surface point of the tumour, creating an approximate enclosing sphere. The calculated volume is confined to the cerebellum to minimise misclassification of other intracranial structures. This process typically takes 5 minutes from start to finish. This method was applied to 97 T2-weighted scans of paediatric medulloblastoma (7 WNT, 6 SHH, 17 Gr3, 26 Gr4, 41 unknown subtype); resulting segmented volumes were compared to manual segmentations. An average Dice coefficient of 0.85±0.07 was found, with the Group 4 subtype demonstrating a significantly higher similarity with manual segmentation than other subgroups (0.88±0.04). When visually assessing the 10 cases with the lowest Dice coefficients, it was found that the misclassification of oedema was the most common source of error. As this method is independent of image contrast, segmentation could be improved by applying it to images that are less sensitive to oedema, such as T1.

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Ferreras, Cristina, Lucía Fernández, Laura Clares-Villa, Marta Ibáñez-Navarro, Carla Martín-Cortázar, Isabel Esteban-Rodríguez, Javier Saceda e Antonio Pérez-Martínez. "Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours". Cells 10, n. 11 (29 ottobre 2021): 2940. http://dx.doi.org/10.3390/cells10112940.

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Central nervous system (CNS) tumours comprise 25% of the paediatric cancer diagnoses and are the leading cause of cancer-related death in children. Current treatments for paediatric CNS tumours are far from optimal and fail for those that relapsed or are refractory to treatment. Besides, long-term sequelae in the developing brain make it mandatory to find new innovative approaches. Chimeric antigen receptor T cell (CAR T) therapy has increased survival in patients with B-cell malignancies, but the intrinsic biological characteristics of CNS tumours hamper their success. The location, heterogeneous antigen expression, limited infiltration of T cells into the tumour, the selective trafficking provided by the blood–brain barrier, and the immunosuppressive tumour microenvironment have emerged as the main hurdles that need to be overcome for the success of CAR T cell therapy. In this review, we will focus mainly on the characteristics of the deadliest high-grade CNS paediatric tumours (medulloblastoma, ependymoma, and high-grade gliomas) and the potential of CAR T cell therapy to increase survival and patients’ quality of life.

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Apps, John R., Shaimaa Sahmoud, Katherine Green, Kriti Hedge, Claire Keeling, Anoop Cherungonath, Banuja Srikumar et al. "MDB-23. MULTICENTRE EVALUATION OF THE MANAGEMENT OF CHILDREN WITH HIGH RISK MEDULLOBLASTOMA: REAL WORLD PERFORMANCE OF THE SJMB03 AND COG99701 PROTOCOLS". Neuro-Oncology 26, Supplement_4 (18 giugno 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.472.

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Abstract BACKGROUND Several treatment protocols are used in the treatment of patients with high risk medulloblastoma (HRMB). In 2015 the UK Children’s Cancer and Leukaemia Group issued interim guidance recommending treatment as per the SJMB03 protocol, whilst also recognising that the COG99701 protocol may be used. Patients were defined as high risk, if metastatic at presentation, large cell anaplastic histology, MYC amplification, significant residual disease or MYCN amplification, the latter two, more recently only if other adverse features present. METHODS We present a retrospective multi-centre service evaluation of treatment of patients with HRMB at 5 tertiary paediatric oncology centres in the UK. Patients were included if treated for HRMB with SJMB03, COG-99701. Patients were excluded if treated for HRMB on other protocols, including the SIOP HRMB trial, or if initially treated for standard risk medulloblastoma and subsequently treated with these protocols due to upstaging or disease progression. Event free, and overall (EFS and OS) survival analyses were calculated from date of primary resection. RESULTS 59 patients were included (median age 8 years, range 3-19): 26 treated as per SJMB03, 33 as per COG-99701. 5-year OS was 83% (95% Confidence Interval, 73-94%) and 5-year EFS was 66% (54-80%). For patients treated as per SJMB03 5-year OS and EFS was 79% (65-97%) and 70% (55-92%)respectively. and for patients treated as per COG99701, 5-year OS and EFS was 86% (73-99%) and 60% (44-83%). There was a higher incidence of grade 3 & 4 ototoxicity (44% vs 6%) and a higher rate of admission to paediatric intensive care (36% vs 6%) in patients treated as per SJMB03 compared to those treated with COG97701 (p<0.05). CONCLUSIONS These real-world outcomes of patients treated in the UK for HRMB are consistent with the published literature for their outcomes for high risk medulloblastoma.

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Talamonti, Cinzia, Stefano Piffer, Leonardo Ubaldi, Daniela Greto, Francesco Laurina, Antonio Ciccarone, Piernicola Oliva et al. "PO-1799 Radiomic and dosiomic profiling of paediatric Medulloblastoma tumours treated with IMRT". Radiotherapy and Oncology 161 (agosto 2021): S1525—S1526. http://dx.doi.org/10.1016/s0167-8140(21)08250-5.

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Mather, Rebecca, Katie Stephenson, Laura Donovan, Michael Taylor, Reinhard Vlasak, Geoffrey Pilkington e Helen Fillmore. "PTPS-20THE GD3 ACETYLATION PATHWAY AS A POTENTIAL THERAPEUTIC TARGET FOR PAEDIATRIC MEDULLOBLASTOMA". Neuro-Oncology 17, suppl 5 (novembre 2015): v183.3—v183. http://dx.doi.org/10.1093/neuonc/nov228.20.

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Newton, Herbert B. "Review of the molecular genetics and chemotherapeutic treatment of adult and paediatric medulloblastoma". Expert Opinion on Investigational Drugs 10, n. 12 (dicembre 2001): 2089–104. http://dx.doi.org/10.1517/13543784.10.12.2089.

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Mather, Rebecca L., Katie F. Loveson, Laura K. Donovan, Michael D. Taylor, Geoffrey J. Pilkington e Helen L. Fillmore. "MB-81THE GD3 ACETYLATION PATHWAY AS A POTENTIAL THERAPEUTIC TARGET FOR PAEDIATRIC MEDULLOBLASTOMA". Neuro-Oncology 18, suppl 3 (giugno 2016): iii115.3—iii115. http://dx.doi.org/10.1093/neuonc/now076.77.

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