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Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning
(Elsevier, 2025-11-21) Lao, Oscar; Acosta, Sandra; Turpin, Isabel; Modrego, Adriana; Martí Sarrias, Andrea; Ortega Gasco, Alba; Haeb, Anna-Christina; García González, Laura; Soriano i Fradera, Jordi; Ruiz, Núria; Peñuelas-Haro I; Espinet, Elisa; Tornero, Daniel
Dravet syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in the SCN1A gene. Brain organoids (BOs) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoid circuitry. However, neuronal circuitry modeling in BOs remains hampered by the notorious inter- and intra-organoid variability. Thus, leveraging deep learning (DL), we developed ImPheNet, a predictive tool grounded in BO live imaging datasets, to overcome the limitations of the intrinsic BOs variability. ImPheNet accurately classified healthy and DS phenotypes at early onset stages, revealing differences between genotypes and upon antiseizure drug exposure. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool to accelerate DEEs research and advance toward treatment discovery in a time- and cost-efficient manner.
Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study
(Elsevier BV, 2024-07-01) S Graybill, Whitney; Pardo Búrdalo, Beatriz; M O’malley, David; Vergote, Ignace; J Monk, Bradley; Auranen, Annika; J Copeland, Larry; Sabbatini, Roberto; J Herzog, Thomas; Follana, Philippe; Pothuri, Bhavana; Ioana Braicu, Elena; Mccormick, Colleen; Yubero, Alfonso; G Moore, Richard; Vuylsteke, Peter; Raaschou-jensen, Nicoline; York, Whitney; Hartman, John; González-martín, Antonio; Stockman, Liz
Objective To identify characteristics associated with long-term progression-free survival (>= 2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. Methods In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or >= 2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). Results Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring >= 2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of >= 2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs >= 2 baseline non-target lesions). Conclusions The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of >= 2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. Trial registration number NCT02655016.
Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy
(Elsevier BV, 2023-09-07) Weinhofer, Isabelle; Rommer, Paulus; Gleiss, Andreas; Ponleitner, Markus; Zierfuss, Bettina; Waidhofer-söllner, Petra; Fourcade, Stéphane; Grabmeier-pfistershammer, Katharina; Reinert, Marie-christine; Göpfert, Jens; Heine, Anne; A F Yska, Hemmo; Casasnovas, Carlos; Cantarín, Verónica; G Bergner, Caroline; Mallack, Eric; Forss-petter, Sonja; Aubourg, Patrick; Bley, Annette; Engelen, Marc; Eichler, Florian; C Lund, Troy; Pujol, Aurora; Köhler, Wolfgang; Kühl, Jörn-sven; Berger, Johannes
Background X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adreno-myeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.Methods We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa (R) and Luminex (R) technologies.Findings Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in eBioMedicineasymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD.Interpretation Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro -inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset.
Asparaginase Hypersensitivity Reactions in NK/T-Cell Lymphomas
(MDPI AG, 2025-11-17) Varela Gonzalez-aller, Javier; Nadal, Pablo; Cañizares, Salome; Muñoz, Carmen; Valer, Anna; Gonzalez-barca, Eva; Domingo, Eva; Sureda, Ana; Novelli, Silvana
Background/Objectives: Asparaginase (ASP)-based chemotherapy has substantially improved clinical outcomes in Epstein-Barr virus (EBV)-positive NK/T-cell lymphomas (NKTCL). However, as a bacterial-derived enzyme, ASP is frequently associated with immune-mediated adverse events, particularly hypersensitivity reactions (HSRs), which may compromise both treatment efficacy and patient safety. This report presents a case of an ASP-related HSR and reviews the incidence within our institutional cohort. Detailed Case Description: A 60-year-old female presented an immediate Grade 2 HSR during her second PEG-asparaginase infusion, with pruritus, vomiting, and presyncope. The infusion was discontinued, and she was subsequently transitioned to crisantaspase-an alternative formulation-which was well tolerated without further adverse events. She remains disease-free to date. A retrospective review of institutional records (2015-2025) identified six patients with NKTCL treated with ASP-containing chemotherapy. The incidence of HSRs in this cohort was 1 of 6 (16.7%). Conclusions: As in acute lymphoblastic leukemia, HSRs to asparaginase remains a major challenge in the management of NKTCL with potential implications for treatment safety and efficacy. The establishment of standardized, consensus-based criteria for the diagnosis, classification, and management of ASP-related HSRs is urgently needed to optimize patient outcomes.
Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914)
(American Association for Cancer Research (AACR), 2025-09-12) Capdevila, Jaume; Hernando, Jorge; Molina-cerrillo, Javier; Benavent Viñuales, Marta; Garcia-carbonero, Rocio; Teulé, Alex; Custodio, Ana; Jimenez-fonseca, Paula; Lopez, Carlos; Hierro, Cinta; Carmona-bayonas, Alberto; Alonso, Vicente; Llanos, Marta; Sevilla, Isabel; Garcia-alvarez, Alejandro; Alonso-gordoa, Teresa; Gallego Jiménez, Inmaculada; Antón-pascual, Beatriz; Modrego Sánchez, Andrea; Grande, Enrique
Purpose: Multikinase inhibitors have shown efficacy in endocrine neoplasms, and synergism with immune checkpoint inhibitors has been noted in other tumors.Patients and Methods: This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1.Results: From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8-42.8] in ATC (N = 14); 8.3% (95% CI, 1.0-27.0) in ACC (N = 24); 15.4% (95% CI, 1.9-45.5) in PPGL (N = 13), and 16.7% (95% CI, 4.7-37.4) in GEP-NET (N = 24). Lung well-differentiated neuroendocrine tumors and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed.Conclusions: Cabozantinib and atezolizumab were safely administered and showed promising ORR, and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.
Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy
(Ovid Technologies (Wolters Kluwer Health), 2024-07-11) C. Blant, Julie; N. De Rossi, Nicola; Gold, Ralf; Maurousset, Aude; Kraemer, Markus; Romero-pinel, Lucía; Misu, Tatsuro; Ouallet, Jean-christophe; Pallix Guyot, Maud; Gerevini, Simonetta; Bakirtzis, Christos; Piñar Morales, Raquel; Vlad, Benjamin; Karypidis, Panajotis; Moisset, Xavier; J. Derfuss, Tobias; Jelcic, Ilijas; Martin-blondel, Guillaume; Ayzenberg, Ilya; Mcgraw, Corey; A. Laplaud, David; A. Du Pasquier, Renaud; Bernard-valnet, Raphael
Background and Objectives Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. Methods A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. Results Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). Discussion S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.
Ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL): GELLC-7 trial from the Spanish group of CLL (GELLC)
(Elsevier, 2024-05-25) Abrisqueta Costa, Pau; González Barca, Eva; Ferrà, Christelle; Rios-Herranz, Eduardo; Fernández de la Mata, Margarita; Delgado, Julio (Delgado González); Andreu, Rafael; Hernandez Rivas, Jose Angel; Terol, María José; Navarro-Bailón, Almudena; Vidriales, Belén; Baltasar, Patricia; De la Serna, Javier; Ramírez, Ángel; Ballester, Carmen; Moreno, Carol; García-Marco, José Antonio; Córdoba, Raúl; Yáñez, Lucrecia; Casado, Luís Felipe; González, Marcos; Bosch Albareda, Francesc
Background: BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending. Methods: This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26). Findings: Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n = 80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively. Interpretation: These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response.
Chronic kidney disease and chronic oral inflammatory diseases: A systematic review and meta-analysis of periodontitis and apical periodontitis
(MDPI, 2025-11-10) López Sanz, Laura; León López, Maria; Egido-Moreno, Sonia; Segura Raya, Carlos; López López, José, 1958-; Segura Sampedro, Juan J.; Cabanillas Balsera, Daniel; Segura Egea, Juan José
Background: Chronic kidney disease (CKD) has been increasingly associated with oral chronic inflammatory conditions, including periodontitis (PD) and apical periodontitis (AP). Both share common pathophysiological pathways involving systemic inflammation, immune dysregulation, and oxidative stress. This systematic review and meta-analysis aimed to synthesize current evidence on the association between CKD and chronic oral inflammatory diseases. Methods: The PRISMA guidelines were followed and the proto-col was registered in PROSPERO: CRD420251167323. A comprehensive electronic search was conducted in PubMed, Scopus, Web of Science, and ProQuest up to September 2025. Observational studies reporting prevalence of chronic oral inflammatory diseases in CKD patients and controls subjects were included. The Newcastle-Ottawa scale was used for assessing risk of bias. Pooled odds ratios (ORs) were calculated using a random-effects model. Results: Seven studies published between 2011 and 2025, including 13,139 participants, met the inclusion criteria. CKD patients had significantly higher prevalence of oral inflammatory disease than controls (OR = 4.2; 95% CI = 2.5-7.2; p < 0.00001). Heterogeneity was high (I2 = 83.0%). Subgroup analysis showed an OR of 4.3 (95% CI = 2.6-7.0; p < 0.0001) for AP and 4.3 (95% CI = 2.2-8.7) for PD. The overall risk of bias was moderate, and the certainty of evidence according to GRADE was rated as low. Conclusions This systematic review and meta-analysis highlight a potential link between chronic oral inflammatory disease, including both AP and PD, and chronic kidney disease (CKD). However, the certainty of the evidence is low, and substantial heterogeneity exists across studies.
