Publications by authors named "Elena Martínez-Sáez"

44 Publications

MR imaging findings in primary spinal cord glioblastoma.

Radiol Case Rep 2021 Jan 2;16(1):72-77. Epub 2020 Nov 2.

Section of Neuroradiology, Department of Radiology, Vall d'Hebron University Hospital, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, 119-129 | 08035, Barcelona, Spain.

Spinal cord glioblastoma is a rare disease, with an aggressive course and a poor prognosis. We describe magnetic resonance imaging (MRI) findings, in 3 adult cases of biopsy-confirmed glioblastoma. Conventional MRI findings were unclear with regard to the differential diagnosis between this rare tumor and other more common spinal cord lesions, including less aggressive tumors such as ependymoma or pilocytic astrocytoma, abscesses or tumefactive demyelinating lesions. After reasonable exclusion of infectious/inflammatory conditions, a final diagnosis of glioblastoma was established based on histopathological analysis. The cases reported reflect the difficulty of early radiological diagnosis of spinal cord glioblastoma, and indicate the need to perform a biopsy once inflammatory-infectious conditions are excluded with appropriate laboratory tests.
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http://dx.doi.org/10.1016/j.radcr.2020.10.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642760PMC
January 2021

Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis.

Cell Stem Cell 2020 Dec 3;27(6):920-936.e8. Epub 2020 Nov 3.

Developmental Biology Department, Instituto de Biología Molecular de Barcelona (IBMB-CSIC), Parc Científic de Barcelona, C/Baldiri i Reixac 20, Barcelona 08028, Spain. Electronic address:

Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. Although the enzymatic activity of ZikV-NS5 appears to be dispensable, the amino acids Y25, K28, and K29 that are involved in NS5 oligomerization are essential for localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation for therapies that target ZikV-NS5 multimerization and prevent the developmental malformations associated with congenital Zika syndrome.
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http://dx.doi.org/10.1016/j.stem.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718408PMC
December 2020

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma.

Nat Commun 2020 10 27;11(1):5376. Epub 2020 Oct 27.

Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain.

The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.
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http://dx.doi.org/10.1038/s41467-020-19175-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591522PMC
October 2020

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models.

Cancers (Basel) 2020 Jul 16;12(7). Epub 2020 Jul 16.

Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.
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http://dx.doi.org/10.3390/cancers12071922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409080PMC
July 2020

CCL23: A Chemokine Associated with Progression from Mild Cognitive Impairment to Alzheimer's Disease.

J Alzheimers Dis 2020 ;73(4):1585-1595

Neurovascular Research Laboratory. Vall d'Hebron Institut de Recerca (VHIR) - Universitat Autònoma de Barcelona, Barcelona, Spain.

CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer's disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n = 53; study 2, n = 200) and two longitudinal (study 3, n = 74; study 4, n = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2-5.3), p = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02-5), p = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOEɛ4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33-597.76) versus 377.94 pg/mL (IQR: 267.16-529.19), p = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression.
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http://dx.doi.org/10.3233/JAD-190753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010612PMC
January 2020

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

Surg Neurol Int 2019 10;10:83. Epub 2019 May 10.

Department of Neurosurgery, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

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.
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http://dx.doi.org/10.25259/SNI-96-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744754PMC
May 2019

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.

Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.

Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.

Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).

Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

Parvovirus B19 Myocarditis: Looking Beyond the Heart.

Pediatr Dev Pathol 2020 Mar-Apr;23(2):158-162. Epub 2019 Jul 23.

Pediatric Critical Care Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Human parvovirus B19 represents the most common etiology of myocarditis in the pediatric population. Although it usually causes a benign exanthematic viral infection, parvovirus B19 may also present as disseminated disease with tropism for the myocardium, causing heart failure with high mortality. We present the case of a 2-year-old patient with fulminating acute myocarditis in whom the histological, immunophenotypic, and microbiological findings in necropsy showed multiorgan involvement caused by parvovirus B19. The autopsy revealed changes due to infection with parvovirus B19 as well as hypoxic-ischemic and secondary autoimmune changes. Medullary aplasia was observed, transmural lymphocyte myocarditis, lymphocytosis in the dermis with endothelial cells positive for parvovirus B19 in immunohistochemistry, cholestatic hepatitis due to ischemia and autoimmune hepatitis, lymphadenitis, and signs of hemophagocytosis. We also found hypoxic-ischemic encephalopathy.
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http://dx.doi.org/10.1177/1093526619865641DOI Listing
January 2021

The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer.

