Risk Factors, Radiological and Clinical Outcomes in Subclinical and Clinical Pituitary Apoplexy.

BACKGROUND: Pituitary apoplexy (PA) can be symptomatic, namely acute apoplexy (APA), or asymptomatic or subclinical (SPA). OBJECTIVE: To describe the clinical characteristics and evolution of the patients with APA compared to SPA Patients and methods: Retrospective, longitudinal database analysis. RESULTS: We identified 58 patients with PA, and 37 accomplished the inclusion criteria (17 men, median age 47.7 years). A total of 29 (78.4%) had APA (17 underwent surgery, and 12 were conservatively managed), and 8 (21.6%) had SPA. The presence of non-functioning pituitary adenoma (NFPA) odds ratio (OR): 29.36 (95% confidence interval (CI): 1.86-462.36) and the largest size OR 1.10 (95% CI: 1.01-1.2) elevated the risk of having surgery. Hypopituitarism developed in 35.1% without significant differences between APA and SPA. In non-surgical patients, adenoma volume shrunk spontaneously at one year magnetic resonance imaging (MRI), without statistical differences between the conservatively treated and SPA group. CONCLUSIONS: APA is more frequent in larger NFPAs, and this subset of patients has a higher risk of surgery. Hypopituitarism is quite frequent even in patients with SPA, and, therefore, long-term follow-up is mandatory. In the non-surgical group, the pituitary tumour shrinkage is clinically relevant after one year of PA. Consequently, surgery indication in NFPA should be delayed and reassessed if patients remain asymptomatic.

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis.

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

Traumatic axonal injury: is the prognostic information produced by conventional MRI and DTI complementary or supplementary?

OBJECTIVE: A traumatic axonal injury (TAI) diagnosis has traditionally been based on conventional MRI, especially on those sequences with a higher sensitivity to edema and blood degradation products. A more recent technique, diffusion tensor imaging (DTI), can infer the microstructure of white matter (WM) due to the restricted diffusion of water in organized tissues. However, there is little information regarding the correlation of the findings obtained by both methods and their use for outcome prognosis. The main objectives of this study were threefold: 1) study the correlation between DTI metrics and conventional MRI findings; 2) evaluate whether the prognostic information provided by the two techniques is supplementary or complementary; and 3) determine the incremental value of the addition of these variables compared to a traditional prognostic model. METHODS: The authors studied 185 patients with moderate to severe traumatic brain injury (TBI) who underwent MRI with DTI study during the subacute stage. The number and volume of lesions in hemispheric subcortical WM, corpus callosum (CC), basal ganglia, thalamus, and brainstem in at least four conventional MRI sequences (T1-weighted, T2-weighted, FLAIR, T2* gradient recalled echo, susceptibility-weighted imaging, and diffusion-weighted imaging) were determined. Fractional anisotropy (FA) was measured in 28 WM bundles using the region of interest method. Nonparametric tests were used to evaluate the colocalization of macroscopic lesions and FA. A multivariate logistic regression analysis was performed to assess the independent prognostic value of each neuroimaging modality after adjustment for relevant clinical covariates, and the internal validation of the model was evaluated in a contemporary cohort of 92 patients. RESULTS: Differences in the lesion load between patients according to their severity and outcome were found. Colocalization of macroscopic nonhemorrhagic TAI lesions (not microbleeds) and lower FA was limited to the internal and external capsule, corona radiata, inferior frontooccipital fasciculus, CC, and brainstem. However, a significant association between the FA value and the identification of macroscopic lesions in distant brain regions was also detected. Specifically, lower values of FA of some hemispheric WM bundles and the splenium of the CC were related to a higher number and volume of hyperintensities in the brainstem. The regression analysis revealed that age, motor score, hypoxia, FA of the genu of the CC, characterization of TAI lesions in the CC, and the presence of thalamic/basal ganglia lesions were independent prognostic factors. The performance of the proposed model was higher than that of the IMPACT (International Mission on Prognosis and Analysis of Clinical Trials in TBI) model in the validation cohort. CONCLUSIONS: Very limited colocalization of hyperintensities (none for microbleeds) with FA values was discovered. DTI and conventional MRI provide complementary prognostic information, and their combination can improve the performance of traditional prognostic models.

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment.

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.

