IR-HUVH - Instituto de Investigación Hospital Universitari Vall d’Hebron (Cataluña)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16987

El IR-HUVH es una institución del sector público que promueve y desarrolla la investigación, la innovación y la docencia biosanitarias del Hospital Universitario Vall d'Hebron. Desde el año 1994, trabajamos para identificar y aplicar nuevas soluciones a los problemas de salud de la sociedad, logrando el liderazgo y la excelencia en investigación biomédica clínica y traslacional, a nivel nacional e internacional. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2009, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

Browse

Now showing 1 - 20 of 78

REIV-TOXO Project: Results from a Spanish cohort of congenital toxoplasmosis (2015-2022). The beneficial effects of prenatal treatment on clinical outcomes of infected newborns
(Public Library of Science (PLOS), 2024-10) Guarch-Ibáñez, Borja; Carreras-Abad, Clara; Frick, Marie Antoinette; Blázquez-Gamero, Daniel; Baquero-Artigao, Fernando; Fuentes Corripio, Isabel; Spanish Research Network of Congenital Toxoplasmosis (REIV-TOXO) group; Soler-Palacín, Pere; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España)
Background: Some regions of Spain are withdrawing their pregnancy screening program for congenital toxoplasmosis (CT). The Spanish Research Network of Congenital Toxoplasmosis (REIV-TOXO) was created to describe the current status of CT in Spain. The aims of this study were to describe the epidemiological and clinical characteristics of CT and to evaluate the effect of prenatal treatment on clinical outcomes to inform decision-making policies. Methods: Ambispective observational study including CT cases recorded in the REIV-TOXO database that includes 122 hospitals (2015-2022). Inclusion criteria were one or more of the following: positive PCR in maternal amniotic fluid; positive Toxoplasma gondii-specific IgM or IgA antibodies at birth; positive PCR in the placenta, newborn blood, urine or CSF; increase of specific IgG levels during infant follow-up; or specific IgG persistence beyond age 12 months. Findings: Fifty-six newborns (54 pregnancies) were included. Prenatal screening allowed 92.8% of cases to be identified. The time of maternal infection was well documented in 90.7% of cases, with 61.1% occurring in the third trimester. A total of 66.6% (36/54) pregnant women received antiparasitic treatment: 24/36 spiramycin, 8/36 pyrimethamine, sulfadiazine, and folinic acid, and 4/36 both treatments sequentially. Most cases were asymptomatic at birth (62.5%, 35/56), and 84% (47/56) newborns completed one year of treatment. Median follow-up was 24 months (IQR = 3-72): 14.2% children exhibited new complications, mainly ocular. Newborns born to mothers treated prenatally had four-fold lower risk of CT clinical features at birth (p = 0.03) and six-fold lower risk of further complications during follow-up (p = 0.04) with no treatment-related differences during pregnancy. Conclusions: While diagnosis based only on neonatal assessment misses a significant number of CT cases, prenatal screening allows treatment to be started during pregnancy, with better clinical outcomes at birth and during follow-up. REIV-TOXO provides valuable information about CT in Spain, highlighting the need for universal maternal screening.
Epidemiological and Clinical Insights into the Enterovirus D68 Upsurge in Europe 2021-2022 and Emergence of Novel B3-Derived Lineages, ENPEN Multicentre Study
(Oxford University Press, 2024-10-16) Pires Simoes, Margarida; Hodcroft, Emma B; Simmonds, Peter; Albert, Jan; Alidjinou, Enagnon K; Ambert-Balay, Katia; Andrés, Cristina; Antón, Andrés; Auvray, Christelle; Bailly, Jean-Luc; Baldanti, Fausto; Bastings, Capser; Beard, Stuart; Berengua, Carla; Berginc, Natasa; Bloemen, Mandy; Blomqvist, Soile; Bosma, Froukje; Böttcher, Sindy; Bubba, Laura; Buderus, Stafan; Cabrerizo, Maria; Calvo, Cristina; Celma, Cristina; Ceriotti, Ferruccio; Clark, Gemma; Costa, Inës; Coste-Burel, Marianne; Couderé, Karen; Cremer, Jeroen; Del Cuerpo Casas, Margarita; Daehne, Theo; de Beer, Jessica; de Ceano-Vivas, Maria; De Gascun, Cillian; de Rougemont, Alexis; Dean, Jonathan; Dembinski, Jennifer L; Diedrich, Sabine; Diez-Domingo, Javier; Dillner, Lena; Dorenberg, Dagny H; Ducancelle, Alexandra; Dudman, Susanne; Dyrdak, Robert; Eis-Huebinger, Anna-Maria; Falces-Romero, Iker; Farkas, Agnes; Feeney, Susan; Fernandez-Garcia, Maria Dolores; Flipse, Jacky; Franck, Kristina T; Galli, Cristina; Garrigue, Isabelle; Geeraedts, Felix; Georgieva, Irina; Giardina, Federica; Guiomar, Raquel; Hauzenberger, Elenor; Heikens, Esther; Henquell, Cécille; Hober, Didier; Hönemann, Mario; Howson-Wells, Hannah; Hruškar, Željka; Ikonen, Niina; Imbert, Berthemarie; Jansz, Arjan