RESUMO
The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is mainly driven by tumor-associated macrophages (TAMs). We explored whether their sustained iron metabolism and immunosuppressive activity were correlated, and whether blocking the central enzyme of the heme catabolism pathway, heme oxygenase-1 (HO-1), could reverse their tolerogenic activity. To this end, we investigated iron metabolism in bone marrow-derived macrophages (BMDMs) isolated from GBM specimens and in in vitro-derived macrophages (Mφ) from healthy donor (HD) blood monocytes. We found that HO-1 inhibition abrogated the immunosuppressive activity of both BMDMs and Mφ, and that immunosuppression requires both cell-to-cell contact and soluble factors, as HO-1 inhibition abolished IL-10 release, and significantly reduced STAT3 activation as well as PD-L1 expression. Interestingly, not only did HO-1 inhibition downregulate IDO1 and ARG-2 gene expression, but also reduced IDO1 enzymatic activity. Moreover, T cell activation status affected PD-L1 expression and IDO1 activity, which were upregulated in the presence of activated, but not resting, T cells. Our results highlight the crucial role of HO-1 in the immunosuppressive activity of macrophages in the GBM TME and demonstrate the feasibility of reprogramming them as an alternative therapeutic strategy for restoring immune surveillance.
Assuntos
Glioblastoma , Heme Oxigenase-1 , Macrófagos Associados a Tumor , Humanos , Antígeno B7-H1/metabolismo , Glioblastoma/patologia , Heme , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Terapia de Imunossupressão , Interleucina-10 , Ferro , Microambiente TumoralRESUMO
BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence can maximize perirolandic glioblastoma (GBM) resection with low rates of postoperative sequelae. Our purpose was to present the outcomes of our experience and compare them with other literature reports to investigate the potential influence of different intraoperative monitoring strategies and to evaluate the role of intraoperative data on neurological and radiological outcomes in our series. METHODS: We retrospectively analyzed our prospectively collected database of GBM involving the motor pathways. Each patient underwent tumor exeresis with intraoperative 5-ALA fluorescence visualization. Our monitoring strategy was based on direct stimulation (DS), combined with cortical or transcranial MEPs. The radiological outcome was evaluated with CRET vs. residual tumor, and the neurological outcome as improved, unchanged, or worsened. We also performed a literature review to compare our results with state-of-the-art on the subject. RESULTS: Sixty-five patients were included. CRET was 63.1%, permanent postoperative impairment was 1.5%, and DS's lowest motor threshold was 5 mA. In the literature, CRET was 25-73%, permanent postoperative impairment 3-16%, and DS lowest motor threshold was 1-3 mA. Our monitoring strategy identified a motor pathway in 60% of cases in faint fluorescent tissue, and its location in bright/faint fluorescence was predictive of CRET (p < 0.001). A preoperative motor deficit was associated with a worse clinical outcome (p < 0.001). Resection of bright fluorescent tissue was stopped in 26%, and fluorescence type of residual tumor was associated with higher CRET grades (p < 0.001). CONCLUSIONS: Based on the data presented and the current literature, distinct monitoring strategies can achieve different onco-functional outcomes in 5-ALA-guided resection of a glioblastoma (GBM) motor pathway. Intraoperatively, functional and fluorescence data close to a bright/vague interface could be helpful to predict onco-functional outcomes.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Glioblastoma/patologia , Ácido Aminolevulínico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Estudos Retrospectivos , Neoplasia Residual/cirurgia , Vias Eferentes/patologiaRESUMO
The role of surgery on central area metastasis remains unclear, and outcome data are still controversial. The aim of our study is to analyze the predictive value of clinical and surgical data on motor and functional outcome of patients, taking into account new emerging data on boundary irregularity of brain metastasis. We retrospectively analyzed 47 consecutive patients who underwent surgery assisted by neurophysiologic monitoring for a solitary metastasis in central area between 2010 and 2013. Inclusion criteria were as follows: good functional status (Karnofsky Performance Status (KPS) ≥70), controlled systemic disease, and absence of extra-cranial dissemination. At 1-month follow up, motor and functional outcomes were compared with preoperative clinical status, response to corticosteroids, extent of tumor resection, boundary irregularity, and size of tumor. Gross total resection was achieved in 93.6% of cases. In preoperative symptomatic patients, motor outcome (according to Medical Research Council grading scale) improved in 55.5% and worsened in 16.7%, while functional outcome (according to KPS score) improved in 50% and worsened in 14.2% of cases. No worsening occurred in preoperative asymptomatic patients. Motor outcome resulted to be not correlated with preoperative deficits, tumor volume, or preoperative response to corticosteroid treatment. Remarkably, motor outcome and extent of surgical resection appeared strongly correlated with tumor boundary irregularity (p < 0.05). Surgery with neurophysiologic monitoring on motor area metastasis can improve functional and motor condition in selected patients. Tumor volume does not represent a limit in surgery. The high correlation between clinical outcome, resection rate, and tumor boundary irregularity strengthens a new belief on the infiltrative growing pattern of brain metastasis. Motor function was evaluated according to Medical Research Council grading scale (Ott et al. 2014) while functional status was assessed according to KPS score.
Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Córtex Motor/patologia , Córtex Motor/cirurgia , Procedimentos Neurocirúrgicos/métodos , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Transtornos dos Movimentos/epidemiologia , Transtornos dos Movimentos/etiologia , Monitorização Neurofisiológica , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Glioma/genética , Alelos , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Glioma/patologia , Humanos , Gradação de Tumores , Razão de Chances , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
Treatment with angiogenesis inhibitors is becoming a cornerstone of modern anticancer therapy. Hypertension (HTN) is a common adverse event during antiangiogenic treatment and might represent a cancer biomarker in patients with recurrent glioblastoma treated with angiogenesis inhibitors. In a retrospective study, we analyzed 53 patients with recurrent glioblastoma treated with antiangiogenic drugs. Thirty patients were treated with sorafenib and 23 patients were treated with bevacizumab. All patients underwent brain gadolinium-enhanced MRI assessments according to the Radiologic Assessment in Neuro-Oncology criteria every 2 months or when clinically indicated. Blood pressure was measured before and during the treatment. We investigated whether treatment-related HTN may be associated with outcome in patients treated with antiangiogenic drugs. After 2 months of treatment, 24 patients (45%) achieved disease control: stable disease (17 patients) or a partial response (seven patients). The median overall survival from the start of antiangiogenic treatment was 7.3 months [95% confidence interval (CI) 6.02-8.5]; the median progression-free survival (PFS) was 2.7 months (95% CI 1.5-3.5); and the 6-month PFS was 32%. Twenty patients (38%) developed grades 2-3 HTN within 2 months of treatment. A significant association was found between HTN and disease control rate, and HTN and 6-month PFS; no significant association was found between HTN and the median PFS. According to univariate and multivariate analyses, HTN was related to a longer survival from antiangiogenic drug administration: 9.8 versus 4.8 months (P=0.001; hazard ratio=3.5, 95% CI 1.6-7.6). Our data indicate that HTN may be an effective biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs; in particular, it may be associated with a favorable effect on disease control, 6-month PFS, and the median overall survival.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Glioblastoma/tratamento farmacológico , Hipertensão/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Pressão Sanguínea/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Estudos Retrospectivos , Sorafenibe , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Medulloblastoma in adulthood is uncommon but not rare; annual incidence is 2-20/1,000,000. Some peculiarities characterize medulloblastoma in adult patients compared with the child type: lateral cerebellar location, heterogeneous signal intensity on magnetic resonance imaging, desmoplastic histological variant, and more favourable prognosis. Preoperative diagnosis is crucial for correct management of these patients. However, because of the low incidence of medulloblastoma in the adult population, preoperative diagnosis remains challenging and prognostic factors and best treatment options are still controversial. In this setting, some unusual findings, for example multifocal presentation and extra-axial location, can confound diagnosis and make treatment difficult. We present a short case-illustrated review on these remarkable issues.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Adulto , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/fisiopatologia , Neoplasias Cerebelares/cirurgia , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/fisiopatologia , Meduloblastoma/cirurgiaRESUMO
Anticonvulsant therapy is usually recommended before surgery in all patients affected by high grade glioma who are planned to be treated with Carmustine 1,3-bis [2 chloroetyl]-1-nitrosurea, or BCNU) wafers. In fact, phase III studies have reported a risk of seizures higher than 30% in this group of patients. The aim of the study was the evaluation of rate type time of occurrence of seizures in BCNU-treated patients in the postoperative period as well as the investigation into possible risk factors for seizure occurrence in this population. From April 2007 to September 2010, 55 patients underwent surgical removal of malignant glioma and BCNU wafers implantation at the Department of Neurosurgery of Padova. All patients were given antiepileptic prophylaxis for 3 months after surgery. Clinical data (including preoperative seizure history), radiological data, surgical treatment, antiepileptic treatment were retrospectively reviewed. Nine percent of the patients treated with BCNU wafers presented seizures in the postoperative course. Seizures were partial in 80% of cases; they occurred within 30 days after surgery and in 80% of cases within the first 7 days. Patients with preoperative seizures presented more frequently postoperative epilepsy than patients who were preoperatively seizure-free [P = 0.0006; OR = 48 (2,4;945)]. Postoperative seizures were more common among patients affected by one or more wafers related adverse event than among patients without adverse events [P = 0.006; OR = 21 (2,06;213)]; however, they did not appear associated to the number of implanted wafers. Patients with a sub-therapeutic level of AED at the seventh day after surgery presented a higher seizure occurrence [P = 0.02; OR = 11 (1,5;79,8)]. In our experience, postoperative seizures in BCNU-treated patients were less frequent than expected. Careful patient selection and postoperative monitoring could probably play a role in order to decrease seizure occurrence.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Carmustina/uso terapêutico , Glioma/terapia , Complicações Pós-Operatórias , Convulsões/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Implantes de Medicamento , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Convulsões/induzido quimicamente , Resultado do TratamentoRESUMO
Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P < 0.0001) and overall survival (73.9 vs. 23.6 months; P < 0.0001). This effect was independent of grade, histologic subtype, and INA expression (P < 0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Filamentos Intermediários/metabolismo , Isocitrato Desidrogenase/metabolismo , Proteínas Mutantes/metabolismo , Neoplasias Neuroepiteliomatosas/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Neoplasias Neuroepiteliomatosas/mortalidade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
In this short case-illustrated review we aimed to analyse the possible nuances of hemifacial spasm (HFS) as the presenting symptom of a tumour of the fourth ventricle. The issue is remarkable since HFS can be secondary to a fourth ventricle tumour, even when no other neurological signs are reported. In addition, the possible presentation with only upper facial muscle involvement, as in the presented case, can be deceitful because this is characteristic of the benign and much more frequent "typical" form. Based on our intra-operative data and on the previously reported cases, we think that pathogenesis could be referable to the facial nerve nucleus involvement and that clinical nuances could be related to the specific somatotropy of the nucleus under the fourth ventricle floor that, as in our case, can be infiltrated by tumour. Resolution of the disorder can usually be obtained after the complete resection of the tumour that in the reported case resulted a subependymoma (WHO grade I), so far never described in literature associated with HFS.
Assuntos
Neoplasias do Ventrículo Cerebral/complicações , Neoplasias do Ventrículo Cerebral/patologia , Quarto Ventrículo/patologia , Glioma Subependimal/complicações , Glioma Subependimal/patologia , Espasmo Hemifacial/etiologia , Neoplasias do Ventrículo Cerebral/cirurgia , Diagnóstico Diferencial , Doenças do Nervo Facial/etiologia , Doenças do Nervo Facial/patologia , Doenças do Nervo Facial/fisiopatologia , Feminino , Quarto Ventrículo/cirurgia , Glioma Subependimal/cirurgia , Espasmo Hemifacial/fisiopatologia , Humanos , Hidrocefalia/etiologia , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Resultado do Tratamento , Ventriculostomia/métodosRESUMO
A 38-year-old pregnant woman in her 24th week of gestation was admitted to our neurosurgical intensive care unit with a 5-cm cerebellar hemangioblastoma and acute hydrocephalus. Initial management included the placement of an external ventricular drain to prevent neurological deterioration. Five days after the initial diagnosis, the patient successfully underwent a neurosurgical intervention to remove the lesion. Transcranial ultrasound was used to determine the optimal ventricular drain level and facilitate weaning, bypassing the need for cerebral computed tomography and cerebral magnetic resonance imaging, which would have otherwise been necessary in postoperative follow-up.
