Venous thromboembolism in pediatric patients with acute lymphoblastic leukemia under chemotherapy treatment. Risk factors and usefulness of thromboprophylaxis. Results of LAL-SEHOP-PETHEMA-2013.

INTRODUCTION: Symptomatic venous thromboembolism (VTE) is diagnosed in 3%-14% of patients during pediatric acute lymphoblastic leukemia (ALL) therapy. There are well-known risk factors, but the role of others as inherited thrombophilia is still controversial. Prophylaxis with low molecular weight heparin (LMWH) has been described, but its use is not globally accepted. METHODS: A retrospective multicentric study in ALL patients 1-18 years old following SEHOP-PETHEMA-2013 treatment guideline was performed to evaluate VTE rate, anticoagulant treatment, outcome, risk factors, and safety and usefulness of LMWH administration as primary thromboprophylaxis in children with inherited thrombophilia. RESULTS: A total of 652 patients were included in the study. VTE incidence was 8.7%. Most of the cases occurred during induction therapy associated with central venous catheter. Univariant analysis showed that family history of thrombosis, presence of mediastinal mass, high-risk treatment group, and inherited thrombophilia were statistically significant risk factors. LMWH administration seemed to decrease VTE rate in patients with inherited thrombophilia and those with T-cell ALL phenotype. CONCLUSION: Most of the VTE cases occurred in patients without inherited thrombophilia, but when it is present, the VTE risk is higher. LMWH administration was useful to decrease VTE in these patients.

Programa educativo de integración del movimiento mediante el juego en Educación Infantil / Educational play-based movement integration program in Early Childhood Education: evaluation and analysis

Los métodos educativos de integración del movimiento son reconocidos como potenciadores de la actividad física, de las funciones ejecutivas y del aprendizaje. Sin embargo, el impacto de estas metodologías sobre la cognición y la actividad física en Educación Infantil ha sido poco estudiado. El objetivo de la investigación fue analizar el efecto de un programa educativo de integración del movimiento basado en el juego en esta etapa, evaluando sus efectos sobre los niveles de actividad física de los niños. Participaron 134 alumnos de 5 años de la provincia de Málaga. Se diseñó e implementó un programa de integración del movimiento basado en actividades de juego motor semi-dirigido que cambiaban cada quince minutos, en las cuales se trabajaron contenidos académicos. Se evaluó la cantidad e intensidad de actividad física mediante acelerometría (Actigraph GT3X). Durante su participación en el programa, los niños realizaron una media de 45,65 minutos de actividad física moderada-vigorosa. El porcentaje más alto corresponde a la actividad sedentaria y a la actividad moderada-vigorosa respectivamente, lo cual concuerda con estudios que afirman que la actividad de los niños pequeños consiste en ráfagas cortas de actividad moderada-vigorosa intercaladas con períodos de menor intensidad. Los datos muestran que el juego como método de integración del movimiento contribuye a alcanzar los niveles de actividad recomendados por las organizaciones internacionales. Nuestros resultados apoyan el uso del juego semi-dirigido como una herramienta especialmente útil para la mejora del proceso de enseñanza-aprendizaje en Educación Infantil y para el aumento de la actividad física del alumnado

Educational movement integration methods have been recognized as enhancers of physical activity, executive functions and learning. However, the impact of these methodologies on cognition and physical activity in Early Childhood Education has been little studied. The aim of this study was to analyze the effect of an educational play-based movement integration program at this stage, evaluating its effects on children's physical activity levels. A total of 134 5-year-old students from the province of Malaga participated. We designed and implemented a movement integration program based on semi-directed motor play activities that changed every fifteen minutes, in which academic content was worked on. The amount and intensity of physical activity was evaluated using accelerometry (Actigraph GT3X). During their participation in the program, children carried out an average of 45.65 minutes of moderate-vigorous physical activity. The highest percentage corresponds to sedentary activity and moderate-vigorous activity respectively, which is consistent with other studies that state the activity of young children consists of short bursts of moderate-vigorous activity interspersed with less-intensity periods. Data shows that play as a movement integration method contributes to reaching the activity levels recommended by international organizations. Our results support the use of semi-directed play as an especially useful tool for the improvement of the teaching-learning process in Early Childhood Education and for increasing students' physical activity

Evaluación de la coordinación motora en alumnado de Educación Infantil. El Trastorno de Coordinación Motora / Assessment of motor coordination in students of Early Childhood Education. Developmental Coordination Disorder