R; Jeannoël, Marion; Jiřincová, Helena; Josset, Laurence; Keeren, Kathrin; Kramer-Lindhout, Naomie; Krokstad, Sidsel; Lazrek, Mouna; Le Guillou-Guillemette, Hélène; Lefeuvre, Caroline; Lind, Andreas; Lunar, Maja M; Maier, Melanie; Marque-Juillet, Stéphanie; McClure, C Patrick; McKenna, James; Meijer, Adam; Menasalvas Ruiz, Ana; Mengual-Chuliá, Beatriz; Midgley, Sofie; Mirand, Audrey; Molenkamp, Richard; Montes, Milagrosa; Moreno-Docón, Antonio; Morley, Ursula; Murk, Jean-Luc; Navascués-Ortega, Ana; Nijhuis, Roel; Nikolaeva-Glomb, Lubomira; Nordbø, Svein A; Numanovic, Sanela; Oggioni, Massimo; Oñate Vergara, Eider; Pacaud, Jordi; Pacreau, Marie L; Panning, Marcus; Pariani, Elena; Pekova, Lili; Pellegrinelli, Laura; Petrovec, Miroslav; Pietsch, Corinna; Pilorge, Léa; Piñeiro, Luis; Piralla, Antonio; Poljak, Mario; Prochazka, Birgit; Rabella, Nuria; Rahamat-Langendoen, Janette C; Rainetova, Petra; Reynders, Marijke; Riezebos-Brilman, Annelies; Roorda, Lieuwe; Savolainen-Kopra, Carita; Schuffenecker, Isabelle; Smeets, Leo C; Stoyanova, Asya; Stefic, Karl; Swanink, Caroline; Tabain, Irena; Tjhie, Jeroen; Thouault, Luc; Tumiotto, Camille; Uceda Renteria, Sara; Uršič, Tina; Vallet, Sophie; Van Ranst, Marc; Van Wunnik, Peter; Verweij, Jaco J; Vila, Jorgina; Wintermans, Bas; Wollants, Elke; Wolthers, Katja C; Xavier López-Labrador, F; Fischer, Thea Kølsen; Harvala, Heli; Benschop, Kimberley SM; Austrian Federal Ministry of Health (Austria); Ministry of Health (República Checa); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); Santé Publique France; Unión Europea. Comisión Europea. NextGenerationEU; Ministry of Health Welfare and Sport (Países Bajos); National Institutes of Health (Estados Unidos); Slovenian Research Agency; Swiss National Science Foundation
Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 infections and its clinical impact during the fall-winter season of 2021-2022. From 19 European countries, 58 institutes reported 10 481 (6.8%) EV-positive samples of which 1004 (9.6%) were identified as EV-D68 (including 852 respiratory samples). Clinical data were reported for 969 cases; 78.9% of infections were reported in children (0-5 years); and 37.9% of cases were hospitalized. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases including 6 diagnosed with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of 2 novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale European EV-D68 upsurge with severe clinical impact and the emergence of B3-derived lineages.
Immunogenicity of a third dose with mRNA-vaccines in the ChAdOx1-S/BNT162b2 vaccination regimen against SARS-CoV-2 variants
(Elsevier, 2024-09-20) García-Pérez, Javier; Borobia, Alberto M; Perez-Olmeda, Mayte; Portolés, Antonio; Castaño, Luis; Campins-Artí, Magdalena; Bertrán, María Jesús; Bermejo, Mercedes; Arribas, José Ramón; López, Andrea; Ascaso-Del-Rio, Ana; Arana-Arri, Eunate; Fuentes Camps, Inmaculada; Vilella, Anna; Cascajero Díaz, Almudena; García-Morales, María Teresa; Castillo de la Osa, María; Pérez Ingidua, Carla; Lora, David; Jiménez Santana, Paloma; Pino-Rosa, Silvia del; Gómez de la Cámara, Agustín; de la Torre-Tarazona, Humberto Erick; Calonge, Esther; Cruces Fernández, Raquel; Belda-Iniesta, Cristobal; Alcamí, José; Frías, Jesús; Carcas, Antonio J; Díez-Fuertes, Francisco; CombiVacS Study Group; Instituto de Salud Carlos III; Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Comisión Europea. H2020
CombiVacS study has demonstrated a strong immune response of the heterologous ChAdOx1-S/BNT162b2 vaccine combination. The primary outcomes of the study were to assess the humoral immune response against SARS-CoV-2, 28 days after a third dose of a mRNA vaccine, in subjects that received a previous prime-boost scheme with ChAdOx1-S/BNT162b2. Secondary outcomes extended the study to 3 and 6 months. The third vaccine dose of mRNA-1273 in naive participants previously vaccinated with ChAdOx1-S/BNT162b2 regimen reached higher neutralizing antibodies titers against the variants of concern Delta and BA.1 lineage of Omicron compared with those receiving a third dose of BNT162b2 at day 28. These differences between BNT162b2 and mRNA-1273 arms were observed against the ancestral variant G614 at day 90. Suboptimal neutralizing response was observed against BQ.1.1, XBB.1.5/XBB.1.9, and JN.1 in a relevant proportion of individuals 180 days after the third dose, even after asymptomatic Omicron breakthrough infections. EudraCT (2021-001978-37); ClinicalTrials.gov (NCT04860739).
Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial
(Elsevier, 2021-07-10) Borobia, Alberto M; Carcas, Antonio J; Perez-Olmeda, Mayte; Castaño, Luis; Bertrán, María Jesús; García-Pérez, Javier; Campins, Magdalena; Portolés, Antonio; Gonzalez-Perez, Maria; García Morales, María Teresa; Arana-Arri, Eunate; Aldea, Marta; Díez-Fuertes, Francisco; Fuentes, Inmaculada; Ascaso, Ana; Lora, David; Imaz-Ayo, Natale; Barón-Mira, Lourdes E; Agustí, Antonia; Pérez-Ingidua, Carla; Gómez de la Cámara, Agustín; Arribas, José Ramón; Ochando, Jordi; Alcamí, José; Belda-Iniesta, Cristobal; Frías, Jesús; CombiVacS Study Group; Portoles, Pilar; Instituto de Salud Carlos III; Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Comisión Europea. H2020
[EN] Background: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). Methods: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. Findings: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. [ES] Antecedentes: No hay datos de eficacia inmunológica procedentes de esquemas de vacunación heteróloga frente a SARS--CoV-2 en humanos. Este estudio evaluó la inmunogenicidad y la reactogenicidad de BNT162b2 (Comirnaty, BioNTech) administrado como segunda dosis en personas que habían recibido previamente una dosis de ChAdOx1-S (Vaxzevria, Astra Zeneca). Método: Realizamos un ensayo clínico de fase 2, abierto, aleatorizado y controlado en adultos de 18 a 59 años, vacunados con una dosis única de ChAdOx1-S entre 8 y 12 semanas antes del cribado, y sin antecedentes de infección por SARS-CoV-2 (EudraCT #2021-001978-37 y NCT04860739). Los participantes fueron asignados al azar (2:1) a un grupo que recibió BNT162b2 (0,3 mL, inyección intramuscular única) y a un grupo de control. Los objetivos principales fueron la reactogenicidad a los 7 días y la respuesta IgG anti-proteína spike a los 14 días, medida ésta a través de inmunoensayos que identificaban la proteína S trimérica del SARS-CoV-2 y el dominio de unión al receptor (RBD) de ésta. La funcionalidad de los anticuerpos y la respuesta inmunitaria celular se evaluaron mediante un ensayo de neutralización de pseudovirus y un inmunoensayo de IFN-gamma, respectivamente. Resultados: Entre el 24 y el 30 de abril de 2021, 676 individuos fueron asignados al azar (n=450 del grupo de intervención, n=226 del grupo de control) en 5 centros de España, y 663 (441 y 222, respectivamente) completaron el estudio al día 14 (edad media de 44 [SD 9], 56% [382] mujeres). En el grupo de intervención, la media geométrica de los títulos de anticuerpos antiRBD (GMT) aumentó de 71.46 BAU/mL (IC del 95%: 59.84-85.33) en el momento inicial a 7756.68 (7371.53; 8161.96) en el día 14 (p < 0-0001). La IgG contra la proteína S trimérica aumentó de 98.4 [85.69-112.99] a 3684.87 [3429.87-3958.83]). La relación respuesta/control fue de 77.69 (IC 95%: 59.57; 101.32) y 36.41 (29.31; 45.23) para la IgG contra la proteína de S trimérica y la RBD, respectivamente. Las reacciones fueron predominantemente leves (1.210; 68%) o moderadas (530; 30%), y la más frecuente consistió en dolor en el lugar de la inyección (395; 88%), induración (159; 35%), dolor de cabeza (199; 44%) y mialgia (194; 43%). No se notificaron acontecimientos adversos graves. Interpretación: El BNT162b2 administrado como segunda dosis en individuos vacunados con una primera dosis de ChAdOx1-S indujo una respuesta inmune robusta con un perfil de reactogenicidad aceptable y manejable.
