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medulloblastoma

Chinese Medical Journal 1999年第4期 10-14页

作者：张荣周良辅

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ＯｂｊｅｃｔｉｖｅＴｏｅｌｕｃｉｄａｔｅｔｈｅｄｉａｇｎｏｓｉｓ，ｔｒｅａｔｍｅｎｔａｎｄｐｒｏｇｎｏｓｉｓｏｆｍｅｄｕｌｏｂｌａｓｔｏｍａｉｎｂｏｔｈｃｈｉｌｄｒｅｎａｎｄａｄｕｌｔｓ．ＭｅｔｈｏｄｓＡｒｅｔｒｏｓｐｅｃｔｉｖｅｒｅｖｉｅｗｗａｓｃ...

关键词： medulloblastoma · therapy · survival rate · Collins’ law

Metabolic determinants of stemness in medulloblastoma

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World Journal of Stem Cells 2022年第8期14卷 587-598页

作者： Paula Martín-Rubio Pilar Espiau-Romera Alba Royo-García Laia Caja Patricia Sancho Hospital Universitario Miguel Servet IIS AragónZaragoza 50009Spain Department of Medical Biochemistry and Microbiology Biomedical CenterUppsala UniversityUppsala SE-751Sweden

medulloblastomas(MBs)are the most prevalent brain tumours in children.They are classified as grade IV,the highest in malignancy,with about 30%metastatic tumours at the time of diagnosis.Cancer stem cells(CSCs)are a small subset of tumour cells that can initiate and support tumour growth.In MB,CSCs contribute to tumour initiation,metastasis,and therapy resistance.Metabolic differences among the different MB groups have started to emerge.Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways,whereas Group 3 MBs upregulate glycolysis,gluconeogenesis,glutamine anabolism,and glutathione-mediated anti-oxidant pathways.Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically.In this review,we summarise the existing knowledge about metabolic rewiring in MB,with a particular focus on MB-CSCs.Finally,we highlight some of the emerging metabolism-based therapeutic strategies for MB.

关键词： medulloblastoma Cancer stem cells Stemness Metabolism Glycolysis Lipids

Immune microenvironment of medulloblastoma:The association between its molecular subgroups and potential targeted immunotherapeutic receptors

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World Journal of Clinical Oncology 2023年第3期14卷 117-130页

作者： Maher Kurdi Nasser Mulla Husam Malibary Ahmed K Bamaga Motaz M Fadul Eyad Faizo Sahar Hakamy Saleh Baeesa Department of Pathology Faculty of MedicineKing Abdulaziz UniversityRabigh 213733Saudi Arabia Neuromuscular Unit King Fahad Medical Research CenterKing Abdulaziz UniversityJeddah 213733Saudi Arabia Department of Internal Medicine Faculty of MedicineTaibah UniversityMedina 213733Saudi Arabia Department of Internal Medicine Faculty of MedicineKing Abdulaziz UniversityJeddah 213733Saudi Arabia Department of Paediatrics Faculty of MedicineKing Abdulaziz UniversityJeddah 213733Saudi Arabia Division of Neurosurgery Department of SurgeryFaculty of MedicineTabuk UniversityTabuk 213733Saudi Arabia Neurmuscular Unit Center of Excellence of Genomic MedicineJeddah 21423Saudi Arabia Department of Neuroscience King Faisal Specialist Hospital and Research CenterJeddahSaudi Arabia

medulloblastoma(MB)is considered the commonest malignant brain tumor in children.Multimodal treatments consisting of surgery,radiation,and chemotherapy have improved patients’survival.Nevertheless,the recurrence occurs in 30%of cases.The persistent mortality rates,the failure of current therapies to extend life expectancy,and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches.Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections.Recently,MBs have been segregated into four molecular subgroups:Wingless-activated(WNT-MB)(Group 1);Sonichedgehog-activated(SHH-MB)(Group 2);Group 3 and 4 MBs.These molecular alterations follow specific gene mutations and disease-risk stratifications.The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival.However,the need to explore new therapies targeting specific receptors in MB microenvironment became essential.The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells.Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment,and their role are still under investigation.In this review,we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment,with an overview of the recent investigations and clinical trials.

