Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival. METHODS: We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment. RESULTS: We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance. CONCLUSIONS: Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.

Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA.

Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo. Absence of ODZ1 by gene deletion or downregulation of ODZ1 by small interfering RNAs drastically reduces the invasive capacity of GBM cells. This activity is mediated by an ODZ1-triggered transcriptional pathway, through the E-box binding Myc protein, that promotes the expression and activation of Ras homolog family member A (RhoA) and subsequent activation of Rho-associated, coiled-coil containing protein kinase (ROCK). Overexpression of ODZ1 in GBM cells reduced survival of xenografted mice. Consistently, analysis of 122 GBM tumour samples revealed that the number of ODZ1-positive cells inversely correlated with overall and progression-free survival. Our findings establish a novel marker of invading GBM cells and consequently a potential marker of disease progression and a therapeutic target in GBM.

High genetic diversity declines towards the geographic range periphery of Adonis vernalis, a Eurasian dry grassland plant.

Genetic diversity is important for species' fitness and evolutionary processes but our knowledge on how it varies across a species' distribution range is limited. The abundant centre hypothesis (ACH) predicts that populations become smaller and more isolated towards the geographic range periphery - a pattern that in turn should be associated with decreasing genetic diversity and increasing genetic differentiation. We tested this hypothesis in Adonis vernalis, a dry grassland plant with an extensive Eurasian distribution. Its life-history traits and distribution characteristics suggest a low genetic diversity that decreases and a high genetic differentiation that increases towards the range edge. We analysed AFLP fingerprints in 28 populations along a 4698-km transect from the geographic range core in Russia to the western range periphery in Central and Western Europe. Contrary to our expectation, our analysis revealed high genetic diversity (range of proportion of polymorphic bands = 56-81%, He = 0.168-0.238) and low genetic differentiation across populations (Φ(ST) = 0.18). However, in congruence with the genetic predictions of the ACH, genetic diversity decreased and genetic differentiation increased towards the range periphery. Spanish populations were genetically distinct, suggesting a divergent post-glacial history in this region. The high genetic diversity and low genetic differentiation in the remaining A. vernalis populations is surprising given the species' life-history traits and points to the possibility that the species has been widely distributed in the studied region or that it has migrated from a diverse source in an East-West direction, in the past.

El receptor del factor de crecimiento epidérmico (EGFR) en el glioblastoma: mecanismo de tumorigénesis y papel como diana terapéutica / Epidermic growth factor receptor (EGFR) in glioblastomas: the mechanism of tumorigenesis and its role as a therapeutic target

El glioblastoma es un tumor cerebral primario muy agresivo y resistente al tratamiento convencional con quimio y radioterapia. Dado que el receptor del factor de crecimiento epidérmico (EGFR) se encuentra alterado en el 50% de los glioblastomas, representa actualmente una de las dianas terapéuticas más prometedoras en este tipo de tumores. Sin embargo, los inhibidores de la actividad cinasa del EGFR han generado escasos resultados en ensayos clínicos con pacientes con glioblastoma. En esta revisión se analiza la función del EGFR en el glioblastoma y se describen las aproximaciones terapéuticas dirigidas frente a dicho receptor en este tipo de tumores. Este tipo de análisis podría constituir un punto de partida para mejorar el diseño de futuras terapias para los glioblastomas, basadas en la inhibición de la función del EGFR (AU)

A glioblastoma is a primary brain tumour that is very aggressive and resistant to conventional treatment with chemo- or radiotherapy. Given that epidermic growth factor receptor (EGFR) is altered in 50% of glioblastomas, it is currently one of the most promising therapeutic targets in this kind of tumour. Yet, inhibitors of the kinase activity of EGFR have yielded poor results in clinical trials with patients with glioblastomas. In this review we analyse the function of EGFR in glioblastomas and outline the therapeutic approaches aimed against this receptor in this kind of tumour. This sort of analysis could be a starting point for improving the design of future therapies for glioblastomas, based on inhibiting the EGFR function (AU)

DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis.

DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a kinase with multiple implications for embryonic development, especially in the nervous system where it regulates the balance between proliferation and differentiation of neural progenitors. The DYRK1A gene is located in the Down syndrome critical region and may play a significant role in the developmental brain defects, early neurodegeneration, and cancer susceptibility of individuals with this syndrome. DYRK1A is also expressed in adults, where it might participate in the regulation of cell cycle, survival, and tumorigenesis, thus representing a potential therapeutic target for certain types of cancer. However, the final readout of DYRK1A overexpression or inhibition depends strongly on the cellular context, as it has both tumor suppressor and oncogenic activities. Here, we will discuss the functions and substrates of DYRK1A associated with the control of cell growth and tumorigenesis with a focus on the potential use of DYRK1A inhibitors in cancer therapy.

Fracturas conminutas de la cabeza radial: estudio comparativo entre resección y fijación interna / Radial head comminuted fractures: a comparative study between resection and internal fixation

Introducción. El tratamiento de las fracturas de cabeza radial continúa siendo controvertido. La reducción abierta y fijación interna (RAFI) está en expansión debido a la mejora de las técnicas y los implantes. Sin embargo, puede ser técnicamente muy demandante y no está exenta de complicaciones. Por otra parte, la resección muestra resultados satisfactorios a largo plazo en codos estables, aunque también asocia complicaciones. Comparamos la resección y la RAFI en fracturas conminutas de la cabeza de radio. Material y método. Se incluyeron 23 pacientes con fracturas Mason tipo iii, 11 sometidos a resección de la cabeza del radio (Grupo A), y 12 a fijación interna de su fractura (Grupo B). La media de edad fue 54 y 45 años, respectivamente. Las fracturas fueron evaluadas clínica y radiológicamente; con un seguimiento medio de 80 meses en el Grupo A y 76 en el B. Resultados. El rango de movilidad fue de 121°–(−11°) de flexo-extensión en el grupo A y de 131°–0° en el grupo B. Según la escala de Broberg y Morrey los resultados funcionales obtenidos son: 82 puntos en el Grupo A y 90,9 puntos en el Grupo B. Discusión. Los pacientes con fracturas conminutas de la cabeza del radio sometidos a reducción abierta y fijación interna tienen un rango de movilidad articular satisfactorio, con mayor fuerza y por tanto, mejor función. Recomendamos la reducción abierta y fijación interna en el tratamiento de estas fracturas, sobre todo en pacientes jóvenes (AU)

Introduction. The treatment of radial head fractures continues to be controversial. The open reduction and internal fixation (ORIF) method is expanding due to improvements in the techniques and the implants. However, it can be very demanding technically and is not free of complications. On the other hand, resection shows satisfactory results in the long term in stable elbows, although it is also associated with complications. We compared resection and ORIF in comminuted fractures of the radial head. Material and Method. A total of 23 patients with type III Mason fractures were included, of which 11 were subjected to resection of the radial head (Group A), and 12 to internal fixation of their fracture (Group B). The mean age was 54 and 45 years, respectively. The fractures were clinically and radiologically evaluated, with a mean follow-up of 80 months in Group A and 76 months in Group B. Results. The flexion-extension movement range was 121°–(−11°) in Group A and 131°–0° in Group B. The functional results obtained according the Broberg and Morrey scale were: 82 points in Group A and 90.9 points in Group B. Discussion. Patients with comminuted fractures of the radial head subjected to open reduction and internal fixation have a satisfactory movement range, with greater strength, and therefore, better function. We recommend open reduction and internal fixation in the treatment of these fractures, particularly in young patients (AU)

Chemical composition and antiradical activity of the essential oil from Satureja intricata, S. obovata and their hybrid Satureja x delpozoi.

Satureja x delpozoi is a hybrid found in south-eastern Spain, in a population in which both parents S. intrincata and S. obovata are found together. This work presents for the first time the volatile profile and antioxidant activity of the essential oils of this hybrid. The volatile profile of the essential oils from S. x delpozoi underlines the hybrid character of these plants since the p-cymene, gamma-terpinene, camphor and thymol concentrations in hybrid 1, and the same components, along with alpha-terpineol concentrations in hybrid 2, showed intermediate values with respect to the values observed in the parents. As regards the antioxidant capacity, the phenolic content of S. intrincata resulted in its essential oil having the greatest activity against the DPPH* and ABTS*+ radicals. Both hybrids showed low activity against these radicals, although S. obovata showed none. On the bases of their essential oil composition and antioxidant capacity, these results corroborate the hybrid character of these two S. x delpozoi plants.

Artrodesis tibioastragalocalcánea con clavo intramedular retrógado / Tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail

Introducción: El objetivo es valorar los resultados de los pacientes intervenidos de artrodesis tibioastragalocalcánea con clavo intramedular retrógrado. Material y métodos: Se presentan 8 pacientes con una edad media de 60 años con afectación de las articulaciones tibioastragalina y subastragalina con alteración importante de la marcha y dolor intenso, secundarias a artrosis primaria o postraumáticas, seudoartrosis de una artrodesis previa o deformidad grave secundaria a accidente cerebrovascular. Se trató a los pacientes mediante artrodesis tibioastragalocalcánea con clavo intramedular retrógrado, con valoración de los resultados funcionales antes y después de la cirugía, según los criterios de la AOFAS (American Orthopaedic Foot and Ankle Society). Resultados: El seguimiento medio fue de 32 meses (rango: 7 a 61), y los resultados fueron muy satisfactorios, con una puntuación media de 88,6 puntos. Resultados: El tiempo medio de consolidación fue de 18,3 semanas. Las complicaciones más frecuentes fueron una leve necrosis cutánea de los bordes de la herida, una úlcera plantar resuelta con tratamiento conservador y una discrepancia de longitud de 2 cm. Conclusión: La artrodesis tibiotalocalcánea con clavo retrógrado puede ser una técnica excelente en pacientes con afectación grave de las articulaciones tibioastragalina y subastragalina que no respondan al tratamiento conservador y como cirugía de rescate en aquellas técnicas de artrodesis que hayan fracasado previamente (AU)

Introduction: The purpose of this study is to assess the results of patients subjected to a tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail. Materials and methods: We studied 8 patients of a mean age of 60 years that showed involvement of the tibiotalar and subtalar joints with significant gait alterations and acute pain, secondary to either primary or post-traumatic arthritis or pseudoarthrosis of a previous arthrodesis. There was also one case of a severe deformity secondary to acute stroke. Patients were treated by means of tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail. The AOFAS scale was used to assess functional results before and after surgery. Results: Mean follow-up was 32 months (range: 7–61). Overall results were highly satisfactory, with a mean score of 88.6 points. Results: Healing occurred alter a mean 18.3 weeks. The most frequent complications were an instance of mild skin necrosis at the edges of the wound, a plantar ulcer that resolved with conservative treatment and a leg length discrepancy of 2cm.ConclusionTibiotalocalcaneal arthrodesis with a retrograde nail can be an excellent technique for patients with severe involvement of the tibiotalar and subtalar joints who are unresponsive to conservative treatment. It can also be used as salvage surgery in previously failed arthrodesis procedures (AU)

Tratamiento de la fractura y luxación de la articulación sacroilíaca mediante un acceso anterior extraperitoneal / Treatment of iliosacral joint fracture dislocations by means of an extraperinoneal approach

Objetivo: Valorar los resultados del tratamiento de las fracturas del ala ilíaca con afectación de la articulación sacroilíaca mediante una reducción abierta y una fijación interna con placas a través de abordaje anterior extraperitoneal de la articulación sacroilíaca. Material y método: Se han revisado las fracturas de pelvis tratadas en el hospital y se han recogido los datos epidemiológicos de aquéllas en las que el patrón de lesión posterior correspondía a una fractura que alcanzaba la articulación sacroilíaca. En los 14 casos incluidos en el estudio se realizó la valoración funcional según la escala de Majeed y la valoración radiológica según la clasificación propuesta por Matta. Resultados: Al realizar la valoración funcional, en 8 casos se consiguió un resultado excelente, en 5 casos se consiguió un resultado bueno y sólo en un caso el resultado fue malo. De acuerdo con la valoración radiológica postoperatoria, la reducción fue excelente en 10 casos y fue buena en los 4 casos restantes. No se produjo ninguna pérdida de reducción ni complicaciones mayores. Conclusiones: La técnica descrita confiere suficiente estabilidad para la consolidación de las fracturas y su incidencia de complicaciones es pequeña. Se indica especialmente en los sujetos politraumatizados a los que se desaconsejan posiciones distintas al decúbito supino, cuando hay compromiso de partes blandas posteriores y en aquellos casos en que se precisa realizar una reducción abierta de la fractura (AU)

Purpose: To assess the outcome of addressing iliac wing fractures with involvement of the iliosacral joint by means of open reduction and internal fixation (ORIF) with plates, using an anterior extraperitoneal approach. Materials and methods: We reviewed pelvic fractures treated in our hospital, collecting epidemiological data of those with a posterior injury pattern that corresponded to a fracture affecting the iliosacral joint. For all 14 cases included in the study, we carried out a functional assessment according to the Majeed scale, as well as a radiological evaluation according to the Matta classification. Results: The functional assessment revealed that an excellent result was achieved in 8 cases and a good result in 5. A poor outcome was obtained in one single case. According to the postoperative radiological evaluation, reduction was excellent in 10 cases and good in the remaining 4. There was no loss of reduction or any major complications. Conclusions: The technique described in our paper affords sufficient stability for fracture healing and it is associated with a low incidence of complications. It is especially indicated for multiple-trauma patients where the only position recommended in the supine one, for cases where the posterior soft tissues are compromised, and for instances when an open reduction of the fracture is needed (AU)

Lesión de Monteggia inveterada. Resultados con la técnica de Bell-Tawse modificada en tres casos / Inveterate Monteggia Injury. Results with the modified Bell-Tawse procedure in three cases

Objetivo: La lesión de Monteggia es poco frecuente (el 2% de las fracturas de la región del codo) y los casos inveterados son muy raros. A continuación se presentan 3 casos tratados mediante reducción abierta y reconstrucción del ligamento anular con fascia tricipital. Casos clínicos: La edad media de los 3 sujetos era de 7 años (rango de 5 a 9), 2 de ellos eran varones y todos presentaban lesiones tipo i de Bado en el lado derecho. Los 3 recibieron tratamiento mediante técnica de Bell-Tawse modificada por Lloyd-Roberts y Bucknill; en un enfermo se asoció osteotomía cubital. Resultados: No se presentaron complicaciones. Tras un seguimiento medio de 35 meses (rango de 9 a 84) todos los sujetos consiguieron un arco de flexoextensión funcional con una pérdida leve de pronosupinación, pero no se detectaron restricciones en las actividades de la vida diaria ni déficit funcional. Conclusiones: La técnica de Bell-Tawse modificada es un método efectivo, aun cuando produce una pérdida leve de movilidad, especialmente de pronosupinación. Los resultados a largo plazo de esta técnica son mejores que los que se consiguen con la escisión tardía de la cabeza radial luxada (AU)

Purpose: Monteggia injuries are a rare occurrence (2% of all elbow fractures), and inveterate cases are extremely unusual. We present 3 cases treated by means of open reduction and reconstruction of the annular ligament with a strip of triceps fascia. Case reports: The mean age of the 3 patients was 7 years (range: 5–9). Two of them were male and all presented with type 1 Bado injuries on the right side. All 3 were treated by means of the Bell-Tawse technique as modified by Lloyd-Roberts and Bucknill; one of the patients was also subjected to ulnar osteotomy. Results: There were no complications. After a mean follow-up of 35 months (range: 9–84) all patients achieve a functional flexion-extension range. They experienced a slight loss of pronosupination but they reported no restrictions to their activities of daily living or any functional impairment. Conclusions: The modified Bell-Tawse technique is an effective method, even if it leads to a slight loss of mobility, especially in terms of pronosupination. The long-term results of this technique are better than those achieved with a late excision of the dislocated radial head (AU)

The phylogeographical history of the Iberian steppe plant Ferula loscosii (Apiaceae): a test of the abundant-centre hypothesis.

The geology and climate of the western Mediterranean area were strongly modified during the Late Tertiary and the Quaternary. These geological and climatic events are thought to have induced changes in the population histories of plants in the Iberian Peninsula. However, fine-scale genetic spatial architecture across western Mediterranean steppe plant refugia has rarely been investigated. A population genetic analysis of amplified fragment length polymorphism variation was conducted on present-day, relict populations of Ferula loscosii (Apiaceae). This species exhibits high individual/population numbers in the middle Ebro river valley and, according to the hypothesis of an abundant-centre distribution, these northern populations might represent a long-standing/ancestral distribution centre. However, our results suggest that the decimated southern and central Iberian populations are more variable and structured than the northeastern ones, representing the likely vestiges of an ancestral distribution centre of the species. Phylogeographical analysis suggests that F. loscosii likely originated in southern Spain and then migrated towards the central and northeastern ranges, further supporting a Late Miocene southern-bound Mediterranean migratory way for its oriental steppe ancestors. In addition, different glacial-induced conditions affected the southern and northern steppe Iberian refugia during the Quaternary. The contrasting genetic homogeneity of the Ebro valley range populations compared to the southern Iberian ones possibly reflects more severe bottlenecks and subsequent genetic drift experienced by populations of the northern Iberia refugium during the Pleistocene, followed by successful postglacial expansion from only a few founder plants.

