Are We Ready for Cell Therapy to Treat Stroke?

Clinical trials of cell therapies that target stroke started at the beginning of this century and they have experienced a significant boost in recent years as a result of promising data from basic research studies. The increase in the information available has paved the way to carry out more innovative and varied human studies. Efforts have focused on the search for a safe and effective treatment to stimulate neuro-regeneration in the brain and to reduce the sequelae of stroke in patients. Therefore, this review aims to evaluate the clinical trials using cell therapy to treat stroke published to date and assess their limitations. From 2000 to date, most of the published clinical trials have focused on phases I or II, and the vast majority of them demonstrate that stem cells are essentially safe to use when administered by different routes, with transient and mild adverse events that do not generally have severe consequences for health. In general, there is considerable variation in the trials in terms of statistical design, sample size, the cells used, the routes of administration, and the functional assessments (both at baseline and follow-up), making it difficult to compare the studies. From this general description, possibly the experimental protocol is the main element to improve in future studies. Establishing an adequate experimental and statistical design will be essential to obtain favorable and reliable results when conducting phase III clinical trials. Thus, it is necessary to standardize the criteria used in these clinical trials in order to aid comparison. Shortly, cell therapy will be a key approach in the treatment of stroke if adequate and comprehensive levels of recovery are to be achieved.

Neurorestoration Approach by Biomaterials in Ischemic Stroke.

Ischemic stroke (IS) is the leading cause of disability in the western world, assuming a high socio-economic cost. One of the most used strategies in the last decade has been biomaterials, which have been initially used with a structural support function. They have been perfected, different compounds have been combined, and they have been used together with cell therapy or controlled release chemical compounds. This double function has driven them as potential candidates for the chronic treatment of IS. In fact, the most developed are in different phases of clinical trial. In this review, we will show the ischemic scenario and address the most important criteria to achieve a successful neuroreparation from the point of view of biomaterials. The spontaneous processes that are activated and how to enhance them is one of the keys that contribute to the success of the therapeutic approach. In addition, the different routes of administration and how they affect the design of biomaterials are analyzed. Future perspectives show where this broad scientific field is heading, which advances every day with the help of technology and advanced therapies.

Dynamic risk control by human nucleus accumbens.

Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established.

Recomendaciones sobre el uso de ácido 5-aminolevulínico en la cirugía de los gliomas malignos. Documento de consenso / Recommendations on the use of 5-amino-levulinic acid in surgery of malignant gliomas. Consensus document. The Neuro-oncology Working Group of the Spanish Neurosurgical Society (SENEC)

Cuando hablamos de pacientes con gliomas de alto grado se encuentra, entre otros factores con interés pronóstico, la radicalidad de la cirugía efectuada. Las limitaciones para su ejecución se deben bien a la extensión del tumor o bien a su localización, en un área elocuente. En un intento de conseguir este objetivo hemos desarrollado en los últimos tiempos diversos métodos que nos permiten maximizar la resección del tumor, intentando siempre causar la menor morbilidad posible. Uno de estos es el empleo del ácido 5-aminolevulínico (5-ALA) y el desarrollo de la cirugía guiada con fluorescencia a partir de su uso. No obstante, para su correcta utilización requiere conocer ante qué producto estamos, la forma de administración, las precauciones a que estamos obligados y cómo poder sacarle el máximo rendimiento. Miembros del Grupo de Trabajo de Neurooncología (GTNO) de la Sociedad Española de Neurocirugía (SENEC) han elaborado esta guía o documento de consenso con el objetivo de homogeneizar y facilitar la toma de decisiones en la utilización del 5-ALA para la cirugía tumoral encefálica guiada con fluorescencia, y en particular en la resección de los gliomas de alto grado (AU)