PREMIO SIXTO OBRADOR SENEC 2019: El uso de la secuencia Tensor de difusión como herramienta pronóstica en los pacientes con traumatismo craneoencefálico grave y moderado. Parte II: Análisis longitudinal de las características del Tensor de difusión y su relación con la evolución de los pacientes / SIXTO OBRADOR SENEC PRIZE 2019: Utility of diffusion tensor imaging as a prognostic tool in moderate to severe traumatic brain injury. Part II: Longitudinal analysis of DTI metrics and its association with patient's outcome

ANTECEDENTES Y OBJETIVOS: La lesión axonal traumática es considerada la principal causa de las alteraciones cognitivas y neuropsicológica de los pacientes tras traumatismo craneoencefálico (TCE). Además, existen algunas evidencias sobre la evolución dinámica de la lesión axonal traumática. La secuencia de RM Tensor de difusión (DTI, diffusion tensor imaging) se considera una técnica útil para la caracterización de la lesión axonal traumática, pero son escasos los estudios que hayan evaluado los cambios longitudinales de las características del DTI y su relación con la evolución de los pacientes. MATERIALES Y MÉTODOS: Ciento dieciocho pacientes con TCE moderado y grave fueron estudiados mediante RM-DTI en la fase subaguda precoz (<60 días) y otros estudios sucesivos a los 6 y/o 12 meses tras TCE. Se ha medido la anisotropía fraccionada, difusión axial y radial en las 3 porciones del cuerpo calloso (rodilla, cuerpo y esplenio) y se han comparado con los valores de un grupo control. Además, se ha determinado la situación clínica de los pacientes mediante la Glasgow Outcome Scale Extended al alta hospitalaria, 6 y 12 meses tras TCE. Para el análisis longitudinal de las características del DTI y su correlación con la evolución de los pacientes se han empleado pruebas no paramétricas y un análisis de regresión ordinal. RESULTADOS: A pesar de haber detectado cambios dinámicos en las características del DTI en las 3 porciones del cuerpo calloso, los pacientes continuaron mostrando valores de anisotropía fraccionada y difusión axial significativamente inferiores y valores de difusión radial mayores en comparación con los controles al final del periodo de estudio. También hemos encontrado diferencias en el patrón de cambio del DTI entre subgrupos de pacientes que presentaron evolución favorable. CONCLUSIONES: El perfil temporal del cambio en las características del DTI parece proporcionar información importante sobre la recuperación clínica de los pacientes tras TCE

BACKGROUND AND OBJECTIVES: Traumatic axonal injury is the main cause of the cognitive and neuropsychological situation of patients after head trauma (TBI). Additionally, there are some evidences about the dynamic evolution of traumatic axonal injury. Although the diffusion tensor MRI (DTI) sequence is considered a useful technique for modifying the extent of the traumatic axonal injury, few studies have evaluated the longitudinal changes in the characteristics of the DTI and its relation to evolution of patients. MATERIALS AND METHODS: We performed a prospective observational study in 118 patients with moderate to severe TBI. The study included clinical outcome assessment based on the Glasgow Outcome Scale Extended and serial DTI studies in the early subacute setting (< 60 days) and 6 and 12 months after injury. Fractional anisotropy, axial and radial diffusivities were measured in the 3 portions of corpus callosum (genu, body, splenium) at each time point and compared to normalized values from an age-matched control group. Longitudinal fractional anisotropy analysis and its correlation with patient improvement was also done by non-parametric testing and ordinal regression analysis. RESULTS: Although dynamic changes in DTI characteristics have been detected in the 3 portions of corpus callosum, patients continue to show lower fractional anisotropy and axial diffusivities values and higher radial diffusivities values compared to controls at the end of the period of study. We have also found differences in the pattern of DTI metrics change between subgroups of patients according with their favorable outcome CONCLUSIONS: The temporal profile of the change in DTI characteristics seems to provide important information about the clinical recovery of patients after TBI

Premio Sixto Obrador SENEC 2019: el uso de la secuencia tensor de difusión como herramienta pronóstica en los pacientes con traumatismo craneoencefálico grave y moderado. Parte I. Análisis de las características del tensor de difusión realizado durante la fase subaguda precoz / Sixto Obrador SENEC prize 2019: Utility of diffusion tensor imaging as a prognostic tool in moderate to severe traumatic brain injury. Part I. Analysis of DTI metrics performed during the early subacute stage

