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PURPOSE: To prospectively evaluate the usefulness of T1-weighted imaging (T1WI) and diffusion-weighted imaging (DWI) sequences in predicting the consistency of macroadenomas. In addition, to determine their values ââas prognostic factors of surgical outcomes. METHODS: Patients with pituitary macroadenoma and surgical indication were included. All patients underwent pre-surgical magnetic resonance imaging (MRI) that included the sequences T1WI before and after contrast administration and DWI with the apparent diffusion coefficient (ADC) map. Post-surgical MRI was performed at least 3 months after surgery. The consistency of the macroadenomas was evaluated at surgery, and they were grouped into soft and intermediate/hard adenomas. Mean ADC values, signal on T1WI and the ratio of tumor ADC values ââto pons (ADCR) were compared with tumor consistency and grade of surgical resection. RESULTS: A total of 80 patients were included. A softened consistency was found at surgery in 53 patients and hardened in 27 patients. The median ADC in the soft consistency group was 0.532 × 10-3 mm2/sec (0.306 - 1.096 × 10-3 mm2/sec), and in the intermediate/hard consistency group was 0.509 × 10-3 mm2/sec (0.308 - 0.818 × 10-3 mm2/sec). There was no significant difference between the median values ââof ADC, ADCR and signal on T1W between the soft and hard tumor groups, or between patients with and without tumor residue. CONCLUSION: Our results did not show usefulness of the DWI and T1WI for assessing the consistency of pituitary macroadenomas, nor as a predictor of the degree of surgical resection.
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Adenoma , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Adenoma/patologia , Estudos RetrospectivosRESUMO
Different cancers have multiple genetic mutations, which vary depending on the affected tumour tissue. Small biopsies may not always represent all the genetic landscape of the tumour. To improve the chances of identifying mutations at different disease stages (early, during the disease course, and refractory stage), liquid biopsies offer an advantage to traditional tissue biopsy. In addition, it is possible to detect mutations related to metastatic events depending on the cancer types analysed as will be discussed in this case report, which describes a patient with brain metastasis and lung cancer that harboured K-RAS mutations both in the brain tumour and in the ctDNA present in the bloodstream.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Biópsia Líquida , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Mutação , Biópsia , Neoplasias Encefálicas/genética , Biomarcadores TumoraisRESUMO
AIMS: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses. METHODS: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging. RESULTS: We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation-confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, "non-specific/diffuse DNTs" corresponded to a heterogeneous molecular group encompassing diverse, newly-described, molecularly distinct entities. CONCLUSIONS: Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS-MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The "non-specific/diffuse DNTs" subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered.
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Neoplasias Encefálicas , Glioma , Neoplasias Neuroepiteliomatosas , Neoplasias Encefálicas/patologia , Genômica , Humanos , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Estudos RetrospectivosRESUMO
PURPOSE: To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR - ) GIPR. METHODS: Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). RESULTS: A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR - tumors. Twenty-eight out of 56 (50%) GIPR - tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). CONCLUSION: We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR - tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors.
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Receptores dos Hormônios Gastrointestinais , Humanos , Feminino , Masculino , Receptores dos Hormônios Gastrointestinais/genética , Mutação , Anticorpos Monoclonais , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
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Ependimoma/genética , Ependimoma/patologia , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/patologia , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fator de Transcrição RelA , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
PURPOSE: RAS genes are among the most frequently mutated genes in cancer, where their mutation frequency varies according to the distinct RAS isoforms and tumour types. Despite occurring more prevalent in malignant tumours, RAS mutations were also observed in few benign tumours. Pituitary adenomas are examples of benign tumours which vary in size and aggressiveness. The present study was performed to investigate, via liquid biopsy and tissue analysis, the presence of K-RAS mutations in a pituitary macroadenoma. METHODS: Molecular analysis was performed to investigate K-RAS mutations using the droplet digital PCR (ddPCR) method by evaluating both plasma (liquid biopsy) and the solid tumour of a patient diagnosed with a giant clinically non-functioning pituitary tumour. RESULTS: The patient underwent surgical resection due to visual loss, and the histopathological analysis showed a gonadotrophic pituitary macroadenoma. The molecular analysis revealed the presence of mutant K-RAS both in the plasma and in the tumour tissue which, to our knowledge, has not been previously reported in the literature. CONCLUSION: Our findings highlight the exceptional capacity of the digital PCR in detecting low frequency mutations (below 1%), since we detected, for the first time, K-RAS mutations in pituitary macroadenoma. The potential impact of K-RAS mutations in these tumours should be further investigated.
