29 results on '"Diana Cantero"'
Search Results
2. Supplementary Figure 5 from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Analysis of differentiation genes after long term dacomitinib treatment.
- Published
- 2023
3. Supplementary Figure 4 from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Analysis of stemmness genes after long term dacomitinib treatment.
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- 2023
4. Supplementary Figure 1 from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
- Author
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Effect of dacomitinib in the in vivo growth of GBMs.
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- 2023
5. Supplementary Figure 2 from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Analysis of EGFR signaling after long term dacomitinib treatment.
- Published
- 2023
6. Supplementary Figure 3 from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
- Author
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Analysis of stemmness genes after 5 days of dacomitinib treatment.
- Published
- 2023
7. Supplementary Methods from Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
- Author
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Juan Manuel Sepúlveda, Pilar Sánchez-Gómez, Aurelio Hernández-Laín, Angel Perez-Nuñez, Diana Cantero, Maria Victoria Bolós, Marta Pajares, Carmen Ramírez-Castillejo, Pilar Aguilera, and Cristina Zahonero
- Abstract
Detailed description of methods used in this study.
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- 2023
8. Myosin myopathy with external ophthalmoplegia associated with a novel homozygous mutation in MYH2
- Author
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Hernández‐Laín, Aurelio, Esteban‐Pérez, Jesús, Montenegro, Diana Cantero, and Domínguez‐González, Cristina
- Published
- 2017
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9. Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab
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R A Manneh Kopp, A Pérez Núñez, Juan M. Sepúlveda-Sánchez, Diana Cantero, Ana Ramos, Amaya Hilario, G. de Velasco, Pilar Sánchez-Gómez, Ó. Toldos, Yolanda Ruano, and Aurelio Hernández-Laín
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Medicine ,DNA Modification Methylases ,Midkine ,biology ,Brain Neoplasms ,Microvascular Density ,General Medicine ,Middle Aged ,Immunohistochemistry ,Bevacizumab ,Vascular endothelial growth factor A ,Cerebrovascular Circulation ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Methylation ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,Mitotic Index ,Humans ,Progression-free survival ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,Tumor Suppressor Proteins ,CD44 ,Gene Amplification ,Genes, erbB-1 ,DNA Repair Enzymes ,Ki-67 Antigen ,030104 developmental biology ,Tissue Array Analysis ,Microvessels ,biology.protein ,Neoplasm Recurrence, Local ,Glioblastoma ,business - Abstract
Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.
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- 2019
10. Autosomal dominant distal myopathy with nemaline rods due to p.Glu197Asp mutation in ACTA1
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Ignacio Pascual, Oscar Toldos, Diana Cantero, Cristina Domínguez-González, Aurelio Hernández-Laín, Ana Camacho-Salas, and Isabel Esteban
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Adult ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,genetic structures ,Biopsy ,Biology ,Myopathies, Nemaline ,03 medical and health sciences ,0302 clinical medicine ,Nemaline rods ,In vivo ,medicine ,Humans ,In vitro study ,Muscle, Skeletal ,Clinical phenotype ,Myopathy ,Genetics (clinical) ,Muscle biopsy ,medicine.diagnostic_test ,Phenotype ,Actins ,Distal Myopathies ,030104 developmental biology ,Neurology ,Mutation ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Female ,sense organs ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
In a previous report of a new phenotype with predominant scapulo-humeral-peroneal-distal myopathy associated with the Glu197Asp mutation in ACTA1, muscle biopsies did not show nemaline rods, nor could nemaline rods formation be demonstrated in an exhaustive functional in vivo or in vitro study. However, muscle biopsy in members of our family, carrying a similar clinical phenotype of some members of the original family and the same ACTA1 mutation, revealed the presence of numerous nemaline rods, suggesting that there must be other factors that explain the absence of nemaline rods.
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- 2019
11. Bethlem myopathy: a series of 16 patients and description of seven new associated mutations
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Claudia Rodríguez-López, Diana Cantero Montenegro, Ana Fernández-Marmiesse, Cristina Domínguez-González, Luísa Panadés-de Oliveira, Jesús Esteban Pérez, María Del Mar Marcos Toledano, and Aurelio Hernández Lain
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Adult ,Male ,Weakness ,Pathology ,medicine.medical_specialty ,Contracture ,Collagen Type VI ,Compound heterozygosity ,Muscular Dystrophies ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,Muscle, Skeletal ,Myopathy ,Creatine Kinase ,Genetic Association Studies ,Aged ,Genes, Dominant ,Retrospective Studies ,Muscle contracture ,Genetic testing ,Sanger sequencing ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Bethlem myopathy ,Middle Aged ,medicine.disease ,Phenotype ,Neurology ,Mutation ,symbols ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations. A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing. The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation. Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.