Cell Rep 2019 05;27(9):2690-2708.e10

Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK; Breast Cancer Programme, Cancer Research UK Cambridge Cancer Centre, Cambridge CB2 2QQ, UK. Electronic address:

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.04.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546974PMC
May 2019

Brain ApoA-I, ApoJ and ApoE Immunodetection in Cerebral Amyloid Angiopathy.

Front Neurol 2019 13;10:187. Epub 2019 Mar 13.

Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.

Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aβ) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aβ fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aβ deposits or without Aβ deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aβ accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aβ diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aβ pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aβ deposition within the brain.
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http://dx.doi.org/10.3389/fneur.2019.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424885PMC
March 2019

Integrating clinical, molecular, proteomic and histopathological data within the tissue context: tissunomics.

Histopathology 2019 Jul 14;75(1):4-19. Epub 2019 May 14.

Translational Molecular Pathology, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue-dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with BRAF mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data.
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http://dx.doi.org/10.1111/his.13828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851567PMC
July 2019

Expression of Bone Morphogenetic Proteins in Multiple Sclerosis Lesions.

Am J Pathol 2019 03 13;189(3):665-676. Epub 2018 Dec 13.

Neurology-Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain. Electronic address:

Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-β superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. Because BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, BMP-4, BMP-5, and BMP-7; BMP type II receptor (BMPRII); and phosphorylated SMAD (pSMAD) 1/5/8 in lesions of MS and other demyelinating diseases. A total of 42 MS lesions, 12 acute ischemic lesions, 8 progressive multifocal leukoencephalopathy lesions, and 10 central nervous system areas from four nonneuropathological patients were included. Lesions were histologically classified according to the inflammatory activity. The expression of BMP-2, BMP-4, BMP-5, BMP-7, BMPRII, and pSMAD1/5/8 was quantified by immunostaining, and colocalization studies were performed. In MS lesions, astrocytes, microglia/macrophages, and neurons expressed BMP-2, BMP-4, BMP-5, and BMP-7; BMPRII; and pSMAD1/5/8. Oligodendrocytes expressed BMP-2 and BMP-7 and pSMAD1/5/8. The percentage of cells that expressed BMPs, BMPRII, and pSMAD1/5/8 correlated with the inflammatory activity of MS lesions, and changes in the percentage of positive cells were more relevant in MS than in other white matter-damaging diseases. These data indicate that BMPs are increased in active MS lesions, suggesting a possible role in MS pathogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2018.11.007DOI Listing
March 2019

Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders.

EMBO J 2019 01 7;38(2). Epub 2018 Dec 7.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann-Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build-up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann-Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.
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http://dx.doi.org/10.15252/embj.201899553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331723PMC
January 2019

Author Correction: STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

Nat Med 2018 Sep;24(9):1481

Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

In the version of this article originally published, the names of three authors were incorrect. The authors were listed as "Coral Fustero-Torres", "Elena Pineiro" and "Melchor Sánchez-Martínez". Their respective names are "Coral Fustero-Torre", "Elena Piñeiro-Yáñez" and "Melchor Sanchez-Martinez". The errors have been corrected in the print, HTML and PDF versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0108-5DOI Listing
September 2018

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

Nat Med 2018 07 11;24(7):1024-1035. Epub 2018 Jun 11.

Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.
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http://dx.doi.org/10.1038/s41591-018-0044-4DOI Listing
July 2018

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

J Neurotrauma 2019 Jan 24;36(1):165-175. Epub 2018 Jul 24.

Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.