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Adenoma , Neoplasias Hipofisárias , Proteínas Proto-Oncogênicas p21(ras) , Adenoma/genética , Genes ras , Humanos , Mutação/genética , Neoplasias Hipofisárias/genética , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
AIMS: Meningeal chondromas constitute a small fraction of central nervous system tumors, with only 61 cases reported in the literature. Somatic mutations of IDH1/2 genes have been described in enchondromas, and, in soft-tissue chondromas, rearrangements of the HMGA2 gene have been reported. The aim of our study was to perform molecular analyses of 3 additional cases and to do a complete review of the literature to better characterize this rare entity. MATERIALS AND METHODS: Here, we report 3 cases of primitive meningeal chondromas in children and young adults. Immunohistochemical analyses for HMGA2 and IDH1R132H, molecular analyses of IDH1/2 mutations, and FISH analysis of the HMGA2 locus were performed. RESULTS: Immunohistochemical analyses of all cases were negative for IDH1R132H and HMGA2 proteins. Molecular analyses failed to reveal IDH1/2 mutations, and FISH analyses did not evidence any HMGA2 rearrangements. Similarly to what is reported in the literature, the 3 meningeal chondromas in this study were benign tumors with no recurrence after complete resection with a follow-up of 85, 46, and 89 months. CONCLUSION: Meningeal chondroma is rare. It affects predominantly young adults and has a good outcome. No molecular alterations have currently been described in this entity.
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Condroma/patologia , Neoplasias Meníngeas/patologia , Adolescente , Adulto , Condroma/genética , Feminino , Humanos , Masculino , Neoplasias Meníngeas/genética , Adulto JovemRESUMO
INTRODUCTION: Young age is an adverse prognostic factor in children with ependymomas. Treatment of these infants is challenging since beneficial therapeutic options are limited. As ependymomas are considered a biologically heterogeneous group, we aimed to characterize infant ependymomas with regard to their histological and genetic features. MATERIALS AND METHODS: We analyzed 28 ependymomas occurring in children younger than 18 months at diagnosis enrolled into the HIT2000-E protocols with the aim to postpone irradiation until the age of 18 months if possible. All cases underwent neuropathological review, including immunohistochemical characterization. Genome-wide copy number alterations (CNA) were assessed by molecular inversion probe assays, and RELA and YAP1 fusions were detected by RT-PCR and sequencing. RESULTS: All infant ependymomas were anaplastic (WHO grade III). Twenty-one (75%) cases were located in the posterior fossa. Gross total resection was accomplished in 12 (57%) of these cases. All posterior fossa tumors showed loss of H3-K27me3 characteristic of PFA ependymomas. CNA analysis showed a stable genome in all cases with lack of chromosome 1q gain, an adverse prognostic marker in PFA ependymomas of older children. However, after a median follow-up of 5.4 years, 15 (71%) relapsed, and 9 (43%) died. Seven ependymomas (25%) occurred in the supratentorial region. Gross total resection could be achieved in only two of these cases. Four tumors carried C11orf95-RELA fusions, and two cases had typical YAP1-MAMLD1 fusions (one case was not analyzable). The RELA-fused cases did not display CDKN2A loss as an adverse indicator of prognosis in this disease entity. Although three infants (43%) with supratentorial ependymomas relapsed, all patients survived (median follow-up, 8.0 years). CONCLUSION: Infant ependymomas seem to fall into three biological entities, with supratentorial tumors carrying RELA or YAP fusions and PFA posterior fossa ependymomas. The latter showed a poor outcome even though chromosome 1q gain was absent.
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Ependimoma , Neoplasias Infratentoriais , Neoplasias Supratentoriais , Adolescente , Criança , Ependimoma/genética , Humanos , Lactente , Neoplasias Infratentoriais/genética , Mutação , PrognósticoRESUMO
BACKGROUND AND PURPOSE: Molecular alterations were recently added to the World Health Organization (WHO) 2016 classification of central nervous system (CNS) tumors. We correlated the histological and radiological features of G34R mutant high-grade gliomas, a recently described hemispheric and supratentorial glioma of children and young adults. MATERIALS AND METHODS: We performed a retrospective multicenter study on the histopathological and MRI results of 12 patients. RESULTS: All tumors were supratentorial. Several radiological aspects were observed. Height over 12 were bulky and well delineated tumors, without visible peritumoral infiltration on MRI and pathologically characterized by highly cellular tissue associated with a moderate peritumoral infiltrative component. Two tumors were ill-defined and hyperintense on T2 sequences and pathologically characterized by diffuse tumoral infiltration. Two tumors were bulky and well delineated with an infiltrative component, both radiologically and histopathologically. CONCLUSIONS: These different patterns may correspond to different pathological mechanisms and a potential link with prognosis should be assessed in further studies.
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Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Histonas/genética , Imageamento por Ressonância Magnética/métodos , Neoplasias Supratentoriais/diagnóstico por imagem , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/patologia , Adolescente , Adulto , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mutação , Gradação de Tumores , Prognóstico , Estudos RetrospectivosAssuntos
Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Ependimoma/patologia , Neoplasias Supratentoriais/patologia , Fator de Transcrição RelA/metabolismo , Estudos de Coortes , Ependimoma/diagnóstico , Ependimoma/tratamento farmacológico , Ependimoma/metabolismo , Humanos , Prognóstico , Neoplasias Supratentoriais/metabolismoRESUMO
Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.
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Neoplasias do Tronco Encefálico/genética , Glioma/genética , Histonas/genética , Mutação , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/efeitos da radiação , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/radioterapia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Glioma/diagnóstico , Glioma/patologia , Glioma/radioterapia , Células HeLa , Humanos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos da radiação , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oligodendroglia/efeitos da radiação , Fenótipo , Ponte/metabolismo , Ponte/patologia , Ponte/efeitos da radiação , Ponte/cirurgia , PrognósticoRESUMO
The 2021 World Health Organization classification of tumors of the central nervous system emphasizes the significance of molecular parameters for an integrated diagnosis. Homozygous deletion of cyclin-dependent kinase inhibitor 2a (CDKN2A) has been associated with an adverse prognosis in IDH -mutant gliomas, supratentorial ependymomas, meningiomas, and MPNST. In this study, we examined the value of p16 protein immunohistochemistry as a rapid and cost-effective screening tool for a homozygous CDKN2A deletion. Genetic analyses for CDKN2A in 30 pleomorphic xanthoastrocytomas, 32 IDH -wild-type high-grade gliomas, 40 supratentorial ependymomas with ZFTA-RELA gene fusion, 21 IDH-mutant astrocytomas, and 24 meningiomas were performed mainly by a molecular inversion probe assay, a high-resolution, quantitative technology for the assessment of chromosomal copy number alterations. Immunohistochemistry for p16 proved to have a high positive predictive value (range 90% to 100%) and an overall low negative predictive value (range 22% to 93%) for a homozygous CDKN2A deletion. In a setting where molecular testing is limited for cost and time reasons, p16 immunohistochemistry serves as a useful and rapid screening tool for identifying cases that should be subjected to further molecular testing for CDKN2A deletions.
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Ependimoma , Glioma , Neoplasias Meníngeas , Meningioma , Humanos , Imuno-Histoquímica , Meningioma/genética , Homozigoto , Deleção de Sequência , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glioma/genética , Neoplasias Meníngeas/genética , Ependimoma/genética , Deleção de GenesRESUMO
Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Embrionárias de Células Germinativas , Humanos , Neoplasias Encefálicas/patologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular , Fatores de Transcrição Forkhead , Proteínas de HomeodomínioRESUMO
Ependymomas are one of the most common pediatric malignant brain tumors. Prognosis, especially in young children, remains poor due to their inherent chemo- and radio-resistance and effective treatment remains one of the more difficult tasks in pediatric oncology: up to half of the patients may die from the disease. The only reproducible prognostic factor is the extent of surgery; neither histological grading nor other biomarkers can be used to reliably make treatment decisions in clinical practice. None of the studies identifying new biomarkers have been conducted prospectively, only few have been undertaken within the context of a clinical trial and most have been conducted with limited samples (often including adults and childhood samples). International collaboration is needed to improve ependymoma prognostication.
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Neoplasias Encefálicas/diagnóstico , Ependimoma/diagnóstico , Adolescente , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Aberrações Cromossômicas , Progressão da Doença , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/mortalidade , Perfilação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , PrognósticoRESUMO
Introduction: Liquid biopsy is a non-invasive method used to detect cancer and monitor treatment responses by analyzing blood or other bodily fluids for cancer biomarkers. Meningiomas are the most common primary central nervous system tumors, and biomarkers play a crucial role in their diagnosis, prognosis, and treatment monitoring. The World Health Organization (WHO) classifies meningiomas based on tumor grades and molecular alterations in genes such as in NF2, AKT1, TRAF7, SMO, PIK3CA, KLF4, SMARCE1, BAP1, H3K27me3, TERT promoter, and CDKN2A/B. Liquid biopsy, specifically cell-free DNA (cfDNA) analysis, has shown potential for monitoring meningiomas as it can detect ctDNA release in the blood, unaffected by the blood-brain barrier. MicroRNAs (miRNAs) have also been found to be deregulated in various cancers, including meningiomas, presenting potential as diagnostic biomarkers. Additionally, studying cytokines in the tumor microenvironment may aid in establishing prognostic or diagnostic panels for meningiomas. Methods: In the present study we analyzed the DNA coming from both the plasma and tumor samples, in addition to analyze miRNA-21 and cytokines in the plasma of 28 meningioma patients. Discussion and Conclusion: Our findings indicate that the detection of ctDNA in the plasma of meningioma patients is feasible. However, it's important to note that certain challenges persist when comparing plasma DNA analysis to that of tumor tissues. In our study, we observed a paired identification of mutations in only one patient, highlighting the complexities involved. Furthermore, we successfully identified miR-21 and cytokines in the plasma samples. Notably, our analysis of Interleukin 6 (IL-6) unveiled higher expression in the clear cell subtype compared to the other types. Despite the ongoing research, the clinical implementation of liquid biopsy in meningiomas remains somewhat limited. Nevertheless, our promising results underscore the need for further investigation.
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BACKGROUND: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study. METHODS: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH. RESULTS: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy. CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.
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Ependimoma , Histonas , Criança , Adolescente , Humanos , Histonas/genética , Tenascina/genética , Hibridização in Situ Fluorescente , Estudos Prospectivos , Biomarcadores , Ependimoma/diagnóstico , Ependimoma/genética , Ependimoma/patologiaRESUMO
Glioblastoma is the most frequent and aggressive primary brain cancer. In preclinical studies, Zika virus, a flavivirus that triggers the death of glioblastoma stem-like cells. However, the flavivirus oncolytic activity has not been demonstrated in human patients. Here we report a glioblastoma patient who received the standard of care therapy, including surgical resection, radiotherapy and temozolomide. However, shortly after the tumor mass resection, the patient was clinically diagnosed with a typical arbovirus-like infection, during a Zika virus outbreak in Brazil. Following the infection resolution, the glioblastoma regressed, and no recurrence was observed. This clinical response continues 6 years after the glioblastoma initial diagnosis.
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The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.
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Neoplasias Encefálicas , Glioma , Adolescente , Humanos , Criança , Multiômica , Glioma/diagnóstico , Glioma/genética , Neuropatologia , Metilação de DNA/genética , Mutação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genéticaRESUMO
Diffuse intrinsic pontine gliomas (DIPG) can not be cured with current treatment modalities. Targeted therapy in this disease would benefit from advanced technologies detecting relevant drugable mutations. Twenty patients with classic newly diagnosed DIPG underwent stereotactic biopsies and were analyzed for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection. Our results identified oncogenic mutations in TP53 (40%), PI3KCA (15%), and ATM/MPL (5%) while none were identified in a large number of other genes commonly mutated in malignant gliomas. The identification of oncogenic mutations in the PI3K pathway offers the potential of a therapeutic target at initial diagnosis in this devastating disease.
Assuntos
Neoplasias do Tronco Encefálico/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares/genética , Ponte , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia , Biópsia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Feminino , Humanos , MasculinoRESUMO
Background: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG). Methods: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists. Results: 465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri. Conclusions: Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact.