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.post-print1360 K

Genetic markers associated with divergent selection against the parasite Marteilia cochillia in common cockle (Cerastoderma edule) using transcriptomics and population genomics data

The common cockle (Cerastoderma edule) plays an important role in marine ecosystems and represents a valuable socioeconomic resource for coastal communities. In 2012, the cockle beds from Rı́a de Arousa (Galicia, NW Spain) were seriously decimated by the protozoan Marteilia cochillia responsible for marteiliosis. We aimed to identify single nucleotide polymorphisms (SNP) markers potentially associated with resilience to marteiliosis to be used in marker-assisted selection programs for restoring affected cockle beds and recovering their production. For this, we carried out a population genomics approach using 2b-RADseq, where 38 naive samples (before the first detection of M. cochillia in 2012) from two beds of Rı́a de Arousa were compared with 39 affected samples collected in 2018/2019 (after several years of marteiliosis occurring in the area), collected either before (15 non-exposed samples) or during (24 exposed samples) the marteiliosis outbreak. Additionally, 767 differentially expressed genes (DEG) from a previous transcriptomic study addressed during the aforementioned 2018/19 marteiliosis outbreak, were evaluated to identify SNPs showing signals of selection. Using 2b-RADseq, 9,154 SNPs were genotyped and among them, 110 consistent outliers for divergent selection were identified. This set of SNPs was able to discriminate the samples according to their marteiliosis status (naive vs affected; exposed vs non-exposed), while another 123 SNPs were identified linked to DEGs associated with the level of infection across a temporal series. Finally, combining the population genomics and transcriptomics information, we selected the 60 most reliable SNPs associated with marteiliosis resilience. These SNPs were close to or within DEGs, and many of them were related to immune response (phagocytosis and cell adhesion), defence, such as apoptosis, stress, and cellular cycle, among other functions. This set of SNPs will eventually be validated to develop a cost-effective genotyping tool for their application for obtaining cockle-resilient strains for marteiliosis

Survival analysis in high-grade glioma: The role of salvage surgery

Objectives: This study addresses the survival of consecutive patients with high-grade gliomas (HGG) treated at the same institution over a period of 10 years. We analyse the importance of associated factors and the role of salvage surgery at the time of progression. Methods: We retrospectively analysed a series of patients with World Health Organization (WHO) grade III/IV gliomas treated between 2008 and 2017 at Hospital Gregorio Marañón (Madrid, Spain). Clinical, radiological, and anatomical pathology data were obtained from patient clinical histories. Results: Follow-up was completed in 233 patients with HGG. Mean age was 62.2 years. The median survival time was 15.4 months. Of 133 patients (59.6%) who had undergone surgery at the time of diagnosis, 43 (32.3%) underwent salvage surgery at the time of progression. This subgroup presented longer overall survival and survival after progression. Higher Karnofsky Performance Status score at diagnosis, a greater extent of surgical resection, and initial diagnosis of WHO grade III glioma were also associated with longer survival. Conclusions: About one-third of patients with HGG may be eligible for salvage surgery at the time of progression. Salvage surgery in this subgroup of patients was significantly associated with longer survival. Resumen: Objetivos: Analizar la supervivencia en el grupo de pacientes con gliomas de alto grado tratados de forma consecutiva en un mismo centro a lo largo de diez años. Establecer la relevancia de los factores asociados y el papel de la cirugía de rescate en el momento de la progresión. Metodos: Fueron analizados de forma retrospectiva los pacientes con gliomas grado III y IV de la Organización Mundial de la Salud (OMS) diagnosticados en el Hospital Gregorio Marañón desde el 1 de Enero de 2008 al 31 de Diciembre de 2017. Se obtuvieron de la historia clínica los datos clínicos, radiológicos y anatomopatológicos. Resultados: Se completó el seguimiento en 233 pacientes con diagnóstico de glioma de alto grado (III o IV de la OMS). La edad media fue de 62,2 años. La mediana de supervivencia se situó en 15,4 meses. De los 133 pacientes (59,6%) que habían sido intervenidos mediante cirugía resectiva en el momento del diagnóstico, en 43 (32,3%) se llevó a cabo cirugía de rescate en el momento de la progresión. La supervivencia global, así como la supervivencia tras la progresión resultó mayor en este subgrupo de pacientes. Otras variables relacionadas con una mayor supervivencia fueron la puntuación en la escala de Karnofsky (KPS), el grado de resección quirúrgica (GR) y el diagnóstico inicial de grado III de la OMS. Conclusiones: Alrededor de una tercera parte de los pacientes con gliomas de alto grado pueden ser candidatos a una cirugía de rescate en el momento de la progresión. Ello está asociado a una mayor supervivencia

