Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 157
Filtrar
1.
Zhonghua Yi Xue Za Zhi ; 100(3): 178-181, 2020 Jan 21.
Artigo em Chinês | MEDLINE | ID: mdl-32008282

RESUMO

Objective: To evaluate the classification of the types of pediatric posterior fossa brain tumors based on routine MRI (T(1)WI, T(2)WI and ADC) using wavelet transformation analysis of whole tumor. Methods: MRI images of medulloblastoma (n=59), ependymoma (n=13) and pilocytic astrocytoma (n=27) confirmed by pathology before treatments in Children's Hospital of Nanjing Medical University from January 2014 to February 2019 were enrolled in this retrospective study as well as the clinical data of age, gender and symptoms. Registration was performed among the three sequences and wavelet features of ROI were acquired. Afterwards, the top ten features were ranked and trained among groups by using random forest classifier. Finally, the results were compared and analyzed according to the classification. Results: The top ten contribution three sequences and wavelet features of ROI were acquired from the ADC sequence. The random forest classifier achieved 100% accuracy on training data and was validated best accuracy (86.8%) when combined of first and third wavelet features. The sensitivity was 100%, 94.8%, 76.9%, and the specificity was 97.6%, 88.0%, 98.8% respectively. Conclusions: Features based on wavelet transformation of ADC sequence of entire tumor can provide more quantitative information, which could provide help in the differential diagnosis of pediatric posterior fossa brain tumors. The optimum combination to distinguish three pediatric posterior fossa brain tumors is sixth and twelfth wavelet features of ADC sequence.


Assuntos
Astrocitoma/classificação , Neoplasias Cerebelares/patologia , Neoplasias Infratentoriais/patologia , Imagem por Ressonância Magnética/métodos , Meduloblastoma/classificação , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Criança , Humanos , Meduloblastoma/patologia , Estudos Retrospectivos
2.
Nature ; 572(7767): 74-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341285

RESUMO

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.


Assuntos
Genômica , Meduloblastoma/genética , Meduloblastoma/patologia , Análise de Célula Única , Transcriptoma , Adolescente , Adulto , Animais , Linhagem da Célula , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Lactente , Meduloblastoma/classificação , Camundongos , Neurônios/metabolismo , Neurônios/patologia
3.
J Neurooncol ; 144(2): 283-291, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236820

RESUMO

PURPOSE: To report outcomes of salvage re-irradiation (re-RT) in recurrent/progressive medulloblastoma (MB). METHODS: Medical records of patients treated with curative-intent re-RT as multi-modality management for recurrent/progressive MB between 2008 and 2018 were analyzed retrospectively. RESULTS: A total of 28 patients (median age 18 years at index diagnosis) were included. Molecular subgrouping was done using real-time reverse transcriptase polymerase chain reaction (RT-PCR) based on the differential expression of select set of 12 protein coding genes and 9 microRNAs. Fifteen of 17 (88%) patients with sonic hedgehog (SHH)-MB developed isolated local recurrence within the index tumor-bed, while 5 of 7 (72%) patients with Group 4 MB developed localized relapse outside the posterior fossa. Diffuse neuraxial dissemination was seen in 2 patients with SHH-MB, and one each of Group 4 and wingless (WNT)-MB. Molecular subgrouping was not known in 3 patients. The dose and volume of re-RT was based on site and patterns of relapse, comprising unifocal in 18 (64%), multi-focal in 3 (11%), and repeat craniospinal irradiation (re-CSI) in 7 (25%) patients. Median interval from primary irradiation to re-RT was 49.5 months (range 24-98 months) with median cumulative biologically effective dose of 117 Gy (range 78-132 Gy). All patients received platinum-based salvage chemotherapy either before or after re-RT. One patient developed symptomatic radiation necrosis following re-CSI. At a median follow-up of 24 months (range 6-84 months), 2-year post-re-RT progression-free survival (PFS) and overall survival (OS) was 46% and 51% respectively. Younger age (< 18 years) at index diagnosis, primary risk stratification (standard-risk) and molecular subgrouping (Group 4) were associated with significantly better post-re-RT outcomes. CONCLUSION: Salvage re-RT provides good local control and encouraging survival outcomes with acceptable toxicity in selected patients with recurrent/progressive MB.