El escaso desarrollo y adquisición de habilidades de coordinación, conocido como Trastorno de Coordinación Motora (TDC) o dispraxia del desarrollo, es un trastorno motor no atribuible a ningún tipo de discapacidad o trastorno neurológico de alteración del movimiento, pero que afecta a funciones tales como el habla, el lenguaje, la escritura o la atención. Se estima que su incidencia es del 5-15% en niños en edad escolar, siendo la prevalencia mayor en varones. En el estudio participaron 91 alumnos de 5 años (x=5,83; SD=0,33) de la provincia de Málaga. Se evaluaron los niveles de adquisición de habilidades de coordinación motora, identificando los niños en situación de normalidad, en riesgo de disminución psicomotora o con sospecha de padecer TDC, y se analizaron las diferencias de desempeño motor en función del sexo. Para la valoración de la coordinación motora se recurrió a la versión española de la batería de evaluación del movimiento para niños (Movement Assessment Battery for Children) MABC-2. Los resultados identifican a un 6,56% de los niños como TDC y un 4,67% en situación de riesgo. En cuanto a las diferencias asociadas al sexo, las niñas alcanzaron puntuaciones significativamente más altas en las áreas de destreza manual y de equilibrio, mientras que los niños logran puntuaciones mayores, aunque no de manera significativa, en el área puntería y atrape

The lacking in coordination skills development and acquisition, known as Developmental Coordination Disorder (DCD) or developmental dyspraxia, is a motor disorder not attributable to any type of disability or neurological disorder of movement alteration, but which affects functions such as speech, language, writing or attention. Its influence is estimated to be 5-15% in school-age children, with the highest prevalence in boys. A total of 91 5-year-old students (x= 5.83; SD=0.33) from the province of Malaga participated in the study. Acquisition levels of motor coordination skills were evaluated, identifying children in a normal situation, at risk of psychomotor decline or with suspected DCD, and the differences in motor performance according to sex were analyzed. For the assessment of motor coordination, the Spanish version of the Movement Assessment Battery for Children - Second Edition (MABC-2) was used. The results identify 6.56% of children as DCD and 4.67% at risk. Regarding the differences associated with sex, girls achieved significantly higher scores in manual dexterity and balance areas, while boys achieved higher scores, although not significantly, in aiming and catching area

¿Para qué llaman los pacientes?: evaluación de consultas telefónicas no urgentes en Atención Primaria / What do patients call for? Evaluation of non-urgent telephone consultations in Primary Care

OBJETIVO: Conocer el uso de las consultas telefónicas no urgentes en medicina de familia, perfil de usuario y factores asociados a su utilización. Comprobar motivos, idoneidad de las llamadas y capacidad de resolución. DISEÑO: Estudio descriptivo transversal. EMPLAZAMIENTO: Zona Básica de Salud urbana. PARTICIPANTES: Todas las llamadas realizadas por ≥ 14 años incluidas en la agenda de consulta telefónica no urgente de tres cupos médicos, durante los meses de septiembre, octubre y noviembre de 2017. MEDICIONES PRINCIPALES: Proporción de consultas telefónicas no urgentes respecto al total, cuantificación de los sujetos, idoneidad de las llamadas y capacidad de resolución. Variables independientes: perfil del usuario (sociodemográficas, Índice de Charlson, polimedicación y uso de servicios sanitarios) y motivos. Análisis multivariante para determinar posibles factores asociados al uso de las llamadas. RESULTADOS: De 6050 citas atendidas, 259 fueron telefónicas (4,28 %; IC95 %: 3,80-4,82) de 184 sujetos. Edad media de 64,6 años (DE: 20,1). El 69,6 % mujeres. Presentaban Índice de Charlson severo el 10,3 %, consumían ≥ 5 fármacos el 59,2 %. Hubo 294 motivos: renovación de recetas (45,9 %) y consultas clínicas (20,9 %, sobre todo osteomusculares). Se resolvieron el 80,5 % de los motivos. Consultas idóneas fueron 211 (81,5 %). Mediante análisis multivariante realizar ≥ 2 llamadas se asoció de modo independiente con: menor número de pacientes visitados/día de la llamada (OR:1,1; p=0,044), mayor número de fármacos usados (OR=1,25; p=0,006) y mayor número de ingresos hospitalarios/último año (OR=2,93; p=0,021). CONCLUSIONES: En nuestro entorno las consultas telefónicas no urgentes representan una proporción baja de la actividad del médico de familia. Sin embargo, parecen tener elevada idoneidad y capacidad de resolución. Sería necesario cuantificar su impacto en la demanda presencial

