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OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.
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Epilepsia Resistente a Medicamentos , Epilepsia do Lobo Temporal , Esclerose Hipocampal , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/patologia , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Filaminas/genética , Variação Genética , Esclerose Hipocampal/genética , Esclerose Hipocampal/patologia , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologiaRESUMO
BACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). METHODS: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. RESULTS: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. CONCLUSION: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Idoso , Glioblastoma/patologia , Prognóstico , Neoplasias Encefálicas/patologia , Encéfalo/patologia , SobreviventesRESUMO
Spontaneous extensive spinal epidural haematoma poses a unique challenge for the neurosurgeon. Performing extensive laminectomies to remove all of the compressive haematoma can destabilise the patient's spinal column, which may require fixation. This is further complicated in patients with significant coagulopathy. We present a novel use of recombinant tissue plasminogen activator (rt-PA) in a patient with therapeutic coagulopathy, presenting with myelopathy secondary to an acute extensive spinal epidural haematoma. To the best of our knowledge, this is the first case of acute multilevel spinal epidural haematoma that has been successfully evacuated via single level laminectomy and topically applied rt-PA.
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Hematoma Epidural Espinal , Ativador de Plasminogênio Tecidual , Humanos , Ativador de Plasminogênio Tecidual/uso terapêutico , Hematoma Epidural Espinal/complicações , Hematoma Epidural Espinal/diagnóstico por imagem , Hematoma Epidural Espinal/tratamento farmacológico , Laminectomia/efeitos adversos , Descompressão Cirúrgica/efeitos adversos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: The surgical management of deep brain lesions is challenging, with significant morbidity. Advances in surgical technology have presented the opportunity to tackle these lesions. METHODS: We performed a complete resection of a thalamic/internal capsule CM using a tubular retractor system via a parietal trans-sulcal para-fascicular (PTPF) approach without collateral injury to the nearby white matter tracts. CONCLUSION: PTPF approach to lateral thalamic/internal capsule lesions can be safely performed without injury to eloquent white matter fibres. The paucity of major vessels along this trajectory and the preservation of lateral ventricle integrity make this approach a feasible alternative to traditional approaches.
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Neoplasias Encefálicas , Cápsula Interna , Neoplasias Encefálicas/cirurgia , Humanos , Cápsula Interna/diagnóstico por imagem , Cápsula Interna/cirurgia , Microcirurgia , Procedimentos Neurocirúrgicos , Tálamo/diagnóstico por imagem , Tálamo/cirurgiaRESUMO
The surgical management of brainstem glioma is challenging and has significant morbidity. Advances in surgical armamentarium has presented the opportunity to tackle these lesions. We present the case of a paediatric patient with a 2.3cm midbrain pilocytic astrocytoma. With the aid of tractography, neuro-navigation, 3-dimensional exoscope and a tubular retractor, near total resection of the tumour was achieved through a trans-sulcal para-fascicular approach without permanent injury to the corticospinal tract. To our knowledge this is the first report of a brainstem tumour resected using this approach and demonstrates what can be achieved with synergistic utility of evolving technologies in neurosurgery.
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DNMT3A codes for a DNA methyl transferase enzyme that plays a central role embryogenesis. Somatic mutations in this gene have been associated with tumorigenesis and are associated with a number of cancers. The recently described Tatton-Brown-Rahman syndrome (TBRS) is due to heterozygous germline mutations in the DNMT3A gene. So far, only one case of hematological malignancy associated with TBRS have been reported. Here, we describe the first case presenting with TBRS and medulloblastoma. We also discuss the associations between mutations in DNMT3A found in TBRS, AML, and medulloblastoma.
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Neoplasias Cerebelares/genética , Deficiência Intelectual/genética , Meduloblastoma/genética , Adolescente , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Feminino , Humanos , Mutação , SíndromeRESUMO
BACKGROUND: Postnatal closure of a myelomeningocele remains the standard of care in many countries. The prenatal closure has given hope for decreasing the damage to the neural placode and has challenged classic management. However, this technique presents potential sources of complications. Patients with MMC with an anatomical level of L4 and below have a better functional prognosis than higher level malformations. Are they still candidates for prenatal surgery? OBJECTIVE: To evaluate outcome of MMC with an anatomical level of L4 and below and discuss, with support of the literature, the indications to perform prenatal closure in this particular group of patients. MATERIALS AND METHODS: Twenty-nine children were included in this observational study. The level of the vertebral malformation was sacral in 12 cases (41.4%) or lumbar (level ≤ L4) in 17 cases (58.6%). All the patients was operated postnatally for closure of the MMC with microsurgical technique as soon as possible after clinical evaluation (range 0-97 days). RESULTS: Only 11 out of 29 patients (37.9%) needed of a CSF diversion. A Chiari II malformation was present before MMC closure in 17 patients (58.6%) and only in 5 (17%) after. Twenty-six patients (89.7%) were able to walk. Seven (23%) and 16 (55%) of our patients have a normal bladder and bowel control, respectively. All school-aged children attend school. CONCLUSIONS: The functional outcome for low-level MMC is good when managed with modern microneurosurgical techniques with a low risk for the patient and the mother. Therefore, we do not suggest prenatal surgery for subgroup of infant with MM.