Fractura-luxación de Lisfranc. Osteosíntesis con tornillos frente a agujas de Kirschner / Lisfranc fracture-dislocation: screw vs. K-wire fixation

Introducción. La fractura-luxación de la articulación tarsometatarsiana es una lesión relativamente infrecuente, pero cuyas consecuencias a largo plazo pueden ser devastadoras para el paciente. El objetivo de este estudio fue analizar los resultados del tratamiento quirúrgico.Material y método. Los autores presentan una revisión de26 pacientes tratados entre los años 1995 y 2006. Las fracturas fueron clasificadas según Myerson y Hardcastle. Todos los pacientes fueron tratados quirúrgicamente de urgencia usando tornillos o agujas de Kirschner. Para la valoración de resultados se utilizó la escala de valoración funcional de la AOFAS para el mediopié, analizando también el grado de satisfacción subjetiva de los pacientes.Resultados. Tras un seguimiento medio de 5 años, la puntuación media en la escala AOFAS fue de 85,38 puntos,siendo el grado de satisfacción alto en casi todos los pacientes. Los resultados conseguidos en la osteosíntesis con tornillos fueron ligeramente superiores a los obtenidos con agujas de Kirschner.Conclusiones. Como la mayoría de autores, recomendamosla urgente reducción y síntesis de la lesión para conseguir los mejores resultados, descartando como opción el tratamiento ortopédico e inclinándonos por una reducción abierta y fijación interna con tornillos, siempre que el estado de las partes blandas lo permita

Introduction. Fracture-dislocations of the tarso-metatarsal joint are a relatively rare injury, but their long-term consequences can be devastating for the patient. The aim of this study is to analyze the results obtained by surgical treatment.Materials and methods. The authors reviewed 26 patientsbetween 1995 and 2006. Fractures were classified according to the Myerson & Hardcastle classification. All patients were treated by emergency surgery by means of either screws or K-wires. The AOFAS functional scale was used to assess results in the midfoot; patient satisfaction was also evaluated.Results. After a mean 5-year follow-up, the mean score onthe AOFAS scale was 85.38 points, with a high level of satisfaction in nearly all patients. Results obtained with screw fixation were slightly better than those with K-wires.Conclusions. Like most authors, we believe that the best results are to be obtained by the immediate reduction and fixation of the injury. We rule out nonoperative treatment and favor an ORIF procedure with screws provided that the condition of the soft tissues allows it

Dolor suprapúbico en escolar de 14 años / Suprapubic pain in a 14 year old schoolchild

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Genetic variability in a narrow endemic snapdragon (Antirrhinum subbaeticum, Scrophulariaceae) using RAPD markers.

Antirrhinum subbaeticum is an endangered species inhabiting fragmented limestone cliffs. In the last 3 years, a drastic population decline has been observed in three of four known populations and the estimated number of surviving individuals is now close to 400. A RAPD study was conducted to evaluate the levels of genetic variation present in this species to improve conservation guidelines. Thirty-nine polymorphic products identified 66.1% of the samples by unique RAPD multilocus profiles. A cluster analysis grouped the samples into two broad groups corresponding to northern or southern provenances. AMOVA analysis showed that only 17.7% of the genetic diversity was partitioned within populations. These results are in contrast to data available for other Antirrhinum species. This genetic structure could be explained by the predominant selfing behaviour exhibited by A. subbaeticum as opposed to the allogamy of other congeners. Genetic diversity within populations does not seem to be strongly related to population size and historical factors could be responsible for the very low levels of genetic diversity found in one population. Given the low genetic diversity within populations, it is suggested that an extensive sampling of individuals be made for recovering appropriate levels of the gene pool for ex situ preservation. However, translocation of individuals to the genetically weakened Bogarra population from other sources is not recommended.