Assuntos
Neoplasias Cerebelares/mortalidade , Meduloblastoma/mortalidade , Recidiva Local de Neoplasia/mortalidade , Reirradiação/mortalidade , Medição de Risco/métodos , Terapia de Salvação , Adolescente , Adulto , Fatores Etários , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/classificação , Meduloblastoma/patologia , Meduloblastoma/radioterapia , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
4.
J Neurooncol ; 143(3): 393-403, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31104222

RESUMO

INTRODUCTION: Molecular classification of medulloblastomas (MB) is prognostically and therapeutically relevant and helps in better risk-stratification. Translation of this subgrouping to routine practice still remains a challenge. The most pathologist accessible techniques for molecular subgrouping include immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH) and NanoString. OBJECTIVES: (1) Molecular subgrouping of MBs by IHC and FISH, and NanoString assay (2) To compare their efficacy and cost for applicability in resource constrained centers. METHODS: Ninety-five cases of MB with adequate tissue were included. Molecular subgrouping was performed by IHC for ß-catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array. RESULTS: IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation. CONCLUSIONS: Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice.


Assuntos
Neoplasias Cerebelares/classificação , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Meduloblastoma/classificação , Nanotecnologia/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Metilação de DNA , Feminino , Seguimentos , Recursos em Saúde , Humanos , Lactente , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
5.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Genética , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
6.
Klin Onkol ; 32(Supplementum1): 171-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31064192

RESUMO

BACKGROUND: Medulloblastoma (MB) is the most common malignant tumour of the central nervous system in children. MB is considered to be high risk tumour propensity to metastasize. In the Czech Republic, approximately 10-12 children are affected annually by this tumour. Recent progress in molecular diagnostics helps to refine the diagnosis and estimate clinical prognosis of the disease. Currently, MBs are subclassified into WNT-activated, SHH-activated, group 3, and 4 based on molecular pathways that drive their tumorigenesis. Each subtype differs in its histopathology, clinical features, genomic changes and gene expressions. The aim of our study is to classify patients MBs into four basic molecular groups and compare our results with published data. MATERIAL AND METHODS: In our study we analysed expression profiles using Affymetrix GeneChip Human Gene 1.0. ST Array (Thermo Fisher Scientific, MA, USA). As input material RNA extracted from the fresh frozen tissue was used. Molecular classification based on the method established by P. Northcott in 2011 was performed. RESULTS: From April 2015 to February 2019, 21 patients with MBs were included in our study. Median age of the patients at the time of diagnosis was 6 years, 14 boys and 7 girls were enrolled. Gene expression profiling and molecular classification of MBs was performed. Based on this methodology, we found the most frequently represented subgroup of MB was group 4 (9 patients, 43%), followed by group 3 (5 patients, 24%), SHH-activated MB (4 patients, 19%) and the least represented subgroup was WNT-activated MB (3 patients, 14%). Results of molecular subgroup classification of MBs were successfully correlated with histopathological findings and other molecular-genetic examinations. CONCLUSION: Molecular classification of MBs has been established in our institution allowing better understanding of this heterogeneous disease and helping clinicians in therapeutic planning in affected patients. This work was supported by the Czech Ministry of Health grant No. 16-33209A. All rights reserved.  he authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 4. 3. 2019.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/patologia , Perfilação da Expressão Gênica , Genoma Humano , Meduloblastoma/classificação , Meduloblastoma/patologia , Neoplasias Cerebelares/genética , Criança , Biologia Computacional/métodos , República Tcheca , Feminino , Humanos , Meduloblastoma/genética , Prognóstico
7.
Cancer Res ; 79(9): 2426-2434, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30890619

