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1.
Pediatr Neurol ; 62: 62-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27426422

RESUMO

BACKGROUND: Langerhans cell histiocytosis is a rare disease of the monocyte-macrophage system. Abnormalities of the hypothalamic-pituitary region are common in individuals with central nervous system involvement. PATIENT DESCRIPTION: This six-year-old boy developed rapidly progressive aggressive behavior, central diabetes insipidus, and repeated complex partial seizures. Magnetic resonance imaging revealed a diffuse leukoencephalopathy-like pattern and numerous infratentorial and supratentorial granulomatous nodules in the brain parenchyma along with infundibular and hypothalamic mass lesions. Stereotactic serial biopsies enabled histopathologic and immunohistochemical diagnosis of Langerhans cell histiocytosis. CONCLUSIONS: Similar MRI findings have rarely been described in the literature. These findings represent part of the broad neuroradiological spectrum of Langerhans cell histiocytosis of the nervous system in children.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/patologia , Encefalopatias/tratamento farmacológico , Criança , Diagnóstico Diferencial , Evolução Fatal , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Masculino
2.
Clin Cancer Res ; 22(15): 3903-14, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27012813

RESUMO

PURPOSE: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature versus Compound-Variety Enriched Response ("DiSCoVER"), to identify novel therapeutics that target this specific disease subtype. EXPERIMENTAL DESIGN: Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. We validated the top hits from this analysis in vitro and in vivo RESULTS: Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile. DiSCoVER analysis predicted that aggressive MYC-driven Group 3 medulloblastoma would be sensitive to cyclin-dependent kinase (CDK) inhibitors. The CDK 4/6 inhibitor palbociclib decreased proliferation, increased apoptosis, and significantly extended the survival of mice with orthotopic medulloblastoma xenografts. CONCLUSIONS: We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK 4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients. Clin Cancer Res; 22(15); 3903-14. ©2016 AACR.


Assuntos
Neoplasias Cerebelares/genética , Biologia Computacional/métodos , Predisposição Genética para Doença , Meduloblastoma/genética , Modelos Biológicos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Linhagem Celular Tumoral , Simulação por Computador , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Descoberta de Drogas , Perfilação da Expressão Gênica , Humanos , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos , Células-Tronco Neurais/metabolismo , Fosforilação , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Piridinas/farmacologia , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Neurorehabil Neural Repair ; 29(10): 1001-12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25857428

RESUMO

Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson's disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft-host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions.


Assuntos
Estimulação Encefálica Profunda , Neurônios Dopaminérgicos/fisiologia , Doença de Parkinson/terapia , Recuperação de Função Fisiológica/fisiologia , Transplante de Células-Tronco/métodos , Núcleo Subtalâmico/fisiologia , Adrenérgicos/toxicidade , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/transplante , Ectodisplasinas/metabolismo , Embrião de Mamíferos , Comportamento Exploratório/fisiologia , Masculino , Feixe Prosencefálico Mediano/lesões , Proteínas do Tecido Nervoso/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
4.
Clin Cancer Res ; 21(9): 2057-64, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25655102

RESUMO

PURPOSE: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. EXPERIMENTAL DESIGN: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. RESULTS: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5] and overall survival [A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation. CONCLUSIONS: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Metilação de DNA/genética , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Regiões Promotoras Genéticas/genética , Modelos de Riscos Proporcionais , Temozolomida , Adulto Jovem
5.
Onco Targets Ther ; 8: 3803-15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26719708