ANTECEDENTES Y OBJETIVOS: La lesión axonal traumática (LAT) contribuye significativamente a la mortalidad y morbilidad tras traumatismo craneoencefálico (TCE). Sin embargo, la caracterización de la LAT supone un reto diagnóstico para las técnicas de neuroimagen habitual. La secuencia de RM tensor de difusión (diffusion tensor imaging [DTI]) es capaz de detectar el grado de difusión de las moléculas de agua tisular y así inferir la afectación traumática de la sustancia blanca. El objetivo principal de este trabajo ha sido caracterizar la LAT a través de la secuencia DTI realizada en la fase subaguda precoz en nuestra serie de pacientes con TCE moderado y grave y evaluar si existe asociación con la evolución de los pacientes. MATERIALES Y MÉTODOS: Se ha realizado RM-DTI a 217 pacientes con TCE moderado y grave en la fase subaguda precoz tras el TCE (mediana = 19 días). El método de análisis elegido es por región de interés para calcular el valor medio de fractional anisotropy (FA) en 28 haces de sustancia blanca. Los valores obtenidos en los pacientes se han comparado con aquellos medidos en 58 sujetos sanos. RESULTADOS: Los resultados principales han sido que los pacientes, independientemente de la gravedad, demostraron valores de FA significativamente inferiores al grupo control en prácticamente todos los haces estudiados. Se detectó asociación entre el valor de FA y algunas variables clínicas de interés. Adicionalmente, los valores de FA de las tres porciones del cuerpo calloso, cíngulo y pedúnculos cerebrales se correlacionaron con la evolución del paciente evaluada a los 6 y 12 meses tras el TCE. CONCLUSIONES: El DTI es una herramienta útil para caracterizar la LAT y la detección de la reducción de FA en la fase subaguda precoz se relaciona con evolución desfavorable de los pacientes a medio y largo plazo

BACKGROUND AND OBJECTIVES: Traumatic axonal injury (TAI) contributes significantly to mortality and morbidity after traumatic brain injury (TBI). Its identification is still a diagnostic challenge because of the limitations of conventional imaging techniques to characterized it. Diffusion tensor imaging (DTI) can indirectly identify areas of damaged white matter integrity by detecting water molecule diffusion alterations. Our main objective is to characterize the TAI using DTI at the early subacute stage in our series of moderate to severe TBI patients and to evaluate if there is a relationship between the information provided by the DTI and patient's outcome. MATERIALS AND METHODS: We have obtained DTI data from 217 patients with moderate to severe TBI acquired at a median of 19 days after TBI, and patient DTI metrics were compared with data obtained from 58 age-matched healthy controls. Region of interest method was applied to obtain mean fractional anisotropy (FA) value in 28 white matter fiber bundles susceptible to TAI. RESULTS: Our main results were that when we compared patients with controls, patients, regardless of TBI severity, showed significantly reduced mean FA in almost all region of interest measured. We found statistically significant correlation between FA metrics and some clinical characteristics. Additionally, the FA values of the three portions of Corpus callosum, Cingulum and cerebral peduncles measured at the early subacute stage were highly associated with outcome assessed at hospital discharge and at 6 and 12 months after TBI. CONCLUSIONS: We conclude that DTI is a useful tool to characterize TAI and the detection of FA reduction in the subacute stage after TBI is associated with long-term unfavorable outcome

SIXTO OBRADOR SENEC PRIZE 2019: Utility of diffusion tensor imaging as a prognostic tool in moderate to severe traumatic brain injury. Part II: Longitudinal analysis of DTI metrics and its association with patient's outcome. / PREMIO SIXTO OBRADOR SENEC 2019: El uso de la secuencia Tensor de difusión como herramienta pronóstica en los pacientes con traumatismo craneoencefálico grave y moderado. Parte II: Análisis longitudinal de las características del Tensor de difusión y su relación con la evolución de los pacientes.

BACKGROUND AND OBJECTIVES: Traumatic axonal injury is the main cause of the cognitive and neuropsychological situation of patients after head trauma (TBI). Additionally, there are some evidences about the dynamic evolution of traumatic axonal injury. Although the diffusion tensor MRI (DTI) sequence is considered a useful technique for modifying the extent of the traumatic axonal injury, few studies have evaluated the longitudinal changes in the characteristics of the DTI and its relation to evolution of patients. MATERIALS AND METHODS: We performed a prospective observational study in 118 patients with moderate to severe TBI. The study included clinical outcome assessment based on the Glasgow Outcome Scale Extended and serial DTI studies in the early subacute setting (<60 days) and 6 and 12 months after injury. Fractional anisotropy, axial and radial diffusivities were measured in the 3 portions of corpus callosum (genu, body, splenium) at each time point and compared to normalized values from an age-matched control group. Longitudinal fractional anisotropy analysis and its correlation with patient improvement was also done by non-parametric testing and ordinal regression analysis. RESULTS: Although dynamic changes in DTI characteristics have been detected in the 3 portions of corpus callosum, patients continue to show lower fractional anisotropy and axial diffusivities values and higher radial diffusivities values compared to controls at the end of the period of study. We have also found differences in the pattern of DTI metrics change between subgroups of patients according with their favorable outcome CONCLUSIONS: The temporal profile of the change in DTI characteristics seems to provide important information about the clinical recovery of patients after TBI.

