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[ES] En el estudio del mecanismo etiopatogénico de la IVC se ha analizado el papel de la hipoxia de la pared venosa como una de las variables en la presentación y progresión de la enfermedad varicosa. Asimismo, el desarrollo de las varices recurrentes por reaparición de un neocayado safenofemoral angiogénico, se produce en un entorno cicatricial donde la hipoxia y la inflamación locales, constituyen estímulos fundamentales en la cascada de señalización. El conocimiento en biología molecular de la respuesta a la hipoxia y la responsabilidad de HIF y de VEGF y sus receptores en la secuencia angiogénica, han sido ampliamente estudiados en oncología, diseñando terapias antiangiogénicas inhibidores de esas moléculas. Sin embargo, su protagonismo en la etiopatogenia de la IVC y de manera especial en la recurrencia varicosa por un neocayado neoangiogénico no ha sido tan extensamente estudiado. Endoglina es una proteína fundamental en la fisiología endotelial y actúa modulando la angiogénesis y la inflamación, junto con otras moléculas proangiogénicas o antiangiogénicas e inflamatorias, por lo que pudiera tener participación en la IVC. Por todo ello, si determinados aspectos biomoleculares de la fisiopatología de la IVC permanecen desconocidos, y la angiogénesis está implicada en el desarrollo de varices y en especial en su recidiva, la hipótesis a plantear es, que ciertas moléculas relacionadas con la angiogénesis y más concretamente endoglina como molécula menos estudiada., podrían estar involucradas tanto en el desarrollo de las varices esenciales como en su recidiva. En cuanto a los objetivos, los primarios serían: 1. Determinar los niveles en muestras de tejido biópsico de diferentes marcadores de angiogénesis HIF, VEGF, VEGFR-1, VEGFR-2 y Endoglina en un subgrupo de pacientes sin enfermedad varicosa, en un segundo subgrupo de pacientes aquejados de varices esenciales y sometidos a safenectomía interna según la técnica standard y en un tercer subgrupo de pacientes con varices recidivadas por la presentación de un neocayado angiogénico. 2. Medir las concentraciones séricas en plasma de tales factores solubles angiogénicos de forma basal previamente a la intervención quirúrgica y a los tres meses de haber sido intervenidos. Y, finalmente, los secundarios son: 1. Analizar si cambios en la expresión de endoglina pudiesen estar relacionados con un mayor riesgo de desarrollo de la enfermedad varicosa primaria y si en las recurrencias por neocayados en la unión safenofemoral, endoglina pudiese estar relacionada con una angiogénesis excesiva o descontrolada. 2. Investigar si hay diferencias entre las concentraciones de factores angiogénicos en dependencia de la zona de tejido biopsiada de la proximidad del cayado de la unión safenofemoral y de las varices tronculares distales. 3. Estudiar si las determinaciones de los marcadores pueden presentar correlación con el grado evolutivo de expresión clínica de la enfermedad en general, y en particular si es enfermedad primaria o recurrente. Si tales hipótesis fuesen correctas, plantear si el uso de fármacos que regulasen la expresión de endoglina pudiese estar indicado en la prevención de la recidiva en subgrupos de pacientes con un mayor riesgo.