Among the prognostic factors when it comes to patients with high-grade gliomas, we find the radicality of the surgery performed. The limitations of this factor are caused by either the extension of the tumour or its location in an eloquent area. To achieve this goal, in the last few years we have developed several methods that allow us to maximise tumour resection, while always trying to cause the least possible co-morbidity. One of these methods includes the use of 5-amino-levulinic acid (5-ALA) and the development of fluorescence guided surgery. However, optimal performance requires knowledge of the product employed, the mode of administration and precautions to consider. Members of the neuro-oncology work group of the Spanish Neurosurgical Society (SENEC) have prepared this guideline or consensus document for anyone who wishes to become familiar with the use of 5-ALA fluorescence-guided surgery in the management of high-grade gliomas. For those who already utilise this technique, this document can be useful for consultation purposes (AU)

[Recommendations on the use of 5-amino-levulinic acid in surgery of malignant gliomas. Consensus document. The Neuro-oncology Working Group of the Spanish Neurosurgical Society (SENEC)]. / Recomendaciones sobre el uso de ácido 5-aminolevulínico en la cirugía de los gliomas malignos. Documento de consenso.

Among the prognostic factors when it comes to patients with high-grade gliomas, we find the radicality of the surgery performed. The limitations of this factor are caused by either the extension of the tumour or its location in an eloquent area. To achieve this goal, in the last few years we have developed several methods that allow us to maximise tumour resection, while always trying to cause the least possible co-morbidity. One of these methods includes the use of 5-amino-levulinic acid (5-ALA) and the development of fluorescence guided surgery. However, optimal performance requires knowledge of the product employed, the mode of administration and precautions to consider. Members of the neuro-oncology work group of the Spanish Neurosurgical Society (SENEC) have prepared this guideline or consensus document for anyone who wishes to become familiar with the use of 5-ALA fluorescence-guided surgery in the management of high-grade gliomas. For those who already utilise this technique, this document can be useful for consultation purposes.

Efectos cognitivos de la radioterapia en gliomas de bajo grado / No disponible

El aumento en las tasas de supervivencia de los pacientes con gliomas de bajo grado está suscitando un elevado interés en los efectos neurotóxicos asociados a los tratamientos, en especial a la radioterapia. En la actualidad, se señala la presencia de alteraciones principalmente en memoria visual asociada a dicha técnica de tratamiento, aunque existen datos contrarios que postulan que la radioterapia, al igual que otros tratamientos, favorece el control de la enfermedad y preserva el rendimiento neuropsicológico de esta población. No obstante, las limitaciones metodológicas de estos estudios y la dificultad en el seguimiento de estos pacientes podrían estar provocando esta divergencia en los resultados hallados en este campo de investigación. Por ello, se reitera la necesidad de realizar estudios que utilicen las técnicas de tratamiento de radioterapia actuales, que aumentan la seguridad y disminuyen los efectos secundarios neurológicos, así como que apliquen cuestionarios con una adecuada sensibilidad a los efectos neurotóxicos de los tratamientos adyuvantes (AU)

The increased survival of patients with low grade gliomas generated increased interest in the neurotoxic effects associated with treatment, especially radiotherapy. Currently, the radiotherapy is associated with visual memory failures in this population. On the contrary, some authors postulate that radiotherapy, as well as other treatments, helps control the disease and preserves the neuropsychological performance. However, methodological limitations of these studies and the difficulty in monitoring these patients could be causing this divergence in the results found in this research field. Therefore, we note the need for studies that use radiation therapy treatment techniques current, which increase safety and reduce neurological side effects, and apply appropriate questionnaires with a sensitivity to the neurotoxic effects of adjuvant treatments (AU)

Subventricular zone in motor neuron disease with frontotemporal dementia.

Investigate how the subventricular proliferation and organisation is modified in a patient with FTLD-ALS. We studied the subventricular zone (SVZ) of a patient with FTLD-ALS immunohistochemical and histologically. We found an increase of Ki-67 positive cells and neuroblast in the subventricular zone, suggesting an activation of proliferating activity in response to FTD-ALS. This proliferation can act as a compensatory mechanism for rapid neuronal death and its modulation could provide a new therapeutic pathway in ALS. These results suggest a modification of neurogenesis in FTD-ALS.

