Clinical, Histopathologic and Genetic Features of Rhabdoid Meningiomas.

Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes.

Whole-Exome Sequencing Reveals Recurrent but Heterogeneous Mutational Profiles in Sporadic WHO Grade 1 Meningiomas.

Human WHO grade 1 meningiomas are generally considered benign tumors; despite this, they account for ≈50% of all recurrent meningiomas. Currently, limited data exist about the mutational profiles of grade 1 meningiomas and patient outcome. We investigated the genetic variants present in 32 WHO grade 1 meningiomas using whole exome sequencing, and correlated gene mutational profiles with tumor cytogenetics and patient outcome. Overall, WHO grade 1 meningiomas harbored numerous and heterogeneous genetic variants, which most frequently affected the NF2 (47%) gene and to a less extent the PNMA6A (22%), TIGD1 (16%), SMO (13%), PTEN (13%), CREG2 (9%), EEF1A1 (6%), POLR2A (6%), ARID1B (3%), and FAIM3 (3%) genes. Notably, non-synonymous genetic variants of SMO and POLR2A were restricted to diploid meningiomas, whereas NF2 mutations were only found among tumors that showed -22/22q─ (with or without a complex karyotype). Based on NF2 mutations and tumor cytogenetics, four genetic profiles were defined with an impact on patient recurrence-free survival (RFS). These included (1) two good-prognosis tumor subgroups-diploid meningiomas (n=9) and isolated -22/22q─ associated with NF2 mutation (n=7)-with RFS rates at 10 y of 100%; and (2) two subgroups of poor-prognosis meningiomas-isolated -22/22q─ without NF2 mutation (n=3) and tumors with complex karyotypes (n=11)-with a RFS rate at 10 y of 48% (p=0.003). Our results point out the existence of recurrent but heterogeneous mutational profiles in WHO grade 1 meningiomas which have an impact on patient outcome.

[Mechanical ventilator test protocol for care of patients with COVID-19 in porcine model]. / Protocolo de prueba de ventilador mecánico para atención de pacientes con COVID-19 en modelo porcino.

As a result of the SARS-CoV-2 pandemic, health systems globally have seen a dramatic increase in the occupancy of intensive care units, with mechanical ventilators being a resource in high demand in the care of these patients. This article proposes a protocol for testing low-cost mechanical ventilators in pig models, as part of the development of locally manufactured biomedical equipment that can support the health crisis caused by the pandemic. The protocol addresses aspects that include the pre-test phase, anesthetic and airway management, laboratory monitoring, recovery and monitoring of the animal. This document presents to the academic community a validation protocol of a mechanical ventilator prototype in a pig specimen that can be a reference for its application and revalidation by other groups interested in the development of local and low-cost technologies.

A raíz de la pandemia generada por el SARS-CoV-2, los sistemas de salud de los distintos países han experimentado un dramático aumento en la ocupación de las unidades de cuidado intensivo y, por ende, una alta demanda de ventiladores mecánicos. En este artículo se propone un protocolo de pruebas de ventiladores mecánicos de bajo costo en modelos porcinos, como parte del desarrollo de equipos biomédicos que pueden apoyar la crisis sanitaria suscitada por la pandemia. El protocolo aborda aspectos que incluyen la fase previa a la prueba, el manejo anestésico, de vía aérea, seguimiento de laboratorio, recuperación y seguimiento del animal. Como resultado, se presenta a la comunidad académica un protocolo de validación de prototipo de ventilador mecánico en espécimen porcino como un referente para su aplicación y revalidación por parte de grupos interesados en el desarrollo de tecnologías locales de bajo costo.

Protocolo de prueba de ventilador mecánico para atención de pacientes con COVID-19 en modelo porcino / Mechanical ventilator test protocol for care of patients with COVID-19 in porcine model

RESUMEN A raíz de la pandemia generada por el SARS-CoV-2, los sistemas de salud de los distintos países han experimentado un dramático aumento en la ocupación de las unidades de cuidado intensivo y, por ende, una alta demanda de ventiladores mecánicos. En este artículo se propone un protocolo de pruebas de ventiladores mecánicos de bajo costo en modelos porcinos, como parte del desarrollo de equipos biomédicos que pueden apoyar la crisis sanitaria suscitada por la pandemia. El protocolo aborda aspectos que incluyen la fase previa a la prueba, el manejo anestésico, de vía aérea, seguimiento de laboratorio, recuperación y seguimiento del animal. Como resultado, se presenta a la comunidad académica un protocolo de validación de prototipo de ventilador mecánico en espécimen porcino como un referente para su aplicación y revalidación por parte de grupos interesados en el desarrollo de tecnologías locales de bajo costo.

ABSTRACT As a result of the SARS-CoV-2 pandemic, health systems globally have seen a dramatic increase in the occupancy of intensive care units, with mechanical ventilators being a resource in high demand in the care of these patients. This article proposes a protocol for testing low-cost mechanical ventilators in pig models, as part of the development of locally manufactured biomedical equipment that can support the health crisis caused by the pandemic. The protocol addresses aspects that include the pre-test phase, anesthetic and airway management, laboratory monitoring, recovery and monitoring of the animal. This document presents to the academic community a validation protocol of a mechanical ventilator prototype in a pig specimen that can be a reference for its application and revalidation by other groups interested in the development of local and low-cost technologies.

Protocolo de prueba de ventilador mecánico para atención de pacientes con COVID-19 en modelo porcino / Mechanical ventilator test protocol for care of patients with COVID-19 in porcine model

RESUMEN A raíz de la pandemia generada por el SARS-CoV-2, los sistemas de salud de los distintos países han experimentado un dramático aumento en la ocupación de las unidades de cuidado intensivo y, por ende, una alta demanda de ventiladores mecánicos. En este artículo se propone un protocolo de pruebas de ventiladores mecánicos de bajo costo en modelos porcinos, como parte del desarrollo de equipos biomédicos que pueden apoyar la crisis sanitaria suscitada por la pandemia. El protocolo aborda aspectos que incluyen la fase previa a la prueba, el manejo anestésico, de vía aérea, seguimiento de laboratorio, recuperación y seguimiento del animal. Como resultado, se presenta a la comunidad académica un protocolo de validación de prototipo de ventilador mecánico en espécimen porcino como un referente para su aplicación y revalidación por parte de grupos interesados en el desarrollo de tecnologías locales de bajo costo.

ABSTRACT As a result of the SARS-CoV-2 pandemic, health systems globally have seen a dramatic increase in the occupancy of intensive care units, with mechanical ventilators being a resource in high demand in the care of these patients. This article proposes a protocol for testing low-cost mechanical ventilators in pig models, as part of the development of locally manufactured biomedical equipment that can support the health crisis caused by the pandemic. The protocol addresses aspects that include the pre-test phase, anesthetic and airway management, laboratory monitoring, recovery and monitoring of the animal. This document presents to the academic community a validation protocol of a mechanical ventilator prototype in a pig specimen that can be a reference for its application and revalidation by other groups interested in the development of local and low-cost technologies.

Tumor cell and immune cell profiles in primary human glioblastoma: Impact on patient outcome.

The distribution and role of tumor-infiltrating leucocytes in glioblastoma (GBM) remain largely unknown. Here, we investigated the cellular composition of 55 primary (adult) GBM samples by flow cytometry and correlated the tumor immune profile with patient features at diagnosis and outcome. GBM single-cell suspensions were stained at diagnosis (n = 44) and recurrence following radiotherapy and chemotherapy (n = 11) with a panel of 8-color monoclonal antibody combinations for the identification and enumeration of (GFAP+ CD45- ) tumor and normal astrocytic cells, infiltrating myeloid cells -i.e. microglial and blood-derived tumor-associated macrophages (TAM), M1-like, and M2-like TAM, neutrophils. and myeloid-derived suppressor cells (MDSC)- and tumor-infiltrating lymphocytes (TIL) -i.e. CD3+ T-cells and their TCD4+ , TCD8+ , TCD4- CD8- , and (CD25+ CD127lo ) regulatory (T-regs) subsets, (CD19+ CD20+ ) B-cells, and (CD16+ ) NK-cells-. Overall, GBM samples consisted of a major population (mean ± 1SD) of tumor and normal astrocytic cells (73% ± 16%) together with a significant but variable fraction of immune cells (24% ± 18%). Within myeloid cells, TAM predominated (13% ± 12%) including both microglial cells (10% ± 11%) and blood-derived macrophages (3% ± 5%), in addition to a smaller proportion of neutrophils (5% ± 9%) and MDSC (4% ± 8%). Lymphocytes were less represented and mostly included TCD4+ (0.5% ± 0.7%) and TCD8+ cells (0.6% ± 0.7%), together with lower numbers of TCD4- CD8- T-cells (0.2% ± 0.4%), T-regs (0.1% ± 0.2%), B-lymphocytes (0.1% ± 0.2%) and NK-cells (0.05% ± 0.05%). Overall, three distinct immune profiles were identified: cases with a minor fraction of leucocytes, tumors with a predominance of TAM and neutrophils, and cases with mixed infiltration by TAM, neutrophils, and T-lymphocytes. Untreated GBM patients with mixed myeloid and lymphoid immune infiltrates showed a significantly shorter patient overall survival versus the other two groups, in the absence of gains of the EGFR gene (p = 0.02). Here we show that immune cell infiltrates are systematically present in GBM, with highly variable levels and immune profiles. Patients with mixed myeloid and T-lymphoid infiltrates showed a worse outcome.