RESUMO

Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. Although risk stratification of patients with MB based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon. In this study, we investigated the potential of rapid tumor characterization with Picosecond infrared laser desorption mass spectrometry (PIRL-MS) for MB subgroup classification based on small molecule signatures. One hundred and thirteen ex vivo MB tumors from a local tissue bank were subjected to 10- to 15-second PIRL-MS data collection and principal component analysis with linear discriminant analysis (PCA-LDA). The MB subgroup model was established from 72 independent tumors; the remaining 41 de-identified unknown tumors were subjected to multiple, 10-second PIRL-MS samplings and real-time PCA-LDA analysis using the above model. The resultant 124 PIRL-MS spectra from each sampling event, after the application of a 95% PCA-LDA prediction probability threshold, yielded a 98.9% correct classification rate. Post-ablation histopathologic analysis suggested that intratumoral heterogeneity or sample damage prior to PIRL-MS sampling at the site of laser ablation was able to explain failed classifications. Therefore, upon translation, 10-seconds of PIRL-MS sampling is sufficient to allow personalized, subgroup-specific treatment of MB during surgery. SIGNIFICANCE: This study demonstrates that laser-extracted lipids allow immediate grading of medulloblastoma tumors into prognostically important subgroups in 10 seconds, providing medulloblastoma pathology in an actionable manner during surgery.


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/patologia , Cuidados Intraoperatórios , Meduloblastoma/classificação , Meduloblastoma/patologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Neoplasias Cerebelares/cirurgia , Humanos , Meduloblastoma/cirurgia
8.
Brain Tumor Pathol ; 36(1): 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30523493

RESUMO

Expression of the ALK gene strongly correlates with the WNT-activated medulloblastomas, which are routinely identified by detection of CTNNB1 mutation. However, some tumors have mutations in other than CTNNB1 genes. Therefore, we investigated if ALK expression may identify WNT-activated tumors without CTNNB1 mutation. In addition, we examined if ALK expression may differentiate WNT-activated medulloblastoma from other malignant posterior fossa tumors. ALK expression was analyzed using immunohistochemistry (clone D5F3) in 70 patients with posterior fossa tumours. Among 55 medulloblastomas, 6 tumors showed ALK expression in > 50% of tumor cells. In one tumor, with ALK positive reaction, negative nuclear reaction against ß-catenin and the lack of CTNNB1 mutation, next generation sequencing revealed a presence of pathogenic variant c.3366_3369del in the APC gene, with homozygous deletion leading to inactivation of both copies in tumor cells. MLPA analysis displayed the presence of chromosome 6 monosomy, therefore, confirming the WNT type of this tumor. All analyzed 19 anaplastic ependymomas, 4 choroid plexus carcinomas and 2 atypical teratoid rhabdoid tumors were immunonegative for ALK expression. Therefore, we propose, that immunohistochemical detection of ALK protein should be highly recommended in routine investigation, in parallel to already established methods for identification and differentiation of WNT-activated medulloblastoma.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Infratentoriais/diagnóstico , Neoplasias Infratentoriais/genética , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Mutação , beta Catenina/genética , Adolescente , Criança , Pré-Escolar , Diagnóstico por Computador , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Neoplasias Infratentoriais/classificação , Masculino , Meduloblastoma/classificação , Via de Sinalização Wnt
9.
Curr Opin Neurol ; 31(6): 747-751, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30300240