Tratamiento del dolor neuropático por desaferentización mediante lesión DREZ, resultados a largo plazo

Resumen: Introducción: El dolor por desaferentización secundario a lesiones medulares, avulsión del plexo braquial y otras lesiones de nervios periféricos, es a menudo refractario a tratamientos convencionales. Este trabajo evalúa la eficacia a largo plazo de la cirugía de lesión DREZ (Dorsal Root Entry Zone) en diversos síndromes de dolor neuropático por desaferentización. Pacientes y métodos: Se presenta una serie de 18 pacientes con dolor refractario por desaferentización tratados mediante lesión DREZ con radiofrecuencia. La eficacia inmediata y a largo plazo se valoró mediante la escala visual analógica (EVA) preoperatoria y postoperatoria, la valoración subjetiva del paciente, la reincorporación laboral y la reducción de la medicación analgésica. Resultados: El dolor en la EVA disminuyó significativamente de 8,6 antes de la cirugía a 2,9 de media al alta (p < 0,001). A largo plazo, con un seguimiento medio de 28 meses (6-108), el dolor se mantuvo en 4,7 en la EVA (p < 0,002). El porcentaje de pacientes con un alivio moderado a excelente del dolor fue de 77% al alta y 68% a largo plazo. El 67% de los pacientes redujo la medicación analgésica y el 28% se reincorporó al trabajo. Los mejores resultados se obtuvieron en los pacientes con avulsión del plexo braquial con una mejoría significativa del dolor a largo plazo en todos los casos. Conclusiones: La lesión DREZ por radiofrecuencia es un tratamiento eficaz y seguro para el dolor neuropático refractario por desaferentización. Abstract: Introduction: Deafferentation pain secondary to spinal cord injury, brachial plexus avulsion and other peripheral nerve injuries is often refractory to conventional treatments. This study evaluates the long-term efficacy of spinal DREZ (Dorsal Root Entry Zone) lesions for the treatment of neuropathic pain syndromes caused by deafferentation. Patients and methods: A series of 18 patients with refractory deafferentation pain treated with radiofrequency DREZ lesions is presented. The immediate and long-term efficacy was measured with the Visual Analogue Scale (VAS) before and after treatment, the patient's subjective evaluation, the percentage of patients returning to work and the reduction in pain medication. Results: Pain on the VAS significantly decreased from 8.6 preoperatively to 2.9 (p < .001) at discharge. Over the long-term, with a mean follow-up of 28 months (6-108) pain remained at 4.7 on the VAS (p < 0.002). The percentage of patients with moderate to excellent pain relief was 77% at discharge and 68% at the last follow-up. Pain medication was reduced in 67% of the patients and 28% returned to work. The best results were obtained in patients with brachial plexus avulsion, with a significant long-term pain relief in all cases. Conclusions: Radiofrequency DREZ lesion is an effective and safe treatment for refractory neuropathic pain caused by deafferentation. Palabras clave: Avulsión plexo braquial, Desaferentización, Dorsal root entry zone, Dolor, Lesión medular, Keywords: Brachial plexus avulsion, Deafferentation, Dorsal root entry zone, Pain, Spinal injur

Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.

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. 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. 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. Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.This work was supported by grants from the “Fondo de Investigaciones Sanitarias” (FIS) (PI17-01489), the Miguel Servet Program (CP11/00147) del Instituto de Salud Carlos III (AAS), and the Ministerio de Economía y Competitividad–FEDERER (RTC-2016-4990-1). IPA was supported by “Ayudas para la contratación de ayudantes de investigación cofinanciadas por el Fondo Social Europeo a través del Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil (YEI),” and SER was supported by FPI-CEU predoctoral fellowship.S