Multivariate analysis reveals differentially expressed genes among distinct subtypes of diffuse astrocytic gliomas: diagnostic implications.

Diagnosis and classification of gliomas mostly relies on histopathology and a few genetic markers. Here we interrogated microarray gene expression profiles (GEP) of 268 diffuse astrocytic gliomas-33 diffuse astrocytomas (DA), 52 anaplastic astrocytomas (AA) and 183 primary glioblastoma (GBM)-based on multivariate analysis, to identify discriminatory GEP that might support precise histopathological tumor stratification, particularly among inconclusive cases with II-III grade diagnosed, which have different prognosis and treatment strategies. Microarrays based GEP was analyzed on 155 diffuse astrocytic gliomas (discovery cohort) and validated in another 113 tumors (validation set) via sequential univariate analysis (pairwise comparison) for discriminatory gene selection, followed by nonnegative matrix factorization and canonical biplot for identification of discriminatory GEP among the distinct histological tumor subtypes. GEP data analysis identified a set of 27 genes capable of differentiating among distinct subtypes of gliomas that might support current histological classification. DA + AA showed similar molecular profiles with only a few discriminatory genes overexpressed (FSTL5 and SFRP2) and underexpressed (XIST, TOP2A and SHOX2) in DA vs AA and GBM. Compared to DA + AA, GBM displayed underexpression of ETNPPL, SH3GL2, GABRG2, SPX, DPP10, GABRB2 and CNTN3 and overexpression of CHI3L1, IGFBP3, COL1A1 and VEGFA, among other differentially expressed genes.

Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival.

BACKGROUND: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. METHODS: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. RESULTS: At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8-9 was found in only two tumors (2%). CONCLUSIONS: Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM.

Prognostic stratification of adult primary glioblastoma multiforme patients based on their tumor gene amplification profiles.

Several classification systems have been proposed to address genomic heterogeneity of glioblastoma multiforme, but they either showed limited prognostic value and/or are difficult to implement in routine diagnostics. Here we propose a prognostic stratification model for these primary tumors based on tumor gene amplification profiles, that might be easily implemented in routine diagnostics, and potentially improve the patients management. Gene amplification profiles were prospectively evaluated in 80 primary glioblastoma multiforme tumors using single-nucleotide polymorphism arrays and the results obtained validated in publicly available data from 267/347 cases. Gene amplification was detected in 45% of patients, and chromosome 7p11.2 including the EGFR gene, was the most frequently amplified chromosomal region - either alone (18%) or in combination with amplification of DNA sequences in other chromosomal regions (10% of cases). Other frequently amplified DNA sequences included regions in chromosomes 12q(10%), 4q12(7%) and 1q32.1(4%). Based on their gene amplification profiles, glioblastomas were subdivided into: i) tumors with no gene amplification (55%); ii) tumors with chromosome 7p/EGFR gene amplification (with or without amplification of other chromosomal regions) (38%); and iii) glioblastoma multiforme with a single (11%) or multiple (6%) amplified DNA sequences in chromosomal regions other than chromosome 7p. From the prognostic point of view, these amplification profiles showed a significant impact on overall survival of glioblastoma multiforme patients (p>0.001). Based on these gene amplification profiles, a risk-stratification scoring system was built for prognostic stratification of glioblastoma which might be easily implemented in routine diagnostics, and potentially contribute to improved patient management.

Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies.

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice.Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550-9. ©2018 AACR.

A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK.

