Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction

Nimodipine is a 1,4-dihydropyridine derivative that shows a preferential cerebrovascular activity in experimental animals. Clinical data suggest that nimodipine has a beneficial effect on the neurologic outcome of patients suffering an acute ischemic stroke. Our double-blind placebo-controlled multicenter trial was designed to assess the effects of oral nimodipine on the mortality rate and neurologic outcome of patients with an acute ischemic stroke. One hundred sixty-four patients were randomly allocated to receive either nimodipine tablets (30 mg q.i.d.) or identical placebo tablets for 28 days. Treatment was always started less than or equal to 48 hours after the acute event. The Mathew Scale, slightly modified by Gelmers et al, was used for neurologic assessment. Mortality rate and neurologic outcome after 28 days were used as evaluation criteria. We considered 123 patients to be valid for the analysis of efficacy. Mortality rates did not differ significantly between groups. Neurologic outcome after 28 days of therapy did not differ between groups. However, when only those patients most likely to benefit from any intervention (Mathew Scale sum score of less than or equal to 65 at baseline) were analyzed separately in post hoc-defined subgroups, the nimodipine-treated subgroups showed a significantly better neurologic outcome. This result suggests that some patients with acute ischemic stroke will benefit from treatment with nimodipine tablets

Magnetic detection of sentinel lymph node in papillary thyroid carcinoma: The MAGIC-PAT study results

Introduction: Despite the controversy concerning sentinel lymph node biopsy (SLNB) in papillary thyroid carcinoma (PTC), successful detection rates can be achieved by radioguidance and vital dyeing. However, the drawbacks in both techniques are notable. Magnetic-guided SLNB (mSLNB) using superparamagnetic iron oxide (SPIO) nanoparticles is appealing as an alternative procedure. Materials and Methods: mSLNB using the Sentimag-Sienna System ® , total thyroidectomy and central compartment dissection (CCD) were performed on all PTC patients. Lymph node involvement was assessed by postoperative pathological examination. Results: From 2014 to 2016, 33 consecutive patients with PTC were enrolled in the study. A total of 20 patients met the eligibility. mSLNB succeeded in 16 patients, with a detection rate of 80%. A median of two SLN per patient were detected. A median of 10.5 non-sentinel lymph nodes (NSLN) from CCD were examined. Among the patients, 56.25% (9/16) had no metastatic nodes, while 12.5% (2/16) had exclusively SLN involvement. No false negative cases were found. The agreement between SLN and NSLN status was 87.5%. The prediction of NSLN involvement by SLN status showed 100% sensitivity, 81.8% specificity, 71.4% PPV and 100% NPV. Subsequently, mSLNB and the final pathological analysis would discriminate 43.75% (7/16) of patients who would certainly benefit from CCD whilst 56.25% of the total would confirm an unnecessary lymphadenectomy and avoid morbidity. Conclusion: mSLNB showed satisfactory performance in PTC with clinical-negative nodes. We have shown mSLNB to be a good predictor of central compartment status that can improve the staging and management of PTC patients

Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer

Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. Methods: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. Results: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. Conclusions: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Oclusión arterial de gran vaso diagnosticada por angiografía por tomografía computarizada en el ictus isquémico agudo: frecuencia, factores predictores y seguridad