RESUMO

PURPOSE OF REVIEW: Medulloblastoma is no more a unique disease. Clinical and biologic classification used so far are challenged by molecular classification(s). Following the consensus article that described four molecular groups of medulloblastoma in 2012, several articles in 2017 provided more relevant classifications that may impact on further clinical trial design. RECENT FINDINGS: Though wingless (WNT) and sonic hedgehog (SHH) are defined by the activation of their respective pathways, the age and type of activation define various subgroups with specific features and outcome. Groups 3 and 4 remain ill defined. The whole population of medulloblastoma may be divided in 12 subgroups: WNTαß, SHHαßγδ, group 3αßγ and group 4αßγ. The paediatric population may be divided in seven subgroups: WNT, SHH of infants and children, and low-risk and high-risk groups 3 and 4. SHH of infants may be divided as iSHH-I vs. iSHH-II that have different prognosis. Moreover, specific drivers of groups 3 and 4 were reported. SUMMARY: These findings have and will have direct implications on the conception of clinical trials. Low-risk groups will benefit from less toxic therapies, and high-risk groups will benefit from targeted therapies.


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Prognóstico , Biomarcadores , Neoplasias Cerebelares/diagnóstico , Humanos , Meduloblastoma/diagnóstico , Valor Preditivo dos Testes
10.
Expert Rev Neurother ; 18(8): 633-647, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30032687

RESUMO

INTRODUCTION: Integrated genomics has significantly advanced our understanding of medulloblastoma heterogeneity. It is now clear that it actually comprises at least four distinct molecular subgroups termed Wnt/Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4 with stark clinical and biological differences. Areas covered: This paper reviews advances in the classification and risk stratification of medulloblastoma, specifically integrating subgroup with clinical and cytogenetic risk factors, with a summary of the potential to lead to more precise therapies. Moreover, the current state of preclinical modeling is summarized with respect to their utility in generating new treatments and correlation with genomic discoveries. Opportunities and challenges in developing new treatment paradigms are summarized and discussed, specifically new therapies for very high-risk metastatic/MYC-amplified Group 3 and TP53-mutant SHH and reductions in therapy for lower risk groups. Expert commentary: Survival across medulloblastoma has been stagnant for over 30 years, and new treatment paradigms are urgently required. Current therapy significantly over treats a high proportion of patients leaving them with lifelong side effects; while many patients still succumb to their disease. Applying biological advances could improve quality of life for a significant proportion of patients while offering new upfront approaches to the highest risk patients.


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Genômica , Meduloblastoma/classificação , Meduloblastoma/genética , Criança , Humanos , Qualidade de Vida , Medição de Risco , Fatores de Risco
11.
Annu Rev Neurosci ; 41: 207-232, 2018 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-29641939

RESUMO

Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25-30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Terapia de Alvo Molecular/métodos , Animais , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/terapia
12.
J Neurooncol ; 138(2): 231-240, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29427151

RESUMO

Medulloblastoma, the most common malignant pediatric brain tumor, is a heterogeneous disease, with the existence of at least four molecular types: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 tumors. The latter two groups, which can be identified by an application of multi-gene expression or methylation profiling, show sometimes ambiguous categorization and are still classified for diagnostic reason as non-SHH/non-WNT medulloblastomas in updated WHO 2016 classification. In order to better characterize non-SHH/non-WNT tumors, we applied the method based on the Nanostring nCounter Technology, using the 26 genes codeset in 68 uniformly treated medulloblastoma patients. This allowed for identification of tumors, which shared common Group 3 and Group 4 gene signatures. We recognized three transcriptional groups within non-WNT/non-SHH tumors: Group 3, Group 4 and the Intermediate 3/4 Group. Group 3, in line with previously published results, showed poor prognosis with survival rate < 40%, frequent metastases, large cell/anaplastic pathology and presence of tumors with MYCC amplification. This is in contrast to patients from the Intermediate 3/4 Group who showed the best survival rate (100%). Overall and progression free survival were better for this group than for Group 3 (p = 0.001, for both) and Group 4 (p = 0.064 and p = 0.066, respectively). Our work supports the view that within the non-WNT/non-SHH tumors different risk groups exist and that the current two groups classifier may be not sufficient for proper clinical categorization of individual patients.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/metabolismo , Meduloblastoma/diagnóstico , Meduloblastoma/metabolismo , Adolescente , Algoritmos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/mortalidade , Criança , Pré-Escolar , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Meduloblastoma/classificação , Meduloblastoma/mortalidade , Prognóstico , RNA/metabolismo , Análise de Sobrevida
13.
Hum Pathol ; 75: 26-33, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29412177