RESUMEN : El cáncer de mama es uno de los tumores de mayor frecuencia a nivel mundial, principalmente en mujeres. Su incidencia se ve influenciada por factores tales como la edad, la predisposición genética o el nivel socioeconómico. Actualmente existe un programa de cribado para detectarlo y tratarlo de manera precoz. La angiogénesis es un proceso fisiológico, pero que en los tumores se da de manera patológica dando lugar a una neovascularización aberrante que favorece el crecimiento y progresión tumorales. En condiciones normales, existe un equilibrio entre factores pro- y anti-angiogénicos. En los tumores ese equilibrio se pierde, predominando aquellos que promueven la neovascularización, y ese desbalance se perpetua influenciado por diversos factores (hipoxia, niveles bajos de melatonina…). En los últimos años se ha estudiado la angiogénesis y se han desarrollado posibles tratamientos dirigidos en base a la hipótesis de que, al detener la formación de neovasos, se impide el crecimiento tumoral y se dificulta la diseminación tanto local como a distancia. En esta revisión recogemos datos actualizados de la angiogénesis, el cáncer de mama, así como de los tratamientos de éste, tanto convencionales como dirigidos a la angiogénesis. ABSTRACT : Breast cancer is one of the most frequent tumors globally, mainly in women. Its incidence is influenced by factors such as age, genetic predisposition, or socioeconomic status. Nowadays there is a screening program to detect and treat it in an early stage. Angiogenesis is a physiological process that occurs aberrantly in cancer, leading to pathological neovascularization which promotes tumor growth and progression. Under normal conditions, there is a balance between proangiogenic and antiangiogenic factors. In tumors, that balance is disrupted, predominating those factors that promote neovascularization, and that imbalance is perpetuated and influenced by various factors, including hypoxia and melatonin decreased levels. Over the last few years, angiogenesis has been studied and there have been developed some potential targeted treatments based on the hypothesis that by stopping the neovessel formation, tumor growth, local and distant metastases are impeded. In this review, we collect data about angiogenesis, breast cancer, conventional treatments, and angiogenesis-targeted treatments. Grado en Medicina

Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX&reg, Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30, 95% CI: 1.52&ndash, 7.14, p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.

Preclinical evidence indicates the potential of targeting mitochondrial respiration as a therapeutic strategy. We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Using molecular imaging, we showed how the same antiangiogenic agent may display different normalizing properties in patients with the same tumor type. This is of key importance, since patients experiencing normalization seem to get more benefit from standard chemotherapy combinations, and also could be eligible for combination with antimitochondrial agents. This scenario emphasizes the need for monitoring vascular normalization in order to optimize the use of antiangiogenics. We have also proposed a method to evaluate anti-mitochondrial agents' pharmacodynamics; despite promising accuracy in animal studies the clinical results were inconclusive, highlighting the need for research in this field. Regarding patients that respond to antiangiogenics increasing vessel abnormality, in this case an immunosuppressive tumor microenvironment is generated. Whether anti-mitochondrial agents can positively modulate the activity of T effector cell subpopulations remains an area of active research. Our research sheds light on the importance of refining the use of antiangiogenics, highlighting the relevance of tracing vascular normalization as a potential biomarker for antiangiogenics to assist patient-tailored medicine and exploring the role of mitochondrial inhibitors in the context of vascular normalization and correction of hypoxia. Sí

[Simple Summary] Solitary fibrous tumor (SFT) is a malignant condition that exhibits different clinical behaviors ranging from low to high aggressive SFT, with dedifferentiated SFT (DD-SFT) being the fastest-growing subtype. Even when surgery alone provides curation rates above 60%, recurrences do occur in a fraction of patients where surgery is unable to provide disease control. Among the systemic therapeutic options, antiangiogenic compounds have shown higher efficacy than chemotherapy by indirect comparisons. Furthermore, rotating different antiangiogenics, at the progression time, has been shown to be effective. The exception is DD-SFT since it is resistant to antiangiogenics but can respond to chemotherapy. This comprehensive review also analyzes the underlying molecular components that play a key role in SFT origin and aggressiveness. The discovery in 2013 of anomalous fusion genes between NAB2 and STAT6 was determinant to increase the knowledge on the molecular drivers in SFT that could be potential targets for future therapies. Solitary fibrous tumor (SFT) is a rare mesenchymal, ubiquitous tumor, with an incidence of 1 new case/million people/year. In the 2020 WHO classification, risk stratification models were recommended as a better tool to determine prognosis in SFT, to the detriment of “typical” or “malignant” classic terms. The risk for metastasis is up to 35–45%, or even greater, in series with a longer follow-up. Over the last few decades, advances in immunohistochemistry and molecular diagnostics identified STAT6 nuclear protein expression and the NAB2–STAT6 fusion gene as more precise tools for SFT diagnosis. Recent evidence taken from retrospective series and from two prospective phase II clinical trials showed that antiangiogenics are active and their sequential use from first line should be considered, except for dedifferentiated SFT for which chemotherapy is the best option. Since the fusion transcript driver’s first description in 2013, new insights have been brought on key molecular events in SFT. This comprehensive review mainly focuses on the superior efficacy of antiangiogenics over chemotherapeutic agents in SFT, provides the current knowledge of key molecules that could co-drive the SFT behavior, and suggests new target candidates that deserve to be explored in preclinical and clinical research in SFT. The authors would also like to thank the SELNET project. SELNET has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 825806. Furthermore, the authors would like to thank the Instituto de Salud Carlos III (ISCIII)—Fondo Europeo de Desarrollo Regional (FEDER), project reference PI18/01728. David S. Moura is the recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155). José L. Mondaza-Hernandez is the recipient of a PFIS predoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (FI19/00184).

Neurokinin-1 receptor (NK-1R) antagonists exert antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exert multiple actions against cancer: antiproliferative and anti-Warburg effects and apoptotic, anti-angiogenic and antimetastatic effects. These multiple effects have been shown for a broad spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as an antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed, as is the possible link, through the substance P (SP)/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant, and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent. Yes

In atherosclerosis, circulating angiogenic cells (CAC), also known as early endothelial progenitor cells (eEPC), are thought to participate mainly in a paracrine fashion by promoting the recruitment of other cell populations such as late EPC, or endothelial colony-forming cells (ECFC), to the injured areas. There, ECFC replace the damaged endothelium, promoting neovascularization. However, despite their regenerative role, the number and function of EPC are severely affected under pathological conditions, being essential to further understand how these cells react to such environments in order to implement their use in regenerative cell therapies. Herein, we evaluated the effect of direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. By using a quantitative proteomics approach, 194 altered proteins were identified in the secretome of pre-conditioned CAC, many of them related to inhibition of angiogenesis (e.g., endostatin, thrombospondin-1, fibulins) and cell migration. Functional assays corroborated that healthy CAC released factors enhanced ECFC angiogenesis, but, after atherosclerotic pre-conditioning, the secretome of pre-stimulated CAC negatively affected ECFC migration, as well as their ability to form tubules on a basement membrane matrix assay. Overall, we have shown here, for the first time, the effect of atherosclerotic factors over the paracrine role of CAC ex vivo. The increased release of angiogenic inhibitors by CAC in response to atherosclerotic factors induced an angiogenic switch, by blocking ECFC ability to form tubules in response to pre-conditioned CAC. Thus, we confirmed here that the angiogenic role of CAC is highly affected by the atherosclerotic environment.

Hipótesis De la compleja red de interrelaciones entre angiogénesis y adipogénesis descripta, se deduce la interdependencia de ambos procesos. Para obtener evidencia experimental que la demuestre, se proponen los siguientes objetivos. Objetivo general Evaluar el efecto in vivo de la inhibición general de la angiogénesis sobre el tejido adiposo visceral y los procesos de proliferación y diferenciación de las CPA de su Fracción Estroma Vascular. Objetivos específicos 1. Desarrollar un modelo in vivo de inhibición farmacológica de la angiogénesis, verificando su efecto a los 15 días post-tratamiento. 2. Determinar la concentración de marcadores metabólicos y endocrinos circulantes que podrían afectar la función del tejido adiposo: glucosa, insulina, colesterol total, triglicéridos, NEFA, leptina y TBARS. 3. Evaluar los cambios morfológicos del TAV como resultado del tratamiento. 4. Evaluar el impacto del tratamiento sobre la capacidad proliferativa in vitro de las células de la FEV 5. Evaluar la expresión de marcadores de superficie de la población de células de la FEV en ambos grupos mediante citometría de flujo. 6. Evaluar las señales intracelulares con acción reguladora conocida sobre la angiogénesis y los procesos de proliferación y diferenciación adipocitaria, en tres estadios celulares: células de la FEV, células proliferadas in vitro sin diferenciar (día 0) y células proliferadas y diferenciadas in vitro (día 10)., Facultad de Ciencias Exactas