OBJECTIVE: To assess the use of non-urgent telephone consultations in family medicine, the user profile, and the factors associated with its use. To check reasons, suitability of phone calls and resolution capacity. DESIGN: Descriptive, cross-sectional study. LOCATION: Urban Primary Healthcare Area. PARTICIPANTS: All phone calls made by persons ≥ 14 years old included in the non-urgent telephone consultation schedule of three doctor's rosters, during September, October and November 2017. MAIN MEASURES: Proportion of non-urgent phone consultations to total calls, quantification of persons, suitability of phone calls, and resolution capacity. Independent variables: user profile (socio-demographic characteristics, Charlson Index, polypharmacy, and use of healthcare services) and reasons for the call. Multivariate analysis to determine possible factors associated with the use of telephone calls. RESULTS: 259 out of 6,050 consultations were telephone calls (4.28%; 95% CI: 3.80-4.82) from 184 persons. The average age was 64.6 (SD: 20.1), 69.6% women. 10.3% presented severe Charlson Index, 59.2% used ≥ 5 drugs. There were 294 reasons: prescription renewal (45.9%) and clinical consultations (20.9%, especially musculoskeletal). 80.5% of reasons were resolved. 211 were suitable consultations (81.5%). Through multivariate analysis, making ≥ 2 calls was independently associated with: lower number of patients seen/day of the call (OR: 1.1; p=0.044), higher number of drugs used (OR: 1.25; p=0.006), and higher number of hospital admissions/last year (OR: 2.93; p=0.021). CONCLUSIONS: In our environment, non-urgent telephone consultations represent a low propor-tion of the family doctor's activity. However, they seem to have high suitability and resolution capacity. It would be necessary to quantify their impact on face-to-face consultations

Selective catalytic synthesis of amino-silanes at part-per million catalyst loadings.

Platinum(ii) complex [Pt(ItBu')(ItBu)][BArF4] (1a) is a highly active and selective catalyst in the dehydrocoupling of amines and silanes at part-per-million catalyst loadings (up to 10 ppm, 0.001 mol%), achieving the highest TON and TOF numbers reported in the literature (up to 1 mmol scale). NMR studies suggest a process taking place through electrophilic activation of the silane by the platinum species, assisted by an amine.

Uso de los nuevos anticoagulantes orales en atención primaria. Calidad de la prescripción / Use of new oral anticoagulants in primary care. Quality of prescription

Objetivo: Evaluar la calidad de la prescripción de los nuevos anticoagulantes orales. Identificar posibles factores asociados a su utilización inadecuada. Diseño: Estudio descriptivo transversal. Emplazamiento: Zona Básica de Salud urbana. Participantes: Todos los pacientes que consumieron nuevos anticoagulantes orales (NACO) durante 2015 (153 sujetos). Mediciones Principales: Adecuación de la prescripción a las recomendaciones de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Otras variables: NACO prescrito (clasificación ATC), indicación y duración del tratamiento, prescriptor, Índice de Charlson, polimedicación (5 o más fármacos), uso de servicios sanitarios y variables sociodemográficas. Análisis multivariante para determinar posibles factores asociados al uso inadecuado. Resultados: 145 sujetos incluidos (23,8 % del total de usuarios de anticoagulantes orales). Edad media 76 años (DE:11,4), un 50,3 % mujeres. Rivaroxaban el más prescrito (41,4 %). Indicación y prescriptor principal: fibrilación auricular no valvular -FANV- (93,1 % de casos) y cardiólogos (71,7 %). Mediana de uso de 20 meses (rango intercuartil: 8 a 32). Utilizaban acenocumarol el 46,9 % de pacientes y el motivo habitual de cambio: mal control del INR. En el 74,1 % (100 casos) (IC 95 %: 65,8 - 81,2) el uso global de NACO (pacientes con FANV) fue inadecuado. Variables asociadas al uso inadecuado: no prescribir de inicio el NACO (OR: 7,0; IC 95 %: 1,8 - 27,1) y la mayor duración del tratamiento anticoagulante (OR: 2,4; IC 95 %: 1,3 - 4,5). Conclusiones: En nuestro entorno una de cada cuatro prescripciones de los nuevos anticoagulantes, en pacientes con FANV, sigue las recomendaciones de la AEMPS. Debemos estar alerta ante posibles riesgos de este elevado uso inadecuado (AU)