RESUMO

The World Health Organization classification of central nervous system neoplasms (2016 update) recognizes 4 histological variants and genetically defined molecular subgroups within medulloblastoma (MB). MB with myogenic differentiation is one of the rare variants, which is usually recognized as a pattern alongside the known histological variants. Because of its rarity, less is known about its molecular landscape and importantly about its placement in the current molecular schema. We aimed to analyze this rare variant for expression of 3 immunohistochemical markers conventionally used in molecular stratification of MB. Demographic profile and imaging details with survival outcome were also analyzed. Sixty-five MB cases were molecularly stratified using immunohistochemical markers (YAP1, GAB1, ß-catenin). MB with myogenic differentiation and MB cases showing variable immunoreactivity with the above 3 antibodies were further evaluated for smooth muscle actin, desmin, myogenin, and HMB45. Seven cases were categorized as MB with myogenic and/or melanotic differentiation. Age ranged from 2 to 40 years with a male-to-female ratio of 1:1.3. In 4 cases, myogenic or melanotic differentiation was evident on histology, whereas in 3, differentiation was highlighted only with muscle markers. Interestingly, all 7 cases showed variable immunoreactivity with 3 molecular markers and did not follow the conventionally accepted algorithm used for molecular stratification. Follow-up period ranged from 9 to 57 months. Overall survival revealed a varied pattern, with 3 deaths and 4 patients being alive with no evidence of disease at last follow-up. Our results provide evidence that these variants are distinct and do not align immunohistochemically with the currently recognized genetic subgroups.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Adolescente , Adulto , Diferenciação Celular , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Masculino , Meduloblastoma/classificação , Meduloblastoma/genética , Adulto Jovem
14.
Neuro Oncol ; 20(1): 13-23, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28449033

RESUMO

Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.


Assuntos
Neoplasias Encefálicas , Meduloblastoma , Neoplasias Meníngeas , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Criança , Humanos , Meduloblastoma/classificação , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/terapia , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/terapia , Inoculação de Neoplasia , Neuroimagem
16.
Nature ; 547(7663): 311-317, 2017 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-28726821

RESUMO

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.


Assuntos
Análise Mutacional de DNA , Genoma Humano/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Sequenciamento Completo do Genoma , Carcinogênese/genética , Proteínas de Transporte/genética , Estudos de Coortes , Metilação de DNA , Conjuntos de Dados como Assunto , Epistasia Genética , Genômica , Humanos , Terapia de Alvo Molecular , Proteínas Musculares/genética , Mutação , Oncogenes/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética
17.
J Clin Oncol ; 35(21): 2355-2363, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28640708

RESUMO

Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric. Distinguishing the four molecular subgroups of medulloblastoma-wingless (WNT), sonic hedgehog (SHH), group 3, and group 4-in the daily treatment of patients, as well in the setting of clinical trials, is an important challenge in the near term for the pediatric neuro-oncology community. The preponderance of morbidity in treating patients with medulloblastoma is secondary to the treatment or prophylaxis of leptomeningeal metastases, and the cause of most deaths is leptomeningeal metastases. Recurrence of medulloblastoma is a nearly universally fatal event, with no significant salvage rate. The extent of spatial and temporal intratumoral heterogeneity as medulloblastoma metastasizes to leptomeninges and as it evolves in the face of radiation and cytotoxic chemotherapy is just beginning to be understood as a major barrier to therapeutic success. Pediatric neuro-oncology clinicians and scientists must now determine how best to incorporate rapid changes in our biologic understanding of medulloblastoma into the next generation of upfront clinical trials, with the goal of both improving survival for the highest-risk patients and improving quality of life for survivors.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/terapia , Meduloblastoma/classificação , Meduloblastoma/terapia , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Proteínas Hedgehog/análise , Humanos , Lactente , Meduloblastoma/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Qualidade de Vida , Medição de Risco , Proteínas Wnt/análise
18.
Cancer Cell ; 31(6): 737-754.e6, 2017 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-28609654

RESUMO

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.


