Francisco Martinez-Ricarte

TGF-β Receptor Inhibitors Target the CD44high/Id1high Glioma-Initiating Cell Population in Human Glioblastoma

Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-β inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-β inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-β pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma

Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.

Decompressive craniectomy in traumatic brain injury after the DECRA trial. Where do we stand

Purpose of reviewThe results of the multicentre, randomized, controlled trial to test the effectiveness of decompressive craniectomy in adults with traumatic brain injury and high intracranial pressure (Decompressive Craniectomy, DECRA) were published in 2011. DECRA concluded that decompressive craniectomy decreased intracranial pressure (ICP) but was associated with more unfavourable outcomes. Our review aims to put the DECRA trial into context, comment on its findings and discuss whether we should include decompressive craniectomy in our clinical armamentarium. Recent findingsThe key message that DECRA conveys is that decompressive craniectomy significantly lowers ICP and shortens the length of the stay in the ICU. However, neither mortality nor unfavourable outcome was reduced when adjusting the significant baseline covariates. SummaryThe claim that decompressive craniectomy increases unfavourable outcome is overstated and not supported by the data presented in DECRA. We believe it premature to change clinical practice. Given the dismal outcome in these patients, it is reasonable to include this technique as a last resort in any type of protocol-driven management when conventional therapeutic measures have failed to control ICP, the presence of operable masses has been ruled out and the patient may still have a chance of a functional outcome. The main lesson to be learned from this study is that an upper threshold for ICP must be used as a cut-off for selecting decompressive craniectomy candidates.

Intra-abdominal pressure: the neglected variable in selecting the ventriculoperitoneal shunt for treating hydrocephalus.

OBJECTIVEIn the selection of a ventriculoperitoneal cerebrospinal fluid shunt, the intra-abdominal pressure (IAP) is traditionally neglected as a result of the idea that its value is close to 0 mmHg. Our aim was to explore the relationship between body mass index (BMI) and IAP with the goal of providing clinically relevant data that could help neurosurgeons to estimate IAP and select the appropriate shunt for patients with hydrocephalus and especially those with normal-pressure hydrocephalus syndrome. METHODSSixty patients requiring the placement of a ventriculoperitoneal shunt were included in the study. We determined weight, BMI, and IAP. IAP was measured through an intraperitoneal catheter during the shunt surgery. To determine whether a linear relationship existed between quantitative variables, linear regression analysis was used. RESULTSBMI was 28.1 ± 4.8 kg/m2. Eighteen patients (30%) had normal weight, 21 (35%) were moderately overweight, and 21 (35%) were obese. IAP was related to patient BMI. A significant positive linear correlation was identified between BMI and IAP (r = 0.52; P = 0.018) with a slope of 0.31 (P < 0.001) and an intercept of −5.5. CONCLUSIONIn our study, we determined that IAP had a strong positive linear relationship with BMI. This correlation was independent of sex. An IAP of 0 mmHg can, therefore, only be assumed for patients with a normal BMI who are recumbent. In obese or overweight patients, neurosurgeons should take IAP into account when selecting both the most adequate differential pressure valve to be implanted and in which distal cavity to place the distal catheter to avoid shunt underdrainage induced by high IAP.

Idiopathic normal pressure hydrocephalus: results of a prospective cohort of 236 shunted patients.

AIM To describe the outcomes and complication rates in 236 patients with idiopathic normal pressure hydrocephalus (INPH) after treatment. PATIENTS AND METHODS Among a cohort of 257 patients with suspected INPH, 244 were shunted and 236 were followed up at 6 months after shunting (145 men [61.4%] and 91 women [38.6%] with a median age of 75 years). The study protocol of these patients included clinical, radiological, neuropsychological and functional assessment. The decision to shunt patients was based on continuous intracranial pressure monitoring and CSF dynamics studies. A differential low-pressure valve system, always combined with a gravity compensating device, was implanted in 99% of the patients. RESULTS After shunting, 89.9% of the patients showed clinical improvement (gait improved in 79.3% of patients, sphincter control in 82.4%, and dementia in 63.7%). Two patients (0.8%) died. Early postsurgical complications were found in 13 of the 244 shunted patients (5.3%). Six months after shunting, the follow-up CT showed asymptomatic hygromas in 8 of the 236 (3.4%). Additional postsurgical complications were found in 7 patients (3%), consisting of 6 subdural hematomas (3 acute and 3 chronic) and 1 distal catheter infection. CONCLUSIONS Currently, a high percentage of patients with INPH can improve after shunting, with early and late complication rates of less than 12%.

Prognostic implications of epilepsy in glioblastomas.

OBJECTIVES The role of seizures and antiepileptic treatments associated with glioblastoma is a current topic of discussion. The objective of this study is to characterize and establish implications of epilepsy associated with glioblastoma. PATIENTS AND METHODS We retrospectively analyzed the medical history, focused on epileptic features of 134 histologically diagnosed glioblastoma over a period of 4 years. RESULTS The sample group had an average age of 56 years and 66% were male. Complete tumor resection was performed in 66% and 64.2% received further radio-oncologic treatment. The average survival rate was 12.4 months and 11.5% survived to 5 years. Epileptic seizures were the presentation symptom in 27% of cases and 51% suffered seizures during the disease, 26% become drug-resistant. Focal evolving to a bilateral convulsive seizures were the most frequent type. Epileptic seizures at presentation independently predicted longer survival (p<0.001). Furthermore, a history of epilepsy or seizures during disease improved survival. Late onset seizures, recurrences or status epilepticus during the course of the disease indicated tumor progression or the final stages of life. Prophylactic antiepileptic drugs did not prevent seizures. Similarly, there was no difference in survival between patients who did not use antiepileptic drugs and those using valproate or levetiracetam. Patients under 60 years, full oncologic treatment and secondary glioblastomas were factors that improved survival (p<0.001). CONCLUSION Previous history of epilepsy or the onset of seizures as a presentation symptom in glioblastomas predict longer survival. Half of patients have seizures during the course of the disease. Antiepileptic drugs alone do not increase survival in glioblastoma patients.