Assuntos
Hidrocefalia , Adulto , Drenagem , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/cirurgia , Imageamento por Ressonância Magnética , Gravidez , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
The p.Arg132His mutation of isocitrate dehydrogenase 1 (IDH1(R132H) ) is a frequent alteration and a major prognostic marker in gliomas. However, direct sequencing of highly contaminated tumor samples may fail to detect this mutation. Our objective was to evaluated the sensitivity of a newly described amplification method, coamplification at lower temperature-PCR (COLD PCR), combined with high-resolution melting (HRM) for the detection of the IDH1(R132H) mutation. To this end, we used serial dilutions of mutant DNA with wild-type DNA. PCR-HRM assay detects IDH1(R132H) at an abundance of 25%, similar to the detection limit of direct Sanger sequencing. Introducing a run of COLD PCR allows the detection of 2% mutant DNA. Using two consecutive runs of COLD PCR, we detected 0.25% mutant DNA in a background of wild-type DNA, that mimics a tumor sample highly contaminated by normal DNA. We then analyzed 10 biopsies of tumor edges, considered free of tumor cells by histological analysis, and showed that immunohistochemistry of IDH1(R132H) was positive in three cases (30%), whereas double COLD PCR HRM was positive in the 10 cases studied (100%). In summary, COLD PCR HRM analysis is 100-fold more sensitive than Sanger sequencing, rendering this rapid and powerful strategy particularly useful for samples highly contaminated with normal tissue.
Assuntos
Temperatura Baixa , Isocitrato Desidrogenase/genética , Mutação/genética , Desnaturação de Ácido Nucleico/genética , Reação em Cadeia da Polimerase/métodos , Biópsia , Glioma/enzimologia , Glioma/genética , Glioma/patologia , Humanos , Imuno-HistoquímicaRESUMO
Prevalence of symptomatic central nervous system (CNS) metastases among patients with breast cancer ranges from 5% to 16%, although autoptic studies have reported prevalence rates of up to 30%. Solid brain tumours are the most common presentation in the CNS (85-95%), and they tend to arise at the grey-white matter junction with a distribution that is proportional to the regional cerebral blood flow. Descriptions of solitary intra-ventricular metastasis are very rare; to date no cases from breast cancer have been reported in the literature. We present the unusual case of a breast cancer patient who developed a solitary choroid plexus metastasis in the left lateral ventricle.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Carcinoma/patologia , Ventrículos Laterais/patologia , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
PURPOSE: Carmustine (1,3-bis[2-chloroetyl]-1-nitrosurea (BCNU)) wafers are approved for the local treatment of newly diagnosed and recurrent malignant glioma. Reassuring data on both safety and efficacy of treatment have been previously reported by phase III studies. Although most of related adverse events are reported in the first few months after surgery, there is a lack in the literature of radiological data regarding this period. Few anecdotal experiences have been reported about surgical bed cyst occurrence. The aim of our study is to analyse the radiological course of patients treated with wafers implantation focusing on the relationship between radiological data, and in particular bed cyst occurrence, and safety data. METHODS: Forty-three patients affected by malignant glioma underwent surgical removal and BCNU wafers implantation at the Department of Neurosurgery of Padova from April 2007 to October 2009. Safety data were collected according to previously reported phase III studies. Patients underwent clinical and radiological evaluation (MRI) postoperatively, then before discharge, at 1 month, then every 2 months. In the study were included only patients whose both 1- and 3-month MRIs were available. Finally, 36 out of 43 patients were available for the revision. FINDINGS: Fifty-eight percent of patients treated