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- 2019
12. Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature
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Teresa Cejalvo, Ricardo Gargini, Berta Segura-Collar, Pablo Mata-Martínez, Beatriz Herranz, Diana Cantero, Daniel García-Pérez, Ángel Pérez-Núñez, Ana Ramos, Yolanda Ruano, Aurelio Hernández-Laín, Mari Cruz Martín-Soberón, Pilar Sánchez-Gómez, and Sepúlveda Sánchez Juan Manuel
- Abstract
Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors. Methods: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocytrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models.Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas and we distinguished two different profiles in their IDH1/2 wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth. Conclusions: Our results confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. Moreover, we have found that the immunological content distinguishes two groups of IDH1/2 wild-type gliomas, one highly enriched in immunosuppressive cells and one with few lymphocytes and myeloid cells. Our data indicated a direct correlation between the presence of vascular alterations and the entrance of leukocytes in gliomas. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.
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- 2020
13. Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature
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Diana Cantero, Pilar Sánchez-Gómez, Yolanda Ruano, Teresa Cejalvo, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Laín, Ricardo Gargini, Berta Segura-Collar, Ana Ramos, Beatriz Herranz, María Cruz Martín-Soberón, Angel Perez-Nuñez, Pablo Mata-Martínez, and Daniel García-Pérez
- Subjects
Immune system ,IDH1 ,medicine.diagnostic_test ,Angiogenesis ,Glioma ,Mutant ,medicine ,Cancer research ,Biology ,medicine.disease ,Phenotype ,Function (biology) ,Flow cytometry - Abstract
BackgroundGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors.MethodsWe designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or withoutisocytrate dehydrogenase 1/2(IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models.ResultsWe observed that few immune cells infiltrate mutantIDH1/2gliomas and we distinguished two different profiles in theirIDH1/2wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutantIDH1/2gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth.ConclusionsThere is a correlation between vascular alterations and the immune profile of gliomas, which could be exploited for the design of more successful clinical trials with immunomodulatory molecules.Key pointsMutantIDH1/2gliomas harbor few immune cells in the tumor microenviroment.We distinguished two different profiles in theIDH1/2wild-type gliomas.There is a correlation between Tau expression, vascular alterations and the immune profile.Importance of the StudyIn the present work we have confirmed that IDHmut gliomas are “cold” tumors and we have identified a subgroup of IDHwt GBMs that also contains a low immune infiltrate. By contrast, a large subgroup of IDHwt GBMs are characterized by an important immune component, particularly enriched in myeloid cells, and an elevated expression of the ligand of PD-L1 in the immune compartment. Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau, a microtubule-binding protein that we described as a negative regulator of angiogenesis. Here, we add that overexpression of Tau reduces the immune content in orthotopic glioma models, delaying tumor growth.This correlation between the vascular phenotype and the entrance and/or the function of the immune cells on gliomas, where Tau could play a central role, opens new venues to find synergistic treatments.
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- 2020
14. TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors
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Nicky D'Haene, Aurelio Hernández-Laín, Diana Cantero, Myriam J Gutiérrez-Guamán, Concepción Fiaño, Juan A. Rey, Javier S. Castresana, Laetitia Lebrun, Isabelle Salmon, Bárbara Meléndez, Manuela Mollejo, Ángel Rodríguez de Lope, and Juan Manuel Sepúlveda
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0301 basic medicine ,IDH1 ,Gene mutation ,Biology ,medicine.disease ,IDH2 ,tumor mutation load ,Giant-cell glioblastoma ,03 medical and health sciences ,ATRX ,030104 developmental biology ,0302 clinical medicine ,MSH2 ,Giant cell ,CDKN2A ,Basic and Translational Investigations ,Cancer research ,medicine ,giant cell glioblastoma ,next-generation sequencing ,TP53 ,neoplasms ,030217 neurology & neurosurgery - Abstract
Background Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than “classic” IDHwt GBM. Methods We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. Results p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1, IDH2, BRAF, or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53, ATRX, RB1, and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53-mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53-mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, P Conclusions gcGBMs have molecular features that contrast to “classic” IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine.