Pupilometría por infrarrojos. Descripción y fundamentos de la técnica y su aplicación en la monitorización no invasiva del paciente neurocrítico

INTRODUCTION Pupil assessment is a fundamental part of the neurological examination. Size and reactivity to light of each pupil should be recorded periodically since changes in these parameters may represent the only detectable sign of neurological deterioration in some patients. However, there is great intraobserver and interobserver variability in pupil examination due to the influence of many factors, such as the difference in ambient lighting, the visual acuity and experience of the examiner, the intensity of the luminous stimulus, and the method used to direct this stimulus. In recent years, digital cameras have incorporated infrared devices allowing the development of user-friendly portable devices that permit repeated, non-invasive examinations of pupil size and its reactivity to light with an objective, accessible and inexpensive method. DEVELOPMENT The purpose of this review is to describe the fundamentals of infrared pupillometry and discuss potential applications in the monitoring of neurocritical patients. We also present some recommendations in the routine assessment of pupils in neurocritical patients. CONCLUSIONS The possibility of evaluating the changes in pupil reactivity in an early, objective and almost continuous way provides a new non-invasive monitoring method. This method could improve the predictive factor of neurological deterioration and the bedside monitoring of the neurological state of the patient, avoiding unnecessary examinations and enabling early therapeutic intervention.

Craniectomía descompresiva primaria en la hemorragia subaracnoidea aneurismática. Resultados de un estudio piloto en 11 casos

Resumen Introduccion A pesar de los avances cientificos y tecnicos de los ultimos anos, la hemorragia subaracnoidea aneurismatica (HSAa) sigue presentando una alta morbilidad y mortalidad. Este hecho, junto con los impresionantes resultados de la craneotomia descompresiva primaria (CDP) en el infarto maligno de la arteria cerebral media sugiere la posibilidad que la CDP sea una alternativa terapeutica a considerar en algunos pacientes con una HSAa. Presentamos nuestra experiencia de un estudio piloto en el que se utilizo la CDP en pacientes con HSAa en mal grado neurologico y hematoma intracerebral asociado. Pacientes y metodos Entre el 1 de marzo de 2002 y el 31 de abril de 2008, se trataron 342 pacientes con HSAa en nuestro hospital. De estos, 64 tenian una puntuacion de 4 o 5 de la escala de la WFNS (World Federation of Neurosurgical Societies). En el presente estudio prospectivo se analizan 11 pacientes en los que se realizo una CDP durante la misma cirugia de clipaje o/y evacuacion del hematoma asociado. Resultados En tres pacientes la CDP se realizo despues del tratamiento endovascular del aneurisma debido a la necesidad de evacuar el hematoma asociado. En los ocho pacientes restantes, la CDP se realizo durante el clipaje y la evacuacion del hematoma asociado. La evaluacion de los resultados de estos once pacientes se llevo a cabo al ano de la cirugia mediante la escala de resultados de Glasgow. La CDP fue eficaz en el control de presion intracraneal en los pacientes que sobrevivieron. Seis pacientes sobrevivieron, cuatro de ellos con un buen resultado neurologico. Sin embargo, dos de estos seis pacientes tuvieron un resultado desfavorable. De los cinco pacientes que no sobrevivieron, un paciente murio a causa de un hematoma subgalealepidural diferido como complicacion de la CDP, y los restantes cuatro pacientes fallecieron a causa de una hipertension intracraneal refractaria. Conclusiones La CDP puede ser una alternativa terapeutica en un grupo seleccionado de pacientes con HSAa con mal grado neurologico. Sin embargo, en la actualidad hay una falta de evidencia para apoyar unas recomendaciones claras para su uso.

peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas

Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities. Brain tumors show considerable phenotypic and genetic heterogeneity. In a series comprising diffuse infiltrating astrocytomas (DIA) and reactive gliosis, we investigated the main factors associated with signaling pathways. We assessed expression levels and their association with tumor progression and survival. We studied 19 grade II astrocytomas, 25 anaplastic astrocytomas (grade III), 60 glioblastomas (grade IV), and 15 cases of reactive gliosis. Epidermal growth factor receptor (EGFR), pMAPK, 4E‐BP1, p4E‐BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi‐square, Students t, Pearson correlation, Spearmans rho, and Mann–Whitney; ROC and Kaplan–Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E‐BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E‐BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples.

Combined pleomorphic xanthoastrocytoma-ganglioglioma with BRAF V600E mutation: case report

Combined pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) is an extremely rare tumor, with fewer than 20 cases reported. The authors report a case of combined PXA-GG in an 18-year-old man with a history of seizures. The tumor showed necrosis and the BRAF V600E mutation on histological examination, with no evidence of tumor recurrence 1 year after gross-total resection. The BRAF V600E mutation was present, which suggests that both cell lineages may share a common cellular origin.