Connexin43 (CX43), a protein that forms gap junction channels and hemichannels in astrocytes, is downregulated in high-grade gliomas. Its relevance for glioma therapy has been thoroughly explored; however, its positive effects on proliferation are counterbalanced by its effects on migration and invasion. Here, we show that a cell-penetrating peptide based on CX43 (TAT-Cx43266-283) inhibited c-Src and focal adhesion kinase (FAK) and upregulated phosphatase and tensin homolog in glioma stem cells (GSCs) derived from patients. Consequently, TAT-Cx43266-283 reduced GSC motility, as analyzed by time-lapse microscopy, and strongly reduced their invasive ability. Interestingly, we investigated the effects of TAT-Cx43266-283 on freshly removed surgical specimens as undissociated glioblastoma blocks, which revealed a dramatic reduction in the growth, migration, and survival of these cells. In conclusion, a region of CX43 (amino acids 266-283) exerts an important anti-tumor effect in patient-derived glioblastoma models that includes impairment of GSC migration and invasion.

[Relevance of Simpson's grading system for resections in WHO grade I meningiomas]. / Relevancia de la escala de Simpson en la resección de meningiomas de grado I de la OMS.

OBJECT: The aim of this study is to assess if the recurrence rates and recurrence/progression-free survivals (RFS) are different after Simpson's grades I, II, III and IV resections in World Health Organization (WHO) grade I meningiomas. MATERIAL AND METHODS: A retrospective review was conducted on the data of patients who underwent surgical treatment of WHO grade I meningiomas located in convexity, falx/parasagittal, and skull base (anterior/media/posterior) between June 1991 and December 2011. In Simpson's grade IV resections, surgical treatment was supplemented with radiotherapy/radiosurgery on the tumour remains. A comparison was made on the recurrence rates and RFSs between Simpson's grades I, II, III, and IV resections, both overall and in tumour subsets according to their location. RESULTS: A total of 208 meningiomas were included in this study. There were no significant differences in recurrence rates and RFSs between Simpson's grades I, II, III, and IV. No significant differences were noted between the different degrees of Simpson in any of the location groups. In convexity meningiomas, the recurrence rates were 7% and 33% in Simpson's grades I and III resections, respectively (P=.131). CONCLUSIONS: It has been shown that the rates of tumour control in meningiomas are not related to Simpson grades. In falx/parasagittal and skull base meningiomas, more aggressive attempts of tumour resection must be balanced against the risks of damaging critical neurovascular structures. In convexity meningiomas, a Simpson's grade I resection should be attempted first.

Estudio sobre la influencia del diámetro de apertura en la fuerza ejercida por cada dedo / A study on the influence of grip span on the strength exerted by each finger

RESUMEN Objetivo Estudiar el efecto de mantener un mismo diámetro de apertura en los dedos sobre la fuerza actuante de éstos en un agarre de fuerza. Métodos Se condujo un experimento con 30 participantes (15 hombres y 15 mujeres) quienes realizaron el gesto de aprehensión en un dispositivo diseñado para mantener constante la apertura para todos los dedos en 4 diámetros diferentes. Resultados Se muestra evidencia que en un rango de accionamiento entre 0-75% de la apertura funcional, los dedos índice, corazón y anular ejercen una fuerza significativamente igual si el diámetro de apertura se mantiene constante. Conclusiones Este hallazgo permitiría reducir la exposición de los operarios de herramientas de corte a factores de riesgo de síndrome del conducto carpiano (SCC). Se sugiere que en el diseño de herramientas, la distancia de apertura para todos los dedos debe mantenerse constante durante el gesto de aprehensión.(AU)

ABSTRACT Objective To study the effect of maintaining the same grip span between the thumb and exerting fingers, on the acting force of these in a power grip. Methods We conducted an experiment with 30 participants (15 men and 15 women) who made the gesture of apprehension in a device designed to maintain constant grip span to all fingers in 4 different diameters. Results In the range between 0-75 percent of functional grip span of the fingers, the index, middle and ring finger exert a force significantly equal when the aperture diameter is maintained constant. Conclusions These findings would reduce exposure to risk factors for carpal canal syndrome (CTS) in cutting activities, by controlling risk factors like strength. We suggest that on the design of tools, the opening distance for all the fingers must remain constant during the act of apprehension.(AU)

Tumor infiltrating immune cells in gliomas and meningiomas.

Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

[A study on the influence of grip span on the strength exerted by each finger]. / Estudio sobre la influencia del diámetro de apertura en la fuerza ejercida por cada dedo.

OBJECTIVE: To study the effect of maintaining the same grip span between the thumb and exerting fingers, on the acting force of these in a power grip. METHODS: We conducted an experiment with 30 participants (15 men and 15 women) who made the gesture of apprehension in a device designed to maintain constant grip span to all fingers in 4 different diameters. RESULTS: In the range between 0-75 percent of functional grip span of the fingers, the index, middle and ring finger exert a force significantly equal when the aperture diameter is maintained constant. CONCLUSIONS: These findings would reduce exposure to risk factors for carpal canal syndrome (CTS) in cutting activities, by controlling risk factors like strength. We suggest that on the design of tools, the opening distance for all the fingers must remain constant during the act of apprehension.