La osteonecrosis de los maxilares asociada a la medicación, es un efecto secundario adverso al uso de ciertos medicamentes que, a pesar de ser relativamente poco frecuente, sus efectos son graves. Si bien la osteonecrosis asociada al tratamiento crónico con bifosfonatos es la más conocida, dicha patología también se encuentra relacionada al uso de otras drogas antirresortivas o antiangiogénicos. El objetivo de este estudio fue revisar la bibliografía disponible y actualizar los conocimientos sobre osteonecrosis de los maxilares. Se buscaron artículos referidos a esta patología en bases de datos PubMed y Scholar Google y se los clasificaron de acuerdo a la temática. Estudios epidemiológicos y clínicos resumen las discusiones y controversias de diferentes grupos de expertos sobre la definición, epidemiología, factores de riesgo, fisiopatología, clasificación, manifestaciones clínicas, tratamiento y prevención de esta patología. La osteonecrosis afecta a los huesos maxilares y generalmente se produce luego de una intervención odontológica. Es importante tomar las medidas necesarias para su prevención antes de comenzar con el tratamiento farmacológico, e indicarle al paciente los riesgos del mismo. Es un proceso extremadamente complejo y multifactorial, que requiere un seguimiento cuidadoso e individual para cada paciente. Esta patología se considera una condición irreversible, y por lo tanto los esfuerzos deben estar dirigidos a su prevención, tanto antes como después del inicio de la terapia farmacológica. Todavía hay controversias con respecto a su etiopatogenia, incidencia o tratamiento. Más estudios son necesarios para poder llegar a un consenso. Osteonecrosis of the jaw, associated with medication, is an adverse side effect of the use of certain medications that, although relatively rare, have serious effects. Although osteonecrosis associated with chronic treatment with bisphosphonates is the best known, this pathology is also related to the use of other anti-resortive or antiangiogenic drugs. The aim of this study was to review the available literature and update the knowledge about osteonecrosis of the jaws. Articles referring to this pathology were searched in PubMed and Scholar Google databases and classified according to the subject. Epidemiological and clinical studies summarize the discussions and controversies of different groups of experts on the definition, epidemiology, risk factors, physiopathology, classification, clinical manifestations, treatment and prevention of this pathology. Osteonecrosis affects the jaw bones and usually follows dental surgery. It is important to take the necessary measures for its prevention before starting the pharmacological treatment, and to indicate its risks to the patient. It is an extremely complex and multifactorial process, which requires careful and individual follow-up for each patient. This pathology is considered an irreversible condition, and therefore efforts should be directed towards its prevention, both before and after the start of drug therapy. There are still controversies regarding its etiopathogenesis, incidence or treatment. More studies are needed to reach a consensus. A osteonecrose dos maxilares associada à medicação é um efeito colateral adverso devido ao emprego de medicamentos que, apesar de relativamente estranhos, seus efeitos são graves. Embora a osteonecrose associada ao tratamento crônico com bifosfonatos seja a mais conhecida, essa patologia também está relacionada ao uso de outras drogas antirreabsortivas ou antiangiogênicas. O objetivo deste estudo foi revisar a bibliografia disponível e atualizar o conhecimento sobre osteonecrose dos maxilares. Consultados os artigos referentes a essa patologia nas bases de dados do PubMed e Scholar Google e eles foram classificados de acordo com o assunto. Estudos epidemiológicos e clínicos resumem as crises e controvérsias de diferentes grupos de especialistas sobre definição, epidemiologia, fatores de risco, fisiopatologia, classificação, manifestações clínicas, tratamento e prevenção dessa doença. A osteonecrose afeta os ossos maxilares e geralmente ocorre após a cirurgia dentária. É importante tomar medidas preventivas antes de iniciar o tratamento farmacológico e indicar ao paciente seus riscos. É um processo extremamente complexo e multifatorial, que requer monitoramento cuidadoso e individual para cada paciente. Essa patologia é considerada uma condição irreversível e, portanto, os esforços devem ser direcionados à sua prevenção, antes e após o início da terapia farmacológica. Ainda existem controvérsias quanto à sua etiopatogenia, incidência ou tratamento. Mais estudos são necessários para chegar a um consenso. Fil: Avendaño, María Eugenia. Universidad Nacional de Cuyo. Facultad de Odontologia; Argentina Fil: Zeni, Susana Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina

El hemangioendotelioma epitelial es una neoplasia poco frecuente, y tiene su origen en el endotelio vascular. Puede crecer en varios órganos y tejidos. No hay ningún esquema terapéutico aprobado y el pronóstico es impredecible. Se presenta el caso de un paciente masculino de 54 años de edad, con el diagnóstico de hemangioendotelioma epitelioide pulmonar, con imagen atípica y la presentación clínica y la participación de múltiples órganos en el momento del diagnóstico. El paciente no comenzó la quimioterapia y murió dos meses después del diagnóstico histológico. Debido a la rareza de esta neoplasia y la inexistencia de régimen terapéutico aprobado, al reportar este caso, tenemos la intención de contribuir a los estudios clínicos futuros.

Previous observations indicated that C3G (RAPGEF1) promotes a-granule release, evidenced by the increase in P-selectin exposure on the platelet surface following its activation. The goal of the present study is to further characterize the potential function of C3G as a modulator of the platelet releasate and its implication in the regulation of angiogenesis. Proteomic analysis revealed a decreased secretion of anti-angiogenic factors from activated transgenic C3G and C3GΔCat platelets. Accordingly, the secretome from both transgenic platelets had an overall pro-angiogenic effect as evidenced by an in vitro capillary-tube formation assay with HUVECs (human umbilical vein endothelial cells) and by two in vivo models of heterotopic tumor growth. In addition, transgenic C3G expression in platelets greatly increased mouse melanoma cells metastasis. Moreover, immunofluorescence microscopy showed that the pro-angiogenic factors VEGF and bFGF were partially retained into a-granules in thrombin- and ADP-activated mouse platelets from both, C3G and C3GΔCat transgenic mice. The observed interaction between C3G and Vesicle-associated membrane protein (Vamp)-7 could explain these results. Concomitantly, increased platelet spreading in both transgenic platelets upon thrombin activation supports this novel function of C3G in a-granule exocytosis. Collectively, our data point out to the co-existence of Rap1GEF-dependent and independent mechanisms mediating C3G effects on platelet secretion, which regulates pathological angiogenesis in tumors and other contexts. The results herein support an important role for platelet C3G in angiogenesis and metastasis., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness [SAF2013-48210-C2-1-R and SAF2016-76588-C2-2-R to CG, SAF2013-48210-C2-2-R and SAF2016-76588-C2-1-R to AP], by two grants from the Council of Education of Junta de Castilla y León, Spain [SA157A12-1 and SA017U16 to CG] and by a grant from the Council of Health of Junta de Castilla y León, Spain [GRS 991/A/14 to FMH]. All funding was cosponsored by the European FEDER Program. VM-G was supported by Dr. Moraza Foundation PhD fellowship. SG-H and CS are recipients of fellowships from the Salamanca University and the Complutense University, respectively

JOURNAL ARTICLE; The emergence of novel drugs corresponds with the determination of the effectiveness of the current treatments used in clinical practice. A retrospective observational study was conducted to evaluate the effectiveness of first-line treatments and to test the influence of the prognostic factors established using the Memorial Sloan-Kettering Cancer Center (MSKCC) and the analysis of Mekhail's study for two or more metastatic sites. The primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS) times. A total of 65 patients were enrolled and the mPFS and mOS of the patients treated with sunitinib (n=51) were 9.0 and 20.1 months, respectively, and for the patients treated with temsirolimus (n=14) these were 3.0 and 6.2 months, respectively. In the poor-prognosis (PP) group, a difference of 1.2 months (P=0.049) was found in mPFS depending on the first-line treatment. A difference of 4.1 months (P=0.023) was also found in mPFS when classified by histology (clear verses non-clear cell) in the sunitinib-treatment group. When stratified by the prognostic group, differences of >7 months (P