Sixto Obrador SENEC prize 2019: Utility of diffusion tensor imaging as a prognostic tool in moderate to severe traumatic brain injury. Part I. Analysis of DTI metrics performed during the early subacute stage. / Premio Sixto Obrador SENEC 2019: el uso de la secuencia tensor de difusión como herramienta pronóstica en los pacientes con traumatismo craneoencefálico grave y moderado. Parte I. Análisis de las características del tensor de difusión realizado durante la fase subaguda precoz.

BACKGROUND AND OBJECTIVES: Traumatic axonal injury (TAI) contributes significantly to mortality and morbidity after traumatic brain injury (TBI). Its identification is still a diagnostic challenge because of the limitations of conventional imaging techniques to characterized it. Diffusion tensor imaging (DTI) can indirectly identify areas of damaged white matter integrity by detecting water molecule diffusion alterations. Our main objective is to characterize the TAI using DTI at the early subacute stage in our series of moderate to severe TBI patients and to evaluate if there is a relationship between the information provided by the DTI and patient's outcome. MATERIALS AND METHODS: We have obtained DTI data from 217 patients with moderate to severe TBI acquired at a median of 19 days after TBI, and patient DTI metrics were compared with data obtained from 58 age-matched healthy controls. Region of interest method was applied to obtain mean fractional anisotropy (FA) value in 28 white matter fiber bundles susceptible to TAI. RESULTS: Our main results were that when we compared patients with controls, patients, regardless of TBI severity, showed significantly reduced mean FA in almost all region of interest measured. We found statistically significant correlation between FA metrics and some clinical characteristics. Additionally, the FA values of the three portions of Corpus callosum, Cingulum and cerebral peduncles measured at the early subacute stage were highly associated with outcome assessed at hospital discharge and at 6 and 12 months after TBI. CONCLUSIONS: We conclude that DTI is a useful tool to characterize TAI and the detection of FA reduction in the subacute stage after TBI is associated with long-term unfavorable outcome.

Evolución de las alteraciones cognitivas tras un traumatismo craneoencefálico: ¿hay mejoría tras controlar el efecto de la práctica? / Evolution of cognitive impairment after a traumatic brain injury: is there any improvement after controlling the practice effect?

Introducción: La importancia de conocer el patrón de evolución de los déficits cognitivos en los primeros meses tras un traumatismo craneoencefálico (TCE) ha fomentado el desarrollo de numerosos estudios longitudinales. Sin embargo, los resultados de la mayoría de ellos deberían tomarse con cautela debido a la falta de un control adecuado del efecto de la práctica, que puede llevar a sobreestimar la recuperación genuina de los procesos cognitivos. Objetivo: Describir los cambios cognitivos entre las fases aguda y subaguda del TCE controlando el efecto de la práctica. Pacientes y métodos: Veintidós pacientes realizaron dos evaluaciones neuropsicológicas tras el TCE (inmediata y tras seis meses) mediante los siguientes tests: Trail Making Test (A, B, B/A y B-A), test de Stroop (P, C, PC e interferencia), clave de números, búsqueda de símbolos, dígitos directos e inversos, fluidez verbal y memoria inmediata. Para controlar el efecto de la práctica se realizó una transformación de las puntuaciones aplicando el procedimiento propuesto por Calamia et al. Resultados: Antes de controlar el efecto de la práctica, se evidenció una mejoría en las puntuaciones de todos los tests (p > 0,001). Sin embargo, tras él, la mejoría permaneció sólo en el Trail Making Test-B, B/A y B-A, la clave de números, la búsqueda de símbolos, el test de Stroop PC y los dígitos inversos. Conclusiones: La falta de control del efecto de la práctica en estudios longitudinales puede generar interpretaciones erróneas sobre el perfil de evolución de los déficits cognitivos. El patrón de recuperación tras un TCE varía en función del proceso cognitivo

Introduction: The importance of knowing the pattern of evolution of cognitive deficits in the first months after a traumatic brain injury (TBI) has encouraged the development of numerous longitudinal studies. However, the results of most of them should be taken with caution due to the lack of adequate control of practice effects that can lead to overestimating the genuine recovery of cognitive processes. Aim. To describe the cognitive changes between the acute and subacute phases of the TBI controlling the effect of the practice. Patients and methods: Twenty-two patients were assessed in two different time points after TBI (immediately and after six months) using the following tests: Trail Making Test (A, B, B/A, B-A), Stroop Test (W, C, CW, interference), Digit Symbol-Coding, Symbol Search, Digits Forward and Backward, Verbal Fluency and Short-term Memory. To control for the practice effects, a transformation of the scores was performed applying the procedure proposed by Calamia et al. Results: Before controlling the practice effects, the scores of all tests improved (p > 0.001). However, afterward, the improvement remained only in the Trail Making Test-B, B/A and B-A, Digit Symbol-Coding, Symbol Search, Stroop CW and Digits Backward. Conclusions: The lack of control of practice effects in longitudinal studies can generate misleading interpretations about the evolution of cognitive deficits. The pattern of recovery after a TBI varies depending on the cognitive process

A rare case of an intramedullary metastasis of a myxopapillary ependymoma.

