RESUMO
Posaconazole diffusion has been documented in various organs, which contrasts with the scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample-to-plasma ratios between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycoses, even those caused by posaconazole-susceptible black fungi.
Assuntos
Antifúngicos/uso terapêutico , Sistema Nervoso Central/metabolismo , Feoifomicose Cerebral/tratamento farmacológico , Triazóis/uso terapêutico , Abscesso Encefálico/tratamento farmacológico , Abscesso Encefálico/metabolismo , Feoifomicose Cerebral/metabolismo , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Ependimoma , Glioma Subependimal , Neoplasias Supratentoriais , Criança , Humanos , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Neoplasias do Sistema Nervoso Central/genética , Ependimoma/patologia , Hibridização in Situ Fluorescente , Neoplasias Supratentoriais/patologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Rhinocladiella mackenziei cerebral phaeohyphomycosis is a rare severe disease that has been typically described in the Middle East. Here, we report 2 cases of R. mackenziei cerebral phaeohyphomycosis in patients from Morocco, diagnosed and treated in France, and raise a concern about the ever-going extension of the area at risk for this devastating invasive fungal infection.
Assuntos
Ascomicetos/isolamento & purificação , Feoifomicose Cerebral/diagnóstico , Antifúngicos/uso terapêutico , Ascomicetos/genética , Feoifomicose Cerebral/tratamento farmacológico , Feoifomicose Cerebral/cirurgia , DNA Fúngico/genética , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , MarrocosRESUMO
BACKGROUND: Giant thoracic disc herniation (gTDH) is a rare condition. It is defined by a herniation that occupies at least 40% of the thoracic spinal canal and is usually calcified. Several surgical techniques have been described to date but this surgery remains a technically difficult procedure. OBJECTIVE: To report the long-term outcome of 53 patients with myelopathy due to gTDH who were operated on by a thoracoscopic approach. The technical details of the preoperative assessment and the surgical procedure are presented. METHOD: We present a retrospective study of a database of 53 patients operated for symptomatic gTDH by a thoracoscopic approach. The following clinical parameters were assessed initially and used during follow-up: Frankel grade and JOA score adapted to the thoracic spine (mJOA), pain in the lower limbs and limitation of the walking perimeter to less than 500 meters. The quality of spinal cord decompression was assessed postoperatively by magnet resonance imaging (MRI). RESULTS: The mean follow-up was 78.1 mo (SD 49.4). At the last follow-up visit, clinical examination showed a mean improvement of 0.91 Frankel grade (P < 0.001) and 2.56 mJOA score respectively (P < 0.001). Lower limb pain and walking perimeter were also improved. Postoperative MRI revealed that the resection was complete in 35 cases, subtotal in 13 cases, and incomplete in 5 cases. CONCLUSION: gTDH is a condition that often evolves favorably after surgery. The thoracoscopic approach is a feasible alternative technique.
Assuntos
Descompressão Cirúrgica/métodos , Deslocamento do Disco Intervertebral/cirurgia , Procedimentos Neurocirúrgicos/métodos , Compressão da Medula Espinal/cirurgia , Vértebras Torácicas , Toracoscopia/métodos , Adulto , Idoso , Calcinose , Vazamento de Líquido Cefalorraquidiano/epidemiologia , Vazamento de Líquido Cefalorraquidiano/cirurgia , Feminino , Humanos , Deslocamento do Disco Intervertebral/complicações , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Compressão da Medula Espinal/etiologiaRESUMO
OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.
Assuntos
Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Terapia por Ultrassom/instrumentação , Administração Intravenosa , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Permeabilidade Capilar/efeitos dos fármacos , Fármacos do Sistema Nervoso Central , Eletroencefalografia , Desenho de Equipamento , Potenciais Somatossensoriais Evocados , Feminino , Fluordesoxiglucose F18 , Estudos Longitudinais , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Microbolhas , Modelos Animais , Papio anubis , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Hexafluoreto de EnxofreRESUMO
PURPOSE: Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model. METHODS: Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry. RESULTS: The brain concentration of platinum was highly enhanced (5.2×) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2× and 1.3× respectively). CONCLUSIONS: This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco-regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212).
Assuntos
Antineoplásicos/farmacocinética , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Carboplatina/farmacocinética , Ultrassonografia/métodos , Animais , Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Infusões Intravenosas , Espectrometria de Massas/métodos , Papio anubis , Distribuição TecidualRESUMO
The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.