Objective: To assess the quality of prescription of the new oral anticoagulants. To identify possible factors associated with its inappropriate use. Design: Descriptive cross-sectional study. Location: Urban primary healthcare district. Participants: All patients who used new oral anticoagulants (NOAC) during 2015 (153 subjects). Main measurements: Prescription compliance to the recommendations of the Spanish Agency of Medicines and Medical Devices (AEMPS). Other variables: NOAC prescribed (ATC classification), indication and duration of treatment, prescriber, Charlson index, polypharmacy (5 or more drugs), use of healthcare services, and socio-demographic variables. Multivariate analysis to determine possible factors associated with inappropriate use. Results: 145 subjects were included (23.8 % of the total users of oral anticoagulants). Average age 76 years (SD:11.4), 50.3 % were women. Rivaroxaban the most prescribed (41.4 %). Indication and usual prescriber: non-valvular atrial fibrillation - NVAF - (93.1 % of cases) and cardiologists (71.7 %). The median of use was 20 months (interquartile range: 8 to 32). 46.9 % of patients used acenocoumarol, and the usual reason for the change was poor INR control. In 74.1 %(100 cases) (CI 95 %: 65.8 - 81.2) the global use of NOAC, in patients with NVAF, was inappropriate. Variables associated with inappropriate use: not to prescribe NOAC from the beginning (OR: 7.0; CI 95 %: 1.8 - 27.1) and longer duration of anticoagulant therapy (OR: 2.4; CI 95 %: 1.3 - 4.5).Conclusion: . In our environment, one of every four prescriptions of new anticoagulants, in patients with NVAF, follows the recommendations of the AEMPS. We must be vigilant against possible risks of this high inappropriate use (AU)

Catalytic dehydrocoupling of amine-boranes and amines into diaminoboranes: isolation of a Pt(ii), Shimoi-type, η(1)-BH complex.

The platinum complex [Pt(I(t)Bu')(I(t)Bu)][BAr(F)] is a very efficient catalyst in the synthesis of diaminoboranes through dehydrocoupling of amine-boranes and amines. Shimoi-type, η(1)-BH complexes are key intermediates in the process.

Synthesis and reactivity of fluorenyl-tethered N-heterocyclic stannylenes.

A fluorenyl (Fl) tethered diamine was synthesised by nucleophilic substitution of (bromoethyl)fluorene with a diisopropylphenyl (Dipp) substituted diamine to give FlC2H4N(H)C2H4N(H)Dipp (1a) in good yield (85%). Lithiation of 1a with n-BuLi proceeded with coordination of the Li cation to the aromatic fluorenide ring (2), and with subsequent equivalents of n-BuLi, the secondary amines were then sequentially deprotonated. A fluorenyl-tethered N-heterocyclic stannylene (NHSn) was synthesised from the reaction of 1a with SnN''2 {N'' = N(SiMe3)2} as a neutral dimeric species (5), and this was deprotonated with LiN'' to give the corresponding dianionic fluorenide-tethered NHSn (6). Reactions of [{Rh(cod)(µ-Cl)}2] with the mono-deprotonated ligand 2 led to the formation of a mixed-donor amide-amine Rh(i) compound (7), whereas reactions with the anionic NHSn 6 led to a Rh-fluorenyl complex of low stability with an uncoordinated pendent NHSn arm, which X-ray crystallography showed to be dimeric in the solid state.

Hemilability of P(X)N-type ligands (X = O, N-H): rollover cyclometalation and benzene C-H activation from (P(X)N)PtMe2 complexes.

The thermolyses of ((tBu)P(O)N)PtMe2 (, (tBu)P(O)N = (di-tert-butylphosphinito)pyridine) and ((tBu)P(N-H)N)PtMe2 (, (tBu)P(N-H)N = (di-tert-butylphosphino)-2-aminopyridine) in benzene-d6 were investigated. With ((tBu)P(O)N)PtMe2, the product of a rollover cyclometalation of the pyridyl ring was observed in 80% yield along with formation of CH4. In contrast, thermolysis of ((tBu)P(N-H)N)PtMe2 resulted in competing rollover cyclometalation and intermolecular benzene C-H activation with production of a mixture of CH4 and CH3D.

Reactivity of coordinatively unsaturated bis(N-heterocyclic carbene) Pt(II) complexes toward H(2). Crystal structure of a 14-electron Pt(II) hydride complex.

The reactivity toward H2 of coordinatively unsaturated Pt(II) complexes, stabilized by N-heterocyclic carbene (NHC) ligands, is herein analyzed. The cationic platinum complexes [Pt(NHC')(NHC)](+) (where NHC' stands for a cyclometalated NHC ligand) react very fast with H2 at room temperature, leading to hydrogenolysis of the Pt-CH2 bond and concomitant formation of hydride derivatives [PtH(NHC)2](+) or hydrido-dihydrogen complexes [PtH(H2)(NHC)2](+). The latter species release H2 when these compounds are subjected to vacuum. The X-ray structure of complex [PtH(IPr)2][SbF6] revealed its unsaturated nature, exhibiting a true T-shaped structure without stabilization by agostic interactions. Density functional theory calculations indicate that the binding and reaction of H2 in complexes [PtH(H2)(NHC)2](+) is more favored for derivatives bearing aryl-substituted NHCs (IPr, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene and IMes = 1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene) than for those containing tert-butyl groups (I(t)Bu). This outcome is related to the higher close-range steric effects of the I(t)Bu ligands. Accordingly, H/D exchange reactions between hydrides [PtH(NHC)2](+) and D2 take place considerably faster for IPr and IMes* derivatives than for I(t)Bu ones. The reaction mechanisms for both H2 addition and H/D exchange processes depend on the nature of the NHC ligand, operating through oxidative addition transition states in the case of IPr and IMes* or by a σ-complex assisted-metathesis mechanism in the case of I(t)Bu.

Dehydrocoupling reactions of dimethylamine-borane by Pt(II) complexes: a new mechanism involving deprotonation of boronium cations.

Coordinatively unsaturated Pt(II) complex [Pt(I(t)Bu')(I(t)Bu)](+) stabilized by N-heterocyclic carbene (NHC) ligands dehydrogenates N,N-dimethylamineborane through a mechanism that involves hydride abstraction, assisted by an amine, to yield a platinum-hydride complex [PtH(I(t)Bu')(I(t)Bu)] with concomitant formation of the boronium cation [(NHMe2)2BH2](+). This latter species is very likely in equilibrium with the THF stabilized borenium cation [(NHMe2)(THF)BH2](+), bearing an acidic NH group that is able to protonate the platinum hydride [PtH(I(t)Bu')(I(t)Bu)] releasing H2, the amino borane H2B-NMe2 and regenerating the catalytic [Pt](+) species.

A simple, general route to 2-pyridylidene transition metal complexes.

Pyridinium 2-carboxylates decompose thermally in the presence of a variety of late transition metal precursors to yield the corresponding 2-pyridylidene-like complexes. The mild reaction conditions and structural diversity that can be generated in the heterocyclic ring make this method an attractive alternative for the synthesis of 2-pyridylidene complexes. IR spectra of the Ir(i) carbonyl compounds [IrCl(NHC)(CO)(2)] indicate that these N-heterocyclic carbene ligands are among the strongest σ-electron donors.

Gene expression profiles of meningiomas are associated with tumor cytogenetics and patient outcome.

Cytogenetic analysis is a powerful tool for predicting recurrence in meningiomas, even among histologically benign/grade I tumors. Despite this, no study has been reported in which the impact of tumor cytogenetics on the gene expression profiles (GEP) has been analyzed in meningiomas. Here, we analyzed the GEP of 47 tumors and correlated them with the most clinical relevant cytogenetic subgroups of meningiomas, as confirmed through the analysis of 172 patients. Additionally three normal meningeal samples were also studied. Overall, our results show a clear association between the clinically relevant cytogenetic subgroups of meningiomas including diploid tumors (n = 18), isolated -22/22q- (n = 12), del(1p36) alone (n = 4) and complex karyotypes associated with del(1p36) and/or -14q (n = 13) and their GEP. Accordingly, based on the expression of 85 genes (40 of which were coded in the altered chromosomes used for patient stratification) the cytogenetic class of the tumor could be predicted with an error of <1%, a clear association being found between the GEP and patient outcome (P = 0.03) but not tumor histopathology. In summary, we show a clear association between GEP of neoplastic cells and clinically relevant cytogenetic subgroups of meningiomas.

Detection of platinum dihydride bisphosphine complexes and studies of their reactivity through para-hydrogen-enhanced NMR methods.

In-situ NMR studies on the reactions of Pt{CH2 = CHSi(Me)2}2O)(PCy3) with phosphines, HSiEt3 and--hydrogen or Pt(L)(L')(Me)(2) alone enable the detection of cis-Pt(L)(L')(H)2 [L = PCy3 and L' = PCy2H, PPh3 or PCy3] which then undergo hydride site interchange and H2 reductive elimination on the NMR timescale.

Array-based comparative genomic hybridization of mapped BAC DNA clones to screen for chromosome 14 copy number abnormalities in meningiomas.

Chromosome 14 loss in meningiomas are associated with more aggressive tumour behaviour. To date, no studies have been reported in which the entire chromosome 14q of meningioma tumour cells has been studied by high-resolution array comparative genomic hybridization (a-CGH). Here, we used a high-resolution a-CGH to define the exact localization and extent of numerical changes of chromosome 14 in meningioma patients. An array containing 807 bacterial artificial chromosome clones specific for chromosome 14q (average resolution of approximately 130 Kb) was constructed and applied to the study of 25 meningiomas in parallel to the confirmatory interphase fluorescence in situ hybridization (iFISH) analyses. Overall, abnormalities of chromosome 14q were detected in 10/25 cases (40%). Interestingly, in seven of these cases, loss of chromosome 14q32.3 was detected by iFISH and confirmed to correspond to monosomy 14 by a-CGH. In contrast, discrepant results were found between iFISH and a-CGH in the other three altered cases. In one patient, a diploid background was observed by iFISH, while monosomy 14 was identified by a-CGH. In the remaining two cases, which showed gains of the IGH gene by iFISH, a-CGH did not detected copy number changes in one case showing a tetraploid karyotype, while in the other tumour, varying genetic imbalances along the long arm of chromosome 14 were detected. In summary, here, we report for the first time, the high-resolution a-CGH profiles of chromosome 14q in meningiomas, confirming that monosomy 14 is the most frequent alteration associated with this chromosome; other numerical abnormalities being only sporadically detected.

Patient gender is associated with distinct patterns of chromosomal abnormalities and sex chromosome linked gene-expression profiles in meningiomas.

The female predominance of meningiomas has been established, but how this is affected by hormones is still under discussion. We analyzed the characteristics of meningiomas from male (n = 53) and female (n = 111) patients by interphase fluorescence in situ hybridization (iFISH). In addition, in a subgroup of 45 (12 male and 33 female) patients, tumors were hybridized with the Affymetrix U133A chip. We show a higher frequency of larger tumors (p = .01) and intracranial meningiomas (p = .04) together with a higher relapse rate (p = .03) in male than in female patients. Male patients had a higher percentage of del(1p36) (p < .001), while loss of an X chromosome was restricted to tumors from female patients (p = .008). In turn, iFISH studies showed a higher frequency of chromosome losses, other than monosomy 22 alone, in meningiomas from male patients (p = .002), while female patients displayed a higher frequency of chromosome gains (p = .04) or monosomy 22 alone (p = .03) in the ancestral tumor clone. Interestingly, individual chromosomal abnormalities had a distinct impact on the recurrence-free survival rate of male versus female patients. In turn, gene expression showed that eight genes (RPS4Y1, DDX3Y, JARID1D, DDX3X, EIF1AY, XIST, USP9Y, and CYorf15B) had significantly different expression patterns (R(2) > 0.80; p < .05) in tumors from male and female patients. In summary, we show the existence of different patterns of chromosome abnormalities and gene-expression profiles associated with patient gender, which could help to explain the slightly different clinical behavior of these two patient groups.

Early recurrences in histologically benign/grade I meningiomas are associated with large tumors and coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone.