BACKGROUND: Myxopapillary ependimoma (MPE) is a benign slow-growing tumor, and it has been designated histologically as a Grade I neoplasm according to the 2016 World Health Organization classification. Despite the benign character, dissemination and metastasis have occasionally been reported. The retrograde dissemination to other levels of the neuraxis is extremely rare, being more frequent to the intracranial compartment. CASE DESCRIPTION: We hereby present a case of medullary metastasis of cauda equina MPE, with a history of having undergone a subtotal resection and postoperative adjuvant radiotherapy. The patient presents complaints of night dorsal pain attributable to intradural metastasis twenty-one years after the first surgical intervention. CONCLUSION: The case reported highlights the importance of long follow-up in patients with MPE, since the possibility of secondary seeding to distant craniospinal sites or local spinal sites after surgery, and radiotherapy should be considered in metastatic disease.

Longitudinal Analysis of Corpus Callosum Diffusion Tensor Imaging Metrics and Its Association with Neurological Outcome.

Traumatic axonal injury (TAI) is the main cause of cognitive and psychological disfunction after a traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is considered a useful technique for indirect assessment of white matter (WM) integrity after a TBI. Scattered WM alterations and its relationship with patient severity have been discovered in normal appearing conventional magnetic resonance imaging (MRI) studies based on DTI sequences. However, there is a lack of large sample studies on the longitudinal changes of DTI metrics to be used to determine the temporal profile after head injury and its association with patient outcome. We performed a prospective observational study in 118 moderate-to-severe TBI patients. The study included clinical outcome assessment based on the Glasgow Outcome Scale Extended (GOSE) and serial DTI studies in the early subacute setting (< 60 days) and 6 and 12 months after injury. Fractional anisotropy (FA) and axial and radial diffusivities (AD and RD, respectively) were measured in the three portions of corpus callosum (genu, body, splenium) at each time-point and compared with normalized values from an age-matched control group. Longitudinal FA analysis and its correlation with patient improvement also was done by non-parametric testing and ordinal regression analysis. Our main results indicated that between all the time-points, dynamic changes in DTI metrics in all three portions of corpus callosum were detected, but TBI patients continued to show significantly lower FA and AD values and higher RD values compared with controls. We also have discovered differences in the change of DTI metrics among different time-points in patient subgroups according with their outcome improvement. In conclusion, even without normalization of DTI metrics in the long-term, knowledge of the temporal profile of change in DTI metrics can provide important information about patients' clinical recovery after TBI.

The added prognostic value of magnetic resonance imaging in traumatic brain injury: The importance of traumatic axonal injury when performing ordinal logistic regression.

BACKGROUND AND PURPOSE: This study was performed to investigate the prognostic value of traumatic axonal injury (TAI) in severe head trauma. METHODS: We attempted to determine whether any MR imaging findings of TAI could be related to prognosis in 264 patients with severe head trauma. We performed an ordinal logistic regression, adjusted for the prognostic factors according to the IMPACT studies, adding each MR feature related to prognosis one at a time. A new prognostic model was described by adding these MR features to the classic prognostic factors. The model was externally validated in a prospective series. Harrel's c-statistic and ordinal c-index (ORC) were calculated to measure its predictive accuracy. RESULTS: We found 178 patients with TAI lesions. Lesions in the basal ganglia/thalamus, corpus callosum (CC) and brain stem were associated with poor outcome (P < 0.01). The highest OR was for TAI lesions in the splenium (OR: 2.6) and brain stem dorsal lesions (OR: 3.1). We only found significant differences in outcome between haemorrhagic and non-haemorrhagic TAI lesions in the subgroup of patients with white matter and basal ganglia/thalamus lesions (P = 0.01). We obtained a superior discriminatory capacity by adding these MR findings to the previous prognostic model (Harrel's c-statistic 0.72 and ORC 0.7) in a prospective series of 93 patients. CONCLUSIONS: The prognostic model including MR findings maintained a superior discriminatory capacity than that obtained for the model with the classic prognostic factors alone.

Kir6.2, the Pore-Forming Subunit of ATP-Sensitive K+ Channels, Is Overexpressed in Human Posttraumatic Brain Contusions.

