Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study

Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDGPET/CT focusing on several territories’ vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory

El ictus en el siglo XXI. Tratamiento de urgencia

La enfermedad vascular, una verdadera epidemia, es la primera causa de muerte en los países desarrollados, responsable de más de una cuarta parte de las muertes documentadas a nivel mundial y la primera causa de discapacidad grave en el adulto. Las tres cuartas partes de los ictus afectan a pacientes mayores de 65 años, y debido a las previsiones de población en las que España será en el 2050 de las poblaciones más envejecidas del mundo, se prevé un incremento de la incidencia de esta patología en los próximos años. Numerosos estudios describen el escaso conocimiento de la población, sobre los signos y síntomas de presentación del ictus. Se recomienda elaborar campañas informativas orientadas a la población general para aumentar su conocimiento sobre los factores de riesgo, facilitar la identificación de los signos y síntomas de alarma y fomentar entre los pacientes el concepto del ictus como urgencia neurológica. El Código Ictus permite un rápido proceso de identificación, notificación y traslado de los pacientes a los servicios de urgencia hospitalarios. Los avances tecnológicos en el diagnóstico y la aparición de medidas terapéuticas eficaces, trombolíticos, hacen necesaria la organización coordinada y multidisciplinar. La Unidad de Ictus es la aproximación más eficaz y eficiente en el manejo de la fase aguda del ictus isquémico o hemorrágico. Los progresos en la investigación permitirán disponer de nuevas y mejores oportunidades para el tratamiento agudo del ictus.Cerebrovascular diseases have reached epidemic proportions worldwide. They are the major cause of mortality in developed countries, accounting for over one-quarter of worldwide documented deaths, and the leading cause of severe disability in adults. Given that Spain will become one of the countries most affected by population ageing, an increase in the incidence of these diseases is expected in coming years. Several studies have reported that public levels of awareness of stroke warning signs, symptoms and risk factors are relatively low. Information campaigns aimed at increasing these levels of awareness and considering stroke as a neurological emergency are needed. The stroke code is a system which allows rapid identification, notification, and transfer of stroke patients to the emergency units. Technological advances in stroke diagnosis, and the development of effective therapeutic measures, such as thrombolytics, require a coordinated multidisciplinary approach. Treating patients in Stroke Units is the most effective and efficient approach in acute ischemic or hemorrhagic stroke management. In coming years research advances will provide new and better strategies in acute stroke treatment

El ictus en el siglo XXI. Tratamiento de urgencia

La enfermedad vascular, una verdadera epidemia, es la primera causa de muerte en los países desarrollados, responsable de más de una cuarta parte de las muertes documentadas a nivel mundial y la primera causa de discapacidad grave en el adulto. Las tres cuartas partes de los ictus afectan a pacientes mayores de 65 años, y debido a las previsiones de población en las que España será en el 2050 de las poblaciones más envejecidas del mundo, se prevé un incremento de la incidencia de esta patología en los próximos años. Numerosos estudios describen el escaso conocimiento de la población, sobre los signos y síntomas de presentación del ictus. Se recomienda elaborar campañas informativas orientadas a la población general para aumentar su conocimiento sobre los factores de riesgo, facilitar la identificación de los signos y síntomas de alarma y fomentar entre los pacientes el concepto del ictus como urgencia neurológica. El Código Ictus permite un rápido proceso de identificación, notificación y traslado de los pacientes a los servicios de urgencia hospitalarios. Los avances tecnológicos en el diagnóstico y la aparición de medidas terapéuticas eficaces, trombolíticos, hacen necesaria la organización coordinada y multidisciplinar. La Unidad de Ictus es la aproximación más eficaz y eficiente en el manejo de la fase aguda del ictus isquémico o hemorrágico. Los progresos en la investigación permitirán disponer de nuevas y mejores oportunidades para el tratamiento agudo del ictus.Cerebrovascular diseases have reached epidemic proportions worldwide. They are the major cause of mortality in developed countries, accounting for over one-quarter of worldwide documented deaths, and the leading cause of severe disability in adults. Given that Spain will become one of the countries most affected by population ageing, an increase in the incidence of these diseases is expected in coming years. Several studies have reported that public levels of awareness of stroke warning signs, symptoms and risk factors are relatively low. Information campaigns aimed at increasing these levels of awareness and considering stroke as a neurological emergency are needed. The stroke code is a system which allows rapid identification, notification, and transfer of stroke patients to the emergency units. Technological advances in stroke diagnosis, and the development of effective therapeutic measures, such as thrombolytics, require a coordinated multidisciplinary approach. Treating patients in Stroke Units is the most effective and efficient approach in acute ischemic or hemorrhagic stroke management. In coming years research advances will provide new and better strategies in acute stroke treatment

Percepción de los médicos sobre los factores que influyen en la elección de un dicumarínico o de un nuevo anticoagulante oral en pacientes con fibrilación auricular no valvular

Objetivo: Estudios recientes han demostrado la eficacia y la seguridad de los nuevos anticoagulantes orales (NACO) en la prevención de tromboembolias en pacientes con fibrilación auricular no valvular (FANV). Nuestro objetivo es evaluar qué factores influyen en los médicos para elegir entre dicumarínicos o NACO. Diseño: Se analizaron distintas variables, que fueron discutidas y puntuadas siguiendo una metodología Workmat®. Emplazamiento: Se realizaron 6 reuniones regionales en España (Levante, Cataluña, Andalucía-Extremadura, Madrid, Noroeste y Norte de España). Participantes: Participaron 39 especialistas (cardiólogos, neurólogos, hematólogos, internistas y médicos de urgencias y atención primaria). Mediciones: Cada participante puntuó de 1 a 10 (de menor a mayor) el grado de acuerdo con cada variable analizada. Resultados: Se elegiría preferiblemente un NACO en pacientes con fracaso previo del tratamiento dicumarínico (9,7 ± 0,5), riesgo hemorrágico elevado (8,7 ± 1), antecedentes de hemorragia (7,8 ± 1,5) y riesgo trombótico alto (7,7 ± 1,2). Se decantarían por un dicumarínico en casos de disfunción renal grave (1,2 ± 0,4) o moderada (4,2 ± 2,5), buen control con dicumarínicos (2,3 ± 1,5), deterioro cognitivo (3,2 ± 3) y riesgo hemorrágico bajo (4,3 ± 3). La edad, el sexo, el peso, el coste del fármaco, la polimedicación y la existencia de un riesgo trombótico bajo obtuvieron puntuaciones intermedias. Conclusiones: El riesgo trombótico y hemorrágico elevado y el fracaso del tratamiento previo con dicumarínicos predisponen a elegir un NACO. La insuficiencia renal, el deterioro cognitivo, el buen control con dicumarínicos y un riesgo hemorrágico bajo inclinan a decantarse por un dicumarínico clásico

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

Background. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods. We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results. Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with nonneoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575)

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

Background. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods. We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results. Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with nonneoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575)

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study

Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDGPET/CT focusing on several territories’ vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring