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Transfacet screws (TFS) are an alternative to the classic bilateral pedicular screws (BPS) in addition to anterior (ALIF) or oblique (OLIF) lumbar interbody fusion. Spinal navigation could help the surgeon in technically demanding procedures in order to avoid screw malposition. Although spinal navigation is commonly used in BPS, its contribution in TFS remains unclear. Our aim here was to assess the feasibility of TFS using spinal navigation in addition to anterior lumbar fusion. Five patients suffering from lumbar degenerative disc disease were included. During the same general anaesthesia, we performed successively an ALIF or OLIF and then a TFS according to Boucher technique using spinal navigation (O-arm). No peri-operative complication occurred, and all the screws were successfully positioned (n = 10). All clinical scores (ODI, VAS L and VAS R) improved at 6-month follow-up. Segmental lordosis increased from 6° [2.4°-12°] to 13.6° [8°-17°]. Fusion was achieved for the five patients. TFS using O-arm in addition to ALIF/OLIF is feasible. To confirm our early favourable outcomes on clinical and radiological data, this technique must be evaluated on larger samples of patients.
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Fusão Vertebral , Cirurgia Assistida por Computador , Parafusos Ósseos , Humanos , Imageamento Tridimensional , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
The purpose of this study was to report an independent real-life experience about the use of recombinant human bone morphogenetic protein 2 in lumbar interbody fusion with a special focus on complications. This is a retrospective single-center cohort study between 2007 and 2013 including 277 patients treated for anterior or posterior lumbar fusion with recombinant human bone morphogenetic protein 2. We report the complications occurring during the 12 first postoperative months and analyze the fusion rate on X-rays. There are 58 cases (22.8%) of clinical complications. In 15 cases (5.9%), these complications were related to the use of recombinant human bone morphogenetic protein 2. Only one patient (0.4%) required a new intervention due to recombinant human bone morphogenetic protein 2. Fusion rate at 1 year was 98%. The low rate of specific complication suggests that recombinant human bone morphogenetic protein 2 can be safe and effective in anterior and posterior interbody fusion when used with simple precautions.
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Proteína Morfogenética Óssea 2/uso terapêutico , Vértebras Lombares , Complicações Pós-Operatórias/epidemiologia , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/efeitos adversos , Fator de Crescimento Transformador beta/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Radiografia , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Doenças da Coluna Vertebral/diagnóstico por imagem , Fusão Vertebral/métodosRESUMO
Stem cell-like properties of glioma initiating cells (GiCs) fuel glioblastoma (GBM) development by providing the different cell types that comprise the tumor. It is therefore likely that the molecular circuitries that regulate their decision to self-renew or commit to a more differentiated state may offer targets for future innovative therapies. In previous micro-RNA profiling studies to search for regulators of stem cell plasticity, we identified miR-18a* as a potential candidate and its expression correlated with the stemness state. Here, using human GiCs we found that miR-18a* expression promotes clonal proliferation in vitro and tumorigenicity in vivo. Mechanistically, ERK-dependent induction of miR-18a* directly represses expression of DLL3, an autocrine inhibitor of NOTCH, thus enhancing the level of activated NOTCH-1. Activated NOTCH-1 in turn is required for sustained ERK activation. This feed-forward loop, driven by miR-18a*, is required to turn on the SHH-GLI-NANOG network, essential for GiC self-renewal. Hence, by tightly regulating expression of DLL3, miR-18a* constitutes an important signaling mediator for fine tuning the level of GiC self-renewal.
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Glioma/genética , MicroRNAs/genética , Receptor Notch1/metabolismo , Idoso , Animais , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Regulação para Baixo , Glioma/metabolismo , Glioma/patologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Receptor Notch1/genética , TransfecçãoRESUMO
BACKGROUND: Although most patients suffering from trigeminal neuralgia (TN) respond to medical or surgical treatment, nonresponders remain in very severe painful condition. CASE RESULT: We describe for the first time a case of severe refractory classical TN treated successfully (follow-up one year) by chronic bilateral occipital nerve stimulation (ONS), because other classic medical and surgical options failed or could not be performed. CONCLUSIONS: This single case suggests that ONS might be offered to TN patients refractory both to standard drugs and interventions, with a favorable risk/benefit ratio, although its long-term efficacy remains unknown.