Assuntos
Meduloblastoma/classificação , Medicina de Precisão , Análise por Conglomerados , Estudos de Coortes , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Genômica , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia
19.
Lancet Oncol ; 18(7): 958-971, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28545823

RESUMO

BACKGROUND: International consensus recognises four medulloblastoma molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4), each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. METHODS: In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0-16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3-16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. FINDINGS: Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNT remained unchanged and each remaining consensus subgroup was split in two. MBSHH was split into age-dependent subgroups corresponding to infant (<4·3 years; MBSHH-Infant; n=65) and childhood patients (≥4·3 years; MBSHH-Child; n=38). MBGrp3 and MBGrp4 were each split into high-risk (MBGrp3-HR [n=65] and MBGrp4-HR [n=85]) and low-risk (MBGrp3-LR [n=50] and MBGrp4-LR [n=73]) subgroups. These biological subgroups were validated in the independent cohort. We identified features of the seven subgroups that were predictive of outcome. Cross-validated subgroup-dependent survival models, incorporating these novel subgroups along with secondary clinicopathological and molecular features and established disease risk-factors, outperformed existing disease risk-stratification schemes. These subgroup-dependent models stratified patients into four clinical risk groups for 5-year progression-free survival: favourable risk (54 [25%] of 215 patients; 91% survival [95% CI 82-100]); standard risk (50 [23%] patients; 81% survival [70-94]); high-risk (82 [38%] patients; 42% survival [31-56]); and very high-risk (29 [13%] patients; 28% survival [14-56]). INTERPRETATION: The discovery of seven novel, clinically significant subgroups improves disease risk-stratification and could inform treatment decisions. These data provide a new foundation for future research and clinical investigations. FUNDING: Cancer Research UK, The Tom Grahame Trust, Star for Harris, Action Medical Research, SPARKS, The JGW Patterson Foundation, The INSTINCT network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Metilação de DNA , Meduloblastoma/classificação , Meduloblastoma/genética , Transcriptoma , Adolescente , Fatores Etários , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Amplificação de Genes , Humanos , Lactente , Recém-Nascido , Fatores de Transcrição Kruppel-Like/genética , Masculino , Meduloblastoma/patologia , Meduloblastoma/radioterapia , Mutação , Proteína Proto-Oncogênica N-Myc/genética , Proteínas Nucleares/genética , Receptor Patched-1/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Receptor Smoothened/genética , Taxa de Sobrevida , Telomerase/genética , Proteína Supressora de Tumor p53/genética , Proteína Gli2 com Dedos de Zinco , beta Catenina/genética
20.
Neurotherapeutics ; 14(2): 265-273, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28386677

RESUMO

Recent advances in cancer genomics have revealed 4 distinct subgroups of medulloblastomas, each with unique transcription profiles, DNA alterations and clinical outcome. Molecular classification of medulloblastomas improves predictions of clinical outcome, allowing more accurate matching of intensity of conventional treatments with chemotherapy and radiation to overall prognosis and setting the stage for the introduction of targeted therapies.


Assuntos
Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Meduloblastoma/classificação , Meduloblastoma/genética , Medicina de Precisão , Transdução de Sinais , Neoplasias Cerebelares/metabolismo , Genômica , Proteínas Hedgehog , Humanos , Meduloblastoma/metabolismo , Mutação , Via de Sinalização Wnt
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA