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BACKGROUND: COVID-19 has overloaded health care systems, testing the capacity and response in every European region. Concerns were raised regarding the impact of resources' reorganization on certain emergency pathology management. The aim of the present study was to assess the impact of the outbreak (in terms of reduction of neurosurgical emergencies) during lockdown in different regions of Spain. METHODS: We analyzed the impact of the outbreak in four different affected regions by descriptive statistics and univariate comparison with same period of two previous years. These regions differed in their incidence level (high/low) and in the time of excess mortality with respect to lockdown declaration. That allowed us to analyze their influence on the characteristics of neurosurgical emergencies registered for every region. RESULTS: 1185 patients from 18 neurosurgical centers were included. Neurosurgical emergencies that underwent surgery dropped 24.41% and 28.15% in 2020 when compared with 2019 and 2018, respectively. A higher reduction was reported for the most affected regions by COVID-19. Non-traumatic spine experienced the most significant decrease in number of cases. Life-threatening conditions did not suffer a reduction in any health care region. CONCLUSIONS: COVID-19 affected dramatically the neurosurgical emergency management. The most significant reduction in neurosurgical emergencies occurred on those regions that were hit unexpectedly by the pandemic, as resources were focused on fighting the virus. As a consequence, life-threating and non-life-threatening conditions' mortality raised. Results in regions who had time to prepare for the hit were congruent with an organized and sensible neurosurgical decision-making.
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COVID-19 , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Atenção à Saúde , Emergências , Humanos , Procedimentos Neurocirúrgicos , Espanha/epidemiologiaRESUMO
Craniopharyngiomas (CPs) are histologically benign tumors that are associated with high levels of morbidity. Two clinicopathological variants - adamantinomatous (ACP) and papillary (PCP) - have been described. They differ in their molecular features, whereby activating mutations in BRAF (V600E) and CTNNB1 genes characterize PCP and ACP, respectively. Recently, both variants have been shown to express elevated PD-L1 protein expression, but ACP also exhibited tumor cell-intrinsic PD-1 expression. In this study we analyze these molecular alterations in 52 cases with a long follow-up and examine their associations with immunohistochemical and clinical characteristics. ACPs comprise 73.1% of cases, while 21.2% are PCPs. Aberrant nuclear immunoreactivity for ß-catenin was observed in all ACPs. BRAF p.V600E mutations were observed in 90.9% of PCPs. Only one ACP case featured both alterations. Both types of CP exhibited strong nuclear staining for p63 with diffuse and basal distribution. ACP and PCP consistently expressed PD-L1, most in a substantial percentage of tumor cells, with a distinctive spatial distribution of expression in each subtype; only ACP demonstrated PD-1 expression. There was no evidence of differences in clinical prognosis between ACPs and PCPs. The identification of hallmark molecular signatures in the two CP variants is useful for sub-categorization in routine histopathology reporting. It is also pertinent to personalized therapy and for the development of improved non-invasive therapeutic strategies in this disease.
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Craniofaringioma/diagnóstico , Craniofaringioma/genética , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Proteínas Proto-Oncogênicas B-raf/genética , beta Catenina/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Craniofaringioma/mortalidade , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Hipofisárias/mortalidade , Prognóstico , Espanha , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than "classic" IDHwt GBM. METHODS: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. RESULTS: p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1, IDH2, BRAF, or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53, ATRX, RB1, and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53-mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53-mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, Pâ <â .002). CONCLUSIONS: gcGBMs have molecular features that contrast to "classic" IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine.
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Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.
