The Release of Soluble Factors Contributing to Endothelial Activation and Damage after Hematopoietic Stem Cell Transplantation Is Not Limited to the Allogeneic Setting and Involves Several Pathogenic Mechanisms

AbstractThis study evaluated the relative impact of the intensity of the conditioning regimen and the alloreactivity in the endothelial dysfunction occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It involved a comparative analysis of the effect of incubating human umbilical vein endothelial cells (ECs) with serum samples from patients receiving autologous HSCT (auto-HSCT) or unrelated donor allo-HSCT. In both groups, blood samples were collected through a central line before conditioning (Pre), before transplantation (day 0), and at days 7, 14, and 21 after transplantation. Changes in the expression of EC receptors and adhesion proteins, adhesion of leukocytes and platelets under flow, and signaling pathways were analyzed. Endothelial activation and damage were observed in both groups, but with differing patterns. All markers of endothelial dysfunction demonstrated a progressive increase from day Pre to day 14 in the auto-HSCT group and exhibited 2 peaks of maximal expression (at days 0 and 21) in the allo-HSCT group. Both treatments induced a proinflammatory state (ie, expression of adhesion receptors, leukocyte adhesion, and p38 MAPK activation) and cell proliferation (ie, morphology and activation of ErK42/44). Prothrombotic changes (ie, von Willebrand factor expression and platelet adhesion) predominated after allo-HSCT, and a proapoptotic tendency (ie, activation of SAPK/JNK) was seen only in this group. These findings indicate that endothelial activation and damage after HSCT also occur in the autologous setting and affect macrovascular ECs. After the initial damage induced by the conditioning regimen, other factors, such as granulocyte colony-stimulating factor (G-CSF) toxicity, engraftment, and alloreactivity, may contribute to the endothelial damage seen during HSCT. Further studies are needed to explore the association between this endothelial damage and the vascular complications associated with HSCT

Avaliação de risco por exposição a hidrocarbonetos aromáticos policíclicos na saúde da população residente ao redor do complexo químico de Tarragona

One of the most important chemical industrial sites of Spain and, indeed, of southern Europe is close to the city of Tarragona and its surrounding villages. Therefore, the aim of this study was to calculate the chronic risk by inhalation of 18 atmospheric Polycyclic Aromatic Hydrocarbons (PAHs) for the population living in municipalities close to this chemical site. The sampling campaign was conducted between June 2008 and June 2009, and around 50 air samples were collected during different meteorological periods, in each of the three sampling sites selected for this study. Samples were taken for 24 h with the simultaneous collection of the particle phase (total suspended particles) on quartz microfiber filters, and the gas phase on polyu- rethane foam cartridges. The PAHs were extracted by pressurized liquid extraction and determined by gas chromatography-mass spectrometry.For calculating inhalation risk assessment, the 18 PAHs were expressed as benzo(a)pyrene equivalents using toxic equivalency factors. Risk was then calculated taking into account the World Health Organization (WHO) unit risk of 8.7 lung cancer cases per 100,000 people, with an exposure of 1 ng m-3 of benzo(a)pyrene over a lifetime of 70 years. The average lifetime lung cancer risk of the global study was 1.2·10-4. This risk is higher than the values recommended by the WHO and the US Environmental Protection Agency (USEPA), but it is lower than the threshold of 10-3, which is considered to be a definite risk.La ciudad de Tarragona y sus alrededores conviven con la actividad industrial de uno de los complejos más importantes de España y del sur de Europa. El objetivo de este estudio ha sido evaluar el riesgo crónico por inhalación de 18 hidrocarburos aromáticos policíclicos (HAP) en la población residente en los municipios ubicados alrededor de este complejo.Para el estudio se eligieron tres municipios y en cada uno de ellos se recogieron alrededor de 50 muestras desde junio de 2008 a junio de 2009. En cada muestra se captó, simultáneamente y durante 24 horas, la fase particulada (partículas totales en suspensión, PST) en filtro de fibra de cuarzo y la fase gaseosa en cilindros de espuma de poliuretano. Los HAP se extrajeron con diclorometano mediante extracción presurizada y se cuantificaron utilizando cromatografía de gases-espectrometría de masas.Para estimar el riesgo por inhalación a los HAP, primero se expresaron los 18 HAP como equivalentes de benzo(a)pireno utilizando factores de toxicidad equivalente, y posteriormente se aplicó el factor de riesgo, definido por la Organización Mundial de la Salud (OMS), de desarrollar cáncer de pulmón a lo largo de toda la vida, de 8,7 x 10-5 por ng m-3 de benzo(a)pireno.El valor medio de riesgo obtenido en el estudio ha sido de 1,2·10-4. Este valor supera los criterios recomendados por la OMS o la Agencia de Protección Medioambiental Americana (USEPA); sin embargo, es inferior a 10-3, umbral considerado como riesgo definitivo para la población.A cidade de Tarragona e os seus arredores convivem com a actividade industrial de um dos complexos mais importantes de Espan- ha e do sul da Europa. O objectivo desde estudo tem sido avaliar o risco crónico por inalação de 18 hidrocarbonetos aromáticos policíclicos (HAP) na população residente nos municípios localizados em redor deste complexo. Para este estudo foram escolhidos três municípios e em cada um deles recolheu-se à volta de 50 amostras desde Junho de 2008 a Julho de 2009. Em cada amostra captou-se, simultaneamente e durante 24 horas, a fase particulada (partículas totais em suspen- são, PST) em filtro de fibra de quartzo e a fase gasosa em cilindros de espuma de poliuretano. Os HAP extraíram-se com diclorometano através de extracção pressurizada e quantificação por cromatografia gasosa e espectrometria de massas. Para estimar o risco por inalação de HAP, primeiro expressaram-se os 18 HAP como equivalentes de benzo(a)pireno utilizando factores de toxicidade de equivalência, e posteriormente aplicou-se o factor de risco, definido pela Organização Mundial de Saúde (OMS), no desenvolvimento de cancro do pulmão para uma esperança de vida de 70 anos, de 8,7 x 10-5 por ng m-3 de benzo(a) pireno. O valor médio de risco obtido no estudo foi de 1,2·10-4. Este valor supera os critérios recomendados pela OMS e pela Agência de Protecção do Meio-ambiental Americana (USEPA); contudo, é inferior a 10-3, limite a partir do qual o risco é assumido para a população

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Background Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Methods Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. Results The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). Conclusions G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

Carga de enfermedad en la comunidad autónoma de Cataluña utilizando años de vida ajustados por discapacidad (2005-2010)

Background: Burden of disease allows measuring the health of the population including mortality and disability. The objectives of this paper are to estimate the burden of disease in Catalonia, to compare the results with Spain and Tarragones area and to assess the contribution of the local registers to the estimation of the disability. Methods: We calculated the disability-adjusted life years (DALYs) for 123 causes using the methodology developed by the World Health Organization. We compared the standardized rates with the Spanish rates. In Tarragones area, we calculated the DALYs, we compared them with the DALYs in Catalonia and moreover we used the cancer incidence local registry to calculate cancer burden disease. Results: There were 801,140 DALYs (annual average) in Catalonia, 60.3% due to disability and 39.7% due to premature mortality. Neuropsychiatric disorders (30.9%), malignant neoplasms (15.8%) and cardiovascular diseases (11.3%) were the leading causes. The standardized rate of respiratory diseases (7.5 per 1,000) was significantly higher compared with the Spanish rate. Perinatal conditions (3.1 per 1,000), intentional injuries (2.2 per 1,000) and digestive diseases (4.9 per 1,000) were significantly higher in Tarragones area. DALYs attributable to cancer showed an increase of 13.4 % when they were calculated using the incidence of cases. Conclusions: Noncommunicable diseases were the leading causes for DALYs in Catalonia. There are differences between territories in respiratory diseases, perinatal conditions, digestive diseases and intentional injures. Local registries can be very useful in order to calculate the DALYs.Fundamentos: La carga de enfermedad permite medir la salud de la población incluyendo mortalidad y morbididad. Los objetivos de este estudio son estimar la carga de enfermedad en Cataluña, comparar los resultados con España y con la comarca del Tarragonés, y evaluar la aportación de los registros locales en la estimación de la discapacidad. Métodos: Se calcularon los años de vida perdidos ajustados por discapacidad (AVAD) para 123 causas utilizando la metodología descrita por la Organización Mundial de la Salud. Las tasas estandarizadas se compararon con las españolas. En la comarca del Tarragonés, se calcularon los AVAD, se compararon con Cataluña, y para los tumores malignos se calcularon los AVAD utilizando el registro local de incidencia de cáncer. Resultados: Los AVAD en Cataluña fueron 801.140 de media anual. El 60,3% se atribuyó a discapacidad y el 39,7% a mortalidad prematura. Neuropsiquiátricas (30,9%), tumores malignos (15,8%) y cardiovasculares (11,3%) fueron las principales causas en AVAD. La tasa estandarizada de las enfermedades respiratorias (7,5 por 1.000) fue significativamente superior a la española. Causas perinatales (3,1 por 1.000), lesiones intencionadas (2,2 por 1.000) y enfermedades del aparato digestivo (4,9 por 1.000) fueron significativamente superiores en el Tarragonés. Los AVAD para los tumores malignos se incrementaron un 13,4% utilizando la incidencia de casos para su cálculo. Conclusiones: Las enfermedades no transmisibles aportan la mayor parte de AVAD en Cataluña. Existen diferencias entre territorios en enfermedades respiratorias, perinatales, digestivas y lesiones intencionadas. Los registros locales pueden ser muy útiles en el cálculo de los AVAD

Health risk assessment of exposure to polycyclic aromatic hydrocarbons for the population living near to the Tarragona chemical industrial site Evaluación del riesgo asociado a la exposición de hidrocarburos aromáticos policíclicos en la salud de la población residente alrededor del complejo químico de Tarragona Avaliação de risco por exposição a hidrocarbonetos aromáticos policíclicos na saúde da população residente ao redor do complexo químico de Tarragona

One of the most important chemical industrial sites of Spain and, indeed, of southern Europe is close to the city of Tarragona and its surrounding villages. Therefore, the aim of this study was to calculate the chronic risk by inhalation of 18 atmospheric Polycyclic Aromatic Hydrocarbons (PAHs) for the population living in municipalities close to this chemical site. The sampling campaign was conducted between June 2008 and June 2009, and around 50 air samples were collected during different meteorological periods, in each of the three sampling sites selected for this study. Samples were taken for 24 h with the simultaneous collection of the particle phase (total suspended particles) on quartz microfiber filters, and the gas phase on polyu- rethane foam cartridges. The PAHs were extracted by pressurized liquid extraction and determined by gas chromatography-mass spectrometry.For calculating inhalation risk assessment, the 18 PAHs were expressed as benzo(a)pyrene equivalents using toxic equivalency factors. Risk was then calculated taking into account the World Health Organization (WHO) unit risk of 8.7 lung cancer cases per 100,000 people, with an exposure of 1 ng m-3 of benzo(a)pyrene over a lifetime of 70 years. The average lifetime lung cancer risk of the global study was 1.2·10-4. This risk is higher than the values recommended by the WHO and the US Environmental Protection Agency (USEPA), but it is lower than the threshold of 10-3, which is considered to be a definite risk.La ciudad de Tarragona y sus alrededores conviven con la actividad industrial de uno de los complejos más importantes de España y del sur de Europa. El objetivo de este estudio ha sido evaluar el riesgo crónico por inhalación de 18 hidrocarburos aromáticos policíclicos (HAP) en la población residente en los municipios ubicados alrededor de este complejo.Para el estudio se eligieron tres municipios y en cada uno de ellos se recogieron alrededor de 50 muestras desde junio de 2008 a junio de 2009. En cada muestra se captó, simultáneamente y durante 24 horas, la fase particulada (partículas totales en suspensión, PST) en filtro de fibra de cuarzo y la fase gaseosa en cilindros de espuma de poliuretano. Los HAP se extrajeron con diclorometano mediante extracción presurizada y se cuantificaron utilizando cromatografía de gases-espectrometría de masas.Para estimar el riesgo por inhalación a los HAP, primero se expresaron los 18 HAP como equivalentes de benzo(a)pireno utilizando factores de toxicidad equivalente, y posteriormente se aplicó el factor de riesgo, definido por la Organización Mundial de la Salud (OMS), de desarrollar cáncer de pulmón a lo largo de toda la vida, de 8,7 x 10-5 por ng m-3 de benzo(a)pireno.El valor medio de riesgo obtenido en el estudio ha sido de 1,2·10-4. Este valor supera los criterios recomendados por la OMS o la Agencia de Protección Medioambiental Americana (USEPA); sin embargo, es inferior a 10-3, umbral considerado como riesgo definitivo para la población.A cidade de Tarragona e os seus arredores convivem com a actividade industrial de um dos complexos mais importantes de Espan- ha e do sul da Europa. O objectivo desde estudo tem sido avaliar o risco crónico por inalação de 18 hidrocarbonetos aromáticos policíclicos (HAP) na população residente nos municípios localizados em redor deste complexo. Para este estudo foram escolhidos três municípios e em cada um deles recolheu-se à volta de 50 amostras desde Junho de 2008 a Julho de 2009. Em cada amostra captou-se, simultaneamente e durante 24 horas, a fase particulada (partículas totais em suspen- são, PST) em filtro de fibra de quartzo e a fase gasosa em cilindros de espuma de poliuretano. Os HAP extraíram-se com diclorometano através de extracção pressurizada e quantificação por cromatografia gasosa e espectrometria de massas. Para estimar o risco por inalação de HAP, primeiro expressaram-se os 18 HAP como equivalentes de benzo(a)pireno utilizando factores de toxicidade de equivalência, e posteriormente aplicou-se o factor de risco, definido pela Organização Mundial de Saúde (OMS), no desenvolvimento de cancro do pulmão para uma esperança de vida de 70 anos, de 8,7 x 10-5 por ng m-3 de benzo(a) pireno. O valor médio de risco obtido no estudo foi de 1,2·10-4. Este valor supera os critérios recomendados pela OMS e pela Agência de Protecção do Meio-ambiental Americana (USEPA); contudo, é inferior a 10-3, limite a partir do qual o risco é assumido para a população.</div

Differential protein expression in endothelial cells exposed to serum from patients with acute graft-vs-host disease, depending on steroid response

Altres ajuts: Fundació La Marató de TV3 (202026-10); Deutsche Forschungsgemeinschaft, Grant/Award Number: PE 1450/7-1 and PE 1450/9-1; Deutsche Krebshilfe, Grant/Award Number: 70113519Graft-versus-host disease (GVHD) is a complication of allogeneic haematopoietic cell transplantation. Endothelial injury is crucial as pathophysiological substrate for GVHD. GVHD first-line treatment is high-dose corticosteroids, although some patients are steroid-refractory. Through the present study, we compared the endothelial proteomic profiles in response to serum from steroid-refractory acute GVHD (SR-aGVHD) and steroid-sensitive acute GVHD (SS-aGVHD) patients. Blood samples from SR-aGVHD (n = 4) and SS-aGVHD (n = 8) patients were collected at aGVHD diagnosis. Endothelial cell cultures were exposed (48 h) to patients' serum. Protein extraction and proteomic analysis were performed. Differences were statistically evaluated by multivariate analysis. Forty-four proteins contributed to separate all samples into the two study groups, among which 15 participated significantly (p 1.2. Differentially expressed proteins were mainly associated with oxidative phosphorylation (Cytochrome C oxidase subunit 6B1, CX6B1), inflammation and angiogenesis (Apolipoprotein D, APOD), cell survival (Rapamycin-insensitive companion of mTOR, RICTR), and oxidative stress (Riboflavin kinase, RIFK). This pilot study used a novel approach to distinguish the aGVHD response to steroid treatment. The proteins differentially expressed could constitute potential biomarkers for steroid-treatment response. These findings signify a step forward to identify the mechanisms of response to steroids, of high clinical relevance considering the SR-aGVHD elevated mortality

Easix Score Correlates With Endothelial Dysfunction Biomarkers and Predicts Risk of Acute Graft-Versus-Host Disease After Allogeneic Transplantation

Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome (SOS) and transplant-associated thrombotic microangiopathy (TA-TMA).This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD.We assessed VCAM-1, TNFR1, and VWF:Ag plasma levels, and EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT), and on days 0, +3, +7, +14, and +21 in an experimental cohort (n=33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cut-off values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution.Plasma biomarkers and EASIX showed similar post-transplant dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day +7 post-transplant with an increased likelihood of developing aGVHD (HR 1, P=0.002; HR 2.31, P=0.013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR 7.19, P=0.006) and Log2-EASIX ≥3 (HR 14.7, P<0.001) at day +7 post-transplant were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥ 3 on day +7 post-transplant presented a significantly higher incidence of grade II-IV aGVHD (HR 1.94, P=0.004) independent of GVHD prophylaxis (HR 0.38, P=0.004), conditioning regimen (HR 0.59, P=0.02) and type of donor (HR 2.38, P=0.014).Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplant period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.Published by Elsevier Inc