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- A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsiesPublication . Baumgartner, Tobias; Carreño, Mar; Rocamora, Rodrigo; Bisulli, Francesca; Boni, Antonella; Brázdil, Milan; Horak, Ondrej; Craiu, Dana; Pereira, Cristina; Guerrini, Renzo; San Antonio‐Arce, Victoria; Schulze‐Bonhage, Andreas; Zuberi, Sameer M.; Hallböök, Tove; Kalviainen, Reetta; Lagae, Lieven; Nguyen, Sylvie; Quintas, Sofia; Franco, Ana; Cross, J. Helen; Walker, Matthew; Arzimanoglou, Alexis; Rheims, Sylvain; Granata, Tiziana; Canafoglia, Laura; Johannessen Landmark, Cecilie; Sen, Arjune; Rattihalli, Rohini; Nabbout, Rima; Tartara, Elena; Santos, Manuela; Pereira Rangel Pinho, Rui Jorge; Krsek, Pavel; Marusic, Petr; Specchio, Nicola; Braun, Kees P. J.; Smeyers, Patricia; Villanueva, Vicente; Kotulska, Katarzyna; Surges, RainerObjective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
- HIPTCN: Prospective Observational Study of Hypocoagulated Head Trauma Patients with Normal Admission Computed Tomography ScanPublication . Duarte-Batista, Pedro; Farinha, Nuno Cubas; Marques, Renata; Pinheiro, João Páscoa; Silva, João; Tuna, Rui; Reis, José Hipólito; Antunes, Cristiano; Machado, Maria João; Lemos, Samuel Sequeira; Branco, Jessica; Roque, Diogo; Simão, Diogo; Simas, Nuno; Teixeira, Wilson; Felício, Cátia; Ferreira, Miguel; Cunha, Eduardo; Rocha, Luís; Figueiredo, Gonçalo; Noronha, Carolina; Pinto, Vasco; Silva, Filipe; Ferreira, Ana; Sousa, OsvaldoIntroduction: Our national protocol for traumatic brain injury dictates that hypocoagulated patients with mild trauma and initial tomography scan with no intracranial traumatic changes must be hospitalized for 24 hours and do a post-surveillance tomography scan. The main goal of this study was to evaluate the clinical relevance of these measures. Material and methods: A prospective observational study was undertaken in four hospitals. Adult hypocoagulated traumatic brain injury patients with a normal tomography scan were included. The main outcomes evaluated were rate of delayed intracranial hemorrhage, rate of admission in a neurosurgical department, rate of complications related with surveillance and rate of prolonged hospitalization due to complications. An analysis combining data from a previously published report was also done. Results: A total of 178 patients were included. Four patients (2.3%) had a delayed hemorrhage and three (1.7%) were hospitalized in a neurosurgery ward. No cases of symptomatic hemorrhage were identified. No surgery was needed, and all patients had their anticoagulation stopped. Complications during surveillance were reported in seven patients (3.9%), of which two required prolonged hospitalization. Discussion: The rate of complications related with surveillance was higher than the rate of delayed hemorrhages. The initial period of in-hospital surveillance did not convey any advantage since the management of patients was never dictated by neurological changes. Post-surveillance tomography played a role in deciding about anticoagulation suspension and prolongation of hospitalization. Conclusion: Delayed hemorrhage is a rare event and the need for surgery even rarer. The need for in-hospital surveillance should be reassessed.
- A novel molecular link between HOXA9 and WNT6 in glioblastoma identifies a subgroup of patients with particular poor prognosisPublication . Gonçalves, Céline S.; Xavier‐Magalhães, Ana; Martins, Eduarda P.; Pinto, Afonso A.; Pires, Manuel; Pinheiro, Célia; Reis, Rui M.; Sousa, Nuno; Costa, Bruno M.Despite much effort to improve treatments, patients with malignant glioma still present a very poor prognosis that has not changed significantly in the last decades. In this context, it is crucial to better understand glioma pathogenesis to identify new molecular prognostic subgroups and therapeutic targets. WNT6 was recently identified as a new oncogenic molecule in glioblastoma (GBM), with prognostic value in patients, but the mechanisms underlying WNT6 aberrant expression in glioma are still unknown. WNT6 was overexpressed in a subset of gliomas independently of IDH mutations, 1p/19q codeletion status, and WNT6 gene copy number. Interestingly, WNT6 expression is associated with the DNA methylation levels of particular CpG regions at both the WNT6 promoter and the gene body in glioma patient samples. HOXA9, a transcription factor previously associated with poorer clinical outcome in GBM, was identified as a novel transcriptional regulator of WNT6, activating the WNT/β-catenin pathway in vitro and in vivo. In various cohorts of glioma patients, mRNA levels of WNT6 and HOXA9 were significantly correlated, extending our in vitro and in vivo findings into the clinical setting. Interestingly, this novel molecular link between WNT6 and HOXA9 was not limited to glioma, as they were co-expressed also in patients with other tumor types. Clinically, WNT6 was a prognostic biomarker of shorter survival in GBM, independently of HOXA9 expression. Concomitant high expression of both WNT6 and HOXA9 identified a subgroup of patients with particularly dismal survival. These findings describe novel WNT6 regulatory mechanisms in GBM, establishing particular DNA methylation patterns and HOXA9 as critical regulators of WNT6 expression in glioma. This HOXA9-WNT6 molecular link supports WNT signaling in GBM cells and is a powerful prognostic biomarker, highlighting the clinical relevance of this axis in patients. Novel therapies targeting WNT6-HOXA9 signaling may thus be useful for this deadly disease.
- Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomasPublication . Miranda-Gonçalves, V.; Granja, S.; Martinho, O.; Honavar, M.; Pojo, M.; Costa, B.; Melo-Pires, M.; Pinheiro, C.; Cordeiro, M.; Bebiano, G.; Costa, P.; Reis, R.; Baltazar, F.BACKGROUND: Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. METHODS: Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. RESULTS: Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. CONCLUSION: Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.
- In utero meconium exposure increases spinal cord necrosis in a rat model of myelomeningocelePublication . Correia-Pinto, J.; Reis, J.; Hutchins, G.; Baptista, M.; Estevão-Costa, J.; Flake, A.; Leite-Moreira, A.Abstract BACKGROUND/PURPOSE: The rationale for in utero repair of myelomeningocele has been supported experimentally by the observation of preserved neural function after prenatal closure of surgically created defects compared with nonrepaired controls. The mechanism of injury to the exposed neural elements is unknown. Postulated mechanisms include trauma to the herniated neural elements or progressive injury from amniotic fluid exposure as gestation proceeds. A component of amniotic fluid that may contribute to neural injury is meconium. In the current study the effect of human meconium on the exposed spinal cord in a fetal rat model of myelomeningocele was examined. METHODS: Twenty time-dated pregnant rats underwent laparotomy at 181/2 days of gestation. The exposed uterus was bathed in ritrodrine for tocolysis. The amniotic cavity was opened over the dorsal midline of the fetal rat, and, under a dissecting microscope (x25), a 2- to 3-level laminectomy was performed. Under magnification (x40), the translucent dura was opened using a 25-gauge needle as a knife. Two fetuses per dam were operated on. In the control group, the amniotic fluid was restored with saline solution, whereas in the experimental group a solution of Human meconium diluted (10%) in saline was used to restore the amniotic fluid. Fetuses were harvested by cesarean section at 211/2 days' gestational age. The liveborn pups were then killed and fixed in 10% formaline. Sections 10 micrometer thick were stained with H&E and studied by light microscopy for evidence of spinal cord injury. RESULTS: Seven of 20 (35%) experimental rat pups and 6 of 20 (30%) control rat pups were liveborn. All liveborn pups had severe paralysis of the hindlimbs and tail, so that functional differences between the 2 groups could not be detected. Histologic examination of 13 spinal cords at the site of surgical exposure showed that necrosis of neural tissue in 5 of 7 meconium-exposed rat pups was increased when compared with that observed in the 6 fetuses exposed to amniotic fluid without meconium. In general, inflammation was greater and repair processes appeared delayed in meconium-exposed rat pups. CONCLUSIONS: Exposure of the spinal cord of fetal rats to amniotic fluid by surgically created myelomeningocele leads to severe functional impairment. Histologically recognizable necrosis of neural elements was increased in those animals that were exposed to diluted human meconium in the amniotic fluid. The results support the hypothesis that meconium may contribute to the pathophysiology of spinal cord injury observed in myelomeningocele.