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Neoplasias Encefálicas/genética , Sobreviventes de Câncer , Marcação de Genes/métodos , Glioblastoma/genética , Mutação/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Purpose To evaluate the prognostic and predictive value of surface-derived imaging biomarkers obtained from contrast material-enhanced volumetric T1-weighted pretreatment magnetic resonance (MR) imaging sequences in patients with glioblastoma multiforme. Materials and Methods A discovery cohort from five local institutions (165 patients; mean age, 62 years ± 12 [standard deviation]; 43% women and 57% men) and an independent validation cohort (51 patients; mean age, 60 years ± 12; 39% women and 61% men) from The Cancer Imaging Archive with volumetric T1-weighted pretreatment contrast-enhanced MR imaging sequences were included in the study. Clinical variables such as age, treatment, and survival were collected. After tumor segmentation and image processing, tumor surface regularity, measuring how much the tumor surface deviates from a sphere of the same volume, was obtained. Kaplan-Meier, Cox proportional hazards, correlations, and concordance indexes were used to compare variables and patient subgroups. Results Surface regularity was a powerful predictor of survival in the discovery (P = .005, hazard ratio [HR] = 1.61) and validation groups (P = .05, HR = 1.84). Multivariate analysis selected age and surface regularity as significant variables in a combined prognostic model (P < .001, HR = 3.05). The model achieved concordance indexes of 0.76 and 0.74 for the discovery and validation cohorts, respectively. Tumor surface regularity was a predictor of survival for patients who underwent complete resection (P = .01, HR = 1.90). Tumors with irregular surfaces did not benefit from total over subtotal resections (P = .57, HR = 1.17), but those with regular surfaces did (P = .004, HR = 2.07). Conclusion The surface regularity obtained from high-resolution contrast-enhanced pretreatment volumetric T1-weighted MR images is a predictor of survival in patients with glioblastoma. It may help in classifying patients for surgery.
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Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise de Sobrevida , Resultado do TratamentoRESUMO
Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP+) and promoter methylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) gene. Among these markers, a predictive value was reported in glioblastomas (GBM) for MGMT promoter methylation, in particular in elderly GBM patients. In this study, methylation data from 46 glioma samples with the Illumina 450K platform were obtained and extended using external data to include a total of 247 glioma samples. Methylation analysis of the whole MGMT gene with this platform revealed two strongly survival-associated CpG regions within the promoter and the gene body, which were confirmed in a reported dataset of high grade-gliomas. Methylation at the promoter (CpG 25, cg12981137 and the prognostic model MGMT-STP27) and at the gene body CpG 165 (cg07933035), were significantly associated with better overall survival, and strongly correlated with G-CIMP+ status. In this series, the prognostic value of MGMT methylation at the promoter was not observed in G-CIMP- cases, although around 50 % of them were MGMT-methylated. These results were also obtained in an homogeneously-treated series of chemoradiated G-CIMP- GBMs analyzed by MSP and qMSP, and confirmed in a reported pyrosequencing-analyzed series of gliomas. Interestingly, in contrast to the MGMT promoter, gene body methylation was of prognostic value in G-CIMP-patients older than 65 years. Our study highlights the relevance of the prognostic value of the different regions of methylation throughout the MGMT gene that could be affected by specific G-CIMP profiles and age groups.
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Neoplasias Encefálicas/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Proteínas Supressoras de Tumor/genética , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Feminino , Perfilação da Expressão Gênica , Glioma/diagnóstico , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Análise de Componente Principal , Prognóstico , Regiões Promotoras Genéticas/genética , Análise de Sobrevida , Adulto JovemRESUMO
Among the prognostic factors when it comes to patients with high-grade gliomas, we find the radicality of the surgery performed. The limitations of this factor are caused by either the extension of the tumour or its location in an eloquent area. To achieve this goal, in the last few years we have developed several methods that allow us to maximise tumour resection, while always trying to cause the least possible co-morbidity. One of these methods includes the use of 5-amino-levulinic acid (5-ALA) and the development of fluorescence guided surgery. However, optimal performance requires knowledge of the product employed, the mode of administration and precautions to consider. Members of the neuro-oncology work group of the Spanish Neurosurgical Society (SENEC) have prepared this guideline or consensus document for anyone who wishes to become familiar with the use of 5-ALA fluorescence-guided surgery in the management of high-grade gliomas. For those who already utilise this technique, this document can be useful for consultation purposes.
