RESUMO
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Humanos , Fosfatidilinositol 3-Quinases/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação , Complexo Repressor Polycomb 2/genética , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologiaRESUMO
BACKGROUND: In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. MATERIALS AND METHODS: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. RESULTS: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). CONCLUSION: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy.
Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Biópsia Líquida , Telômero/genética , Proteína Nuclear Ligada ao X/genéticaRESUMO
OBJECTIVE: The aim of this study was to describe progestin-associated meningiomas' characteristics, outcome and management. MATERIAL AND METHODS: We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. RESULTS: Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n=24) and ChlA/NomA (n=11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. CONCLUSIONS: Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.
Assuntos
Neoplasias Meníngeas , Meningioma , Acetato de Ciproterona , Humanos , Neoplasias Meníngeas/induzido quimicamente , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/cirurgia , Meningioma/induzido quimicamente , Meningioma/tratamento farmacológico , Meningioma/cirurgia , Progestinas , Base do CrânioRESUMO
BACKGROUND: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). OBJECTIVE: The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. MATERIALS AND METHODS: We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. RESULTS: The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas. CONCLUSION: Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.
Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Terapia Combinada , Feminino , Seguimentos , Predisposição Genética para Doença , Glioma/genética , Glioma/terapia , Humanos , Masculino , Prognóstico , Taxa de SobrevidaAssuntos
Neoplasias Encefálicas/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Neuroepiteliomatosas/genética , Proteínas Repressoras/genética , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/patologia , Feminino , Humanos , Lactente , Neoplasias Neuroepiteliomatosas/patologia , Fusão Oncogênica/genéticaRESUMO
AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Cromossomos Humanos Par 14/genética , Glioma/genética , Glioma/patologia , Metilação de DNA , Feminino , Humanos , Masculino , Monossomia , Neurocitoma/genética , Neurocitoma/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologiaRESUMO
PURPOSE: This work describes the clinical epidemiology and pathology for patients undergoing surgery for newly diagnosed meningiomas in France between 2006 and 2010. METHODS: The methodology is based on a multidisciplinary national network previously established by the French Brain Tumor DataBase (FBTDB) (in French: Recensement national histologique des tumeurs primitives du système nerveux central [RnhTPSNC]), and the active participation of the scientific societies involved in neuro-oncology in France. RESULTS: From 2006 to 2010, 13,038 incident cases of meningioma with histological validation were identified and analyzed (9769 women, 3269 men, resection 98.2%, cryopreservation 20.5%). For each histological subtype of meningioma (meningothelial, fibrous, transitional, psammomatous, angiomatous, rare variety, microcystic, secretory, lymphoplasmacyte-rich, clear-cell, chordoid, rhabdoid, metaplastic, atypical, papillary, anaplastic and not otherwise specified), number of cases, sex, median age, cryopreservation and surgery were reported. Among the various histological subtypes, atypical meningioma (grade II) slightly, but significantly, increased after 2007. Headache, sensory-motor impairments and seizures were the most frequent clinical symptoms. Time between the first clinical symptom and surgery ranged from 0 to 314 months, and was <3 months in 37% of cases. At the time of surgery, 9% of patients were asymptomatic. DISCUSSION/CONCLUSION: Given the number of meningiomas not histologically-validated, we can estimate that the gross incidence rate for meningiomas operated in France is about 4.2 per 100,000 person/year. To our knowledge, this work is the most important study evaluating the different subtypes of meningiomas and it validates the relevance of histological databases for central nervous system tumors.
Assuntos
Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , França/epidemiologia , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologiaRESUMO
Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.
Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Glioblastoma/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/patologia , beta Catenina/metabolismo , Adulto , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Encéfalo/patologia , Núcleo Celular/metabolismo , Proliferação de Células , Retroalimentação Fisiológica , Proteínas Ativadoras de GTPase/genética , Glioblastoma/genética , Glioblastoma/mortalidade , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/genética , Mitose , Células-Tronco Neoplásicas/citologia , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , beta Catenina/genéticaRESUMO
PURPOSE: The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and 18F-FDOPA uptake on PET in newly diagnosed gliomas. METHODS: A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone 18F-FDOPA PET at an initial stage before surgery and histological diagnosis. 18F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S). RESULTS: Patients with IDH mutation showed higher 18F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p < 0.05). CONCLUSION: This study showed paradoxically higher 18F-FDOPA uptake in diffuse grade II and III gliomas with IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of 18F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation.
Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Glioma/metabolismo , Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação , Tomografia por Emissão de Pósitrons , Adulto , Transporte Biológico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Di-Hidroxifenilalanina/metabolismo , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos RetrospectivosRESUMO
Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse.
Assuntos
Cicloexanos/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Proteínas Inibidoras de Apoptose/metabolismo , Terapia de Alvo Molecular , Pirróis/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia , Humanos , Imuno-Histoquímica , Camundongos Nus , Pessoa de Meia-Idade , Inclusão em Parafina , Prognóstico , Fixação de Tecidos , Adulto JovemRESUMO
INTRODUCTION: Phenotype changes between primary tumor and the corresponding brain metastases are recent reported data. Breast cancer, with biological markers predicting prognosis and guiding therapeutic strategy remains an interesting model to observe and evaluate theses changes. The objective of our study was to compare molecular features (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor type 2, [HER2]) between brain metastases and its primary tumor in patients presenting with pathologically confirmed breast cancer. MATERIAL AND METHODS: This retrospective study was based on the immunohistochemical analysis of the brain metastases paraffin embedded samples stored in our institutional tumor bank, after surgical resection. The level of expression of hormonal receptors and HER2 on brain metastases were centrally reviewed and compared to the expression status in primary breast cancer from medical records. RESULTS: Forty-four samples of brain metastases were available for analysis. Hormonal receptor modification status was observed in 11/44 brain metastases (25%) for ER and 6/44 (13.6%) for PR. A modification of HER2 overexpression was observed in brain metastases in 6/44 (13.6%). Molecular subtype modification was shown in 17 cases (38.6%). A significant difference was demonstrated between time to develop brain metastases in cases without status modification (HER2, ER and PR) (med=49.5months [7.8-236.4]) and in cases in which brain metastases status differs from primary tumor (med=27.5months [0-197.3]), (P=0.0244, IC95=3.09-51.62, Mann and Whitney test). CONCLUSION: the main interest of this study was to focus on the molecular feature changes between primary tumor and their brain metastases. Time to develop brain metastases was correlated to phenotypic changes in brain metastases.
Assuntos
Adenocarcinoma/secundário , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Estrogênios , Proteínas de Neoplasias/análise , Neoplasias Hormônio-Dependentes/secundário , Progesterona , Receptor ErbB-2/análise , Adenocarcinoma/química , Adenocarcinoma/terapia , Adulto , Idoso , Neoplasias Encefálicas/química , Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Imunofenotipagem , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/química , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Estudos Retrospectivos , Fatores de TempoAssuntos
Contratura/genética , Contratura/fisiopatologia , Golpe de Calor/genética , Golpe de Calor/fisiopatologia , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Temperatura Corporal , Estudos de Coortes , Variação Genética , Humanos , Hipertermia Maligna/fisiopatologia , Militares , Rianodina/farmacologiaRESUMO
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade glioma that frequently occurs in pediatric patients. OBJECTIVE: To analyze adult patients diagnosed with PXA and to search for pathological and molecular markers of diagnosis and prognosis. METHODS: We retrospectively included patients older than 16 years with PXA who were referred to our institution between October 2003 and September 2013. All pathological diagnoses were reviewed by a neuropathologist. Histological characteristics and immunostaining of GFAP, OLIG2, neurofilament, CD34, Ki67, p53, p16, and IDH1 R132H were analyzed. The following molecular alterations were analyzed: mutations of IDH1/2, BRAF and the histone H3.3 and the EGFR amplification. Clinical data, treatment modalities, and patient outcome were recorded. RESULTS: We identified 16 adult patients with reviewed PXA diagnosis. No IDH neither histone H3.3 mutations were found; BRAF V600E mutation was recorded in six patients. Ten patients presented with anaplastic features. BRAF mutations were associated with lower Ki67, OLIG2 expression, and lack of p16 expression. Median PFS and OS were 41.5 months (95% CI: 11.4-71.6) and 71.4 months (95% CI: 15.5-127.3), respectively. BRAF mutation tended to be associated with greater PFS (p = 0.051), whereas anaplastic features were associated with minimal PFS (p = 0.042). CONCLUSION: PXA in adults PXA may present features distinct from pediatric PXA. Anaplastic features and BRAF mutation may potentially identify specific subgroups with distinct prognoses.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , DNA de Neoplasias/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Idoso , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.
Assuntos
Miofibrilas/patologia , Miopatias Congênitas Estruturais/patologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Músculo Esquelético/patologia , Miofibrilas/genética , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/terapia , Adulto JovemAssuntos
Neoplasias do Sistema Nervoso/patologia , Oligodendroglioma/patologia , Biomarcadores Tumorais , França/epidemiologia , Deleção de Genes , Humanos , Neoplasias do Sistema Nervoso/epidemiologia , Neoplasias do Sistema Nervoso/genética , Oligodendroglioma/epidemiologia , Oligodendroglioma/genéticaRESUMO
BACKGROUND: To discuss the therapeutic approach for primary neurolymphomatosis. METHODS: We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents. RESULTS: Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months. CONCLUSIONS: Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results.
Assuntos
Linfoma de Células B , Neoplasias do Sistema Nervoso Periférico , Idoso , Alquilantes/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Eletromiografia , Evolução Fatal , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Imageamento por Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Neuroimagem , Neoplasias do Sistema Nervoso Periférico/diagnóstico , Neoplasias do Sistema Nervoso Periférico/tratamento farmacológico , Neoplasias do Sistema Nervoso Periférico/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: IDH mutations and BRAF mutations are classically mutually exclusive and usually associated with infiltrative or circumscribed gliomas and glioneuronal tumors respectively. CASE REPORT: We report the case of a 26-year old man with intracranial hypertension revealing voluminous right frontal lesion. Surgical resection was performed and pathological examination found two distinct tumoral areas: a glioma-like area with calcification without mitosis; a second with pleomorphic glial cells with higher Mib index, high CD34 expression and endothelial proliferation. No necrosis was recorded. Molecular analyses revealed both IDH1 I113T and BRAF V600E mutations. Although this glioma was difficult to clarify, diagnosis of pleomorphic xanthoastrocytoma with anaplastic feature was suggested based on the association of some pathological feature (eosinophilic granular bodies, reticulin network and diffuse CD34 expression) and the BRAF V600E mutation. CONCLUSION: We report a new IDH1 mutation associated with BRAF mutation in a very unusual glial tumor.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Humanos , MasculinoRESUMO
Recently, a broader role of inhibitor of apoptosis (IAP) proteins besides their antiapoptotic functions has been described. Therefore, we investigated the effect of non-toxic concentrations of the small-molecule Smac mimetic BV6, which antagonizes IAP proteins, on differentiation of cancer stem-like cells (CSLCs) derived from primary glioblastoma (GBM) specimens. Here, we identify a novel function of BV6 in regulating differentiation of GBM CSLCs by activating NF-κB. BV6 at non-lethal doses stimulates morphological changes associated with the differentiation of GBM CSLCs. BV6 increases transcriptional activity, mRNA and protein levels of the astrocytic marker GFAP without altering expression of the neuronal marker ß-III-tubulin, indicating that BV6 induces astrocytic differentiation of GBM CSLCs. Molecular studies reveal that BV6 triggers processing of the NF-κB subunit p100 to p52, nuclear translocation of p52 and p50 and increased NF-κB DNA-binding. Intriguingly, inhibition of NF-κB by overexpression of dominant-negative IκBα super-repressor (IκBα-SR) blocks the BV6-stimulated increase in GFAP and differentiation. Interestingly, this BV6-stimulated differentiation is associated with reduced expression of stemness markers such as CD133, Nanog and Sox2 in GBM CSLCs. In contrast, BV6 does not alter cell morphology, differentiation and expression of stemness markers in non-malignant neural stem cells. Importantly, BV6 treatment reduces clonogenicity of GBM CSLCs in vitro and in vivo, suppresses their tumorigenicity in orthotopic and subcutaneous mouse models and significantly increases the survival of mice. By identifying a novel role of BV6 in promoting differentiation of GBM CSLCs, these findings provide new insights into Smac mimetic-regulated non-apoptotic functions with important implications for targeting GBM CSLCs.