Treball Final de Màster Universitari en Química Aplicada i Farmacològica. Codi: SIM138. Curs: 2015/2016 El cáncer no es una única enfermedad sino un término unitario que abarca a más de 200 enfermedades diferentes caracterizadas por el crecimiento y diseminación por el organismo de células mutadas. El cáncer y los problemas cardiovasculares son la principal causa de mortalidad en los países desarrollados. En la figura 1.1 se muestra el porcentaje de incidencia y mortalidad por tipo de cáncer en el año 2012 para toda la población mundial. Se estiman unos 1.4 millones de nuevos casos de cáncer y unos decesos de alrededor de 8.2 millones causa de esta enfermedad.1 Entre los distintos tipos de cáncer destacan, por su elevado nivel de incidencia, el de colon, pulmón, mama y próstata. Las causas del cáncer son muy variadas y dependen de diversos factores de riesgo tales como el tabaquismo, las dietas poco saludables, las radiaciones (rayos X, rayos UV, etc), los virus y las bacterias, la inmunodeficiencia, los agentes carcinogénicos, etc.

BACKGROUND: Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. METHODS: 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE 'rim' geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. RESULTS: Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. CONCLUSION: Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results. This work has been supported by Ministerio de Economía y Competitividad/FEDER, Spain [grant number MTM2015-71200-R], Consejería de Educación Cultura y Deporte from Junta de Comunidades de Castilla-La Mancha, Spain [grant number PEII-2014-031-P] and James S. Mc. Donnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [Special Initiative Collaborative – Planning Grant 220020420 and Collaborative award 220020450]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

La Neurocisticercosis (NCC) es una infección helmíntica que afecta al sistema nervioso central (SNC) causada por el estadio larval de T. solium (cisticerco). Debido a que la alteración vascular y la disrupción de la barrera hematoencefálica (BHE) contribuyen con la patología de NCC, se postula que la angiogénesis podría contribuir con la patogénesis de esta enfermedad. El presente estudio emplea un modelo animal de NCC en ratas y evalúa la expresión de dos factores angiogénicos: el factor de crecimiento vascular endotelial (VEGF-A) y el factor de crecimiento de fibroblastos (FGF2), junto a tres marcadores de disrupción de la BHE: el antígeno de barrera endotelial (EBA), la inmunoglobulina G (IgG) y el fibrinógeno, mediante técnicas de inmunohistoquímica e inmunofluorescencia. Se encontró sobreexpresión de VEGF-A (P=0.0005) y FGF2 (P=0.0233) en el tejido que rodea al cisticerco y se observó sobreexpresión de VEGF-A en astrocitos. Además se encontró la presencia de IgG (P

Background: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. Methods: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. Results: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS >= 2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. Conclusions: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials., We thank the participating investigators: Veronica Calderero, Hospital de Barbastro (Huesca); Juana Cano, Hospital General de Ciudad Real; Nieves Diaz, Hospital Universitario (San Juan - Alicante); Emma Dotor, Hospital Parc Tauli (Sabadell) Barcelona; Maria Pilar Escudero, Hospital Clinico Universitario Lozano Blesa (Zaragoza); Jose Luis Firvida, Complexo Hospitalario Universitario de Ourense; Maria Jose Gomez, Hospital Puerta del Mar (Cadiz); Encarnacion Jimenez, Hospital de Jerez (Cadiz); Luis Leon, Hospital Clinico Universitario (Santiago de Compostela); Natalia Lupion, Hospital de Merida (Badajoz); David Marrupe, Hospital de Mostoles (Madrid); Miguel Navarro, Hospital Clinico Universitario (Salamanca); Miguel Ruiz Lopez de Tejada, Hospital Punta de Europa (Algeciras - Cadiz); Raquel Serrano, Hospital Reina Sofia (Cordoba); Diego Soto, Hospital Clinico Universitario (Valladolid); Alexandre Teule, Institut Catala d'Oncologia, Hospital Duran i Reynals (Barcelona); Francisca Vazquez, Hospital Clinico Universitario (Santiago de Compostela). We thank Ignasi Gich Saladich who provided support for the statistical analyses at the behest of the coordinating investigators and Aurora O'Brate who provided medical writing services subsequent to the initial draft of the manuscript, including requesting additional statistical analyses, collation of all author comments, formatting to adapt to publishing requirements, and help with submission. External commercial funding was not received for the retrospective analysis, but Ipsen Pharma, Spain provided funding for the medical writing services.

Introducción: La retinopatía del prematuro (ROP) se presenta hasta en el 73% de los neonatos pretérmino por debajo de la semana 27, los agentes antiangiogénicos se presentan como una herramienta para su tratamiento con resultados prometedores. En el presente estudio se pretendió evaluar los resultados de la terapia antiangiogénica con ranibizumab en pacientes con retinopatía del prematuro según la evidencia descrita hasta la fecha. Metodología: se realizó una revisión sistemática de literatura con componente meta-analítico de los datos sociodemográficos y clínicos, incluyendo todos los artículos sobre el tema sin límite de fecha de publicación. Se usó una estrategia de búsqueda en diferentes bases de datos, todos los estudios relacionados con el pronóstico de la enfermedad fueron elegibles. Resultados: Se encontraron un total de 13 artículos que cumplieron criterios de elegibilidad para su inclusión, que incluyeron 75 pacientes en total (133 ojos evaluados). La edad promedio al nacimiento fue 23.6 semanas, la edad al momento de aplicación de tratamiento fue 36.3 semanas. 11/13 artículos reportaron que el tratamiento con ranibizumab fue satisfactorio en términos de resolución completa de la enfermedad sin efectos secundarios (64 pacientes) Discusión: Los resultados de la terapia con ranibizumab para retinopatía del prematuro según la evidencia hasta la fecha permiten recomendar el uso de terapia antiangiogénica con el fin de mejorar la salud visual a mediano y largo plazo y por ende disminución en la prevalencia de ceguera por esta causa. Introduction: Retinopathy of prematurity (ROP) occurs in up to 73% of preterm infants before 27 weeks, antiangiogenic agents are presented as a tool for treatment with promising results. This study aimed to evaluate the results of antiangiogenic therapy using ranibizumab in ROP patients according to current described evidence. Methods: A systematic literature review was performed using constituent meta-analysis of the sociodemographic and clinical data, including all articles on the subject without limit on the date of publication. A strategy of searching different databases was used, all studies related to prognosis of the disease were eligible. Results: A total of 13 articles that met eligibility criteria for inclusion were found, which included 75 patients in total (133 evaluated eyes). The average age at birth was 23.6 weeks, the age at time of treatment application was 36.3 weeks. 11/13 papers reported that treatment with ranibizumab was satisfactory in terms of complete resolution of the disease without side effects (64 patients). Discussion: The results of ranibizumab therapy for ROP according to the evidence to date allow the recommendation of use of antiangiogenic therapy in order to improve the visual health in the medium and long term and thus decrease the prevalence of blindness from this cause.

JOURNAL ARTICLE During the last decade, we have been developing new therapeutic strategies for the treatment of renal cancer, based on knowledge derived from molecular biology. We report a case of long-term renal metastatic cancer progression despite therapy with sunitinib and interleukin, which are the most active drugs in renal cancer. Disease stabilization for 58 weeks was achieved upon sequential use of temsirolimus, following the occurrence of disease progression during angiogenic therapy. The patient demonstrated excellent tolerance without marked symptoms for 10 months. Hypothyroidism and mumps-related adverse events were present. The survival time from diagnosis to lung metastasis was 8 years. Thus, this case demonstrates promising therapeutic effects of the sequential use of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors during different stages of the disease. Yes

Introduction: Chondroitin sulfate (CS) is a symptomatic slow-acting drug for osteoarthritis (OA) widely used in the clinic. The aim of this work is to find proteins whose secretion from cartilage cells under proinflammatory stimuli (IL-1β) is regulated by CS, employing a novel quantitative proteomic approach. Methods: Human articular chondrocytes released from three normal cartilages were grown in SILAC medium. When complete incorporation of the heavy isotope was achieved, chondrocytes were stimulated with IL-1β 5 ng/ml with or without CS pretreatment (200 µg/ml). Forty-eight hours later, chondrocyte secretomes were analyzed by nano-scale liquid chromatography-mass spectrometry. Real-time PCR, western blot and immunohistochemistry analyses were employed to confirm some of the results. Results: We could identify 75 different proteins in the secretome of human articular chondrocytes. Eighteen of these were modulated by CS with statistical significance (six increased and 12 decreased). In normal chondrocytes stimulated with IL-1β, CS reduces inflammation directly by decreasing the presence of several complement components (CFAB, C1S, CO3, and C1R) and also indirectly by increasing proteins such as TNFα-induced protein (TSG6). TSG6 overexpression correlates with a decrease in pro-matrix metalloproteinase activation (observed in MMP1 and MMP3 levels). Finally, we observed a strong CS-dependent increase of an angiogenesis inhibitor, thrombospondin-1. Conclusion: We have generated a quantitative profile of chondrocyte extracellular protein changes driven by CS in the presence of IL-1β. We have also provided novel evidences of its anti-angiogenic, anti-inflammatory, and anti-catabolic properties. Demonstration of the anti-angiogenic action of CS might provide a novel therapeutic approach for OA targeting.