Tumor recurrence is the major clinical complication in meningiomas, and its prediction in histologically benign/grade I tumors remains a challenge. In this study, we analyzed the prognostic value of specific chromosomal abnormalities and the genetic heterogeneity of the tumor, together with other clinicobiological disease features, for predicting early relapses in histologically benign/grade I meningiomas. A total of 149 consecutive histologically benign/grade I meningiomas in patients who underwent complete tumor resection were prospectively analyzed. Using interphase fluorescence in situ hybridization, we studied the prognostic impact of the abnormalities detected for 11 different chromosomes, together with other relevant clinicobiological and histopathological characteristics of the disease, on recurrence-free survival (RFS) at 2.5, 5, and 10 years. From the prognostic point of view, losses of chromosomes 9, 10, 14, and 18 and del(1p36) were associated with a shorter RFS at 2.5, 5, and 10 years. Similarly, histologically benign/grade I meningiomas showing coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone displayed a higher frequency of early relapses. In fact, coexistence of -14 and del(1p36) in the ancestral tumor cell clone, together with tumor size, represented the best combination of independent prognostic factors for the identification of those patients with a high risk of an early relapse. Our results indicate that patients with large histologically benign/grade I meningiomas carrying monosomy 14 and del(1p36) in their ancestral tumor cell clone have a high probability of relapsing early after diagnostic surgery. These findings suggest the need for closer follow-up in this small group of patients.

Microarray-based analysis of spinal versus intracranial meningiomas: different clinical, biological, and genetic characteristics associated with distinct patterns of gene expression.

It has long been recognized that spinal meningiomas show particular clinical and histological features. Here, we compare the clinico-biological characteristics as well as the genetic abnormalities and patterns of gene expression of spinal and intracranial meningiomas. Fourteen spinal and 141 intracranial meningioma patients were analyzed at diagnosis. In all tumors, interphase fluorescence in situ hybridization (iFISH) studies were performed for the detection of quantitative abnormalities for 11 different chromosomes. Additionally, microarray analyses were performed on a subgroup of 18 histologically benign meningiomas (7 spinal and 11 intracranial). Upon comparison with intracranial tumors, spinal meningiomas showed a marked predominance of psammomatous and transitional tumors (p = 0.001), together with a higher proportion of cases displaying a single tumor cell clone by iFISH (p = 0.004). In 86% of the spinal versus 56% of the intracranial tumors (p = 0.01), the ancestral tumor cell clone detected showed either absence of any chromosomal abnormality or monosomy 22/22q- alone. Analysis of gene expression profiles showed differential expression between spinal and intracranial meningiomas for a total of 1555 genes, 35 of which allowed a clear distinction between both tumor types. Most of these 35 genes (n = 30) showed significantly higher expression among spinal tumors and corresponded to genes involved in signal transduction pathways, which did not show a significantly different expression according to tumor histopathology. In summary, we show the occurrence of unique patterns of genetic abnormalities and gene expression profiles in spinal as compared to intracranial meningiomas that provide new insights into the molecular pathways involved in the tumorigenesis and progression of spinal meningiomas, and could help explain their particular clinical and histological features.

The cytogenetic relationship between primary and recurrent meningiomas points to the need for new treatment strategies in cases at high risk of relapse.

PURPOSE: Recurrence is the major factor influencing the clinical outcome of meningioma patients although the exact relationship between primary and recurrent tumors still needs to be clarified. The aim of the present study is to analyze the cytogenetic relationship between primary and subsequent recurrent meningiomas developed within the same individual. EXPERIMENTAL DESIGN: Multicolor interphase fluorescence in situ hybridization was done for the identification of numerical abnormalities of 12 chromosomes in single-cell suspensions from 59 tumor samples corresponding to 25 recurrent meningioma patients. In 47 of these tumors, the distribution of different tumor cell clones was also analyzed in paraffin-embedded tissue sections. In parallel, 132 nonrecurrent cases were also studied. RESULTS: Most recurrent meningiomas showed complex cytogenetic aberrations associated with two or more tumor cell clones in the first tumor analyzed. Interestingly, in most individuals (74%), exactly the same tumor cell clones identified in the initial lesion were also detected in the subsequent recurrent tumor samples. In the recurrent tumor samples of the remaining cases (26%), we observed tumor cell clones related to those detected in the initial lesion but which had acquired one or more additional chromosome aberrations associated with either the emergence of new clones with more complex karyotypes or the disappearance of the most representative clones from the primary lesions. Multivariate analysis of prognostic factors showed that the Maillo et al. prognostic score, based on age of patient, tumor grade, and monosomy 14, together with tumor size was the best combination of independent variables for predicting tumor recurrence at diagnosis. CONCLUSION: Overall, our results indicate that the development of recurrent meningiomas after complete tumor resection is usually due to regrowth of the primary tumor and rarely to the emergence of an unrelated meningioma, underlining the need for alternative treatment strategies in cases at high risk of relapse, particularly those with a high Maillo et al. prognostic score and larger tumors.