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Meningomielocele/patologia , Meningomielocele/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Procedimentos Neurocirúrgicos/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: Grade II and III intramedullary ependymomas [IME] are circumscribed with a plane of cleavage that should facilitate high gross total resection rates (GTR). Gross total resection of grade II/III IME is superior to subtotal resection (STR) and radiotherapy (RTx) for progression-free and overall survival. We sought to compare our GTR with other series that have utilised standard intraoperative monitoring techniques and we explored factors that may influence rates of resection. MATERIALS AND METHODS: Database search and retrospective chart and radiological review of all grade II or III spinal ependymomas over a 10-year period from the senior authors practice. Comprehensive PubMed search to identify similar series that identified histology, McCormick Function scores (MCC) preoperatively and post-operatively, surgical strategy and use of intraoperative monitoring. Standard statistical analysis was performed. RESULTS: Seventeen patients were identified: 16 grade II and one grade 3. GTR was 94.12%. Factors that correlated with a decline in MCC were longitudinal extension of the tumour (p = 0.0238) and presentation with motor signs and symptoms (p = 0.0223). There was no statistical difference between preoperative factors that influence post-operative outcomes in the current study when compared with other published series. There was no statistical difference between preoperative and postoperative MCC scores between our series and other published series. DISCUSSION: The current series with a GTR of 94.12% compares favourably with other published series with GTRs of 55.8-84% with no significant difference in functional outcomes. Series with low GTRs should examine their operative strategy or false-positive alarm rates which may lead to higher STRs. This series should be viewed as a unique opportunity to benchmark GTRs of circumscribed intramedullary tumours.
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Ependimoma/cirurgia , Neoplasias da Medula Espinal/cirurgia , Adolescente , Adulto , Idoso , Benchmarking , Biometria , Bases de Dados Factuais , Progressão da Doença , Ependimoma/patologia , Feminino , Humanos , Monitorização Neurofisiológica Intraoperatória/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Medula Espinal/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Pancreatic neuroendocrine tumor (NET) is frequently encountered in patients with von Hippel-Lindau disease (VHL) and uncommonly metastasizes to the central nervous system. Here, we present the case of a VHL patient with symptomatic pancreatic NET metastases to both the cervical spinal cord and a preexisting brainstem hemangioblastoma (e.g., tumor- to-tumor metastasis).
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Sistema Nervoso Central/cirurgia , Neoplasias Cerebelares/cirurgia , Hemangioblastoma/cirurgia , Neoplasias Pancreáticas/cirurgia , Doença de von Hippel-Lindau/cirurgia , Neoplasias do Tronco Encefálico/complicações , Sistema Nervoso Central/patologia , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/diagnóstico , Hemangioblastoma/complicações , Hemangioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/diagnósticoRESUMO
Isolated intracranial Rosai-Dorfman Disease is rare. Here, we describe a patient who developed an asymptomatic, right parietal RDD lesion over 18 months while being followed radiographically for another brain lesion. To our knowledge, rapid, de novo radiographic formation of isolated intracranial RDD has never been reported in an asymptomatic patient.
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Claudin-5 is one of the most essential tight junction proteins at the blood-brain barrier. A single nucleotide polymorphism rs10314 is located in the 3'-untranslated region of claudin-5 and has been shown to be a risk factor for schizophrenia. Here, we show that the pumilio RNA-binding protein, pumilio-1, is responsible for rs10314-mediated claudin-5 regulation. The RNA sequence surrounding rs10314 is highly homologous to the canonical pumilio-binding sequence and claudin-5 mRNA with rs10314 produces 25% less protein due to its inability to bind to pumilio-1. Pumilio-1 formed cytosolic granules under stress conditions and claudin-5 mRNA appeared to preferentially accumulate in these granules. Added to this, we observed granular pumilio-1 in endothelial cells in human brain tissues from patients with psychiatric disorders or epilepsy with increased/accumulated claudin-5 mRNA levels, suggesting translational claudin-5 suppression may occur in a brain-region specific manner. These findings identify a key regulator of claudin-5 translational processing and how its dysregulation may be associated with neurological and neuropsychiatric disorders.
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Barreira Hematoencefálica , Claudina-5 , Proteínas de Ligação a RNA , Humanos , Claudina-5/metabolismo , Claudina-5/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Barreira Hematoencefálica/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Animais , Biossíntese de Proteínas/fisiologia , Células Endoteliais/metabolismoRESUMO
Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. 'glszm Zone Entropy'), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical 'discovery' radiomics in the neuro-oncology space.
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Neoplasias Encefálicas , Radiômica , Humanos , Animais , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Encefálicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor. METHODS: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action. RESULTS: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype. CONCLUSION: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.
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Malignant gliomas are a type of primary brain tumour that originates in glial cells. Among them, glioblastoma multiforme (GBM) is the most common and the most aggressive brain tumour in adults, classified as grade IV by the World Health Organization. The standard care for GBM, known as the Stupp protocol includes surgical resection followed by oral chemotherapy with temozolomide (TMZ). This treatment option provides a median survival prognosis of only 16-18 months to patients mainly due to tumour recurrence. Therefore, enhanced treatment options are urgently needed for this disease. Here we show the development, characterization, and in vitro and in vivo evaluation of a new composite material for local therapy of GBM post-surgery. We developed responsive nanoparticles that were loaded with paclitaxel (PTX), and that showed penetration in 3D spheroids and cell internalization. These nanoparticles were found to be cytotoxic in 2D (U-87 cells) and 3D (U-87 spheroids) models of GBM. The incorporation of these nanoparticles into a hydrogel facilitates their sustained release in time. Moreover, the formulation of this hydrogel containing PTX-loaded responsive nanoparticles and free TMZ was able to delay tumour recurrence in vivo after resection surgery. Therefore, our formulation represents a promising approach to develop combined local therapies against GBM using injectable hydrogels containing nanoparticles.
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Neoplasias Encefálicas , Glioblastoma , Nanocompostos , Nanopartículas , Adulto , Humanos , Glioblastoma/patologia , Preparações de Ação Retardada/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Temozolomida/uso terapêutico , Paclitaxel , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Hidrogéis/uso terapêutico , Linhagem Celular TumoralRESUMO
OBJECTIVE: Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE. METHODS: We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort. RESULTS: Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy. SIGNIFICANCE: Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted.
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Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Mioclonia , Estimulação do Nervo Vago , Adulto , Humanos , Feminino , Masculino , Estimulação do Nervo Vago/métodos , Estudos Retrospectivos , Epilepsia Generalizada/terapia , Epilepsia Resistente a Medicamentos/terapia , Convulsões , Imunoglobulina E , Resultado do Tratamento , Nervo VagoRESUMO
Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26-33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to achieve the optimal extent of resection (EOR), with 5-Aminolevulinic Acid (5-ALA) the only clinically approved intra-operative fluorophore for GBM. This review aims to highlight the requirement for improved intra-operative imaging techniques, focusing on fluorescence-guided imaging (FGS) and the use of novel dyes with the potential to overcome the limitations of current FGS. The review was performed based on articles found in PubMed an.d Google Scholar, as well as articles identified in searched bibliographies between 2001 and 2022. Key words for searches included 'Glioblastoma' + 'Fluorophore'+ 'Novel' + 'Fluorescence Guided Surgery'. Current literature has favoured the approach of using targeted fluorophores to achieve specific accumulation in the tumour microenvironment, with biological conjugates leading the way. These conjugates target specific parts overexpressed in the tumour. The positive results in breast, ovarian and colorectal tissue are promising and may, therefore, be applied to intracranial neoplasms. Therefore, this design has the potential to produce favourable results in GBM by reducing the residual tumour, which translates to decreased tumour recurrence, morbidity and ultimately, mortality in GBM patients. Several preclinical studies have shown positive results with targeted dyes in distinguishing GBM cells from normal brain parenchyma, and targeted dyes in the Near-Infrared (NIR) emission range offer promising results, which may be valuable future alternatives.
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Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF ßPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of ßPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of ßPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover ßPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with ßPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF ßPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.