Abordajes transesfenoidales endoscópicos de los adenomas hipofisarios: una revisión crítica de nuestra experiencia / Transphenoidal endoscopic approaches for pituitary adenomas: a critical review of our experience

Introducción: El abordaje quirúrgico de la región hipofisaria ha evolucionado desde las vías transcraneales, a las sublabiales y transseptales microscópicas hasta los abordajes endoscópicos actuales. Objetivos: El objetivo de este trabajo es exponer y reflexionar sobre nuestra experiencia en el abordaje transnasal transesfenoidal endoscópico de los tumores hipofisarios, con las modificaciones que hemos introducido para mejorar la exéresis del tumor y disminuir la iatrogenia. Material y métodos: A lo largo de 9 años hemos intervenido a 37 pacientes afectos de adenomas hipofisarios mediante abordaje transesfenoidal endoscópico. Utilizamos lentes de 0 y 30 grados, navegador óptico, instrumental habitual de endoscopia nasal y brazo articulado para fijación de la óptica en el tiempo neuroquirúrgico. Se accede a la celda hipofisaria mediante esfenoidotomía bilateral. Resultados: La neumatización esfenoidal ha sido suficiente en todos los pacientes. Las complicaciones postperatorias más frecuentes han sido la diabetes insípida y los transtornos endocrinológicos. Rinolicuorrea postoperatoria en un paciente. Secuela nasal definitiva ninguna. Tiempo medio de estancia hospitalaria 5 días. Conclusiones: El abordaje endoscópico guiado con el navegador aporta grandes ventajas: rapidez, seguridad, disminución de la iatrogenia, preservación de la vía aérea nasal. La resección de un fragmento de tabique nasal adyacente al rostrum mejora la manejabilidad de los instrumentos hacia los márgenes tumorales. La fijación del endoscopio estabiliza la visión y permite al segundo cirujano ayudar con más eficacia (AU)

Background: The surgical approach to the pituitary fossae has evolved from transcranial to sublabial and transseptal microscopic ones, up to the current transsphenoidal endoscopic approach. Objectives: To present our experience in the transnasal transsphenoidal approach for pituitary adenomas and the modifications introduced to improve tumoral resection and to lower iatrogenia. Material and methods: Over nine years, we operated on 37 patients with pituitary adenomas using the transsphenoidal endoscopic approach. We utilised optical lens of 0° (approach) and 30° (adenoma resection), optic navigator, surgical instruments for nasal endoscopic and pituitary surgery. During the neurosurgical step, the endoscope was fixed by an articulated arm. We acceded to the pituitary fossae by a bilateral sphenoidotomy. Results: Sphenoid pneumatisation was sufficient in all the patients. The more common postoperative complications were diabetes insipidus and endocrinology deficiencies. Postoperative rhinoliquorrhea affected only one patient. No alterations of nasal fossae were observed. Mean patient hospitalisation was five days. Conclusions: Transsphenoidal endoscopic approach guided by navigator gives significant advantages: Shorter operating time and fewer complications, greater safety and preservation of the nasal passages. Resecting the sphenoidal rostrum and a fragment of adjacent nasal septum improves surgical instrument management into the pituitary fossae and therefore adenoma resection. Endoscope fixation stabilises the vision and allows the second surgeon to help more effectively (AU)

[Transphenoidal endoscopic approaches for pituitary adenomas: a critical review of our experience]. / Abordajes transesfenoidales endoscópicos de los adenomas hipofisarios: una revisión crítica de nuestra experiencia.

BACKGROUND: The surgical approach to the pituitary fossae has evolved from transcranial to sublabial and transseptal microscopic ones, up to the current transsphenoidal endoscopic approach. OBJECTIVES: To present our experience in the transnasal transsphenoidal approach for pituitary adenomas and the modifications introduced to improve tumoral resection and to lower iatrogenia. MATERIAL AND METHODS: Over nine years, we operated on 37 patients with pituitary adenomas using the transsphenoidal endoscopic approach. We utilised optical lens of 0° (approach) and 30° (adenoma resection), optic navigator, surgical instruments for nasal endoscopic and pituitary surgery. During the neurosurgical step, the endoscope was fixed by an articulated arm. We acceded to the pituitary fossae by a bilateral sphenoidotomy. RESULTS: Sphenoid pneumatisation was sufficient in all the patients. The more common postoperative complications were diabetes insipidus and endocrinology deficiencies. Postoperative rhinoliquorrhea affected only one patient. No alterations of nasal fossae were observed. Mean patient hospitalisation was five days. CONCLUSIONS: Transsphenoidal endoscopic approach guided by navigator gives significant advantages: Shorter operating time and fewer complications, greater safety and preservation of the nasal passages. Resecting the sphenoidal rostrum and a fragment of adjacent nasal septum improves surgical instrument management into the pituitary fossae and therefore adenoma resection. Endoscope fixation stabilises the vision and allows the second surgeon to help more effectively.