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Oligopeptídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma multiforme (GBM) are highly invasive and angiogenic malignancies with a median survival time from diagnosis of <15 months. Previous work has revealed robust overexpression of fibronectin (FN) mRNA in GBM, although immunohistochemical staining of FN in these tumors is typically associated with the angiogenic vasculature. Here we sought to examine the expression of tumor cell FN and address its possible involvement in the invasive phenotype of GBM. We found that FN was expressed and assembled into fibrillar arrays in human tumors and in established GBM lines. Cultured cells spontaneously formed dense cellular networks and spheroid-like domes. Depletion of FN by targeted-short hairpin RNA expression disrupted matrix assembly and multicellular network organization by exerting profound effects on cell adhesion and motility. Although FN depletion enhanced persistent directional migration of single cells, it compromised collective invasion of spheroids through a laminin-rich matrix and sensitized cells to ionizing radiation. In orthotopic grafts, FN depletion significantly reduced tumor growth and angiogenesis. Together our results show that FN produced by the tumor cells has a role in GBM pathophysiology and they provide insights into the implications that targeting FN interactions may have for combating this dreaded disease.
Assuntos
Adesão Celular/genética , Fibronectinas/metabolismo , Glioblastoma/patologia , Animais , Membrana Basal/citologia , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Matriz Extracelular , Fibronectinas/biossíntese , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Integrina alfa5beta1/metabolismo , Camundongos , Invasividade Neoplásica , Neovascularização Patológica/genética , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Interferência de RNA , RNA Interferente Pequeno , Esferoides Celulares , Células Tumorais CultivadasRESUMO
Necrotizing myopathies (NM) are defined by histological features. Muscle biopsy demonstrates marked muscle necrosis with regeneration, with little or an absence of inflammatory infiltrate. Histological pattern of NM is unspecific and can be encountered in diverse conditions as acquired myopathies and muscular dystrophies. Among acquired forms of NM, necrotizing autoimmune myopathy (NAM) is a recently recognized sub-group of the idiopathic inflammatory myopathies. Classically, patients present with a subacute severe proximal myopathy, associated with a markedly elevated creatine kinase level, usually greater than 10 times the upper limit of normal. Nevertheless, the clinical presentation can be misleading, with chronic course mimicking muscular dystrophy. Different forms of NAM can be distinguished with various underlying inciting conditions, including autoantibodies to the SRP, autoantibodies to the HMG-CoA reductase, association to connective tissue disease or underlying malignancy. Other associated conditions need yet to be identified. To confirm a diagnosis of NAM, other causes of NM should be excluded as toxic myopathies, muscular dystrophies and other inflammatory myopathies with a misleading histological pattern. NAM is a rare condition but is probably underdiagnosed. Both clinicoserologic and pathologic data must be taken into account to improve this diagnosis. We propose guidelines for diagnosis of NAM according to clinical course, to be used in clinical practice.