Low anti-SARS-CoV-2 S antibody levels predict increased mortality and dissemination of viral components in the blood of critical COVID-19 patients
(Wiley, 2022-02) Martin-Vicente, Maria; Almansa, Raquel; Martinez, Isidoro; Tedim, Ana P; Bustamante, Elena; Tamayo, Luis; Aldecoa, César; Gómez, José Manuel; Renedo, Gloria; Berezo, Jose Ángel; Cedeño, Jamil Antonio; Mamolar, Nuria; García Olivares, Pablo; Herrán-Monge, Rubén; Cicuendez, Ramón; Enríquez, Pedro; Ortega, Alicia; Jorge, Noelia; Doncel, Cristina; de la Fuente, Amanda; Bustamante-Munguira, Juan; Muñoz-Gómez, María José; González-Rivera, Milagros; Puertas, Carolina; Mas-Lloret, Vicente; Vazquez-Alcaraz, Monica; Perez-Garcia, Felipe; Rico-Feijoo, Jesús; Martín, Silvia; Motos, Anna; Fernandez-Barat, Laia; Eiros, José María; Domínguez-Gil, Marta; Ferrer, Ricard; Barbé, Ferrán; Trapiello, Wysali; Kelvin, David J; Bermejo-Martin, Jesús F; Resino, Salvador; Torres, Antoni; Canadian Institutes of Health Research; Nova Scotia Health Research Foundation; Atlantic Genome (Canada); Li Ka Shing Foundation; Dalhousie Medical Research Foundation; Canada Research Chairs; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERES (Enfermedades Respiratorias); Junta de Castilla y León (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Background: Anti-SARS-CoV-2 S antibodies prevent viral replication. Critically ill COVID-19 patients show viral material in plasma, associated with a dysregulated host response. If these antibodies influence survival and viral dissemination in ICU-COVID patients is unknown. Patients/methods: We studied the impact of anti-SARS-CoV-2 S antibodies levels on survival, viral RNA-load in plasma, and N-antigenaemia in 92 COVID-19 patients over ICU admission. Results: Frequency of N-antigenaemia was >2.5-fold higher in absence of antibodies. Antibodies correlated inversely with viral RNA-load in plasma, representing a protective factor against mortality (adjusted HR [CI 95%], p): (S IgM [AUC ≥ 60]: 0.44 [0.22; 0.88], 0.020); (S IgG [AUC ≥ 237]: 0.31 [0.16; 0.61], <0.001). Viral RNA-load in plasma and N-antigenaemia predicted increased mortality: (N1-viral load [≥2.156 copies/ml]: 2.25 [1.16; 4.36], 0.016); (N-antigenaemia: 2.45 [1.27; 4.69], 0.007). Conclusions: Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. Our findings support that these antibodies contribute to prevent systemic dissemination of SARS-CoV-2.
Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021.
(Elsevier, 2024-10) GBD 2021 Tobacco Forecasting Collaborators; Padron-Monedero, Alicia; Bill & Melinda Gates Foundation; Bloomberg Philanthropies
Background: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies. Methods: In this analysis, we use the Institute for Health Metrics and Evaluation's Future Health Scenarios platform to forecast the effects of three smoking prevalence scenarios on all-cause and cause-specific YLLs and life expectancy at birth until 2050. YLLs were computed for each scenario using the Global Burden of Disease Study 2021 reference life table and forecasts of cause-specific mortality under each scenario. The reference scenario forecasts what could occur if past smoking prevalence and other risk factor trends continue, the Tobacco Smoking Elimination as of 2023 (Elimination-2023) scenario quantifies the maximum potential future health benefits from assuming zero percent smoking prevalence from 2023 onwards, whereas the Tobacco Smoking Elimination by 2050 (Elimination-2050) scenario provides estimates for countries considering policies to steadily reduce smoking prevalence to 5%. Together, these scenarios underscore the magnitude of health benefits that could be reached by 2050 if countries take decisive action to eliminate smoking. The 95% uncertainty interval (UI) of estimates is based on the 2·5th and 97·5th percentile of draws that were carried through the multistage computational framework. Findings: Global age-standardised smoking prevalence was estimated to be 28·5% (95% UI 27·9-29·1) among males and 5·96% (5·76-6·21) among females in 2022. In the reference scenario, smoking prevalence declined by 25·9% (25·2-26·6) among males, and 30·0% (26·1-32·1) among females from 2022 to 2050. Under this scenario, we forecast a cumulative 29·3 billion (95% UI 26·8-32·4) overall YLLs among males and 22·2 billion (20·1-24·6) YLLs among females over this period. Life expectancy at birth under this scenario would increase from 73·6 years (95% UI 72·8-74·4) in 2022 to 78·3 years (75·9-80·3) in 2050. Under our Elimination-2023 scenario, we forecast 2·04 billion (95% UI 1·90-2·21) fewer cumulative YLLs by 2050 compared with the reference scenario, and life expectancy at birth would increase to 77·6 years (95% UI 75·1-79·6) among males and 81·0 years (78·5-83·1) among females. Under our Elimination-2050 scenario, we forecast 735 million (675-808) and 141 million (131-154) cumulative YLLs would be avoided among males and females, respectively. Life expectancy in 2050 would increase to 77·1 years (95% UI 74·6-79·0) among males and 80·8 years (78·3-82·9) among females. Interpretation: Existing tobacco policies must be maintained if smoking prevalence is to continue to decline as forecast by the reference scenario. In addition, substantial smoking-attributable burden can be avoided by accelerating the pace of smoking elimination. Implementation of new tobacco control policies are crucial in avoiding additional smoking-attributable burden in the coming decades and to ensure that the gains won over the past three decades are not lost.
Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021
(Elsevier, 2024-10) GBD 2021 Stroke Risk Factor Collaborators; Padron-Monedero, Alicia; Bill & Melinda Gates Foundation
Background: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021. Methods: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]). Interpretation: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden.
Prevalence of use of physical restraints in pediatric intensive care units and correlated variables: A Spanish multicenter study
(Elsevier, 2024-12) Bosch Alcaraz, Alejandro; Belda Hofheinz, Sylvia; Corrionero Alegre, Jesús; García Piñero, José Miguel; Gil Domínguez, Sonia; Fernández Lorenzo, Rocío; Mata Ferro, María; Martín Gómez, Ainhoa; Serradell Orea, Marta; Luna Castaño, Patricia; Saz Roy, M Ángeles; Zuriguel Pérez, Esperanza; Martínez Oliva, Marta; González Rivas, Susana; Añaños Montoto, Nerea; Espildora González, María José; Martín-Peñasco Osorio, Elena; Carracedo Muñoz, Eva; López Fernández, Eduardo; Lozano Almendral, Gema; Ureste Parra, Maria Victoria; Gomez Merino, Alicia; García Martínez, Alexandra; Morales Cervera, David; Frade Pardo, Laura; Díaz Lerma, Ainhoa; Piqueras Rodríguez, Pedro
Objective: To calculate the prevalence of physical restraint (PR) use in Spanish PICUs and (2) to analyze the correlation between the prevalence of PR use and the sociodemographic, clinical variables of the patients and the PICU structural and organizational variables. Methods: We conducted a multicenter prevalence study from January 2022 to January 2023 in Spanish PICUs. The method of data collection was by direct observation, review of the patient's medical history, and asking the professionals involved in the patient's care. Three weekly 24-hour prevalence observations (morning, afternoon, and night) were conducted for 6 months. Results: A total of 336 patients were included in the study, obtaining an overall crude prevalence of PR use of 16 % (95 %CI: 15 %-17.7 %). Pediatric patients with respiratory pathology received the highest number of hours of PR, with significant differences observed when comparing respiratory cases with post-surgical cases. Statistical significance was also observed when comparing the mean scores of hours of PR according to admission diagnosis (p = 0.01), with respiratory patients being the ones who were restrained the longest (24 h [20-24]) and infectious patients the least (15 h [14-20]). Patients who receive PR upon admission remain in this situation for more hours (24 h [15-24] and in the PICUs that specifically recorded PR application, fewer hours of PR occurred (20 h [4-24]). Conclusions: The use of PR is still present in the PICUs analyzed, with a crude prevalence of 16%. Factors such as the reason for admission, the use of respiratory support, and the reason for application of PR were linked to the hours of use of PR. Implications for clinical practice: Knowing the prevalence of PR use will make professionals aware that it is still necessary to implement policies that avoid its use to prevent the side effects they have in pediatric patients.
The CARBA-MAP study: national mapping of carbapenemases in Spain (2014-2018)
(Frontiers Media, 2023) Gracia-Ahufinger, Irene; López-González, Laura; Vasallo, Francisco José; Galar, Alicia; Siller, María; Pitart, Cristina; Bloise, Iván; Torrecillas, Miriam; Gijón-Cordero, Desirée; Viñado, Belén; Castillo-García, Javier; Campo, Rainer; Mulet, Xavier; Madueño-Alonso, Ana; Chamizo-López, Francisco Javier; Arrastia-Erviti, Maitane; Galán-Sánchez, Fátima; Fernández-Quejo, Melisa; Rodríguez-Díaz, Juan Carlos; Gutiérrez-Zufiaurre, María Nieves; Rodríguez-Maresca, Manuel Angel; Ortega-Lafont, María Del Pilar; Yague-Guirao, Genoveva; Chaves-Blanco, Lucía; Colomina-Rodríguez, Javier; Vidal-Acuña, María Reyes; Portillo, María Eugenia; Franco-Álvarez de Luna, Francisco; Centelles-Serrano, María José; Azcona-Gutiérrez, José Manuel; Delgado-Iribarren García Campero, Alberto; Rey-Cao, Sonia; Muñoz, Patricia; Calvo-Montes, Jorge; Zboromyrska, Yuliya; Grandioso, David; Càmara, Jordi; Cantón, Rafael; Larrosa-Escartín, Nieves; Díaz-Regañón, Jazmín; Martínez-Martínez, Luis
Introduction: Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018. Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0. Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016. Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms.
Early-Stage Breast Cancer Detection in Breast Milk.
(American Association for Cancer Research, 2023-09-14) Saura, Cristina; Ortiz, Carolina; Matito, Judit; Arenas, Enrique J; Suñol, Anna; Martín, Ágatha; Córdoba, Octavi; Martínez-Sabadell, Alex; García-Ruiz, Itziar; Miranda, Ignacio; Morales-Comas, Clara; Carrasco, Estela; Viaplana, Cristina; Peg, Vicente; Nuciforo, Paolo; Bayó-Puxan, Neus; Gonzalez-Medina, Alberto; Miquel, Josep M; Gómez-Rey, Marina; Villacampa, Guillermo; Arévalo, Silvia; Espinosa-Bravo, Martín; Balmaña, Judith; Dienstmann, Rodrigo; Arribas, Joaquin; Tabernero, Josep; Vivancos, Ana; Sansó, Miriam
Breast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. Significance: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image. See related commentary by Cunningham and Turner, p. 2125. This article is featured in Selected Articles from This Issue, p. 2109.
Survival analyses in cardiovascular research, part II: statistical methods in challenging situations
(Elsevier, 2022-01) Rosselló, Xavier; González-Del-Hoyo, Maribel
This article is the second of a series of 2 educational articles. In the first article, we described the basic concepts of survival analysis, summarizing the common statistical methods and providing a set of recommendations to guide the strategy of survival analyses in randomized clinical trials and observational studies. Here, we introduce stratified Cox models and frailty models, as well as the immortal time bias arising from a poor assessment of time-dependent variables. To address the issue of multiplicity of outcomes, we provide several modelling strategies to deal with other types of time-to-event data analyses, such as competing risks, multistate models, and recurrent-event methods. This review is illustrated with examples from previous cardiovascular research publications, and each statistical method is discussed alongside its main strengths and limitations. Finally, we provide some general observations about alternative statistical methods with less restrictive assumptions, such as the win ratio method, the restrictive mean survival time, and accelerated failure time model.
Survival analyses in cardiovascular research, part I: the essentials
(Elsevier, 2022-01) Rosselló, Xavier; González-Del-Hoyo, Maribel
This review provides a practical guide to the essentials of survival analysis and their reporting in cardiovascular studies, although most of its key content can be extrapolated to other medical fields. This is the first in a series of 2 educational articles laying the groundwork to address the most relevant statistical issues in survival analyses, which will smoothly drive the reader from the most basic analyses to the most complex situations. The focus will be on the type and shape of survival data, and the most common statistical methods, such as nonparametric, parametric and semiparametric models. Their adequacy, interpretation, advantages and disadvantages are illustrated by examples from the field of cardiovascular research. This article ends with a set of recommendations to guide the strategy of survival analyses for a randomized clinical trial and observational studies. Other topics, such as competing risks, multistate models and recurrent-event methods will be addressed in the second article.