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 upregulation sulfonylurea receptor (SUR) 1, the regulatory subunit of adenosine triphosphate (ATP)-sensitive potassium (K) channels and other channels, in human BCs. Our aim here was to study the expression of the pore-forming subunit of K, 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.
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http://dx.doi.org/10.1089/neu.2017.5619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872003PMC
January 2019

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

Clin Cancer Res 2018 06 3;24(12):2812-2819. Epub 2018 Apr 3.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

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. We performed an analysis of , ATRX, , and 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. Analysis of the mutational status of the , and 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. The genomic analysis of , and 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. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3800DOI Listing
June 2018

Pasireotide in acromegaly by aggressive tumors, description of four clinical cases. Towards a personalized medicine.

Endocrinol Diabetes Nutr 2018 02 20;65(2):130-132. Epub 2018 Jan 20.

Servicio de Endocrinología y Nutrición, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, España.

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http://dx.doi.org/10.1016/j.endinu.2017.12.001DOI Listing
February 2018

Non traumatic giant aneurysm of middle meningeal artery. Case report and review of the literature.

Neurocirugia (Astur) 2018 Sep - Oct;29(5):250-254. Epub 2017 Dec 29.

Servicio de Neurocirugía, Hospital Vall d'Hebron, Barcelona, España.

A case of a non-traumatic giant aneurysm of the middle meningeal artery is presented in a 59-year-old patient with a history of liver transplantation, liver cirrhosis and hepatocarcinoma, chronic renal disease, hypertension and chronic bronchitis who presented with tonic-clonic seizures. CT and MRI showed a lesion suggestive of metastasis without ruling out a glial type tumor. He was operated through a left FT craniotomy. During the surgery there was an arterial hemorrhage. The histological sample oriented toward an aneurysmal origin that was confirmed with ARM and angiography. A second intervention allowed the removal of a giant middle meningeal aneurysm partially thrombosed. Aneurysms of the middle meningeal artery are rare and generally present a traumatic history. No case of giant aneurysm has been found in the medical literature.
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http://dx.doi.org/10.1016/j.neucir.2017.11.003DOI Listing
October 2019

Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia.

Mol Cell Proteomics 2018 01 13;17(1):175-189. Epub 2017 Nov 13.

From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain;

Cerebral ischemia entails rapid tissue damage in the affected brain area causing devastating neurological dysfunction. How each component of the neurovascular unit contributes or responds to the ischemic insult in the context of the human brain has not been solved yet. Thus, the analysis of the proteome is a straightforward approach to unraveling these cell proteotypes. In this study, post-mortem brain slices from ischemic stroke patients were obtained corresponding to infarcted (IC) and contralateral (CL) areas. By means of laser microdissection, neurons and blood brain barrier structures (BBB) were isolated and analyzed using label-free quantification. MS data are available via ProteomeXchange with identifier PXD003519. Ninety proteins were identified only in neurons, 260 proteins only in the BBB and 261 proteins in both cell types. Bioinformatics analyses revealed that repair processes, mainly related to synaptic plasticity, are outlined in microdissected neurons, with nonexclusive important functions found in the BBB. A total of 30 proteins showing < 0.05 and fold-change> 2 between IC and CL areas were considered meaningful in this study: 13 in neurons, 14 in the BBB and 3 in both cell types. Twelve of these proteins were selected as candidates and analyzed by immunohistofluorescence in independent brains. The MS findings were completely verified for neuronal SAHH2 and SRSF1 whereas the presence in both cell types of GABT and EAA2 was only validated in neurons. In addition, SAHH2 showed its potential as a prognostic biomarker of neurological improvement when analyzed early in the plasma of ischemic stroke patients. Therefore, the quantitative proteomes of neurons and the BBB (or proteotypes) after human brain ischemia presented here contribute to increasing the knowledge regarding the molecular mechanisms of ischemic stroke pathology and highlight new proteins that might represent putative biomarkers of brain ischemia or therapeutic targets.
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http://dx.doi.org/10.1074/mcp.RA117.000419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750846PMC
January 2018

Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature.

Eur J Med Genet 2017 Oct 12;60(10):517-520. Epub 2017 Jul 12.