Brain contusions (BCs) are one of the most frequent lesions in patients with moderate and severe traumatic brain injury (TBI). BCs increase their volume due to peri-lesional edema formation and/or hemorrhagic transformation. This may have deleterious consequences and its mechanisms are still poorly understood. We previously identified de novo upregulation sulfonylurea receptor (SUR) 1, the regulatory subunit of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels and other channels, in human BCs. Our aim here was to study the expression of the pore-forming subunit of KATP, Kir6.2, in human BCs, and identify its localization in different cell types. Protein levels of Kir6.2 were detected by western blot (WB) from 33 contusion specimens obtained from 32 TBI patients aged 14-74 years. The evaluation of Kir6.2 expression in different cell types was performed by immunofluorescence in 29 contusion samples obtained from 28 patients with a median age of 42 years. Control samples were obtained from limited brain resections performed to access extra-axial skull base tumors or intraventricular lesions. Contusion specimens showed an increase of Kir6.2 expression in comparison with controls. Regarding cellular location of Kir6.2, there was no expression of this channel subunit in blood vessels, either in control samples or in contusions. The expression of Kir6.2 in neurons and microglia was also analyzed, but the observed differences were not statistically significant. However, a significant increase of Kir6.2 was found in glial fibrillary acidic protein (GFAP)-positive cells in contusion specimens. Our data suggest that further research on SUR1-regulated ionic channels may lead to a better understanding of key mechanisms involved in the pathogenesis of BCs, and may identify novel targeted therapeutic strategies.

What Can Be Learned from Diffusion Tensor Imaging from a Large Traumatic Brain Injury Cohort?: White Matter Integrity and Its Relationship with Outcome.

Traumatic axonal injury (TAI) contributes significantly to mortality and morbidity after traumatic brain injury (TBI), but its identification is still a diagnostic challenge because of the limitations of conventional imaging techniques to characterized it. Diffusion tensor imaging (DTI) can indirectly identify areas of damaged white matter (WM) integrity by detecting water molecule diffusion alterations. Therefore, DTI may improve detection and description of TAI lesions after TBI. We have obtained DTI data from 217 patients with moderate to severe TBI acquired at a median of 19 days after TBI, and patient DTI metrics were compared with data obtained from 58 age-matched healthy controls. Region of interest (ROI) method was applied to obtain mean fractional anisotropy (FA) value in 28 WM fiber bundles susceptible to TAI. Our main results were that when we compared patients with controls, patients, regardless of TBI severity, showed significantly reduced mean FA in almost all ROI measured. We found statistically significant correlation between FA metrics and some demographic, clinical, and conventional imaging characteristics. Additionally, these FA metrics were highly associated with outcome assessed at hospital discharge and at 6 and 12 months after TBI. We conclude that FA reduction in the subacute stage after TBI assessed by DTI may be a useful prognostic factor for long-term unfavorable outcome.

Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid.

Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies.Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors.Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas.Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812-9. ©2018 AACR.

Resonancia magnética en el traumatismo craneal grave: estudio comparativo de las diferentes secuencias de resonancia magnética convencional y su valor diagnóstico en la lesión axonal difusa / Magnetic resonance in traumatic brain injury: a comparative study of the different conventional magnetic resonance imaging sequences and their diagnostic value in diffuse axonal injury

Objetivo: El objetivo de este estudio es determinar qué secuencias de resonancia magnética (RM) convencional diagnostican de manera más sensible las lesiones asociadas a lesiones axonales difusas (LAD) en pacientes con TCE grave. Material y métodos: Se analizaron de manera retrospectiva los datos de 264 pacientes con TCE grave y RM realizada dentro de las primeras 8 semanas tras el TCE. Se recogieron todas las variables clínicas potencialmente relacionadas con el pronóstico de los enfermos, así como los datos dla tomografía computarizada inicial. A todos los enfermos se les practicó un estudio de RM convencional con secuencias spin-eco potenciadas en T1 y T2, secuencia FLAIR y eco de gradiente T2 (EGRT2*). Las diferentes LAD visualizadas fueron caracterizadas según su localización y clasificadas siguiendo las escalas de Gentry y Firsching en cada secuencia. Se calculó el grado de concordancia entre la clasificación obtenida en las diferentes secuencias y la obtenida de forma definitiva por el paciente, así como el área bajo la curva ROC de cada una de ellas con respecto al pronóstico final de los pacientes. Resultados: En las secuencias T2, FLAIR y EGRT2* se visualizan las LAD de manera adecuada en más del 80% de los casos. En FLAIR se visualizan mejor las LAD hemisféricas a nivel subcortical y el EGRT2* resalta las LAD hemorrágicas. En nuestra serie hemos visto que el grado de concordancia para diagnosticar LAD entre las secuencias T2, FLAIR y EGRT2* es alto (0,8). La secuencia T2 es la que tuvo un valor más alto en las curvas ROC tanto en la clasificación de Gentry (0,68; IC 95%: 0,61-0,76; p<0,001, Nagerlkerke-R2 0,26) como en la de Firsching (0,64; IC 95%: 0,57-0,72; p<0,001, Nagerlkerke-R2 0,19), seguida de la secuencia FLAIR y de la EGRT2*. Se observó, tras realizar un análisis multivariable, que las clasificaciones de Gentry y Firsching determinadas de forma independiente en cada secuencia se relacionaban con el pronóstico final de los enfermos al año del traumatismo (p<0,02). Conclusiones: Para el diagnóstico adecuado de LAD en el TCE grave recomendamos la realización de una RM convencional en fase subaguda que incluya al menos las secuencias T2, FLAIR y eco de gradiente en los diferentes planos de corte. Estos hallazgos aumentan el valor pronóstico de los modelos descritos en el TCE grave

