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BACKGROUND: Postoperative delirium (POD) is a severe perioperative complication that may increase mortality and length-of-stay in older patients. Moreover, POD is a major economic burden to any healthcare system. An altered expression of Acetylcholine- and Butyrylcholinesterases (AChE, BuChE) due to an unbalanced neuroinflammatory response to trauma or an operative stimulus has been reported to play an essential role in the development of POD. We investigated if perioperative measurement of cholinesterases (ChEs) can help identifying patients at risk for the occurrence of POD in both, scheduled and emergency surgery patients. METHODS: This monocentric prospective observational cohort study was performed in a tertiary hospital (departments of orthopaedic surgery and traumatology). One hundred and fifty-one patients aged above 75 years were enrolled for scheduled (n = 76) or trauma-related surgery (n = 75). Exclusion criteria were diagnosed dementia and anticholinergic medication. Plasma samples taken pre- and postoperatively were analysed regarding AChE and BuChE activity. Furthermore, perioperative assessment using different cognitive tests was performed. The type of anaesthesia (general vs. spinal anaesthesia) was analysed. Primary outcome was the incidence of POD assessed by the approved Confusion Assessment Method (CAM) in combination with the expression of AChE and BuChE. RESULTS: Of 151 patients included, 38 (25.2%) suffered from POD; 11 (14%) in scheduled and 27 (36%) in emergency patients. AChE levels showed no difference throughout groups or time course. Trauma patients had lower BuChE levels prior to surgery than scheduled patients (p < 0.001). Decline in BuChE levels correlated positively with the incidence of POD (1669 vs. 1175 U/l; p < 0.001). Emergency patients with BuChE levels below 1556 U/L were at highest risk for POD. There were no differences regarding length of stay between groups or incidence of POD. The type of anaesthesia had no influence regarding the incidence of POD. Only Charlson Comorbidity Index and Mini Nutrition Assessment demonstrated reliable strength in respect of POD. CONCLUSIONS: Perioperative measurement of BuChE activity can be used as a tool to identify patients at risk of POD. As a point-of-care test, quick results may alter the patients' course prior to the development of POD. TRIAL REGISTRATION: https://drks.de/search/de/trial/DRKS00017178 .
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Delirio , Delirio del Despertar , Humanos , Anciano , Estudios Prospectivos , Complicaciones Posoperatorias/epidemiología , Delirio/diagnóstico , Sistemas de Atención de Punto , Dolor/complicaciones , Factores de RiesgoRESUMEN
There was a typo in the third author's name in the initial online publication.
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INTRODUCTION: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with peak incidence in patients older than 65 years. These patients are mostly underrepresented in clinical trials and often undertreated due to concomitant diseases. Recently, different therapeutic approaches for elderly patients with GBM were discussed. To date, there is no defined standard treatment. The aim of the present study is to evaluate the functional and oncological outcome in surgical treatment of elderly patients. MATERIALS AND METHODS: A total of 342 elderly patients aged ≥ 65 years were retrospectively analyzed in our neurosurgical center. Surgical therapy, adjuvant treatment, overall survival (OS) and functional outcome using Karnofsky performance scale (KPS) and Neurological assessment of neuro-oncology-score were analyzed. RESULTS: The median age at GBM diagnosis was 73.4 (IQR 9.28) years. Median overall survival was 7.5 (CI 95% 6.0-9.1) months and median preoperative or postoperative KPS was 80 (IQR 20). Surgical resection was performed in 216 (63.2%) patients, in 125 patients (36.5%) patients a stereotactic biopsy was performed. The median OS was significantly higher in patients with gross total resection (GTR) compared to partial resection and biopsy (10.8 months; CI 95% 9.5-12.3). Patients with combined radio- and chemo-therapy (RCT) showed significant longer OS, particularly MGMT-negative GBM. Higher preoperative KPS was found to be associated with improved overall survival. CONCLUSION: GTR and adjuvant combined RCT provides benefits for overall survival in elderly patients. Therapy decision should be made in regard to preoperative functional status instead of biological age.
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Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , Anciano , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Terapia Combinada , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Estado de Ejecución de Karnofsky , Procedimientos Neuroquirúrgicos , Estudios Retrospectivos , Factores de Tiempo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.
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Mapeo Encefálico , Encéfalo/diagnóstico por imagen , Epilepsia/patología , Adulto , Encéfalo/patología , Correlación de Datos , Estudios Transversales , Epilepsia/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Cooperación Internacional , Imagen por Resonancia Magnética , Masculino , Metaanálisis como AsuntoRESUMEN
The biology of recurrent glioblastoma multiforme (GBM) is a dynamic process influenced by selection pressure induced by different antitumoural therapies. The poor clinical outcome of tumours in the recurrent stage necessitates the development of effective therapeutic strategies. Checkpoint-inhibition (PD1/PD-L1 Inhibition) is a hallmark of immunotherapy being investigated in ongoing clinical trials. The purpose of this study was to analyse the PD-L1 expression in de-novo and recurrent glioblastoma multiforme and to explore associated genetic alterations and clinical traits. We show that PD-L1 expression was reduced in recurrent GBM in comparison to de-novo GBM. Additionally, patients who received an extended dose of temozolomide (TMZ) chemotherapy showed a significantly reduced level of PD-L1 expression in the recurrence stage compared to the corresponding de-novo tumour. Our findings may provide an explanation for potentially lower response to immunotherapy in the recurrent stage due to the reduced expression of the therapeutic target PD-L1.
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BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).
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Neoplasias Encefálicas/patología , Encéfalo/patología , Epilepsia/patología , Hipocampo/patología , Malformaciones del Desarrollo Cortical/patología , Adulto , Factores de Edad , Edad de Inicio , Neoplasias Encefálicas/complicaciones , Niño , Bases de Datos como Asunto , Epilepsia/etiología , Epilepsia/cirugía , Europa (Continente) , Femenino , Humanos , Masculino , Malformaciones del Desarrollo Cortical/complicaciones , Lóbulo Temporal/patologíaRESUMEN
In the past, changes of the Apparent Diffusion Coefficient in glioblastoma multiforme have been shown to be related to specific genes and described as being associated with survival. The purpose of this study was to investigate diffusion imaging parameters in combination with genome-wide expression data in order to obtain a comprehensive characterisation of the transcriptomic changes indicated by diffusion imaging parameters. Diffusion-weighted imaging, molecular and clinical data were collected prospectively in 21 patients. Before surgery, MRI diffusion metrics such as axial (AD), radial (RD), mean diffusivity (MD) and fractional anisotropy (FA) were assessed from the contrast enhancing tumour regions. Intraoperatively, tissue was sampled from the same areas using neuronavigation. Transcriptional data of the tissue samples was analysed by Weighted Gene Co-Expression Network Analysis (WGCNA) thus classifying genes into modules based on their network-based affiliations. Subsequent Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the expression modules. Network analysis showed a strong association between FA and epithelial-to-mesenchymal-transition (EMT) pathway activation. Also, patients with high FA had a worse clinical outcome. MD correlated with neural function related genes and patients with high MD values had longer overall survival. In conclusion, FA and MD are associated with distinct molecular patterns and opposed clinical outcomes.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Imagen de Difusión por Resonancia Magnética , Perfilación de la Expresión Génica , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Biología Computacional/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Genómica/métodos , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , TranscriptomaRESUMEN
Glioblastoma multiforme are highly malignant brain tumours with frequent genetic and epigenetic alterations. The poor clinical outcome of these tumours necessitates the development of new treatment options. Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of this study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations. We show that PD-L1 is up-regulated in IDH1/2 wildtype glioblastoma multiforme compared to lower-grade gliomas. In addition, a strong association of PD-L1 with the mesenchymal expression subgroup was observed. Consistent with that, NF1 mutation and corresponding activation of the MAPK pathway was strongly connected to PD-L1 expression. Our findings may explain different response to PD-L1 inhibition of patients in ongoing trials and may help to select patients that may profit of immunotherapy in the future.
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Antígeno B7-H1/genética , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Variaciones en el Número de Copia de ADN , Metilación de ADN , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Inmunomodulación , Mutación , Clasificación del Tumor , Proteoma , Proteómica/métodosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Músculo Esquelético/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Proteínas/genética , Ubiquitina/fisiología , Esclerosis Amiotrófica Lateral/complicaciones , Biopsia , Proteína C9orf72 , Proteínas de Unión al ADN/genética , Resultado Fatal , Humanos , Cuerpos de Inclusión/patología , Masculino , Persona de Mediana Edad , Sarcoidosis/complicaciones , Sarcoidosis/genética , Proteína Sequestosoma-1RESUMEN
INTRODUCTION: Pompe disease (PD), a lysosomal storage disease as well as a neuromuscular disorder, is a rare disease marked by progressive muscle weakness. Enzyme replacement therapy (ERT) in recent years allowed longer survival but brought new problems to the treatment of PD with increasing affection of the musculoskeletal system, particularly with a significantly higher prevalence of scoliosis. The present paper deals with the orthopedic problems in patients with PD and is the first to describe surgical treatment of scoliosis in PD patients. PATIENTS AND METHODS: The orthopedic problems and treatment of eight patients with PD from orthopedic consultation for neuromuscular disorders are retrospectively presented. We analyzed the problems of scoliosis, hip dysplasia, feet deformities, and contractures and presented the orthopedic treatment options. RESULTS: Six of our eight PD patients had scoliosis and two young patients were treated by operative spine stabilization with benefits for posture and sitting ability. Hip joint surgery, operative contracture release, and feet deformity correction were performed with benefits for independent activity. CONCLUSION: Orthopedic management gains importance due to extended survival and musculoskeletal involvement under ERT. Surgical treatment is indicated in distinct cases. Further investigation is required to evidence the effect of surgical spine stabilization in PD.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedades Musculoesqueléticas/etiología , Enfermedades Musculoesqueléticas/cirugía , Procedimientos Ortopédicos , Adolescente , Adulto , Niño , Preescolar , Femenino , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/etiología , Fracturas Óseas/cirugía , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculoesqueléticas/diagnóstico , Radiografía , Escoliosis/diagnóstico por imagen , Escoliosis/etiología , Escoliosis/cirugía , Resultado del Tratamiento , Adulto JovenRESUMEN
Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective "survival motor neuron" (SMN) protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach.