8 research outputs found
18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results
Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose
(FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or
assisted image reading is not well established to evaluate hypometabolism/hypermetabolism.
We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018.
Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF)
sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard
visual reading and assisted by voxel-based analyses, compared to a normal database. For the
latter, three different methods were performed: two based on statistical surface projections (Siemens
syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric
mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific
patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had
anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative.
18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis.
Medial–temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based
analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface
projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive
and localized larger hypermetabolic areas. As it may lead to comparable and accurate results,
visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from
voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG
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
Estudio de la placa carotÃdea vulnerable: correlación entre los niveles de metaloproteasas y la presencia de actividad inflamatoria intraplaca
Introducción: La estenosis carotÃdea es responsable de un 20% de todos los
ictus isquémicos. Teniendo en cuenta que la aterosclerosis es una enfermedad
inflamatoria crónica, es posible que determinados marcadores de inflamación
permitan predecir el riesgo de recurrencia de ictus, y otras complicaciones
vasculares en pacientes con estenosis carotÃdea grave (>70%) sometidos a
endarterectomÃa carotÃdea. El objetivo principal del presente estudio fue
determinar si los niveles circulantes de metaloproteasas (MMPs) de matriz
extracelular (MMP-1, MMP-2, MMP-7, MMP-9 y MMP-10), el inhibidor tisular de
MMPs (TIMP-1) y la cuantificación de la inflamación in vivo de la placa carotÃdea
estudiada de forma no invasiva mediante 18F-FDG-PET / CT son útiles para
diferenciar entre pacientes con estenosis carótidea sintomáticas y asintomáticas,
o en la predicción de eventos vasculares recurrentes en pacientes con estenosis
carotÃdea sometidos a endarterectomÃa.
Pacientes y métodos: Estudio de cohorte prospectivo, longitudinal
multicéntrico. Se reclutaron pacientes atendidos en la Unidad de Ictus del
Hospital de Navarra y la ClÃnica Universidad de Navarra con edades
comprendidas entre 50-80 años con diagnóstico de infarto cerebral (con déficit
menor) o AIT de origen aterotrombótico por estenosis carotÃdea grave, y
pacientes con estenosis carotÃdea grave asintomática, que fueron sometidos a
endarterectomÃa carotÃdea. Se obtuvieron muestras de plasma y suero 2 dÃas
antes de la cirugÃa y se analizaron los niveles de MMP-1, MMP-2, MMP-7, MMP9, MMP-10, TIMP-1, HDL, LDL, proteÃna C reactiva y velocidad de sedimentación
globular. Se realizó un estudio 18F-FDG-PET / CT para cuantificar el metabolismo
de la pared vascular de ambas carótidas y otros territorios vasculares, como
reflejo de la presencia de inflamación intraplaca. Se realizaron estudios
histológicos e inmunohistoquÃmicos con anticuerpos dirigidos frente a MMP-10,
MMP-9, TIMP-1 y CD68 en la placa carotÃdea extraÃda quirúrgicamente mediante
endarterectomÃa. Asimismo, se incluyeron en el estudio 26 controles sanos,
trabajadores de la Universidad de Navarra, comparables en edad y sexo a la
población de pacientes.
Resultados: Se incluyeron 31 pacientes consecutivos con estenosis carotÃdea
sintomática (n=23) o asintomática (n=8) grave a los que se les realizó
endarterectomÃa carotÃdea entre julio de 2013 y marzo de 2016. Los pacientes
con estenosis carotÃdea presentaron niveles circulantes de MMP-1, MMP-7 y
MMP-10 significativamente más elevados que los controles sanos. No se
encontró ninguna correlación entre las MMPs circulantes y el grado de
inflamación en la placa carotÃdea in vivo evaluado mediante 18F-FDG-PET / CT.
El TIMP-1 intraplaca se correlacionó moderadamente con su nivel plasmático (r
= 0,42 p = 0,02) y con la captación de 18F-FDG-PET / CT (r = 0,38 p = 0,05).
Después de una mediana de seguimiento de 1077 dÃas, se registraron 4 eventos
cerebrovasculares, 7 eventos cardiovasculares y 11 eventos vasculares
periféricos que requirieron hospitalización. El nivel de MMP-7 circulante fue
capaz de predecir eventos más allá de los factores de riesgo tradicionales (HR
= 1,15 p = 0,006). Cuando el modelo de regresión se asoció con las variables de
interés, la capacidad de la 18F-FDG-PET / CT para predecir eventos vasculares
no fue significativa.
Conclusiones: Los hallazgos del presente estudio no apoyan el uso de 18FFDG-PET / CT o los niveles de metaloproteasas o sus inhibidores para
diferenciar estenosis carotÃdeas sintomáticas o asintomáticas y tampoco para
establecer el riesgo de recurrencia de ictus. Nuestros hallazgos proporcionan
evidencia de que la MMP-7 circulante podrÃa representar un biomarcador de
eventos cardiovasculares recurrentes en pacientes con estenosis carotÃdea
grave
Estudio de la placa carotÃdea vulnerable: correlación entre los niveles de metaloproteasas y la presencia de actividad inflamatoria intraplaca
Introducción: La estenosis carotÃdea es responsable de un 20% de todos los
ictus isquémicos. Teniendo en cuenta que la aterosclerosis es una enfermedad
inflamatoria crónica, es posible que determinados marcadores de inflamación
permitan predecir el riesgo de recurrencia de ictus, y otras complicaciones
vasculares en pacientes con estenosis carotÃdea grave (>70%) sometidos a
endarterectomÃa carotÃdea. El objetivo principal del presente estudio fue
determinar si los niveles circulantes de metaloproteasas (MMPs) de matriz
extracelular (MMP-1, MMP-2, MMP-7, MMP-9 y MMP-10), el inhibidor tisular de
MMPs (TIMP-1) y la cuantificación de la inflamación in vivo de la placa carotÃdea
estudiada de forma no invasiva mediante 18F-FDG-PET / CT son útiles para
diferenciar entre pacientes con estenosis carótidea sintomáticas y asintomáticas,
o en la predicción de eventos vasculares recurrentes en pacientes con estenosis
carotÃdea sometidos a endarterectomÃa.
Pacientes y métodos: Estudio de cohorte prospectivo, longitudinal
multicéntrico. Se reclutaron pacientes atendidos en la Unidad de Ictus del
Hospital de Navarra y la ClÃnica Universidad de Navarra con edades
comprendidas entre 50-80 años con diagnóstico de infarto cerebral (con déficit
menor) o AIT de origen aterotrombótico por estenosis carotÃdea grave, y
pacientes con estenosis carotÃdea grave asintomática, que fueron sometidos a
endarterectomÃa carotÃdea. Se obtuvieron muestras de plasma y suero 2 dÃas
antes de la cirugÃa y se analizaron los niveles de MMP-1, MMP-2, MMP-7, MMP9, MMP-10, TIMP-1, HDL, LDL, proteÃna C reactiva y velocidad de sedimentación
globular. Se realizó un estudio 18F-FDG-PET / CT para cuantificar el metabolismo
de la pared vascular de ambas carótidas y otros territorios vasculares, como
reflejo de la presencia de inflamación intraplaca. Se realizaron estudios
histológicos e inmunohistoquÃmicos con anticuerpos dirigidos frente a MMP-10,
MMP-9, TIMP-1 y CD68 en la placa carotÃdea extraÃda quirúrgicamente mediante
endarterectomÃa. Asimismo, se incluyeron en el estudio 26 controles sanos,
trabajadores de la Universidad de Navarra, comparables en edad y sexo a la
población de pacientes.
Resultados: Se incluyeron 31 pacientes consecutivos con estenosis carotÃdea
sintomática (n=23) o asintomática (n=8) grave a los que se les realizó
endarterectomÃa carotÃdea entre julio de 2013 y marzo de 2016. Los pacientes
con estenosis carotÃdea presentaron niveles circulantes de MMP-1, MMP-7 y
MMP-10 significativamente más elevados que los controles sanos. No se
encontró ninguna correlación entre las MMPs circulantes y el grado de
inflamación en la placa carotÃdea in vivo evaluado mediante 18F-FDG-PET / CT.
El TIMP-1 intraplaca se correlacionó moderadamente con su nivel plasmático (r
= 0,42 p = 0,02) y con la captación de 18F-FDG-PET / CT (r = 0,38 p = 0,05).
Después de una mediana de seguimiento de 1077 dÃas, se registraron 4 eventos
cerebrovasculares, 7 eventos cardiovasculares y 11 eventos vasculares
periféricos que requirieron hospitalización. El nivel de MMP-7 circulante fue
capaz de predecir eventos más allá de los factores de riesgo tradicionales (HR
= 1,15 p = 0,006). Cuando el modelo de regresión se asoció con las variables de
interés, la capacidad de la 18F-FDG-PET / CT para predecir eventos vasculares
no fue significativa.
Conclusiones: Los hallazgos del presente estudio no apoyan el uso de 18FFDG-PET / CT o los niveles de metaloproteasas o sus inhibidores para
diferenciar estenosis carotÃdeas sintomáticas o asintomáticas y tampoco para
establecer el riesgo de recurrencia de ictus. Nuestros hallazgos proporcionan
evidencia de que la MMP-7 circulante podrÃa representar un biomarcador de
eventos cardiovasculares recurrentes en pacientes con estenosis carotÃdea
grave
18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results
Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose
(FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or
assisted image reading is not well established to evaluate hypometabolism/hypermetabolism.
We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018.
Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF)
sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard
visual reading and assisted by voxel-based analyses, compared to a normal database. For the
latter, three different methods were performed: two based on statistical surface projections (Siemens
syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric
mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific
patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had
anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative.
18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis.
Medial–temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based
analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface
projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive
and localized larger hypermetabolic areas. As it may lead to comparable and accurate results,
visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from
voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG
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
Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells
The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with
longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because
of immunosuppression. New immunotherapy-based combinations are under investigation in an
attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition
and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung
adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant
correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro
in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant
syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade
targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth
impairment and overall survival improvement. Mechanistically, multiplex quantification of
CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor
infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration.
Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor
effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute
to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1
expression and harnessing tumor infiltration of CD8+ T lymphocytes
Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells
The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with
longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because
of immunosuppression. New immunotherapy-based combinations are under investigation in an
attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition
and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung
adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant
correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro
in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant
syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade
targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth
impairment and overall survival improvement. Mechanistically, multiplex quantification of
CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor
infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration.
Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor
effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute
to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1
expression and harnessing tumor infiltration of CD8+ T lymphocytes