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Terapia por Estimulação Elétrica/métodos , Terapia de Salvação/métodos , Neuralgia do Trigêmeo/terapia , Idoso , Eletrodos Implantados , Feminino , HumanosRESUMO
BACKGROUND: Although visual field (VF) defects are common in compressive pituitary adenoma (CPA), their pathophysiology has not been fully elucidated. The mechanical theory (i.e., direct compression of the optic chiasm by the CPA) and the vascular theory (i.e., compression of the vessels supplying the visual path by the CPA) or their association could explain the visual impairment. The aim of this study was to determine whether the vascular density (VD) improved after surgical decompression of the optic chiasm in CPA patients and whether OCT-A could help to identify predictive factors for postoperative visual recovery. METHODS: A prospective controlled study was conducted in patients who underwent transsphenoidal pituitary adenoma surgery. Patients were divided into two groups: with CPA and without CPA (NCPA). All patients underwent a neuro-ophthalmological examination, VF testing, macular and optic disc structural OCT [retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses] and OCT-A before and then 1 and 6 months after surgery. RESULTS: Twenty-four eyes and fourteen eyes were included, respectively, in the CPA and NCPA groups. None of the VD parameters assessed by OCT-A were significantly improved after surgery in the CPA group. In the CPA group, the mean macular superficial VD was significantly decreased at 6 months. The multivariate analysis failed to identify any preoperative parameters predictive of postoperative VF improvement. CONCLUSIONS: Our preliminary findings suggest that the visual impairment observed in CPA patients could not be explained by the vascular theory. None of the preoperative OCT-A parameters allowed a postoperative VF recovery assessment. Trial registration number NCT04074642, ID-RCB 2019-A01186-51 date of registration 30 July 2019.
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UNLABELLED: The aim of this study was to assess the safety and efficacy of intraventricular fibrinolysis (IVF) for aneurysmal subarachnoid hemorrhage (aSAH) with severe intraventricular hemorrhage (IVH). In this randomized controlled trial, between 2005 and 2009, patients with aSAH and severe IVH were randomly assigned into two groups: one treated with external ventricular drainage (EVD) combined with intraventricular recombinant tissue plasminogen activator (rt-PA) and the second with EVD alone. The primary end-point was mortality rate within the first 30 days. We performed meta-analysis including all published articles that compared IVF + EVD to EVD alone in patients with aSAH IVH. Eleven patients were included in the rt-PA group, eight in the control group. At 30 days, mortality rate was lower in the rt-PA group (45.5 vs. 62.5%), but results were not statistically significant (p = 0.65). Clearance of third and fourth ventricles was obtained previously in the rt-PA group (4.25 days) compared to the control group (10.67 days) (p = 0.001). There was no statistically significant difference concerning the occurrence of complications. The meta-analysis showed a better survival rate with IVF without raised statistical significance (odds ratio = 0.32 [95% confidence interval, 0.10-1.03]). This study shows that IVF is as safe as EVD alone for aSAH with severe IVH. It accelerates blood clot resolution in the ventricular system. Mortality rate could be improved by IVF but without significant results. Because of the severity and rarity of this pathology, a multicenter study is required. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov (NCT00823485).
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Ventrículos Cerebrais , Aneurisma Intracraniano/terapia , Hemorragias Intracranianas/terapia , Terapia Trombolítica/métodos , Adulto , Idoso , Determinação de Ponto Final , Feminino , Humanos , Aneurisma Intracraniano/complicações , Hemorragias Intracranianas/etiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neuroimagem , Razão de Chances , Análise de Sobrevida , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Vasoespasmo Intracraniano/epidemiologia , Vasoespasmo Intracraniano/etiologiaRESUMO
OBJECTIVE: The role of surgery in the treatment of malignant gliomas in the elderly is not settled. The authors conducted a randomized trial that compared tumor resection with biopsy only-both followed by standard therapy-in such patients. METHODS: Patients ≥ 70 years of age with a Karnofsky Performance Scale (KPS) score ≥ 50 and presenting with a radiological suspicion of operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy groups. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008-2017), with the addition of adjunct therapy with temozolomide when this regimen became standard (2017-2019). The primary endpoint was survival, and secondary endpoints were progression-free survival (PFS), cognitive status (Mini-Mental State Examination), autonomy (KPS), quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-BN20), and perioperative morbidity and mortality. RESULTS: Between 2008 and 2019, 107 patients from 9 centers were enrolled in the study; 101 were evaluable for analysis because a GBM was histologically confirmed (50 in the surgery arm and 51 in the biopsy arm). There was no statistically significant difference in median survival between the surgery (9.37 months) and the biopsy (8.96 months, p = 0.36) arms (adjusted HR 0.79, 95% CI 0.52-1.21, p = 0.28). However, the surgery group had an increased PFS (5.06 vs 4.02 months; p = 0.034) (adjusted HR 0.50, 95% CI 0.32-0.78, p = 0.002). Less deterioration of quality of life and KPS score evolution than in the biopsy group was observed. Surgery was not associated with increased mortality or morbidity. CONCLUSIONS: This study suggests that debulking surgery is safe, and-compared to biopsy-is associated with a less severe deterioration of quality of life and autonomy, as well as a significant although modest improvement of PFS in elderly patients suffering from newly diagnosed malignant glioma. Although resection does not provide a significant survival benefit in the elderly, the authors believe that the risk/benefit analysis favors an attempt at optimal tumor resection in this population, provided there is careful preoperative geriatric evaluation. Clinical trial registration no.: NCT02892708 (ClinicalTrials.gov).