Paediatric Neurology Research Group, Vall d'Hebron University Hospital, Passeig Vall d'Hebrón 119-129, 08035 Barcelona, Spain; Autonomous University of Barcelona, Barcelona, Spain.

Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.
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http://dx.doi.org/10.1016/j.ejmg.2017.07.007DOI Listing
October 2017

Target location after deep cerebral biopsies using low-volume air injection in 75 patients. Results and technical note.

Acta Neurochir (Wien) 2017 10 4;159(10):1939-1946. Epub 2017 May 4.

Department of Neurosurgery and Neurotraumatology and Neurosurgery Research Unit, Vall d'Hebron University Hospital, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.

Background: Stereotactic biopsy is a minimally invasive technique that allows brain tissue samples to be obtained with low risk. Classically, different techniques have been used to identify the biopsy site after surgery.

Objective: To describe a technique to identify the precise location of the target in the postoperative CT scan using the injection of a low volume of air into the biopsy cannula.

Methods: Seventy-five biopsies were performed in 65 adults and 10 children (40 males and 35 females, median age 51 years). Frame-based biopsy was performed in 46 patients, while frameless biopsy was performed in the remaining 29 patients. In both systems, after brain specimens had been collected and with the biopsy needle tip in the center of the target, a small volume of air (median 0.7 cm) was injected into the site.

Results: A follow-up CT scan was performed in all patients. Intracranial air in the selected target was present in 69 patients (92%). No air was observed in two patients (air volume administered in these 2 cases was below 0.7 cm), while in the remaining four patients blood content was observed in the target. The diagnostic yield in this series was 97.3%. No complications were found to be associated with intracranial air injection in any of the 75 patients who underwent this procedure.

Conclusions: The air-injection maneuver proposed for use in stereotactic biopsies of intracranial mass lesions is a safe and reliable technique that allows the exact biopsy site to be located without any related complications.
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http://dx.doi.org/10.1007/s00701-017-3191-3DOI Listing
October 2017

Successful multiple organ donation after donor brain death due to Actinomyces israelii meningitis.

Transpl Infect Dis 2017 Aug 9;19(4). Epub 2017 Jun 9.

Donation and Transplantation Programs Department, Vall d'Hebron University Hospital, Barcelona, Spain.

The increasing gap between availability of solid organs for transplantation and the demand has led to the inclusion of donor organs that, according to current guidelines, may be discarded, some of them because of the possibility for transmission of infection to the recipients. We present the first report, to the best of our knowledge, of a case of a brain-dead donor with a localized and treated Actinomyces israelii central nervous system infection who, after a thorough evaluation, provided organs for successful transplant procedures in four recipients. There was no evidence of transmission of infection within a 6-month follow-up. Relative contraindications must be individualized in order to expand the number of real organ donors, emphasizing caution in rare causes for brain death in which patients should be thoroughly evaluated for possible donation.
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http://dx.doi.org/10.1111/tid.12711DOI Listing
August 2017

Epileptic features and survival in glioblastomas presenting with seizures.

Epilepsy Res 2017 02 26;130:1-6. Epub 2016 Dec 26.

Neuropathology Unit, Pathology Department, Vall d́Hebron University Hospital, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.

Introduction: The prognostic value of seizures in patients with glioblastoma is currently under discussion. The objective of this research was to study the risk factors associated with seizures occurring at the diagnosis of glioblastoma and the role of seizures as a predictive factor for survival.

Material And Methods: We prospectively analyzed the clinical data over the course of the disease, baseline MR imaging, and histological characteristics (p53 overexpression, the Ki67 proliferation index, and presence of the IDH1 R132H mutation), in glioblastomas treated in a single hospital from November 2012 to July 2014. The study follow-up cutoff point was October 2015.