with BCNU wafers presented a bed cyst of the surgical cave at the 1-month MRI. Forty-eight percent of them were symptomatic. Conversely, among patients who presented one or more adverse event (27%), bed cyst was detected in up to 90% of cases (OR 7.35), being intracranial hypertension more frequently associated (OR 7.35; p value <0.05). In general, cysts presented a benign behaviour in the sense that patients promptly improved with corticosteroid treatment, never required surgery, never reported permanent neurological deficits. CONCLUSIONS: Surgical bed cyst occurrence in BCNU wafer-treated patients resulted more frequent than expected. Familiarity with the event is important to correctly handle a possible evolving phenomenon. However, only further larger experiences and prospective studies could reveal how the understanding of such event might be helpful to improve safety data.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/administração & dosagem , Glioma/tratamento farmacológico , Bombas de Infusão Implantáveis , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Carmustina/efeitos adversos , Feminino , Glioma/diagnóstico por imagem , Glioma/radioterapia , Humanos , Bombas de Infusão Implantáveis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Radiografia , Estudos RetrospectivosRESUMO
BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence is a validated technique for resection of high grade gliomas (HGG); the aim of this study was to evaluate the surgical outcome and the intraoperative findings in a consecutive series of patients. METHODS: Clinical and surgical data from patients affected by HGG who underwent surgery guided by 5-ALA fluorescence at our Department between June 2011 and February 2014 were retrospectively evaluated. Surgical outcome was evaluated by assessing the resection rate as gross total resection (GTR) > 98% and GTR > 90%. We finally stratified data for recurrent surgery, tumor location, tumor size, and tumor grade (IV versus III grade sec. WHO). RESULTS: 94 patients were finally enrolled. Overall GTR > 98% and GTR > 90% was achieved in 93% and 100% of patients. Extent of resection (GTR > 98%) was dependent on tumor location, tumor grade (P < 0.05), and tumor size (P < 0.05). In 43% of patients the boundaries of fluorescent tissue exceeded those of tumoral tissue detected by neuronavigation, more frequently in larger (57%) (P < 0.01) and recurrent (60%) tumors. CONCLUSIONS: 5-ALA fluorescence in HGG surgery enables a GTR in 100% of cases even if selection of patients remains a main bias. Recurrent surgery, and location, size, and tumor grade can predict both the surgical outcome and the intraoperative findings.
Assuntos
Ácido Aminolevulínico/administração & dosagem , Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Cuidados Intraoperatórios/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Fluorescência , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos RetrospectivosRESUMO
IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.
Assuntos
Glioma/genética , Glioma/mortalidade , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1/genética , Intervalo Livre de Doença , Feminino , Glioma/enzimologia , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Retrospectivos , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
OBJECTIVE: To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs). METHODS: We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS). RESULTS: TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS = 13.8 vs 18.4 months), in both IDH-mutated (OS = 13.8 vs 37.6 months, p = 0.022) and IDH-wt GBMs (OS = 13.7 vs 17.5 months, p = 0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS = 26.6 vs 13.3 months; p = 0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS = 26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS = 15.8 vs 13.3 months, p = 0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation). CONCLUSIONS: The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs.