OBJETIVO: Estudiar el efecto de mantener un mismo diámetro de apertura en los dedos sobre la fuerza actuante de éstos en un agarre de fuerza. MÉTODOS: Se condujo un experimento con 30 participantes (15 hombres y 15 mujeres) quienes realizaron el gesto de aprehensión en un dispositivo diseñado para mantener constante la apertura para todos los dedos en 4 diámetros diferentes. RESULTADOS: Se muestra evidencia que en un rango de accionamiento entre 0-75% de la apertura funcional, los dedos índice, corazón y anular ejercen una fuerza significativamente igual si el diámetro de apertura se mantiene constante. CONCLUSIONES: Este hallazgo permitiría reducir la exposición de los operarios de herramientas de corte a factores de riesgo de síndrome del conducto carpiano (SCC). Se sugiere que en el diseño de herramientas, la distancia de apertura para todos los dedos debe mantenerse constante durante el gesto de aprehensión.

Genetic/molecular alterations of meningiomas and the signaling pathways targeted.

Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g., AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features.

Molecular and Genomic Alterations in Glioblastoma Multiforme.

In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.

The protein expression profile of meningioma cells is associated with distinct cytogenetic tumour subgroups.

AIMS: Limited information exists about the impact of cytogenetic alterations on the protein expression profiles of individual meningioma cells and their association with the clinicohistopathological characteristics of the disease. The aim of this study is to investigate the potential association between the immunophenotypic profile of single meningioma cells and the most relevant features of the tumour. METHODS: Multiparameter flow cytometry (MFC) was used to evaluate the immunophenotypic profile of tumour cells (n = 51 patients) and the Affymetrix U133A chip was applied for the analysis of the gene expression profile (n = 40) of meningioma samples, cytogenetically characterized by interphase fluorescence in situ hybridization. RESULTS: Overall, a close association between the pattern of protein expression and the cytogenetic profile of tumour cells was found. Thus, diploid tumours displayed higher levels of expression of the CD55 complement regulatory protein, tumours carrying isolated monosomy 22/del(22q) showed greater levels of bcl2 and PDGFRß and meningiomas carrying complex karyotypes displayed a greater proliferation index and decreased expression of the CD13 ectoenzyme, the CD9 and CD81 tetraspanins, and the Her2/neu growth factor receptor. From the clinical point of view, higher expression of CD53 and CD44 was associated with a poorer outcome. CONCLUSIONS: Here we show that the protein expression profile of individual meningioma cells is closely associated with tumour cytogenetics, which may reflect the involvement of different signalling pathways in the distinct cytogenetic subgroups of meningiomas, with specific immunophenotypic profiles also translating into a different tumour clinical behaviour.

Proposal for a new risk stratification classification for meningioma based on patient age, WHO tumor grade, size, localization, and karyotype.

BACKGROUND: Tumor recurrence remains the major clinical complication of meningiomas, the majority of recurrences occurring among WHO grade I/benign tumors. In the present study, we propose a new scoring system for the prognostic stratification of meningioma patients based on analysis of a large series of meningiomas followed for a median of >5 years. METHODS: Tumor cytogenetics were systematically investigated by interphase fluorescence in situ hybridization in 302 meningioma samples, and the proposed classification was further validated in an independent series of cases (n = 132) analyzed by high-density (500K) single-nucleotide polymorphism (SNP) arrays. RESULTS: Overall, we found an adverse impact on patient relapse-free survival (RFS) for males, presence of brain edema, younger patients (<55 years), tumor size >50 mm, tumor localization at intraventricular and anterior cranial base areas, WHO grade II/III meningiomas, and complex karyotypes; the latter 5 variables showed an independent predictive value in multivariate analysis. Based on these parameters, a prognostic score was established for each individual case, and patients were stratified into 4 risk categories with significantly different (P < .001) outcomes. These included a good prognosis group, consisting of approximately 20% of cases, that showed a RFS of 100% ± 0% at 10 years and a very poor-prognosis group with a RFS rate of 0% ± 0% at 10 years. The prognostic impact of the scoring system proposed here was also retained when WHO grade I cases were considered separately (P < .001). CONCLUSIONS: Based on this risk-stratification classification, different strategies may be adopted for follow-up, and eventually also for treatment, of meningioma patients at different risks for relapse.