Differentiation of postnatal neural stem cells into glia and functional neurons on laminin-coated polymeric substrates.

A series of polymeric biomaterials, including poly(methyl acrylate), chitosan, poly(ethyl acrylate) (PEA), poly(hydroxyethyl acrylate) (PHEA), and a series of random copolymers containing ethyl acrylate, hydroxyethyl acrylate, and methyl acrylate were tested in vitro as culture substrates and compared for their effect on the differentiation of neural stem cells (NSCs) obtained from the subventricular zone of postnatal rats. Immunocytochemical assay for specific markers and scanning electron microscopy techniques were employed to determine the adhesion of the cultured NSCs to the different biomaterials and the respective neuronal differentiation. The functional properties and the membrane excitability of differentiated NSCs were investigated using a patch-clamp. The results show that the substrate's surface chemistry influences cell attachment and neuronal differentiation, probably through its influence on adsorbed laminin, and that copolymers based on PEA and PHEA in a narrow composition window are suitable substrates to promote cell attachment and differentiation of adult NSCs into functional neurons and glia.

Toma de decisiones en el paciente diagnosticado de tumor cerebral. A propósito de un caso clínico / Decision making process in patients with brain tumor. Concerning a case report

Justificación: La decisión sobre la alternativa terapéutica más conveniente, que corresponde al paciente asesorado por el equipo sanitario, se hace especialmente difícil en casos de mal pronóstico. Pacientes: Paciente joven con tumor cerebral, reintervenido en diversas ocasiones, al que se detecta una recidiva. Resultados: En contra de la opinión del equipo multidisciplinar, el paciente decide someterse a una reintervención, falleciendo a los cuatro meses presentado una calidad de vida aceptable. Conclusiones: Se plantea la necesidad, a través de un counselling adecuado, de permitir que el paciente escoja el resultado clínico preferido tras la transmisión clara de las distintas consecuencias de cada decisión y de la probabilidad de que cada una de ellas ocurra, evitando el uso de términos confusos, como la descripción técnica de procedimientos y las sugerencias globales sobre las decisiones. Se enfatiza el respeto a la autonomía del paciente, bajo condiciones de no maleficencia (AU)

The patient´s decisión regarding the most advisable therapeutic alterantive is difficult, speccially in patients with por prognosis. Patients: Young patient who was operated on several times by brain tumour and he was admitted again by tumour recurrence. Results: The patient preferred to be reoperated against the multidisciplinary team decision. His quality of life was acceptable gut the patient died four months later. Conclusion: We think that the patient could be able to choose the preferred therapeutic option after adequate counseling. Confusing term such as technical description should be avoided. We emphasize the respect to the patient´s autonomy under non-maleficent conditions (AU)

Survival and differentiation of embryonic neural explants on different biomaterials.

Biomaterials prepared from polyacrylamide, ethyl acrylate (EA), and hydroxyethyl acrylate (HEA) in various blend ratios, methyl acrylate and chitosan, were tested in vitro as culture substrates and compared for their ability to be colonized by the cells migrating from embryonic brain explants. Neural explants were isolated from proliferative areas of the medial ganglionic eminence and the cortical ventricular zone of embryonic rat brains and cultured in vitro on the different biomaterials. Chitosan, poly(methyl acrylate), and the 50% wt copolymer of EA and HEA were the most suitable substrates to promote cell attachment and differentiation of the neural cells among those tested. Immunofluorescence microscopy analysis showed that progenitor cells had undergone differentiation and that the resulting glial and neuronal cells expressed their intrinsic morphological characteristics in culture.