Respiratory symptoms and their determinants in the general Spanish population: changes over 20 years
(ERS Journals, 2022-10) Miravitlles, Marc; Soler-Cataluña, Juan José; Soriano, Joan B; García-Río, Francisco; de Lucas, Pilar; Alfageme, Inmaculada; Casanova, Ciro; Rodriguez Gonzalez-Moro, Jose Miguel; Sánchez, Guadalupe; Ancochea, Julio; García-Cosío, Borja
Background: Few large epidemiological studies have analysed the prevalence of respiratory symptoms and their determinants in the general adult population. We investigated the prevalence and determinants of respiratory symptoms and compared their prevalence with that of two previous studies conducted in 1999 and 2009. Method: EPISCAN II was a multicentre, cross-sectional, population-based epidemiological study in individuals older than 40 years. Results: A total of 9092 individuals were included. Up to 47.5% reported at least one respiratory symptom, being more frequent in women than in men (49.4% versus 45.5%, p=0.0002) and with wheezing being the most frequent (33.7%) followed by dyspnoea (26.8%). The presence of any symptom was associated with female sex, higher body mass index (BMI), lower forced expiratory volume in 1 s (FEV1 % pred), reduced physical activity, a higher Charlson index and the presence of anxiety and depression. Smoking was also significantly associated with having at least one respiratory symptom in a dose-response fashion (OR: 1.415, 1.916, 2.192 and 2.987 for 0-10, 10-20, 20-30 and >30 pack-years, respectively, all p<0.0001). The prevalence of symptoms remained quite similar over the last 20 years (wheezing 40%, 36% and 33.7% and dyspnoea 10.4%, 9.9% and 13.1% in 1999, 2009 and 2019, respectively). Conclusions: Approximately half of the adult Spanish population have respiratory symptoms and this prevalence has remained quite stable over the last 20 years. Smoking remains the main factor associated with respiratory symptoms, but female sex, comorbidities, high BMI and low FEV1 and low physical activity are also significantly associated with respiratory symptoms.
The External Validity of Sluggish Cognitive Tempo Versus Inattention in Behavioral, Social Interaction, and Academic Performance Measures
(Consejo General de la Psicología (España), 2022) Moreno-García, Inmaculada; Servera, Mateu; Morales-Ortiz, Manuel; Cano-Crespo, Almudena; Sáez, Belén
[EN] Background: The main objective was to replicate data on the external validity of the Sluggish Cognitive Tempo (SCT) dimension, versus ADHD Inattention (IN), with the Spanish version of the Child and Adolescent Behavior Inventory (CABI) SCT subscale [ Cuestionario sobre el Comportamiento de Niños ] (Burns et al., 2015). Method: 273 mothers and 255 fathers evaluated their 9 to13 year old children on SCT, IN and other CABI internalizing externalizing, academic impairment and social interaction measures. Results: As hypothesized, the relationship between SCT and externalizing measures, in contrast to IN, was practically nonexistent, whereas both measures were related to internalizing and social interaction measures. Thus, the unique predictive capacity of SCT and IN was significant and similar on internalizing measures, except in the case of shyness, where SCT was better, while IN was better on externalizing measures. Conclusions: The data largely replicated previous results: SCT, despite its relationship with IN, is capable of predicting a significant proportion of anxiety, depression, and excessive shyness problems and, unlike IN, functions as a protective measure for externalizing problems. [ES] Antecedentes: El objetivo principal del presente trabajo ha sido replicar datos de la validez externa de la dimensión Tempo Cognitivo Lento (TCL), frente a inatención del TDAH (IN), con la versión española de la medida del TCL del Child and Adolescent Behavior Inventory (CABI) [Cuestionario sobre el Comportamiento de Niños] (Burns et al., 2015). Método: 273 madres y 255 padres evaluaron a sus hijos entre 9 y 13 años en TCL, IN y otras medidas internalizadas, externalizadas, de dificultades académicas e interacción social del CABI. Resultados: La relación de TCL con las medidas externalizadas, al contrario de IN, fue prácticamente nula, en cambio ambas medidas se relacionaron con las medidas internalizadas y de interacción social. La capacidad predictiva única de TCL e IN fue significativa y similar sobre las medidas internalizadas, excepto en el caso de timidez, donde TCL fue superior y, en cambio, en las medidas externalizadas fue superior IN. Conclusiones: Los datos replican en gran parte los resultados previos: el TCL, a pesar de su relación con IN, es capaz de predecir una parte significativa de problemas de ansiedad, depresión y timidez excesiva y, en cambio, al contrario de IN, resulta una medida protectora para los problemas externalizados.
Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature
(2022-07) Deyà-Martínez, Angela; Rivière, Jaques G; Roxo-Junior, Pérsio; Ramakers, Jan; Bloomfield, Markéta; Guisado Hernandez, Paloma; Blanco Lobo, Pilar; Abu Jamra, Soraya Regina; Esteve-Sole, Ana; Kanderova, Veronika; García-García, Ana; Lopez-Corbeto, Mireia; Martinez Pomar, Natalia; Martín-Nalda, Andrea; Alsina, Laia; Neth, Olaf; Olbrich, Peter
Introduction: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. Methods: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
Determinants of blood eosinophil levels in the general population and patients with COPD: a population-based, epidemiological study
(BioMed Central (BMC), 2022-03-05) Miravitlles, Marc; Soler-Cataluna, Juan Jose; Soriano, Joan B; Garcia-Rio, Francisco; de Lucas, Pilar; Alfageme, Inmaculada; Casanova, Ciro; Rodriguez Gonzalez-Moro, Jose Miguel; Sanchez-Herrero, M Guadalupe; Ancochea, Julio; García-Cosío, Borja
Background: Blood eosinophils are considered a biomarker for the treatment of chronic obstructive pulmonary disease (COPD). Population-based studies are needed to better understand the determinants of the blood eosinophil count (BEC) in individuals with and without COPD. Methods: EPISCAN II is a multicentre, cross-sectional, population-based epidemiological study aimed at investigating the prevalence and determinants of COPD in Spain. Study subjects were randomly selected from the general population, and COPD was defined by a post-bronchodilator FEV1/FVC < 0.7. For the pre-specified outcomes related to BEC, the first 35 COPD and 35 non-COPD subjects were consecutively recruited in 12 of the participating centres with the objective of analysing 400 individuals in each group. Baseline BEC and its association with demographic, clinical and functional variables were analysed. Results: A total of 326 COPD and 399 non-COPD subjects were included in the analysis. The mean age (standard deviation [SD]) was 63.2 years (11.0), 46.3% were male, and 27.6% were active smokers. BEC was significantly higher in individuals with COPD [192 cells/μL (SD: 125) vs. 160 cells/μL (SD: 114); p = 0.0003]. In a stepwise multivariate model, being male, active smoker and having a previous diagnosis of asthma were independently associated with having a higher BEC. Conclusions: This population-based study estimated the distribution of eosinophils in the healthy adult population and concluded that COPD patients have a significantly higher BEC. Male sex, active smoking and concomitant asthma were significantly associated with a higher BEC.
A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype
(Frontiers Media, 2022) Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel; Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel
Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10-8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.
Evolution of Angiogenic Factors in Pregnant Patients with Breast Cancer Treated with Chemotherapy
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-02) Saura, Cristina; Sanchez, Olga; Martinez, Sandra; Dominguez, Carmen; Dienstmann, Rodrigo; Ruiz-Pace, Fiorella; Cespedes, Maria Concepcio; Penuelas, Angeles; Cortes, Javier; Llurba, Elisa; Córdoba, Octavi
Simple Summary Anthracyclines and taxanes are being used as a standard treatment for breast cancer diagnosed during pregnancy. These chemotherapy regimens allow the continuation of pregnancy without delaying cancer treatment with relatively good maternal and neonatal outcomes. However, their effects on placental function and fetal development are not completely understood. Maternal serum angiogenic factors are a surrogate of placental function and are abnormal weeks before placental complications such as preeclampsia or intrauterine growth restriction development. In our cohort, pregnant women with breast cancer treated with chemotherapy during pregnancy show an antiangiogenic state with significantly higher levels of soluble fms-like tyrosine kinase (sFlt-1), sFlt-1/PGF ratio, and soluble endoglin (sEng) at the end of the third trimester. Angiogenic factors could be useful in the clinical obstetric management of these patients, although more studies are guaranteed. High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT). Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes. Methods: Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls. Results: Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1; sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover; there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth. Conclusions: Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients; although further studies will be required to guide clinical decision-making.
Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
(Nature Publishing Group, 2023-05-23) Capdevila, J; Hernando, J; Teule, A; Lopez, C; Garcia-Carbonero, R; Benavent, M; Custodio, A; Garcia-Alvarez, A; Cubillo, A; Alonso, V; Carmona-Bayonas, A; Alonso-Gordoa, T; Crespo, G; Jimenez-Fonseca, P; Blanco, M; Viudez, A; La Casta, A; Sevilla, I; Segura, A; Llanos, M; Landolfi, S; Nuciforo, P; Manzano, J L; García-Carbonero, Rocio; Grupo Espanol de Tumores Neuroendocrinos y Endocrinos (GETNE); AstraZeneca
Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours
(Elsevier, 2023-07) Hernando, Jorge; Roca-Herrera, Maria; García-Álvarez, Alejandro; Raymond, Eric; Ruszniewski, Philippe; Kulke, Matthew H; Grande, Enrique; García-Carbonero, Rocio; Castellano, Daniel; Salazar, Ramón; Ibrahim, Toni; Teule, Alex; Alonso, Vicente; Fazio, Nicola; Valle, Juan W; Tafuto, Salvatore; Carmona, Ana; Navarro, Victor; Capdevila, Jaume
PURPOSE: There is an increasing interest in the role of sex and gender in cancer patients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET. METHODS: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment. RESULTS: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female patients. CONCLUSIONS: Sex-related differences in toxicity with the MKI treatment require targeted information and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published.

Browse

Recent Submissions