RESUMEN: En 1998 la administración federal para medicamentos y alimentos de los Estados Unidos de América (FDA) aprobó la comercialización (con restricciones) de la talidomida para el tratamiento del Eritema nodoso asociado a la lepra. Brasil y México también han reglamentado su uso. Dado que actualmente se utiliza este fármaco teratogénico en enfermedades reumatológicas, dermatológicas, infecciosas y neoplásicas, se impone actualizar al médico general y al especialista, en los tópicos más relevantes del principio activo y sus efectos benéficos y deletéreos. Materiales y métodos: Se realizó una revisión textual mediante la lectura y análisis de los ensayos clínicos controlados, las series de casos y las revisiones de tema concernientes a la talidomida y sus posibles usos, reseñados en Medline entre enero de 1993 y diciembre de 2003, con el fin de extraer indicaciones y contraindicaciones a la luz de las pruebas que en ellos se describen. Además, se revisaron algunos informes de estudios anteriores a 1993, considerados de utilidad en el análisis. Resultados: Se encontraron 46 ensayos controlados aleatorizados y se revisaron 22 con al menos 50 pacientes al inicio del estudio; además, se analizaron 22 series de casos y 10 revisiones de tema que permiten conocer las indicaciones del uso de la talidomida en humanos, las bases farmacocinéticas que explican los efectos benéficos y/o deletéreos y las recomendaciones tendientes a garantizar que no se repita la teratogénesis. Conclusión: Se dispone de la talidomida, con restricciones, para el tratamiento del Eritema nodoso lepromatoso (primera línea) y del Mieloma múltiple refractario a la quimioterapia múltiple. Parece tener efectos benéficos en muchas otras condiciones graves y refractarias a enfoques de primera línea: SIDA, cáncer de esófago, cáncer de próstata y algunas dermatosis severas, reumatológicas o no. No debe recomendarse en pacientes con Epidermolisis necrótica tóxica ni en la Enfermedad crónica injerto contra huésped. ABSTRACT: Background: in 1998 the FDA approved the restricted commercialization of Thalidomide for the treatment of Erithema Nodosum Leprosum. Brazil and Mexico have also regulated its use. Because of the current use of this teratogenic drug in rheumatological, dermatological, infectious and neoplasic diseases, it is necessary to instruct General Practitioners and specialists on its most relevant topics, active principle, benefic and deleterious effects. We carried out a revision by reading and analyzing controlled clinical trials, randomized or not, case series and reviews about thalidomide and its potential uses, that appeared in Medline from January 1993 to December 2003, to draw indications and contraindications in light of the evidence found in them. Results: forty six randomized controlled studies were found and 22 (with at least 50 patients described) were reviewed (complete articles and/or including design and end points measured - ex-pressed abstracts), plus 10 reviews and 22 cases series. The analysis allowed us to inform potential or restricted and not indicated uses of thalidomide in humans, its pharmacokynetic principles which explain its benefic and deleterious effects, and recommendations to prevent teratogenesis. Conclusion: thalidomide is available, with restrictions, for the treatment of Erithema Nodosum Leprosum (first line) and Multiple Myeloma (refractory to multiple chemotherapy). It appears to have beneficial effects in many other serious conditions refractory to first line treatments: AIDS, esophagus and prostate cancer and some severe dermatosis, rheumatological or not.