关键词： medulloblastoma Tumour microenvironment Tumour associated macrophages Tumour infiltrating lymphocyte Immunotherapies

1H magnetic resonance spectroscopy and diffusion weighted imaging findings of medulloblastoma in 3.0T MRI A retrospective analysis of 17 cases

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Neural Regeneration Research 2012年第32期7卷 2554-2559页

作者： Prasanna Ghimire MR Room Zhongnan Hospital of Wuhan University

1H magnetic resonance spectroscopy and diffusion weighted imaging features of the cerebellar vermis in 17 medulloblastoma patients were retrospectively analyzed, and 17 healthy volunteers were selected as controls. 1H magnetic resonance spectroscopy showed that in all 17 medulloblastoma patients, N-acetyl aspartate and creatine peaks were significantly decreased, the choline peak was significantly increased, and there was evidence of a myo-inositol peak. Further, 11 patients showed a low taurine peak at 3.4 ppm, five patients showed a lipid peak at 0.9-1.3 ppm, and three patients showed a negative lactic acid peak at 1.33 ppm. Compared with the control group, the ratios of N-acetyl aspartate/choline and N-acetyl aspartate/creatine were significantly decreased, and the ratio of choline/creatine was increased, in medulloblastoma patients. Diffusion weighted imaging displayed hyperintensity and decreased apparent diffusion coefficient in medulloblastoma patients. These findings indicate that 1H magnetic resonance spectroscopy and diffusion weighted imaging are useful for qualitative diagnosis of medulloblastoma.

关键词： medulloblastoma proton magnetic resonance spectroscopy diffusion weighted imaging apparent diffusion coefficient N-acetyl aspartate choline creatine taurine lactic acid myo-inositol

Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

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Acta Pharmaceutica Sinica B 2021年第2期11卷 488-504页

作者： Xiaohua Liu Yu Zhang Yalei Li Juan Wang Huaqian Ding Wenjing Huang Chunyong Ding Hongchun Liu Wenfu Tan Ao Zhang CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica(SIMM)Chinese Academy of SciencesShanghai 201203China Department of Pharmacology School of PharmacyFudan UniversityShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia Medica(SIMM)Chinese Academy of SciencesShanghai 201203China School of Pharmacy Shanghai Jiao Tong UniversityShanghai 200240China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Esophageal Cancer Prevention and Treatment Ministry of Education of ChinaZhengzhou UniversityZhengzhou 450001China

medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tumor,however,clinically effective molecular targeted therapy is lacking.Modulation of hedgehog(HH)signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4(BRD4)has recently spurred new interest as potential treatment of HH-driven MB.Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog(GLI)protein,the BRD4 inhibitor 2 was selected as the lead for further structural optimization,which led to the identification of compounds 25 and 35 as the high potency HH inhibitors.Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI,and were equally potent against the clinical resistant mutants and the wild type of smoothened(SMO)receptor with IC50 values around 1 nmol/L.In the resistant MB allograft mice,compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg(TGI=83.3%)and 10 mg/kg(TGI=87.6%)doses.Although further modification is needed to improve the pharmacokinetic(PK)parameters,compound 25 represents an efficacious lead compound of GLI inhibitors,possessing optimal safety and tolerance to fight against HH-driven MB.

关键词： medulloblastoma Hedgehog signaling pathway Drug resistance GLI BRD4

Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism in medulloblastoma/PNET and Hodgkin lymphoma:a prospective cohort study

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Frontiers of Medicine 2021年第1期15卷 101-107页

作者： Maura Massimino Marta Podda Lorenza Gandola Emanuele Pignoli Ettore Seregni Carlo Morosi Filippo Spreafico Andrea Ferrari Emilia Pecori Monica Terenziani Pediatric Oncology Unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Pediatric Radiotherapy Unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Medical Physics Unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Department of Nuclear Medicine Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Department of Radiology Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy

Primary hypothyroidism commonly occurs after radiotherapy(RT),and coincides with increased circulating thyroid-stimulating hormone(TSH)levels.We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma(HL)in a prospective cohort study.From 1998 to 2001,a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL,scheduled for craniospinal irradiation and mediastinum/neck radiotherapy,respectively,underwent thyroid ultrasound and free triiodothyronine(FT3),free thyroxine(FT4),and TSH evaluation at the beginning and end of craniospinal iiradiation.From 14 days before and up to the end of radiotherapy,patients were administered L-thyroxine checking every 3 days TSH to ensure a valuemedulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels˂0.3μIU/mL and well matched for other variables.Twenty years on,hypothyroidism-free survival rates differed significantly,being 60%±15%and 15.6%±8.2%in TSH-suppressed vs.not-TSH suppressed patients,respectively(P=0.001).These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae,but it should be confirmed in a larger cohort.