Resumen: Introducción: Con la creciente disponibilidad de las terapias endovasculares, la demostración de oclusión arterial en el ictus isquémico agudo ha cobrado mayor relevancia. Este estudio evalúa la frecuencia de oclusión arterial y los factores asociados a la misma, así como las complicaciones derivadas del uso de angio-TC en el ictus agudo. Métodos: Se analizan retrospectivamente a los pacientes con ictus isquémico entre el 1 de julio y el 31 de diciembre del 2011. Resultados: Ciento cincuenta y siete pacientes (edad media de 74 ± 11 años, NIHSS 5 [2-13]). Un 56,7% llegó al hospital con menos de 8 h de evolución. Se realizó angio-TC en 71 casos (45,2%), detectando oclusión de gran vaso en 37 (52,1%). La localización más frecuente fue M1 (40%). En el análisis univariante se halló asociación de la escala NIHSS (17 vs. 7, p < 0,001) y la fibrilación auricular (64% vs. 32%, p = 0,006) con la presencia de oclusión arterial. Posteriormente, se realizó una regresión logística, confirmando dicha asociación. No se observó ningún caso de nefropatía por contraste. El tiempo puerta-aguja para fibrinólisis intravenosa fue de 61,2 ± 24,5 min en los pacientes en que se realizó angio-TC y 53,5 ± 34,3 en los que no se realizó (p = 0,495). Conclusiones: La oclusión de gran vaso se detecta en el 23,6% de la muestra, especialmente en los pacientes traídos en las primeras horas. La escala NIHSS es un buen factor predictor. Abstract: Introduction: Demonstrating artery occlusion in ischaemic stroke has gained importance due to the increasing availability of endovascular therapies. This study evaluates the frequency of artery occlusion, its associated factors, and complications following the use of CT-angiography in acute stroke. Methods: We retrospectively analysed a cohort of patients who suffered acute ischaemic stroke between July and-December 2011. Results: We included 157 patients (mean age, 74 ± 11; mean NIHSS score, 5 [2-13]). Of that total, 56.7% of the patients were admitted to hospital during the first 8 hours. CT-angiography was performed in 71 cases (45.2%); arterial large-vessel occlusion was detected in 37 (52.1%) of these cases, and the most frequent site was M1 (40%). Univariate analysis showed that the NIHSS score (17 vs 7, P < .001) and atrial fibrillation (64% vs 32%, P = .006) were associated with artery occlusion. A logistic regression analysis was performed subsequently, confirming these associations. There were no cases of contrast-induced nephropathy. Door-to-needle time for intravenous thrombolysis was 61.2 ± 24.5 minutes in patients who underwent CT-angiography, and 53.5 ± 34.3 minutes in those who did not (P = .495). Conclusions: Arterial occlusions are seen in 23.6% of patients, especially in those who are admitted during the first few hours. NIHSS score serves as a useful predictive factor. Palabras clave: Ictus, Diagnóstico, Angio-TC, Oclusión, Fibrinólisis, Endovascular, Keywords: Stroke, Diagnosis, CT-angiography, Occlusion, Thrombolysis, Endovascula

Vitamina D y remielinización en la esclerosis múltiple

Resumen: Introducción: Diferentes estudios han asociado la deficiencia en VD a la esclerosis múltiple, lo que ha llevado a plantear su potencial papel en la respuesta inmunitaria. Existe menos información sobre su papel en la remielinización. Desarrollo: En las células del SNC existe el receptor VD, así como las enzimas que transforman los metabolitos de la VD para poder activar este receptor, lo que plantea un potencial efecto de la VD. Tanto estudios in vitro como modelos animales han mostrado que la VD puede tener un papel sobre la mielinización actuando en factores que influyen en el microambiente que favorece la mielinización como en la proliferación y la diferenciación tanto de las células madre neuronales en células precursoras de oligodendrocitos como en estas en oligodendrocitos. No se conoce si los mecanismos de internalización de la VD en el SNC son sinérgicos o antagónicos a los que permiten la entrada de los metabolitos de la VD en las células inmunitarias. Conclusiones: La VD debe tener un papel en el SNC y se puede hipotetizar si actúa en la remielinización. El conocimiento de los mecanismos básicos de los efectos de la VD en la mielinización parece necesario para poder aconsejar a los pacientes con esclerosis múltiple ante deficiencias de VD en la clínica. Abstract: Introduction: Several studies have found an association between multiple sclerosis and vitamin D (VD) deficiency, which suggests that VD may play a role in the immune response. However, few studies have addressed its role in remyelination. Development: The VD receptor and the enzymes transforming VD into metabolites which activate the VD receptor are expressed in central nervous system (CNS) cells, which suggests a potential effect of VD on the CNS. Both in vitro and animal model studies have shown that VD may play a role in myelination by acting on factors that influence the microenvironment which promotes both proliferation and differentiation of neural stem cells into oligodendrocyte progenitor cells and oligodendrocytes. It remains unknown whether the mechanisms of internalisation of VD in the CNS are synergistic with or antagonistic to the mechanisms that facilitate the entry of VD metabolites into immune cells. Conclusions: VD seems to play a role in the CNS and our hypothesis is that VD is involved in remyelination. Understanding the basic mechanisms of VD in myelination is necessary to manage multiple sclerosis patients with VD deficiency. Palabras clave: Mielina, Vitamina D, Receptor de vitamina D, Oligodendrocito, Células precursoras de oligodendrocitos, Esclerosis múltiple, Keywords: Myelin, Vitamin D, Vitamin D receptor, Oligodendrocyte, Oligodendrocyte progenitor cells, Multiple sclerosi