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Ácido Aminolevulínico , Neoplasias Encefálicas/cirurgia , Corantes Fluorescentes , Glioma/cirurgia , Neurocirurgia/métodos , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/efeitos adversos , Ácido Aminolevulínico/farmacocinética , Neoplasias Encefálicas/metabolismo , Medicina Baseada em Evidências , Oftalmopatias/induzido quimicamente , Oftalmopatias/prevenção & controle , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Glioma/metabolismo , Humanos , Hipotensão/induzido quimicamente , Hipotensão/prevenção & controle , Luz/efeitos adversos , Microscopia de Fluorescência/instrumentação , Imagem Óptica/instrumentação , Transtornos de Fotossensibilidade/induzido quimicamente , Transtornos de Fotossensibilidade/prevenção & controle , Cuidados Pré-Operatórios , Cirurgia Assistida por Computador/instrumentação , Distribuição TecidualRESUMO
Meningiomas are the most common primary brain tumors; they arise from the coverings of the brain. Although meningiomas are generally benign, some are more clinically aggressive, as reflected by their histopathological features or by their unexpected recurrence. We hypothesized that recurrent histologically benign meningiomas might have genetic features in common with those showing a more aggressive histology. By comparing gene expression profiles associated with meningioma progression and recurrence in 128 tumor samples (i.e. 83 benign World Health Organization [WHO] Grade I, 37 atypical WHO Grade II, and 8 anaplastic WHO Grade III) from 121 patients, we identified a 49-gene signature of meningioma aggressivity. This signature classified the tumors into 2 groups showing different clinical and pathological behaviors. The signature was composed of genes involved in the cell cycle (TMEM30B, CKS2, and UCHL1) and other pathways previously described as being altered in meningiomas, that is, WNT (SFRP1 and SFRP4) and transforming growth factor-ß pathways (LTBP2 and LMO4). Overall, gene downregulation was observed in advanced and recurrent samples versus benign and original ones. We propose that this gene repression may be caused by gene promoter hypermethylation, as in the case of UCHL1 and SFRP1, suggesting that this epigenetic event, together with loss of specific chromosomal regions, may play an important role in meningioma progression and recurrence.
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Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Adulto JovemRESUMO
The majority of meningiomas are probably benign but a number of tumors display considerable histological and/or clinical aggressivity, sometimes with unexpectedly high recurrence rates after radical removal. Understanding the potential behavior of these tumors in individual patients is critical for rational therapeutic decision-making. This study aimed to identify gene expression profiles and candidate markers associated with original and recurrent meningiomas. Unsupervised hierarchical clustering of the samples confirmed 2 main groups of meningiomas with distinct clinical behaviors. The gene expression profiling study identified genes and pathways potentially associated with meningioma recurrence, revealing an overall lower level of gene expression. The differential gene expression profiling analyses of original and recurrent meningiomas identified 425 known genes and expressed sequence tags related to meningioma recurrence, with SFRP1 (8p12), TMEM30B (14q23), and CTGF (6q23) showing the most disparate expression. Most of the differentially expressed genes were located at 1p, 6q, and 14q and were underexpressed in recurrences. Loss of such chromosomal regions has previously been associated with a higher risk of meningioma recurrence or malignant progression. Thus, at these locations, we propose the existence of novel candidate genes that could be involved in meningioma recurrence. In addition, the overexpression of genes of histone cluster 1 (6p) in recurrent meningiomas is reported here for the first time. Finally, the altered genes related to meningioma recurrence are involved in pathways such as Notch, TGFß, and Wnt, as described previously, and in other pathways such as cell cycle, oxidative phosphorylation, PPAR, and PDGF, not related before to meningioma recurrence.
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Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 6/genética , Histonas/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Masculino , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Knowledge of the molecular mechanisms involved in the biology of glioblastoma multiforme (GBM) is essential for the identification of candidate prognostic markers, new putative therapeutic targets, and early detection strategies predictive of survival. METHODS: The authors performed expression-profiling analyses in a series of primary GBMs by using complementary DNA microarrays. Validation of putative targets was performed in large series of GBMs by immunohistochemistry on tissue microarrays, real-time quantitative reverse transcription-polymerase chain reaction analysis, and Western blot analysis. RESULTS: The expression signature consisted of 159 up-regulated genes and 186 down-regulated genes. Most of these genes were involved in cell adhesion, signal transduction, cell cycle, apoptosis, and angiogenesis. Among the genes from the molecular signature, annexin 1 (ANXA1) and ubiquitin-specific protease 7 (USP7) were evaluated in wider series of GBMs. ANXA1 analysis carried out in different types of gliomas revealed exclusive overexpression in astrocytomas. Furthermore, survival analysis by using functional clusters of genes related with cancer and glioma biology revealed 7 genes involved in the PI3K-signaling pathway that presented a significant association with clinical outcome. Among these genes, positive expression of BCL2-associated X protein (BAX) was associated significantly with better survival in a larger series of tumors. In addition, activation of the PI3K/Akt pathway was demonstrated in this set of GBMs. CONCLUSIONS: The authors concluded that there is a significant role for PI3K pathway survival-related genes in patients with GBM, and putative prognostic markers associated with glioma tumorigenesis were identified. The detailed study of these candidate genes and the molecular pathways regulating PI3K activation reveal that they are promising targets for the clinical management of patients with glioma.