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) is the standard neuroimaging method to diagnose neoplastic brain lesions, as well as to perform stereotactic biopsy surgical planning. MRI has the advantage of providing structural anatomical details with high sensitivity, though histological specificity is limited. Although combining MRI with other imaging modalities, such as positron-emission tomography (PET), has proven to increment specificity, exact correlation between PET threshold uptake ratios (URs) and histological diagnosis and grading has not yet been described. OBJECTIVES: The aim of this study was to correlate exactly the histopathological criteria of the biopsy site to its PET uptake value with high spatial resolution (mm(3)), and to analyze the diagnostic value of PET using the amino acid O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) PET in patients with newly diagnosed brain lesions in comparison to histological findings obtained from stereotactic serial biopsy. PATIENTS AND METHODS: A total of 23 adult patients with newly diagnosed brain tumors on MRI were enrolled in this study. Subsequently to diagnoses, all patients underwent a (18)F-FET PET-guided stereotactic biopsy, using an original newly developed software module, which is presented here. Conventional MRI, stereotactic computed tomography series, and (18)F-FET PET images were semiautomatically fused, and hot-spot detection was performed for target planning. UR was determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR values ≥1.6 were considered positive for glioma. High-grade glioma (HGG) was suspected with URs ≥3.0, while low-grade glioma (LGG) was suspected with URs between 1.6 and 3.0. Stereotactic serial biopsies along the trajectory at multiple sites were performed in millimeter steps, and the FET URs for each site were correlated exactly with a panel of 27 different histopathological markers. Comparisons between FET URs along the biopsy trajectories and the histological diagnoses were made with Pearson product-moment correlation coefficients. Analysis of variance was performed to test for significant differences in maximum UR between different tumor grades. RESULTS: A total of 363 biopsy specimens were taken from 23 patients by stereotactic serial biopsies. Histological examination revealed eight patients (35%) with an LGG: one with a World Health Organization (WHO)-I lesion and seven with a WHO-II lesion. Thirteen (57%) patients revealed an HGG (two with a WHO-III and three with a WHO-IV tumor), and two patients (9%) showed a process that was neither HGG nor LGG (group X or no-grade group). The correlation matrix between histological findings and the UR revealed five strong correlations. Low cell density in tissue samples was found to have a significant negative correlation with the measured cortical uptake rate (r=-0.43, P=0.02), as well as moderate cell density (r=-0.48, P=0.02). Pathological patterns of proliferation (r=0.37, P=0.04), GFAP (r=0.37, P=0.04), and Olig2 (r=0.36, P=0.05) showed a significant positive correlation with cortical URs. Analysis of variance tests showed a significant difference between the LGG and the HGG groups (F=8.27, P<0.002), but no significant differences when differentiating between the X group and the HGG (P=0.2)/LGG (P=0.8) groups, nor between the no-grade group and the WHO-I group. CONCLUSION: (18)F-FET PET is a valuable tool, as it allows the differentiation of HGGs from LGGs. Its use is not limited to preoperative evaluation; it may also refine biopsy targeting and improve tumor delimitation for radiotherapy. Histology is still necessary, and remains the gold standard for definitive diagnosis of brain lesions.

7.
BMC Cancer ; 14: 115, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24555482

RESUMO

BACKGROUND: Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically proven brainstem gliomas. METHODS: Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. RESULTS: The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS ≤ 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age ≥ 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. CONCLUSION: Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age ≥ 40 and higher tumor grade have a negative impact on overall survival.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Glioma/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/terapia , Terapia Combinada , Feminino , Glioma/diagnóstico , Glioma/mortalidade , Glioma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neuroimagem , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
8.
Sci Rep ; 4: 3849, 2014 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-24458018

RESUMO

The impact of pressure waves on cells may provide several possible applications in biology and medicine including the direct killing of tumors, drug delivery or gene transfection. In this study we characterize the physical properties of mechanical pressure waves generated by a nanosecond laser pulse in a setup with well-defined cell culture conditions. To systematically characterize the system on the relevant length and time scales (micrometers and nanoseconds) we use photon Doppler velocimetry (PDV) and obtain velocity profiles of the cell culture vessel at the passage of the pressure wave. These profiles serve as input for numerical pressure wave simulations that help to further quantify the pressure conditions on the cellular length scale. On the biological level we demonstrate killing of glioblastoma cells and quantify experimentally the pressure threshold for cell destruction.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Lasers , Pressão , Simulação por Computador , Humanos , Fluxometria por Laser-Doppler , Fótons , Células Tumorais Cultivadas
9.
J Neurooncol ; 117(1): 141-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24442484

RESUMO

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Quimioterapia Adjuvante , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Progressão da Doença , Feminino , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Temozolomida , Resultado do Tratamento
10.
Cell Transplant ; 23(8): 995-1007, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23635602

RESUMO

Restorative cell therapy concepts in neurodegenerative diseases are aimed at replacing lost neurons. Despite advances in research on pluripotent stem cells, fetal tissue from routine elective abortions is still regarded as the only safe cell source. Progenitor cells isolated from distinct first-trimester fetal CNS regions have already been used in clinical trials and will be used again in a new multicenter trial funded by the European Union (TRANSEURO). Bacterial contamination of human fetal tissue poses a potential risk of causing infections in the brain of the recipient. Thus, effective methods of microbial decontamination and validation of these methods are required prior to approval of a neurorestorative cell therapy trial. We have developed a protocol consisting of subsequent washing steps at different stages of tissue processing. Efficacy of microbial decontamination was assessed on rat embryonic tissue incubated with high concentrations of defined microbe solutions including representative bacterial and fungal species. Experimental microbial contamination was reduced by several log ranks. Subsequently, we have analyzed the spectrum of microbial contamination and the effect of subsequent washing steps on aborted human fetal tissue; 47.7% of the samples taken during human fetal tissue processing were positive for a microbial contamination, but after washing, no sample exhibited bacterial growth. Our data suggest that human fetal tissue for neural repair can carry microbes of various species, highlighting the need for decontamination procedures. The decontamination protocol described in this report has been shown to be effective as no microbes could be detected at the end of the procedure.


Assuntos
Transplante de Tecido Encefálico/métodos , Encéfalo/embriologia , Encéfalo/microbiologia , Descontaminação/métodos , Transplante de Tecido Fetal/métodos , Doenças Neurodegenerativas/terapia , Animais , Humanos , Ratos , Resultado do Tratamento
11.
J Synchrotron Radiat ; 21(Pt 1): 242-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24365943

RESUMO

Gold nanoparticles are excellent intracellular markers in X-ray imaging. Having shown previously the suitability of gold nanoparticles to detect small groups of cells with the synchrotron-based computed tomography (CT) technique both ex vivo and in vivo, it is now demonstrated that even single-cell resolution can be obtained in the brain at least ex vivo. Working in a small animal model of malignant brain tumour, the image quality obtained with different imaging modalities was compared. To generate the brain tumour, 1 × 10(5) C6 glioma cells were loaded with gold nanoparticles and implanted in the right cerebral hemisphere of an adult rat. Raw data were acquired with absorption X-ray CT followed by a local tomography technique based on synchrotron X-ray absorption yielding single-cell resolution. The reconstructed synchrotron X-ray images were compared with images obtained by small animal magnetic resonance imaging. The presence of gold nanoparticles in the tumour tissue was verified in histological sections.


Assuntos
Encéfalo/citologia , Ouro/química , Nanopartículas Metálicas , Análise de Célula Única , Síncrotrons , Tomografia Computadorizada por Raios X/métodos , Animais , Neoplasias Encefálicas/patologia , Glioma/patologia , Imageamento por Ressonância Magnética , Ratos , Ratos Wistar
12.
Front Cell Neurosci ; 7: 155, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24065885

RESUMO

The molecular mechanisms underlying the differentiation of neural progenitor cells (NPCs) remain poorly understood. In this study we investigated the role of Ca(2+) and cAMP (cyclic adenosine monophosphate) in the differentiation of NPCs extracted from the subventricular zone of E14.5 rat embryos. Patch clamp recordings revealed that increasing cAMP-signaling with Forskolin or IBMX (3-isobutyl-1-methylxantine) significantly facilitated neuronal functional maturation. A continuous application of IBMX to the differentiation medium substantially increased the functional expression of voltage-gated Na(+) and K(+) channels, as well as neuronal firing frequency. Furthermore, we observed an increase in the frequency of spontaneous synaptic currents and in the amplitude of evoked glutamatergic and GABAergic synaptic currents. The most prominent acute effect of applying IBMX was an increase in L-type Ca(2+)currents. Conversely, blocking L-type channels strongly inhibited dendritic outgrowth and synapse formation even in the presence of IBMX, indicating that voltage-gated Ca(2+) influx plays a major role in neuronal differentiation. Finally, we found that nifedipine completely blocks IBMX-induced CREB phosphorylation (cAMP-response-element-binding protein), indicating that the activity of this important transcription factor equally depends on both enhanced cAMP and voltage-gated Ca(2+)-signaling. Taken together, these data indicate that the up-regulation of voltage-gated L-type Ca(2+)-channels and early electrical excitability are critical steps in the cAMP-dependent differentiation of SVZ-derived NPCs into functional neurons. To our knowledge, this is the first demonstration of the acute effects of cAMP on voltage-gated Ca(+2)channels in NPC-derived developing neurons.

13.
Neuro Oncol ; 15(9): 1251-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23814266

RESUMO

BACKGROUND: The prognosis for glioma remains dismal, and little is known about the final disease phase. To obtain information about this period, we surveyed caregivers of patients who were registered in the German Glioma Network and who died from the disease. METHODS: A questionnaire with 15 items, focusing on medical, logistic, and mental health support and symptom control during the final 4 weeks, was sent to caregivers. For some of the questions, a scale from 1 (inadequate) to 10 (excellent) was used. RESULTS: Of 1655 questionnaires, 605 were returned (36.6%) and evaluated. We found that 67.9% of the patients were taken care of at home for the last 4 weeks; 47.7% died at home, 22.6% died in hospitals, and 19.3% died in hospice facilities. Medical support was provided by general practitioners in 72.3% of cases, by physicians affiliated with a nursing home or hospice in 29.9%, and by general oncologists in 17%. Specialized neuro-oncologists were involved in 6%. The caregivers ranked the medical support with a mean of 7.2 (using a 10-point scale), nursing service with 8.1, and mental health support with 5.5. In 22.9% of cases, no support for the caregivers themselves was offered by medical institutions. CONCLUSIONS: Although these data reflect the caregivers' subjective views, they are useful in understanding and improving current patterns of care. While patients and their caregivers are supported mainly by neuro-oncologists for most of the disease phase, the end-of-life phase is managed predominantly by general practitioners and specialists in palliative care. Close cooperation between these specialties is necessary to meet the specific needs of glioma patients.


Assuntos
Neoplasias Encefálicas/psicologia , Cuidadores/psicologia , Glioma/psicologia , Assistência Terminal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/enfermagem , Feminino , Alemanha , Glioma/enfermagem , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
14.
Oncotarget ; 4(7): 1050-64, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23846349

RESUMO

The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs.


Assuntos
Neoplasias Encefálicas/genética , Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/patologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/metabolismo , Glioblastoma/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas de Ligação a RNA , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Acta Neurochir Suppl ; 117: 13-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23652651

RESUMO

OBJECTIVE: In order to improve image quality in a simultaneous fMRI-EEG study with patients suffering from the involuntary movements typical for Huntington's disease, the aim was to develop a technique for immobilizing the heads of our patients inside an MRI head coil. METHODS: We modified a mask technique previously used for reliable repositioning in temporally fractionated radiotherapy. The mask was tested in three patients with Huntington's disease, acquiring structural and functional MR images with simultaneous EEG with and without the mask. RESULTS: Image as well as EEG signal quality were significantly improved in patients wearing the mask. However, the image quality with mask was comparable to acquisitions from patients without movement disorders only in patients with light to moderate dyskinesia. Although image quality was also significantly improved in a patient suffering from severe dyskinesia with quasi-continuous involuntary movements, the quality of both the MR images as well as the EEG signal was lower than what would be expected in a healthy control person. CONCLUSION: We have succeeded in developing a mask that fits into the MRI head coil, does not disturb the MRI signal, and significantly improves both fMRI and EEG signal quality.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Doença de Huntington/diagnóstico , Imageamento por Ressonância Magnética/métodos , Eletroencefalografia/métodos , Desenho de Equipamento , Humanos , Doença de Huntington/fisiopatologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/instrumentação , Máscaras , Oxigênio/sangue , Restrição Física/instrumentação , Restrição Física/métodos , Índice de Gravidade de Doença
16.
Acta Neurochir Suppl ; 117: 47-51, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23652656

RESUMO

INTRODUCTION: The effects of deep brain stimulation (DBS) on cognitive functions, and its psychiatric side-effects, are still controversial. The present study investigated psychiatric comorbidity and postoperative effects of DBS of different targets on mood and psychological functions in 81 patients with a mean follow-up of 37 months. METHODS: A total of 109 patients underwent implantation of DBS electrodes between 2001 and 2006; it was possible to evaluate 81 patients by a psychiatric test battery using the "Neuropsychiatric Inventory". To evaluate the possible influence of the target, we analyzed the data without 16 patients with DBS surgery for other diseases (e.g., epilepsia, cluster headache) or unilateral implantation only. The resulting population (n = 65, mean age 61 years, range 23-78 years, male:female 42:23) consisted of 43 Parkinson's disease patients stimulated in the subthalamic nucleus, ten dystonia patients stimulated in the globus pallidus internus, and 12 tremor patients in the ventral intermediate nucleus. RESULTS: There was a high rate of preoperative psychiatric comorbidity, which is reflected by a high rate of patients with preoperative medication of neuroleptic drugs (18.4 %, especially clozapin 14.7 %) and antidepressive drugs (16.5 %). Depression was the most common psychiatric side-effect after DBS, occurring in 47.7 % of all patients (31/65 patients), without significant preference to a specific target (STN: 42 %, Gpi: 60 %, VIM: 58 %). Delusion (n = 5 out of 43 PD patients, 11.6 %), euphoria (n = 1, 2.3 %) and disinhibition (n = 3, 7.0 %) were seen in the PD patients only. CONCLUSION: A wide range of behavioural changes may be seen following DBS. Depression was the most common side-effect after DBS, and occurred independently of the target. PD patients, in contrast to dystonia and tremor patients, developed complications in all tested subgroups, with varying frequencies. Preoperative evaluation for psychiatric and cognitive dysfunction is crucial to identify patients who are at specific risk for psychiatric complications.


Assuntos
Transtornos Cognitivos/etiologia , Estimulação Encefálica Profunda/efeitos adversos , Transtornos Mentais/etiologia , Complicações Pós-Operatórias/fisiopatologia , Adulto , Idoso , Encéfalo/fisiologia , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Neurologia , Testes Neuropsicológicos , Doença de Parkinson/terapia , Segurança do Paciente , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Adulto Jovem
17.
Acta Neurochir Suppl ; 117: 93-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23652663

RESUMO

OBJECTIVE: The aim of this study was to explore the impact of automated hotspot detection on surgical planning of (18)FET PET-guided stereotactic serial biopsy. METHOD: Imaging of ten patients with brain lesions detected by MRI and showing increased (18)FET uptake on PET who were retrospectively and randomly assigned to compose the study. Stereotactic biopsy plans (PET-guided and MR-guided) were performed by two neurosurgeons for each patient, independently and blinded. For PET-guided plans, biopsy target was achieved by means of an automated hotspot detection system. MR-guided plans targeted contrast enhancement areas or hyperintense areas in T2-weighted sequences. FET uptake ratio (UR) was determined in the biopsy trajectory across the lesion. Highest UR (HUR) from both planning techniques was compared. RESULTS: Each single HUR obtained through PET-guided technique was higher than correspondent values from MR-guided technique. Mean HUR of 2.41 (SE ± 0.23) for PET-guided plans and 1.85 (±0.16) for MR-guided plans were respectively obtained. This difference was statistically significant (p = 0.002). CONCLUSION: The use of an automated hotspot detection system was able to provide higher FET HUR along stereotactic biopsy trajectories in comparison to those from MR-guided plans. The use of specially designed computational tools may refine surgical planning by improving biopsy targeting.


Assuntos
Biópsia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Fluordesoxiglucose F18 , Técnicas Estereotáxicas , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X
18.
Acta Neurochir Suppl ; 117: 101-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23652664

RESUMO

In a retrospective single-centre study, we analysed data of 1,378 patients (55 % male, 45 % female) who underwent interstitial radiotherapy with 1,596 implanted Iodine-125 seeds in the Department of Stereotactic and Functional Neurosurgery in Freiburg from January 1990 to December 2011. The medical prerequisites and physical parameters of the treatment with Iodine-125 seeds are given. The method used in Freiburg relying on temporary Iodine-125 seed implants is described in detail and analysed. The survival rates and the peri-operative risk are evaluated. We conclude that interstitial radiosurgery with Iodine-125 seeds is a safe and useful tool, offering a wide range of treatment options for benign and also malignant intracranial lesions, especially if they are small, deep-seated, in eloquent areas, or not suitable for micro-surgery.


Assuntos
Braquiterapia/métodos , Neoplasias Encefálicas/dietoterapia , Neoplasias Encefálicas/cirurgia , Encéfalo/patologia , Glioma/terapia , Radioisótopos do Iodo/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/cirurgia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Criança , Pré-Escolar , Feminino , Glioma/patologia , Humanos , Lactente , Radioisótopos do Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
19.
Neuro Oncol ; 15(8): 1017-26, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23595628

RESUMO

BACKGROUND: The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients. METHODS: Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial. RESULTS: IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival. CONCLUSIONS: Despite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.


Assuntos
Astrocitoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Metilação de DNA , Glioblastoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Astrocitoma/mortalidade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Feminino , Seguimentos , Glioblastoma/genética , Glioblastoma/mortalidade , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores , Fenótipo , Prognóstico , Regiões Promotoras Genéticas/genética , Taxa de Sobrevida , Adulto Jovem
20.
PLoS One ; 8(1): e54960, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23383014

RESUMO

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.


Assuntos
Encéfalo/efeitos da radiação , Radioterapia/métodos , Animais , Comportamento Animal/efeitos da radiação , Encéfalo/citologia , Relação Dose-Resposta à Radiação , Dose Letal Mediana , Camundongos , Modelos Animais , Radioterapia/instrumentação , Síncrotrons
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