Vitamin D and remyelination in multiple sclerosis

Introduction: Several studies have found an association between multiple sclerosis and vitamin D (VD) deficiency, which suggests that VD may play a role in the immune response. However, few studies have addressed its role in remyelination. Development: The VD receptor and the enzymes transforming VD into metabolites which activate the VD receptor are expressed in central nervous system (CNS) cells, which suggests a potential effect of VD on the CNS. Both in vitro and animal model studies have shown that VD may play a role in myelination by acting on factors that influence the microenvironment which promotes both proliferation and differentiation of neural stem cells into oligodendrocyte progenitor cells and oligodendrocytes. It remains unknown whether the mechanisms of internalisation of VD in the CNS are synergistic with or antagonistic to the mechanisms that facilitate the entry of VD metabolites into immune cells. Conclusions: VD seems to play a role in the CNS and our hypothesis is that VD is involved in remyelination. Understanding the basic mechanisms of VD in myelination is necessary to manage multiple sclerosis patients with VD deficiency. Resumen: Introducción: Diferentes estudios han asociado la deficiencia en VD a la esclerosis múltiple lo que ha llevado a plantear su potencial papel en la respuesta inmune. Existe menos información sobre su papel en la remielinización. Desarrollo: En las células del SNC existe el receptor VD así como las enzimas que transforman los metabolitos de la VD para poder activar este receptor, lo que plantea un potencial efecto de la VD. Tanto estudios in vitro como modelos animales han mostrado que la VD puede tener un papel sobre la mielinización actuando en factores que influyen en el microambiente que favorece la mielinización como en la proliferación y diferenciación tanto de las células madre neuronales en células precursoras de oligodendrocitos como en éstas en oligodendrocitos. No se conoce si los mecanismos de internalización de la VD en el SNC son sinérgicos o antagónicos a los que permiten la entrada de los metabolitos de la VD en las células inmunes. Conclusiones: La VD debe tener un papel en el SNC y se puede hipotetizar si actúa en la remielinización. El conocimiento de los mecanismos básicos de los efectos de la VD en la mielinización parece necesario para poder aconsejar a los pacientes con esclerosis múltiple ante deficiencias de VD en la clínica. Keywords: Myelin, Vitamin D, Vitamin D receptor, Oligodendrocyte, Oligodendrocyte progenitor cells, Multiple sclerosis, Palabras clave: Mielina, Vitamina D, Receptor de Vitamina D, Oligodendrocito, Células precursoras de oligodendrocitos, Esclerosis multipl

La infusión intracerebroventricular prolongada de líquido cefalorraquídeo procedente de pacientes con esclerosis lateral amiotrófica provoca cambios histológicos en el cerebro y la médula espinal de la rata similares a los hallados en la enfermedad

Resumen: Introducción: La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro. Material y métodos: Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados: Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobre expresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones: Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad. Abstract: Introduction: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. Material and methods: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43 days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82 days after surgery. Results: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. Conclusion: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease. Palabras clave: Esclerosis lateral amiotrófica, Modelo experimental ELA, Periferina, TDP-43, Enfermedades neurodegenerativas, Citotoxicidad, Keywords: Amyotrophic lateral sclerosis, ALS experimental model, Peripherin, TDP-43, Neurodegenerative diseases, Cytotoxicit

Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease

Introduction: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. Materials and methods: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43 days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82 days after surgery. Results: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. Conclusion: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease. Resumen: Introducción: La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro. Material y métodos: Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados: Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobreexpresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones: Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad. Keywords: Amyotrophic lateral sclerosis, ALS experimental model, Peripherin, TDP-43, Neurodegenerative diseases, Cytotoxicity, Palabras clave: Esclerosis lateral amiotrófica, Modelo experimental ELA, Periferina, TDP-43, Enfermedades neurodegenerativas, Citotoxicida

Supplementary Material for: Endovascular Treatment of Distal Internal Carotid Artery Occlusions with Retrievable Stents

<b><i>Background:</i></b> Acute stroke due to distal intracranial internal carotid artery (ICA) occlusion has a poor natural history. Outcome in patients who receive intravenous tissue plasminogen activator (tPA) is also unsatisfactory. The objective of this study is to evaluate the effectiveness and safety of endovascular treatment with retrievable stents in these patients. <b><i>Methods:</i></b> Data from a prospective register of patients with acute stroke treated with an endovascular procedure in a single centre were analysed. <b><i>Results:</i></b> A total of 20 patients with distal ICA occlusion were collected. Mean baseline National Institutes of Health Stroke Scale score was 18. Eight cases (40%) had received previous intravenous tPA. Mean time from stroke to recanalization was 393 min. Retrievable stents with proximal occlusion and aspiration were used in all cases. In 3 patients, 2 retrievable stents were used simultaneously. Complete recanalization (thrombolysis in cerebral infarction 2b/3) was accomplished in 85% of cases. A favourable clinical outcome (modified Rankin Scale score 0-2) was achieved in 13 patients (65%). Mortality occurred in 2 cases (10%). <b><i>Conclusions:</i></b> Endovascular treatment of patients with distal ICA occlusion seems safe and effective. Retrievable stents may be the treatment of choice, although randomized clinical trials are necessary. The use of 2 retrievable stents at the same time could be an alternative technique useful in thrombi of larger size