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Idoso , Glioblastoma/cirurgia , Antineoplásicos Alquilantes/uso terapêutico , Qualidade de Vida , Dacarbazina/uso terapêutico , Neoplasias Encefálicas/cirurgia , Glioma/tratamento farmacológicoRESUMO
Deep brain stimulation of the posterior hypothalamus is a therapeutic approach to the treatment of refractory chronic cluster headache, but the precise anatomical location of the electrode contacts has not been clearly assessed. Our aim was to study the location of the contacts used for chronic stimulation, projecting each contact centre on anatomic atlases. Electrodes were implanted in a series of 10 patients (prospective controlled trial) in the so-called 'posteroinferior hypothalamus' according to previously described coordinates, i.e. 2 mm lateral, 3 mm posterior and 5 mm below the mid-commissural point. The coordinates of the centre of each stimulating contact were measured on postoperative computed tomography or magnetic resonance imaging scans, taking into account the artefact of the electrode. Each contact centre (n=10; left and right hemispheres pooled) was displayed on the Schaltenbrand atlas and a stereotactic three dimensional magnetic resonance imaging atlas (4.7 tesla) of the diencephalon-mesencephalic junction for accurate anatomical location. Of the 10 patients with 1-year follow-up, 5 responded to deep brain stimulation (weekly frequency of attacks decrease >50%). In responders, the mean (standard deviation) coordinates of the contacts were 2.98 (1.16) mm lateral, 3.53 (1.97) mm posterior and 3.31 (1.97) mm below the mid-commissural point. All the effective contacts were located posterior to the hypothalamus. In responders, structures located <2 mm from the centres of effective contacts were: the mesencephalic grey substance (5/5), the red nucleus (4/5), the fascicle retroflexus (4/5), the fascicle longitudinal dorsal (3/5), the nucleus of ansa lenticularis (3/5), the fascicle longitudinal medial (1/5) and the thalamus superficialis medial (1/5). The contact coordinates (Wilcoxon test) and the structures (Fisher's exact test) were not significantly different between responders and non-responders. These findings suggest that failure of deep brain stimulation treatment in cluster headache may be due to factors unrelated to electrode misplacement. They also suggest that the therapeutic effect is probably not related to direct hypothalamic stimulation. Deep brain stimulation might modulate either a local cluster headache generator, located in the hypothalamus or in the mesencephalic grey substance, or non-specific anti-nocioceptive systems.
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Encéfalo/anatomia & histologia , Cefaleia Histamínica/patologia , Cefaleia Histamínica/terapia , Estimulação Encefálica Profunda/instrumentação , Estimulação Encefálica Profunda/métodos , Adolescente , Adulto , Idoso , Eletrodos Implantados , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: To identify radiological factors and functional outcomes associated with good results after implantation of a single lumbar disc prosthesis or a hybrid construct (anterior lumbar interbody fusion and lumbar disc prosthesis) in the setting of painful degenerative lumbar discopathy. METHODS: This single-center, retrospective 10-year study included 92 patients Ë18 years old with chronic low back pain evolving for at least 1 year. The patients had degenerative disc disease and had failed conservative treatment and underwent lumbar arthroplasty. Radiographic and clinical outcomes were assessed preoperatively and 1 year after surgery. Functional evaluation was based on the Oswestry Disability Index (ODI) and a numerical rating scale. Radiological analysis was based on lumbar x-rays and magnetic resonance imaging parameters. Patients were assigned to 2 groups according to the reduction in ODI score (>15 points or <15 points), and statistical analysis was done in both groups to find predictive radiological factors for a satisfactory functional outcome. RESULTS: Clinically, 60 patients (65.2%) had a satisfactory functional result and 32 patients (34.8%) had a poor outcome according to ODI score. Radiographically, gain in segmental lordosis was statistically associated with good functional outcomes (8.9° for ODI decrease >15 vs. 3.2° for ODI decrease <15). CONCLUSIONS: This study determined that gain in segmental lordosis is associated with a satisfactory functional outcome after a single-level lumbar disc prosthesis or a hybrid construct. Our study demonstrates that segmental lordosis gain may represent a significative useful positive predictor factor of patient outcome.
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Degeneração do Disco Intervertebral/cirurgia , Lordose , Recuperação de Função Fisiológica , Substituição Total de Disco/métodos , Adulto , Feminino , Humanos , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity,sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions.During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation(weekly frequency of attacks decrease [50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).
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Cefaleia Histamínica/terapia , Estimulação Encefálica Profunda/métodos , Adulto , Cefaleia Histamínica/psicologia , Estudos Cross-Over , Método Duplo-Cego , Eletrodos Implantados/efeitos adversos , Feminino , Seguimentos , Lateralidade Funcional/fisiologia , Humanos , Hipotálamo/fisiologia , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Qualidade de Vida , Fatores de Tempo , Resultado do TratamentoRESUMO
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells. SIGNIFICANCE: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.See related commentary by Koncar and Agnihotri, p. 3195.
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Glioblastoma , MicroRNAs , Desdiferenciação Celular , Diferenciação Celular , Proteína 1 de Resposta de Crescimento Precoce , Glioblastoma/genética , Humanos , MicroRNAs/genética , Proteína Homeobox Nanog/genética , Células-Tronco NeoplásicasRESUMO
We report a case in which motor cortex stimulation (MCS) improved neuropathic facial pain due to peripheral nerve injury and restored tactile and thermal sensory loss. A 66-year-old man developed intractable trigeminal neuropathic pain after trauma of the supraorbital branch of the Vth nerve, associated with tactile and thermal sensory loss in the painful area. MCS was performed using neuronavigation and transdural electric stimulation to localize the upper facial area on the motor cortex. One month after surgery, pain was decreased from 80/100 to 20/100 on visual analogic scale, and sensory discrimination improved in the painful area. Two months after surgery, quantitative sensory testing confirmed the normalization of thermal detection thresholds. This case showed that MCS could restore tactile and thermal sensory loss, resulting from peripheral nerve injury. Although the mechanisms leading to this effect remain unclear, this observation enhanced the hypothesis that MCS acts through modulation of the sensory processing.
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Terapia por Estimulação Elétrica/métodos , Córtex Motor/fisiologia , Neuralgia/complicações , Nervo Oftálmico/patologia , Transtornos de Sensação/etiologia , Transtornos de Sensação/terapia , Idoso , Humanos , MasculinoRESUMO
INTRODUCTION: Based on the radiological responses obtained with a schedule of ten mg/kg every two weeks bevacizumab was approved by the FDA for recurrent glioblastomas. Due to the negative results concerning overall survival of patients receiving bevacizumab, the European application was rejected. Despite this, many centers apply an off-label prescription. Our aim was to evaluate the safety and efficacy of schedules of low doses of bevacizumab. METHODS: From September 2013 to August 2016, we recruited patients with progressive glioblastoma, whatever the previous treatments. We compared a routine control group (CG) of ten mg/kg, to a low dose group (LDG) composed of 5 subgroups: G5: five mg/kg, G4: four mg/kg, G3: three mg/kg, G2: two mg/kg, G1: one mg/kg; each patient was treated with the same dose every two weeks. RESULTS: Fifty-three patients were treated: 20 women and 33 men, 24 in the CG and 29 in the LDG. The median age at diagnosis was 62 years [35.0-77.0]. No statistical difference was found in overall survival either for the CG or the LDG (P=0.086) or among groups (P=0.251), with even a trend toward improvement for LDG: 62 weeks [20-145] versus 73 weeks [18-178]. The median progression free survival was comparable: 19.5 weeks [6.0-54.0] for the CG and 15.0 weeks [0.0-134.0] for the LDG (P=0.221). Bevacizumab was stopped either due to progression (45.1%) or toxicity (52.9%), without significant differences between doses but maybe less toxicities in the LDG (16.7% for toxicity in G1). DISCUSSION: Use of bevacizumab at progression at lower than usual doses seems to give the same results as the standard dose without giving additional toxicity.
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Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Bevacizumab/efeitos adversos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
We propose a dynamic model of cerebrospinal fluid and intracranial pressure regulation. In this model, we investigate the coupling of biological parameters with a 3-D model, to improve the behavior of the brain in surgical simulators. The model was assessed by comparing the simulated ventricular enlargement with a patient case study of communicating hydrocephalus. In our model, cerebro-spinal fluid production-resorption system is coupled with a 3-D representation of the brain parenchyma. We introduce a new bi-phasic model of the brain (brain tissue and extracellular fluid) allowing for fluid exchange between the brain extracellular space and the venous system. The time evolution of ventricular pressure has been recorded on a symptomatic patient after closing the ventricular shunt. A finite element model has been built based on a computed tomography scan of this patient, and quantitative comparisons between experimental measures and simulated data are proposed.
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Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Derivações do Líquido Cefalorraquidiano/métodos , Hidrocefalia/fisiopatologia , Hidrocefalia/cirurgia , Modelos Neurológicos , Líquido Cefalorraquidiano , Circulação Cerebrovascular , Simulação por Computador , Humanos , Pressão Intracraniana , Modelos Cardiovasculares , Procedimentos Neurocirúrgicos/métodos , Cirurgia Assistida por Computador/métodos , Procedimentos Cirúrgicos Vasculares/métodosRESUMO
Myxopapillary ependymoma is a rare tumour of the central nervous system (CNS); this subtype of ependymoma occurs most frequently in cauda equina, conus medullaris or filum terminale. The treatment consists of complete removal of the tumour including its capsule when possible since it is usually a solitary lesion. Non-Hodgkin lymphoma of the CNS is found in only 1.3% of cauda equina tumours. We report the case of a 62-year-old man who presented to our institution with progressive weakness of his right lower extremity, with numbness and paresthesia of both feet. He was suffering from one month of right sciatica. Lumbosacral MRI displayed two intradural extramedullary lesions, the first one was located posteriorly to L1-L2 and the second one was spreading from L4 to S2 presenting as a mucoid cyst in its superior part with hyperintense T2 signal, isointense on T1-weighted with high and homogeneous contrast enhancement in the inferior solid component. Imaging also found three additional intradural, extramedullary tumor formations with contrast enhancement, located respectively at C5-C6, C7 and T4. A L1-L2 and S1-S2 laminectomy was performed in emergency and total removal was achieved. Neuropathologist concluded that the tumor was a myxopapillary ependymoma infiltrated by large B-cell lymphoma. Although rare, this phenomenon (coexisting tumors within the same lesion) should be known by neurosurgeons because the occurrence of collision tumors affects the treatment and the patient's prognosis. In our case, two different types of tissue were mingled in the same location-this finding is very uncommon and has, to our knowledge, never been reported before.
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Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.
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Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , MicroRNAs/biossíntese , Família Multigênica , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , Animais , Terapia Baseada em Transplante de Células e Tecidos , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Camundongos , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genéticaRESUMO
PURPOSE: Brain tumor radiotherapy requires the volume measurements and the localization of several individual brain structures. Any tool that can assist the physician to perform the delineation would then be of great help. Among segmentation methods, those that are atlas-based are appealing because they are able to segment several structures simultaneously, while preserving the anatomy topology. This study aims to evaluate such a method in a clinical context. METHODS AND MATERIALS: The brain atlas is made of two three-dimensional (3D) volumes: the first is an artificial 3D magnetic resonance imaging (MRI); the second consists of the segmented structures in this artificial MRI. The elastic registration of the artificial 3D MRI against a patient 3D MRI dataset yields an elastic transformation that can be applied to the labeled image. The elastic transformation is obtained by minimizing the sum of the square differences of the image intensities and derived from the optical flow principle. This automatic delineation (AD) enables the mapping of the segmented structures onto the patient MRI. Parameters of the AD have been optimized on a set of 20 patients. Results are obtained on a series of 6 patients' MRI. A comprehensive validation of the AD has been conducted on performance of atlas-based segmentation in a clinical context with volume, position, sensitivity, and specificity that are compared by a panel of seven experimented physicians for the brain tumor treatments. RESULTS: Expert interobserver volume variability ranged from 16.70 cm(3) to 41.26 cm(3). For patients, the ratio of minimal to maximal volume ranged from 48% to 70%. Median volume varied from 19.47 cm(3) to 27.66 cm(3) and volume of the brainstem calculated by AD varied from 17.75 cm(3) to 24.54 cm(3). Medians of experts ranged, respectively, for sensitivity and specificity, from 0.75 to 0.98 and from 0.85 to 0.99. Median of AD were, respectively, 0.77 and 0.97. Mean of experts ranged, respectively, from 0.78 to 0.97 and from 0.86 to 0.99. Mean of AD were, respectively, 0.76 and 0.97. CONCLUSIONS: Results demonstrate that the method is repeatable, provides a good trade-off between accuracy and robustness, and leads to reproducible segmentation and labeling. These results can be improved by enriching the atlas with the rough information of tumor or by using different laws of deformation for the different structures. Qualitative results also suggest that this method can be used for automatic segmentation of other organs such as neck, thorax, abdomen, pelvis, and limbs.
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Algoritmos , Neoplasias Encefálicas/patologia , Tronco Encefálico/anatomia & histologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Anatomia Artística/métodos , Neoplasias Encefálicas/radioterapia , Humanos , Ilustração Médica , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: To assess the occurrence and development of cerebral radiologic changes (cerebral atrophy and white matter lesions) in patients treated with boron neutron capture therapy (BNCT) for primary supratentorial glioblastoma multiforme within the European Organization for Research and Treatment of Cancer (EORTC) trial 11961. METHODS AND MATERIALS: Magnetic resonance imaging (MRI) scans were performed before and after surgery and at 1 week and 2, 4.5, 6, 9, 12, 15, and 18 months after BNCT. For the current study, MRI scans of all assessable patients were analyzed, with emphasis on cerebral atrophy and white matter abnormalities. RESULTS: Twenty-six patients had been treated with BNCT according to the EORTC trial 11961, of whom 24 were assessable for the current study. The development of possible BNCT-related cerebral changes was observed in 12 patients (50%), 10 of whom had cerebral atrophy (42%) and 10 white matter changes (42%) after a median interval of 7.5 and 4.5 months, respectively. CONCLUSION: In this study, cerebral radiologic changes appeared in 50% of patients within the first year after BNCT. Although a clear correlation between the BNCT dose and the development of cerebral changes could not be demonstrated, a relationship between the occurrence of these radiologic abnormalities and BNCT seems likely.
Assuntos
Terapia por Captura de Nêutron de Boro/efeitos adversos , Neoplasias Encefálicas/radioterapia , Encéfalo/efeitos da radiação , Glioblastoma/radioterapia , Idoso , Atrofia/etiologia , Atrofia/patologia , Encéfalo/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECT: The application accuracy of the Neuromate neurosurgical robot has been validated in vitro but has not been evaluated in vivo for deep brain stimulation (DBS) electrode implantations. The authors conducted a study to evaluate this application accuracy in routine frame-based DBS procedures, with an independent system of measurement. METHODS: The Euclidian distance was measured between the point theoretically targeted by the robot and the point actually reached, based on their respective stereotactic coordinates. The coordinates of the theoretical target were given by the robot's dedicated targeting software. The coordinates of the point actually reached were recalculated using the Stereoplan localizer system. This experiment was performed in vitro, with the frame fixed in the robot space without a patient, for 21 points spatially distributed. The in vivo accuracy was then measured in 30 basal ganglia targets in 17 consecutive patients undergoing DBS for movement disorders. RESULTS: The mean in vitro application accuracy was 0.44 ± 0.23 mm. The maximal localization error was 1.0 mm. The mean (± SD) in vivo application accuracy was 0.86 ± 0.32 mm (Δx = 0.37 ± 0.34 mm, Δy = 0.32 ± 0.24 mm, Δz = 0.58 ± 0.31 mm). The maximal error was 1.55 mm. CONCLUSIONS: The in vivo application accuracy of the Neuromate neurosurgical robot, measured with a system independent from the robot, in frame-based DBS procedures was better than 1 mm. This accuracy is at least similar to the accuracy of stereotactic frame arms and is compatible with the accuracy required in DBS procedures.