Objective: To compare the identification capability of traumatic axonal injury (TAI) by different sequences on conventional magnetic resonance (MR) studies in traumatic brain injury (TBI) patients. Material and methods: We retropectevely analyzed 264 TBI patients to whom a MR had been performed in the first 60 days after trauma. All clinical variables related to prognosis were registered, as well as the data from the initial computed tomography. The MR imaging protocol consisted of a 3-plane localizer sequence T1-weighted and T2-weighted fast spin-echo, FLAIR and gradient-echo images (GRET2*). TAI lesions were classified according to Gentry and Firsching classifications. We calculated weighted kappa coefficients and the area under the ROC curve for each MR sequence. A multivariable analyses was performed to correlate MR findings in each sequence with the final outcome of the patients. Results: TAI lesions were adequately visualized on T2, FLAIR and GRET2* sequences in more than 80% of the studies. Subcortical TAI lesions were well on FLAIR and GRET2* sequences visualized hemorrhagic TAI lesions. We saw that these MR sequences had a high inter-rater agreement for TAI diagnosis (0.8). T2 sequence presented the highest value on ROC curve in Gentry (0.68, 95%CI: 0.61-0.76, p<0.001, Nagerlkerke-R2 0.26) and Firsching classifications (0.64, 95%CI 0.57-0.72, p<0.001, Nagerlkerke-R2 0.19), followed by FLAIR and GRET2* sequences. Both classifications determined by each of these sequences were associated with poor outcome after performing a multivariable analyses adjusted for prognostic factors (p<0.02). Conclusions: We recommend to perform conventional MR study in subacute phase including T2, FLAIR and GRET2* sequences for visualize TAI lesions. These MR findings added prognostic information in TBI patients

[Magnetic resonance in traumatic brain injury: A comparative study of the different conventional magnetic resonance imaging sequences and their diagnostic value in diffuse axonal injury]. / Resonancia magnética en el traumatismo craneal grave: estudio comparativo de las diferentes secuencias de resonancia magnética convencional y su valor diagnóstico en la lesión axonal difusa.

OBJECTIVE: To compare the identification capability of traumatic axonal injury (TAI) by different sequences on conventional magnetic resonance (MR) studies in traumatic brain injury (TBI) patients. MATERIAL AND METHODS: We retropectevely analyzed 264 TBI patients to whom a MR had been performed in the first 60 days after trauma. All clinical variables related to prognosis were registered, as well as the data from the initial computed tomography. The MR imaging protocol consisted of a 3-plane localizer sequence T1-weighted and T2-weighted fast spin-echo, FLAIR and gradient-echo images (GRET2*). TAI lesions were classified according to Gentry and Firsching classifications. We calculated weighted kappa coefficients and the area under the ROC curve for each MR sequence. A multivariable analyses was performed to correlate MR findings in each sequence with the final outcome of the patients. RESULTS: TAI lesions were adequately visualized on T2, FLAIR and GRET2* sequences in more than 80% of the studies. Subcortical TAI lesions were well on FLAIR and GRET2* sequences visualized hemorrhagic TAI lesions. We saw that these MR sequences had a high inter-rater agreement for TAI diagnosis (0.8). T2 sequence presented the highest value on ROC curve in Gentry (0.68, 95%CI: 0.61-0.76, p<0.001, Nagerlkerke-R2 0.26) and Firsching classifications (0.64, 95%CI 0.57-0.72, p<0.001, Nagerlkerke-R2 0.19), followed by FLAIR and GRET2* sequences. Both classifications determined by each of these sequences were associated with poor outcome after performing a multivariable analyses adjusted for prognostic factors (p<0.02). CONCLUSIONS: We recommend to perform conventional MR study in subacute phase including T2, FLAIR and GRET2* sequences for visualize TAI lesions. These MR findings added prognostic information in TBI patients.