Results: In total, 56 patients were recruited (57% men, mean age 57 years). Median baseline score on the Karnofsky performance scale was 80. Complete tumor debulking followed by radiochemotherapy was achieved in 58.9%. Mean survival was 13.6 months. Epileptic seizures were the presenting symptom in 26.6% of patients, and 44.6% experienced seizures at some point during the course of the disease. On multivariate analysis, the single factor predicting shorter survival was age older than 60 years (hazard ratio 3.565 (95%CI, 1.491-8.522), p=0.004). Seizures were associated with longer survival only in patients younger than 60 years (p=0.035). Younger age, the IDH1 R132H mutation, and p53 overexpression (>40%) were related to seizures at presentation. Baseline MRI findings, including tumor size, and the Ki67 proliferation index were not associated with the risk of epileptic seizures or with survival. Prophylactic antiepileptic drugs did not increase survival time.

Conclusions: Seizures as the presenting symptom of glioblastoma predicted longer survival in adults younger than 60 years. The IDH1 R132H mutation and p53 overexpression (>40%) were associated with seizures at presentation. Seizures showed no relationship with the tumor size or proliferation parameters.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.12.013DOI Listing
February 2017

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

Cancer Med 2016 09 20;5(9):2501-12. Epub 2016 Jul 20.

Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.

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, Student's t, Pearson correlation, Spearman's 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.
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http://dx.doi.org/10.1002/cam4.817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055163PMC
September 2016

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

J Neurosurg Pediatr 2016 Jul 25;18(1):53-7. Epub 2016 Mar 25.

Department of Neurosurgery, Neurotraumatology, and Neurosurgery Research Unit; and.

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.
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http://dx.doi.org/10.3171/2016.1.PEDS15558DOI Listing
July 2016

Role of [(11)C] methionine positron emission tomography in the diagnosis and prediction of survival in brain tumours.

Clin Neurol Neurosurg 2015 Dec 4;139:328-33. Epub 2015 Nov 4.

Department of Neurosurgery, Universitat Autònoma de Barcelona, Hospital Vall d'Hebron, Barcelona, Spain.

Objective: [(11)C] methionine (MET) positron-emission tomography (PET) is a useful diagnostic and therapeutic tool in neuro-oncology. The aim of this study was to evaluate the relationship between MET uptake and the histopathological grade in both primary brain tumours and brain metastases. A secondary goal was to assess the relationship between MET uptake and patients' survival after surgery.

Methods: We reviewed a consecutive series of 43 PET studies performed at our institution. Out of the 43 patients studied, 35 harboured primary brain tumours (3 grade I, 12 grade II, 7 grade III and 13 grade IV) and 8 patients had brain metastases. We measured the tumour/cortex ratio (T/C ratio) on each PET study and we investigated the correlations among the tracer uptake, tumour grade, tumour type, MRI parameters and outcome.

Results: The mean T/C ratio was 1.8 ± 0.9 for benign lesions and low grade gliomas (grade I and II) and 2.7 ± 1 for high grade gliomas (grade III and IV). In brain metastases it was 2.5 ± 0.7, with a significant difference in MET uptake between low and high grades gliomas (P=0.03). There was no statistically significant difference among all different histologic types. We found that both contrast enhancement and perfusion studies correlate with MET uptake in brain tumours. Moreover, in Kaplan-Meier curves, the T/C ratio adversely affects long term survival in patients with brain tumours (P=0.01).

Conclusions: MET PET appears to be useful in diagnosis and evaluation of potential malignancy in brain tumours. MET uptake is also related with the overall survival in patients with brain tumours. Nevertheless, further studies are needed in order to define its possible clinical implications in identifying patients at high risk of tumour progression or resistance to therapy.
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http://dx.doi.org/10.1016/j.clineuro.2015.10.035DOI Listing
December 2015

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

Nat Commun 2015 11 10;6:8839. Epub 2015 Nov 10.

Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain.

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.
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http://dx.doi.org/10.1038/ncomms9839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426516PMC
November 2015

Prognostic implications of epilepsy in glioblastomas.

Clin Neurol Neurosurg 2015 Dec 22;139:166-71. Epub 2015 Oct 22.

Neuropathology Unit, Pathology Department, Vall d́Hebron University Hospital, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

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.
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http://dx.doi.org/10.1016/j.clineuro.2015.10.002DOI Listing
December 2015