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- 2020
15. Persistent asymptomatic or mild symptomatic hyperCKemia due to mutations in ANO5: the mildest end of the anoctaminopathies spectrum
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Luísa Panadés-de Oliveira, Laura Bermejo-Guerrero, Aurelio Hernández Lain, Nuria Muelas, Juan J. Vílchez, Diana Cantero Montenegro, Cristina Domínguez-González, Carlos Pablo de Fuenmayor-Fernández de la Hoz, and P Martí
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Weakness ,medicine.medical_specialty ,Neurology ,Exercise intolerance ,Calf hypertrophy ,Anoctamins ,Asymptomatic ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Chloride Channels ,Internal medicine ,medicine ,Myocyte ,Humans ,030212 general & internal medicine ,Muscle, Skeletal ,Neuroradiology ,Retrospective Studies ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,ANO5 gene ,Magnetic resonance imaging ,Asymptomatic hyperCKemia ,Middle Aged ,STIR sequences ,Mutation ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Inflammatory biopsy - Abstract
Background The ANO5 gene encodes for anoctamin-5, a chloride channel involved in muscle cell membrane repair. Recessive mutations in ANO5 are associated with muscular diseases termed anoctaminopathies, which are characterized by proximal or distal weakness, or isolated hyperCKemia. We present the largest series of patients with asymptomatic/paucisymptomatic anoctaminopathy reported so far, highlighting their clinical and radiological characteristics. Methods Twenty subjects were recruited retrospectively from the Neuromuscular Disorders Units database of two national reference centers. All had a confirmed genetic diagnosis (mean age of diagnosis was 48 years) established between 2015 and 2019. Clinical and complementary data were evaluated through clinical records. Results None of the patients complained about weakness or showed abnormal muscular balance. Among paucisymptomatic patients, the main complaints or findings were generalized myalgia, exercise intolerance and calf hypertrophy, occasionally associated with calf pain. All patients showed persistent hyperCKemia, ranging from mild-moderate to severe. Muscle biopsy revealed inflammatory changes in three cases. Muscle magnetic resonance imaging revealed typical signs (preferential involvement of adductor and gastrocnemius muscles) in all but one patient. In two cases, abnormal findings were detectable only in STIR sequences (not in T1). Three patients showed radiological progression despite remaining asymptomatic. Twelve different mutations in ANO5 were detected, of which seven are novel. Conclusions Recessive mutations in ANO5 are a frequent cause of undiagnosed asymptomatic/paucisymptomatic hyperCKemia. Patients with an apparent indolent phenotype may show muscle involvement in complementary tests (muscle biopsy and imaging), which may progress over time. Awareness of anoctaminopathy as the cause of nonspecific muscular complaints or of isolated hyperCKemia is essential to correctly diagnose affected patients.
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- 2020
16. Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype
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Beatriz Herranz, Diana Cantero, Berta Segura-Collar, Daniel García-Pérez, Pablo Mata-Martínez, Ricardo Gargini, Angel Perez-Nuñez, Ana Ramos, Pilar Sánchez-Gómez, Juan M. Sepúlveda-Sánchez, María Cruz Martín-Soberón, Teresa Cejalvo, Yolanda Ruano, Aurelio Hernández-Laín, Ministerio de Economía y Competitividad (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Sociedad Española de Oncología Médica, and European Regional Development Fund (ERDF/FEDER)
- Subjects
0301 basic medicine ,Cancer Research ,IDH1 ,Mutant ,Biology ,lcsh:RC254-282 ,Article ,Immune profiling ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,tumor microenvironment ,Gliomas ,Tumor microenvironment ,medicine.diagnostic_test ,immune profiling ,IDH mutations ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phenotype ,gliomas ,030104 developmental biology ,Isocitrate dehydrogenase ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Tau ,Infiltration (medical) - Abstract
Simple Summary In the present work we have confirmed that gliomas with isocitrate dehydrogenase 1/2 mutations are “cold” tumors, whereas the immune content of their wild-type counterparts is more heterogeneous. A large subgroup of wild-type glioblastomas is characterized by an important immune component, particularly enriched in myeloid cells, and an elevated expression of the ligand of programmed death ligand 1 (PD-L1) in the immune compartment. The rest contain few lymphocytes and myeloid cells. Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau, a microtubule-binding protein that we described as a negative regulator of angiogenesis. Using syngeneic mouse models, we show that overexpression of Tau reduces the immune content, delaying tumor growth. Abstract Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. Methods: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. Conclusions: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.
- Published
- 2020
17. Phase II Trial of Palbociclib in Recurrent Retinoblastoma-Positive Anaplastic Oligodendroglioma: A Study from the Spanish Group for Research in Neuro-Oncology (GEINO)
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A. Sánchez, Elena Vicente, Vanessa Pachón, Juan M. Sepúlveda-Sánchez, Laura Oleaga, José Muñoz-Langa, Miguel Navarro Martín, Amaya Hilario, María Cruz Martín-Soberón, Miriam Alonso-García, Carlos Mesia Barroso, Gema Durán, Guillermo Velasco, Miguel Gil-Gil, Yolanda Ruano, Diana Cantero Montenegro, Robert Morales-Llombart, Aurelio Hernández-Laín, Estela Pineda, Manuel Benavides, María Ángeles Vaz Salgado, Ramon De Las Penas, Pilar Sánchez-Gómez, and Pfizer
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pyridines ,medicine.medical_treatment ,Population ,Oligodendroglioma ,Neutropenia ,Palbociclib ,Piperazines ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,Pharmacology (medical) ,education ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,education.field_of_study ,Chemotherapy ,business.industry ,Retinoblastoma ,Middle Aged ,medicine.disease ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business - Abstract
[Background]: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). [Objective]: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. [Patients and Methods]: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. [Results]: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6–3.1] and the median overall survival was 32.1 months (95% CI 5.1–59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. [Conclusion]: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO., Palbociclib was provided by Pfizer under a cooperative research agreement with the Spanish Group for Research in NeuroOncology (GEINO). Funding research was supported by Pfzer under the Investigator-Initiated Research Award, number WI174842.
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- 2020
18. Tumor cell vanishing with radiological changes suggesting progression in IDH-mutated diffuse astrocytoma treated only with surgery
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Diana Cantero, Aurelio Hernández-Laín, Angel Perez-Nuñez, Juan Manuel Sepúlveda, Ana Ramos, and Amaya Hilario
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Adult ,Reoperation ,medicine.medical_specialty ,medicine.medical_treatment ,Astrocytoma ,Fluid-attenuated inversion recovery ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Diffuse Astrocytoma ,Glioma ,medicine ,Humans ,030212 general & internal medicine ,Craniotomy ,Chemotherapy ,Brain Neoplasms ,business.industry ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Isocitrate Dehydrogenase ,Hyperintensity ,Surgery ,Radiation therapy ,Treatment Outcome ,Neurology ,030220 oncology & carcinogenesis ,Radiological weapon ,Mutation ,Disease Progression ,Female ,Neurology (clinical) ,Neoplasm Grading ,business - Abstract
The radiological diagnosis of glioma progression is still challenging. A 33-year-old woman diagnosed with a frontal tumor underwent awake craniotomy with total tumor resection. The diagnosis was IDH-mutated diffuse astrocytoma, WHO grade II. The patient did not receive additional radiotherapy or chemotherapy. Periodic MRI scans showed a T2/FLAIR nodular enlargement which appeared de novo and grew slowly and gradually until 4 years post surgery. The patient underwent a second craniotomy to completely resect the T2/FLAIR hyperintensity. In the histological and molecular study of the second resection, no tumor cells were identified. We could hypothesize that the reactive changes favored by surgery could explain the ongoing radiologic findings. .
- Published
- 2018
19. Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next-Generation Sequencing
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Nicky D'Haene, Isabelle Salmon, Juan F. García, Bárbara Meléndez, José M. Borrás, Ángel Rodríguez de Lope, Juan A. Rey, Raquel Moreno de la Presa, Juan Manuel Sepúlveda, Manuela Mollejo, Diana Cantero, Javier S. Castresana, and Aurelio Hernández-Laín
- Subjects
Adult ,Male ,IDH1 ,Brain tumor ,PDGFRA ,medicine.disease_cause ,IDH2 ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Death-associated protein 6 ,Cancer Survivors ,Humans ,Medicine ,Gene ,ATRX ,Aged ,Mutation ,Brain Neoplasms ,business.industry ,Sequence Analysis, DNA ,General Medicine ,Middle Aged ,medicine.disease ,Neurology ,030220 oncology & carcinogenesis ,Gene Targeting ,Cancer research ,Female ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery - Abstract
Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.
- Published
- 2018
20. Milder forms of α-sarcoglicanopathies diagnosed in adulthood by NGS analysis
- Author
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Diana Cantero, Juan Francisco Gonzalo Martínez, Cristina Domínguez-González, María Rabasa Pérez, Eduard Gallardo, Cinta Lleixà, Yolanda Ruano, and Aurelio Hernández-Laín
- Subjects
0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Compound heterozygosity ,Genetic analysis ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Sarcoglycans ,medicine ,Sarcoglycanopathies ,Humans ,Genetic Testing ,Muscle, Skeletal ,Gene ,Creatine Kinase ,SGCA ,Retrospective Studies ,business.industry ,Computational Biology ,Middle Aged ,Magnetic Resonance Imaging ,Sarcoglycan ,030104 developmental biology ,Neurology ,Mutation ,Immunohistochemistry ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Introduction: Sarcoglycanopathies (LGMD 2C 2F) are a subgroup of limb-girdle muscular dystrophies (LGMD), caused by mutations in sarcoglycan genes. They usually have a childhood onset and rapidly progressive course with loss of ability to walk over 12–16 years. Methods : Next generation sequencing (NGS) targeted gene panel was performed in three adult patients with progressive muscle weakness in which routine muscle histology and immunohistochemistry were not diagnostic. Results: Genetic analysis revealed homozygous or compound heterozygous mutations in SGCA gene and Western Blot demonstrated protein reduction confirming the diagnosis of α-sarcoglicanopathy. Discussion: Our cases evidence that the diagnosis of mild forms of alfa sarcoglicanopathy could be a challenge and suggest the possibility that they could be underdiagnosed. The use of Next generation Sequencing targeted gene panels is very helpful in the diagnosis of these patients.
- Published
- 2018
21. Late onset distal myopathy: A new telethoninopathy
- Author
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David Uriarte-Pérez de Urabayen, Cristina Domínguez-González, Diana Cantero-Montenegro, Montse Olivé, Víctor Antonio Blanco-Palmero, and Aurelio Hernández-Laín
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Late onset ,Diagnosis, Differential ,Distal Myopathies ,Neurology ,Pediatrics, Perinatology and Child Health ,Mutation ,medicine ,Humans ,Connectin ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Myopathy ,Muscle, Skeletal ,Genetics (clinical) ,Aged - Published
- 2018
22. Myosin myopathy with external ophthalmoplegia associated with a novel homozygous mutation inMYH2
- Author
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Cristina Domínguez-González, Diana Cantero Montenegro, Jesús Esteban-Pérez, and Aurelio Hernández-Laín
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Physiology ,External ophthalmoplegia ,Magnetic resonance imaging ,030105 genetics & heredity ,Biology ,medicine.disease ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cataracts ,Physiology (medical) ,Mutation (genetic algorithm) ,Myosin ,medicine ,Neurology (clinical) ,medicine.symptom ,Myopathy ,030217 neurology & neurosurgery - Published
- 2016
23. Phase II trial of palbociclib in recurrent RB-positive anaplastic oligodendroglioma: A Spanish group for research in neurooncology (GEINO) trial
- Author
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Gema Durán, Miguel Gil, Pilar Sánchez-Gómez, Juan M. Sepúlveda-Sánchez, Guillermo Velasco, Elena Vicente, Ramon De Las Penas, José Muñoz-Langa, Yolanda Ruano, Amaya Hilario, Laura Oleaga, A. Sánchez, María Ángeles Vaz Salgado, Diana Cantero, Aurelio Hernández-Laín, Estela Pineda, Carlos Mesia Barroso, L Miguel Navarro, Manuel Benavides, and Miriam Alonso
- Subjects
Cancer Research ,Cell cycle checkpoint ,Oncology ,business.industry ,CDKN2A ,Anaplastic oligodendroglioma ,Neurooncology ,Cancer research ,Medicine ,Palbociclib ,business ,RB Positive - Abstract
2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.
- Published
- 2019
24. Study of tumor infiltrating immune CELLS and vasculature in human gliomas: Differences in IDH1/2 mutant versus IDH1/2WT tumors
- Author
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Luis Jimenez Roldan, Diana Cantero, Berta Segura, Teresa Cejalvo, Guillermo Velasco, Juan Manuel Manuel Sepulveda Sanchez, Ricardo Gargini, Yolanda Ruano, Patricia Marín, Jacquelin Gutierrez, Angel Perez-Nuñez, Aurelio Hernández-Laín, Daniel Castellano, Maria Cruz Martin Soberón, and Pilar Sánchez-Gómez
- Subjects
Cancer Research ,IDH1 ,Immune system ,Oncology ,business.industry ,Mutant ,Wild type ,Cancer research ,Overall survival ,Medicine ,business - Abstract
2030 Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b+ cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206+) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1+ was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.