Prognostic value of corpus callosum injuries in severe head trauma.

BACKGROUND: This study was performed to investigate the relationship between corpus callosum (CC) injury and prognosis in traumatic axonal injury (TAI). METHOD: We retrospectively reviewed 264 patients with severe head trauma who underwent a conventional MR imaging in the first 60 days after injury. They were selected from a prospectively collected database of 1048 patients with severe head trauma admitted in our hospital. TAI lesions were defined as areas of increased signal intensity on T2 and FLAIR or areas of decreased signal on gradient-echo T2. We attempted to determine whether any MR imaging findings of TAI lesions at CC could be related to prognosis. Neurological impairment was assessed at 1 year after injury by means of GOS-E (good outcome being GOS-E 4/5 and bad outcome being GOS-E <4). We adjusted the multivariable analysis for the prognostic factors according to the IMPACT studies: the Core model (age, motor score at admission, and pupillary reactivity) and the Extended model (including CT information and second insults). RESULTS: We found 97 patients (37 %) with TAI at CC and 167 patients (63 %) without CC lesions at MR. A total of 62 % of the patients with CC lesions had poor outcome, whereas 38 % showed good prognosis. The presence of TAI lesions at the corpus callosum was associated with poor outcome 1 year after brain trauma (p < 0.001, OR 3.8, 95 % CI: 2.04-7.06). The volume of CC lesions measured on T2 and FLAIR sequences was negatively correlated with the GOS-E after adjustment for independent prognostic factors (p = 0.01, OR 2.23, 95 % CI:1.17-4.26). Also the presence of lesions at splenium was statistically related to worse prognosis (p = 0.002, OR 8.1, 95 % CI: 2.2-29.82). We did not find statistical significance in outcome between hemorrhagic and non-hemorrhagic CC lesions. CONCLUSIONS: The presence of CC is associated with a poor outcome. The total volume of the CC lesion is an independent prognostic factor for poor outcome in severe head trauma.

Ganglioglioma atípico con mutación de BRAF V600E: caso clínico y revisión de la bibliografía / Atypical ganglioglioma with BRAF V600E mutation: a case report and review of the literature

Introducción. Los gangliogliomas son tumores raros que afectan a pacientes jóvenes, aparecen predominantemente en el lóbulo temporal y suelen comenzar con crisis epilépticas. Histológicamente corresponden a un grado I de malignidad, con una forma anaplásica catalogada como de grado III en la clasificación de la Organización Mundial de la Salud (OMS) de 2007. Sin embargo, existen tumores que no cumplen criterios de uno u otro grado y que presentan claras diferencias pronósticas respecto a los de grado I. Estos tumores corresponderían a gangliogliomas atípicos (grado II), no contemplados en la citada clasificación. Desde el punto de vista molecular, la alteración más conocida en los gangliogliomas es la mutación de BRAF V600E, que confiere peor pronóstico a la lesión. La posibilidad de utilizar tratamientos dirigidos a esta proteína mutada otorga una especial relevancia a esta alteración. Caso clínico. Varón de 21 años, intervenido de un ganglioglioma en dos ocasiones, en el que el examen neuropatológico objetivó características histológicas compatibles con un grado de malignidad intermedio (grado II) con mutación positiva a BRAF. Conclusiones. El caso presentado, junto con los descritos previamente en la bibliografía, reabre las controversias sobre la definición de los gangliogliomas en la clasificación de la OMS de 2007, y apoya el hecho de que la próxima clasificación de la OMS debería volver a incluir los gangliogliomas atípicos (grado II) e integrar posibles mutaciones genéticas y alteraciones moleculares (AU)

Introduction. Gangliogliomas are rare tumours that affect young patients, appear predominantly in the temporal lobe and usually begin with epileptic seizures. Histologically they have a grade I of malignancy, with an anaplastic form that is catalogued as grade III in the 2007 WHO classification. Yet, there are tumours that do not meet the criteria of either grade and which offer clear prognostic differences with respect to those of grade I. These tumours would be atypical gangliogliomas (grade II), which are not considered in this classification. From the molecular point of view, the best known alteration in gangliogliomas is the BRAF V600E mutation, which worsens the prognosis of the lesion. The possible use of treatments targeted towards this mutated protein is especially relevant in this disorder. Case report. A 21-year-old male, who had undergone surgery due to a ganglioglioma on two occasions. The neuropathological examination revealed histological features consistent with an intermediate grade of malignancy (grade II), with positive BRAF mutation. Conclusions. The case presented here, together with those previously reported in the literature, reopens the debate on the definition of gangliogliomas in the 2007 WHO classification, and lends support to the fact that the next classification should again include atypical gangliogliomas (grade II), together with possible genetic mutations and molecular disorders (AU)