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BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary brain tumour having a median survival of just 12-18 months following standard therapy protocols. Local recurrence, post-resection and adjuvant therapy occurs in most cases. NEW METHOD: U87MG-luc2-bearing GBM xenografts underwent 4.5mm craniectomy and tumour resection using microsurgical techniques. The cranial defect was repaired using a novel modified cranial window technique consisting of a circular microscope coverslip held in place with glue. RESULTS: Immediate post-operative bioluminescence imaging (BLI) revealed a gross total resection rate of 75%. At censor point 4 weeks post-resection, Kaplan-Meier survival analysis revealed 100% survival in the surgical group compared to 0% in the non-surgical cohort (p=0.01). No neurological defects or infections in the surgical group were observed. GBM recurrence was reliably imaged using facile non-invasive optical bioluminescence (BLI) imaging with recurrence observed at week 4. COMPARISON WITH EXISTING METHOD(S): For the first time, we have used a novel cranial defect repair method to extend and improve intracranial surgical resection methods for application in translational GBM rodent disease models. Combining BLI and the cranial window technique described herein facilitates non-invasive serial imaging follow-up. CONCLUSION: Within the current context we have developed a robust methodology for establishing a clinically relevant imageable GBM surgical resection model that appropriately mimics GBM recurrence post resection in patients.
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Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Transplante de Neoplasias/métodos , Procedimentos Neurocirúrgicos , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Seguimentos , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Medições Luminescentes/métodos , Recidiva Local de Neoplasia , Imagem Óptica , Distribuição Aleatória , Ratos , Reprodutibilidade dos TestesRESUMO
OBJECT: McLone and Knepper's unified theory of Chiari malformation Type II (CM-II) describes how the loss of CSF via the open posterior neuropore fails to create adequate distending pressure for the developing rhomboencephalic vesicle. The authors of the present article describe the relationship between the posterior fossa volume and intracranial cerebellar volume as being related to the distance from the obex of the fourth ventricle to the myelomeningocele lesion using a common mathematical model, the Hagen-Poiseuille law. METHODS: All newborns who required closure of a myelomeningocele at the authors' institution between 2008 and 2011 and who were between 4 weeks premature and 2 months, corrected gestational age, at the time of MRI were included in this study. Volumes and measurements were obtained from axial and sagittal T2-weighted MR images of the brain and spine. RESULTS: A total of 56 newborn infants met the inclusion criteria. There was a direct linear relationship between both posterior fossa volume and cerebellar volume and the spinal level of the myelomeningocele lesion (p = 0.0012 and p = 0.0041, respectively). There was a negative linear relationship between the cerebellar descent, the spinal level of the lesion, and posterior fossa volume and cerebellar volume. These relationships strengthen in patients with no syringomyelia and are not significant in those groups with syringomyelia. The results of a 1-way ANOVA for the 3 groups did not reach significance. CONCLUSIONS: Using a linear equation derived from the Hagen-Poiseuille law that describes pressure in the fourth ventricle as being directly related to the length of the central canal from the obex to the myelomeningocele lesion, the authors were able to explain the directly observed linear relation between posterior fossa volume, intracranial cerebellar volume, and cerebellar descent to the level of the spinal lesion. As this model assumes a uniform radius of the central canal they were able to validate this model when they observed a strengthening in relationships in the no syringomyelia group and statistically insignificant correlations in the groups with syringomyelia. They therefore propose that the spinal level of the lesion is one of the major determinants of posterior fossa volume, intracranial cerebellar volume, and cerebellar ectopia.
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Malformação de Arnold-Chiari/diagnóstico , Cerebelo/patologia , Coristoma/diagnóstico , Fossa Craniana Posterior/patologia , Modelos Lineares , Imageamento por Ressonância Magnética , Meningomielocele/diagnóstico , Medula Espinal/patologia , Siringomielia/diagnóstico , Análise de Variância , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/patologia , Cerebelo/diagnóstico por imagem , Coristoma/diagnóstico por imagem , Fossa Craniana Posterior/cirurgia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Irlanda , Masculino , Meningomielocele/diagnóstico por imagem , Meningomielocele/patologia , Tamanho do Órgão , Radiografia , Medula Espinal/diagnóstico por imagem , Siringomielia/diagnóstico por imagemRESUMO
Current therapeutic strategies against glioblastoma (GBM) have failed to prevent disease progression and recurrence effectively. The part played by molecular imaging (MI) in the development of novel therapies has gained increasing traction in recent years. For the first time, using expertise from an integrated multidisciplinary group of authors, herein we present a comprehensive evaluation of state-of-the-art GBM imaging and explore how advances facilitate the emergence of new treatment options. We propose a novel next-generation treatment paradigm based on the targeting of multiple hallmarks of cancer evolution that will heavily rely on MI.