Assuntos
Neoplasias Encefálicas/genética , Receptores ErbB/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: The IDH1(R132H) mutation is both a strong prognostic predictor and a diagnostic hallmark of gliomas and therefore has major clinical relevance. Here, we developed a new technique to detect the IDH1(R132H) mutation in the plasma of patients with glioma. METHODS: Small-size DNA (150-250 base pairs) was extracted from the plasma of 31 controls and 80 patients with glioma with known IDH1(R132H) status and correlated with MRI data. The IDH1(R132H) mutation was detected by a combination of coamplification at lower denaturation temperature and digital PCR. RESULTS: The small size DNA concentration was 1.2 ng/mL (range 0.1-6.6) in controls vs 1.2 ng/mL (range 0.1-50.3) in patients with glioma (p = not significant) and 0.9 ng/mL (0.0-3.0) in low-grade gliomas vs 1.5 ng/mL in high-grade gliomas (p < 0.01). The small size DNA concentration correlated with enhancing tumor volume (1.6 ng/mL [0.4-24.9] when <10 cm(3) and 14.0 ng/mL [0.6-50.3] when ≥10 cm(3)). The IDH1(R132H) mutation was detected in 15 out of 25 plasma DNA mixtures (60%) from patients with mutated tumors and in none of the 14 patients with a nonmutated tumor. The sensitivity increased with enhancing tumor volume (3/9 in nonenhancing tumors, 6/10 for enhancing volume <10 cm(3), and 6/6 for enhancing volume ≥10 cm(3)). CONCLUSION: With a specificity of 100% and a sensitivity related to the tumor volume and contrast enhancement, IDH1(R132H) identification has a valuable diagnostic accuracy in patients not amenable to biopsy.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Adulto , Idoso , DNA/sangue , DNA/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase , Curva ROC , Reprodutibilidade dos Testes , Temperatura , Adulto JovemRESUMO
BACKGROUND: Implantation of carmustine (1,3-bis (2 chloroetyl)-1-nitrosurea [BCNU]) wafers is an approved local treatment after surgical removal of high-grade gliomas. Safety data have been largely reported by phase III studies. The communication between the final surgical cavity and the ventricular cavities is supposed to be a relative contraindication for positioning of the wafers because of the possible development of hydrocephalus. However, at present there are neither data about this topic published with the exception of a few case reports, nor any proposals for selection criteria for wafer implantation in such circumstances. Furthermore, there are no technical suggestions in literature put forward for the surgical repairing of ventricular defects. Our study was particularly focused on addressing these 3 issues. METHODS: Forty-three patients affected by a high-grade glioma underwent surgical removal and BCNU wafer implantation between March 2007 and September 2009 at the Department of Neurosurgery of Padua. Among them, we retrospectively reviewed clinical, surgical, and radiological data of 9 patients who had been treated with carmustine wafers after surgical repair of communication between the surgical cavity and the ventricular cavities. We also focused on the technical details concerning wafers positioning in this particular situation. RESULTS: Ventricular defects were present in the atrium in 4, frontal horn in 3, and temporal horn in 2 cases. The maximum diameter of the defect was between 6 and 10 mm. In all cases, the defect was intraoperatively repaired in the same way, and up to 8 wafers were implanted in the surgical cavity. In the series reported, no cases of hydrocephalus were detected. CONCLUSIONS: In our experience, integrity of wafers, size of ventricular wall defect, and accuracy in repairing the defect were crucial issues. Nevertheless, more experience and prospective studies would be helpful to clarify both in what measure ventricular opening affects safety data and the best reliable way of repairing ventricular defects when BCNU wafers are implanted.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Carmustina/administração & dosagem , Carmustina/uso terapêutico , Ventrículos Cerebrais/cirurgia , Glioma/tratamento farmacológico , Glioma/cirurgia , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/patologia , Carmustina/efeitos adversos , Ventrículos Cerebrais/patologia , Terapia Combinada , Implantes de Medicamento , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Astroblastoma is a rare primary brain neoplasm that accounts for 0.45-2.8% of brain gliomas. Intraventricular localization is extremely rare. The authors report a case of well-differentiated completely intraventricular astroblastoma in a 6-year-old girl and review the relevant literature. Their patient presented with a 5-week history of progressive nausea and vomiting. Magnetic resonance (MR) imaging revealed a large, well-demarcated, solid-cystic mass in the left temporooccipital ventricular horn. Macroscopic radical resection of the tumor was performed via the superior temporal sulcus. The postoperative course was uneventful and no adjuvant therapy was administered after surgery. No recurrence was detected at 9-months follow-up. Gross-total resection has the greatest impact on patient survival. In differentiated tumors, recurrence is usually local, and adjuvant therapy is recommended after repeated resection for the treatment of recurrence. In patients harboring anaplastic astroblastoma, gross-total resection and adjuvant therapy after the initial surgery seems to be the best choice. It is important to distinguish astroblastoma from ependymoma in clinical practice because of the differences in therapeutic approaches.