- Published
- 2019
25. Myosin myopathy with external ophthalmoplegia associated with a novel homozygous mutation in MYH2
- Author
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Aurelio, Hernández-Laín, Jesús, Esteban-Pérez, Diana Cantero, Montenegro, and Cristina, Domínguez-González
- Subjects
Male ,Myosin Type II ,Ophthalmoplegia ,Muscular Diseases ,Homozygote ,Mutation ,Humans ,Middle Aged ,Muscle, Skeletal ,Magnetic Resonance Imaging - Published
- 2016
26. Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma
- Author
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Maria Victoria Bolós, Juan Manuel Sepúlveda, Carmen Ramírez-Castillejo, Cristina Zahonero, Angel Perez-Nuñez, Marta Pajares, Diana Cantero, Aurelio Hernández-Laín, Pilar Sánchez-Gómez, Pilar Aguilera, Fundación Mutua-madrileña, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), and Fondo de Investigaciones Sanitarias
- Subjects
Cancer Research ,Time Factors ,Cell Survival ,Blotting, Western ,Mice, Nude ,Pharmacology ,chemistry.chemical_compound ,In vivo ,Tumor Cells, Cultured ,PTEN ,Animals ,Humans ,Viability assay ,Phosphorylation ,Receptor ,EGFR inhibitors ,Quinazolinones ,biology ,Dose-Response Relationship, Drug ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Amplification ,Xenograft Model Antitumor Assays ,Survival Analysis ,Dacomitinib ,Tumor Burden ,ErbB Receptors ,Oncology ,chemistry ,Cell culture ,biology.protein ,Cancer research ,Systemic administration ,Drug Screening Assays, Antitumor ,Glioblastoma ,Signal Transduction - Abstract
Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified ± EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. This work was supported by grants from the Fundación Mutua-madrileña (FMM2011/89) to J.M. Sepúlveda and from Ministerio de Economía y Competitividad, Fondo de Investigación Sanitaria (FIS): PI12/00775 to P. Sánchez-Gómez and PI13/01258 to A. Hernández-Laín, and from Ministerio de Economía y Competitividad, Red Temática de Investigación Cooperativa en Cancer (RTICC) (RD12/0036/0027) to J.M. Sepúlveda, P. Sánchez-Gómez, A. Pérez-Núñez and A. Hernández-Laín. Sí
- Published
- 2015
27. Temozolomide induces radiologic pseudoprogression and tumor cell vanishing in oligodendroglioma
- Author
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Angel Perez-Nuñez, Aurelio Hernández-Laín, Amaya Hilario, Diana Cantero, Ana Ramos, and Juan Manuel Sepúlveda
- Subjects
Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Dacarbazine ,Oligodendroglioma ,education ,Tumor cells ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Temozolomide ,Humans ,Medicine ,Antineoplastic Agents, Alkylating ,Pseudoprogression ,Chemotherapy ,Brain Neoplasms ,business.industry ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,Radiation therapy ,Diffusion Magnetic Resonance Imaging ,Isocitrate dehydrogenase ,Disease Progression ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Diagnosis of radiologic pseudoprogression remains a challenge because its radiologic pattern is often indistinguishable from tumor recurrence.1 Pseudoprogression has been attributed to radiation therapy; the role of chemotherapy in pseudoprogression is uncertain. Acknowledgment: The authors thank Dr. Joaquin Arenas, director of Instituto de Investigacion Hospital 12 de Octubre (i+12), for correcting this manuscript.
- Published
- 2016
28. Comparison on the calibrations of hydrometers for liquids density determination between SIM laboratories
- Author
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Aldo Quiroga, Francisco Sequeira, Luis Carlos Castro, Luis Omar Becerra, Manuel Salazar, Abed Morales, Diana Cantero, Arturo Daued, and Maria Vega
- Subjects
General Engineering ,Environmental science ,Remote sensing - Abstract
A supplementary comparison was made between SIM laboratories concerning the calibration of four hydrometers within the range of 600 kg/m3 to 2000 kg/m3. The main objectives of the comparison were to evaluate the degree of equivalences SIM NMIs in the calibration of hydrometers of high accuracy. The participant NMIs were: CENAM, IBMETRO, INEN, INDECOPI, INM, INTN and LACOMET. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
- Published
- 2017
29. Myosin myopathy with external ophthalmoplegia associated with a novel homozygous mutation in MYH2
- Author
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Hernández‐Laín, Aurelio, primary, Esteban‐Pérez, Jesús, additional, Montenegro, Diana Cantero, additional, and Domínguez‐González, Cristina, additional
- Published
- 2016
- Full Text
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