关键词： iatrogenic primary hypothyroidism late effects of radiotherapy long-term follow-up medulloblastoma Hodgkin lymphoma

Treatment of pediatric average-risk medulloblastoma using craniospinal irradiation less than 2500 cGy and chemotherapy: single center experience in Korea

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World Journal of Pediatrics 2017年第4期13卷 367-373页

作者： Jong Hyung Yoon Kyung Duk Park Hyoung Jin Kang Hyery Kim Ji Won Lee Seung-Ki Kim Kyu-Chang Wang Sung-Hye Park Il Han Kim Hee Young Shin Department of Pediatrics Cancer Research InstituteSeoul National University College of MedicineSeoul Department of Pediatrics Hallym University College of medicineChuncheon Sacred Heart HospitalChuncheonKorea Departments of Neurosurgery Seoul National University College of MedicineSeoul Pathology Seoul National University College of MedicineSeoul Radiation Oncology Seoul National University College of MedicineSeoul

Background:Although craniospinal irradiation (CSI) of 2340 cGy plus tumor booster with chemotherapy have been established as a standard treatment of childhood average-risk (AvR) medulloblastoma (MBL) in Western counties,there are a few recent reports in outcomes ofAvR MBL using this strategy in Korean and other Asian children.We investigated the outcome of the Korean children with AvR MBL who were treated with CSI <2500 cGy and chemotherapy.Methods:Between January 2001 and December 2010,clinical characteristics and outcomes of 42 patients who were diagnosed with AvR MBL postoperatively and treated with radiation including CSI <2500 cGy and chemotherapy in Seoul National University Children's Hospital were analyzed.Results:Their median age was 9 years (range:3-18.8),and 29 were male.Histological subtypes were classic type in 28 patients,nodular/desmoplastic in 7,and large cell/anaplastic (LCA) in 7.All the patients received adjuvant radiotherapy (CSI with median 2340 cGy and booster) and multiagent chemotherapy as the first-fine treatment.With a median follow-up of 54 months,12 patients experienced relapse or progression of the tumor.The 3-and 5-year disease-free survival (DFS) rates were 78.0%±6.5% and 75.0%±6.9%,respectively,and overall survival (OS) rates were 85.3%±5.6% and 76.8%±6.9%,respectively.The LCA subtype was associated with poorer DFS (P=0.023) and OS (P=0.008),compared with non-LCA subtypes.Conclusion:The outcomes of children and adolescents with AvR MBL treated with radiation including CSI <2500 cGy and chemotherapy,are compatible to those in Western countries;however,the LCA subtype has a poor outcome with this strategy.

关键词： average-risk craniospinal irradiation medulloblastoma

Immune cell landscape and immunotherapy of medulloblastoma

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Pediatric Investigation 2021年第4期5卷 299-309页

作者： Jin Zhang Tianyou Wang Department of Pediatrics Beijing Shijitan HospitalCapital Medical UniversityBeijingChina Hematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityBeijingChina

medulloblastoma is the most common primary pediatric malignancy of the central nervous system.Recurrent and refractory patients account for approximately 30%of them.Immune cells are an important component of the brain tumor microenvironment,including tumor-associated macrophages,T lymphocytes,natural killer cells,dendritic cells,neutrophils and B lymphocytes.Understanding how they behave and interact is important in the investigation of the onset and progression of medulloblastoma.Here,we overview the features and recent advances of each component of immune cells in medulloblastoma.Meanwhile,immunotherapy is a promising but also challenging treatment strategy for medulloblastoma.At present,there are a growing number of immunotherapeutic approaches under investigation including immune checkpoint inhibitors,oncolytic viruses,cancer vaccines,chimeric antigen receptor T cell therapies,and natural killer cells in recurrent and refractory medulloblastoma patients.

关键词： medulloblastoma Tumor microenvironment Immune cells Immunotherapy

Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of medulloblastoma

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Natural Products and Bioprospecting 2015年第2期5卷 91-97页

作者： Zhen-Nan Ye Mu-Yuan Yu Ling-Mei Kong Wei-Hua Wang Yuan-Feng Yang Jie-Qing Liu Ming-Hua Qiu Yan Li State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunming 650201YunnanChina University of Chinese Academy of Sciences Beijing 100049China

medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefore,Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer.In our present study,we undertook a screening for antagonists of Wnt signaling from 600 natural compounds,and identified Ginkgetin,a biflavone isolated from Cephalotaxus fortunei var.alpina.Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 lM and structure–activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group.Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells.Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells.Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes,including Axin2,cyclinD1 and survivin in MB cells.The phosphorylation level of b-catenin also decreased in a time-and concentration-dependent manner.Collectively,our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling,and as such warrants further exploration as a promising antimedulloblastoma candidate.

关键词： Wnt signaling medulloblastoma Inhibitor Biflavone Ginkgetin