Co-clinical trial targeting ER, FGFR and CDK4/6 in resistant hormone-positive breast cancer with FGFR alterations
(Springer Science and Business Media LLC, 2025-11-07) Martinez-jañez, Noelia; Ángel García-saenz, José; Pernas, Sonia; Bermejo, Begoña; Morales, Serafín; Guerra, Juan; Silva, Jorge; Manso, Luis; Ciruelos, Eva; Tolosa, Pablo; Sánchez-bayona, Rodrigo; Alva, Manuel; Calabuig-fariñas, Silvia; Gallach, Sandra; Muinelo-romay, Laura; Piñeiro-yáñez, Elena; Caleiras, Eduardo; J. Bueno, Maria; Mouron, Silvana; Quintela-fandino, Miguel
Management of advanced hormone receptor-positive, HER2-negative breast cancer after progression on endocrine therapy plus CDK4/6 inhibitors is challenging due to mutational heterogeneity. Current therapies yield limited efficacy, achieving 4-6 months PFS. FGFR signaling is implicated in resistance to endocrine plus CDK4/6 inhibitors, but FGFR inhibitors have shown limited activity in unselected populations. Co-clinical trials bridge preclinical and clinical findings, optimize resources, and enable biomarker identification. Using patient-derived organoids (PDOs), we demonstrated that FGFR-amplified PDOs respond to fulvestrant, palbociclib, and rogaratinib only when PIK3CA and ESR1 are wild-type. In a dose-escalation trial pre-screening 66 patients with FGFR1/2-amplification (FISH) and/or overexpression (RNAScope) patients, >40% harbored FGFR alterations. Nine patients were enrolled; the combination showed activity specifically in PIK3CA- and ESR1-wild type patients (9.1 vs. 1.9 months PFS; P = 0.0005). Toxicity was manageable and consistent with prior data. Our findings highlight biomarker-driven approaches as essential for refining FGFR-targeted strategies in this resistant population.
Dynamic modelling of the ALSFRS-R: leveraging population-based scores using neural networks
(Elsevier BV, 2025-11-20) Ross, Robert; Mac Domhnaill, Éanna; Chiò, Adriano; Corcia, Philippe; Ingre, Caroline; J Mcdermott, Christopher; Povedano Panadés, Mónica; J Shaw, Pamela; Van Damme, Philip; Van Den Berg, Leonard; Al-chalabi, Ammar; Walsh, Cathal; Hardiman, Orla
Background Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with highly heterogeneous trajectories. The Revised ALS Functional Rating Scale (ALSFRS-R) is challenging to model due to irregularly spaced data and patient-level variability. Here we sought to develop and validate a short-horizon prediction tool leveraging a fully connected neural network (FCNN) to forecast individual ALSFRS-R trajectories, providing a natural history benchmark for trials and clinical practice. Methods We retrospectively analysed 29,992 ALSFRS-R measurements from 5319 people living with ALS (plwALS) in the population-based PRECISION-ALS dataset. plwALS were randomised (80:20) into a training and test cohort using group-based splitting. A three-layer FCNN was built in TensorFlow to predict a third ALSFRS-R score given two historical scores and their respective time intervals. Performance was evaluated on the PRECISION-ALS test set and externally on the PROACT database. Linear extrapolation served as a baseline comparator. Findings On the PRECISION-ALS test set, the FCNN achieved a mean absolute error (MAE) of 0.0552 (95% CI 0.0547-0.0576) on a normalised 0-1 scale, corresponding to 2.65 (2.63, 2.76) points on the 48-point ALSFRS-R. This remained consistent across all post-diagnostic periods. The model generalised well to the PROACT dataset, with an improved MAE of 0.0485 (95% CI 0.0481, 0.0489). Linear extrapolation performed significantly worse across all metrics. Error remained consistent across all clinical groups investigated, such as sex, genotype, site of onset, age at diagnosis, age at onset and diagnostic delay. Interpretation A short-horizon FCNN can provide clinically interpretable, individualised ALSFRS-R forecasts from sparse, irregularly spaced data. By supporting rapid identification of those who step outside of the model, this approach holds promise for optimising patient counselling, clinical trial monitoring, and early intervention strategies. This approach allows us to better utilise our growing bank of ALS patient data to support decision making. Funding R McFarlane is supported by a grant from Target ALS, Precision ALS is funded by Taighde & Eacute;ireann (Research Ireland, formerly Science Foundation Ireland). Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Generation and External Validation of a Histologic Transformation Risk Model for Patients with Follicular Lymphoma
(Elsevier BV, 2024-05-17) Fernández-miranda, Ismael; Pedrosa, Lucía; González-rincón, Julia; Espinet, Blanca; De La Cruz Vicente, Fátima; Climent, Fina; Gómez, Sagrario; Royuela, Ana; I. Camacho, Francisca; Martín-acosta, Paloma; Yanguas-casás, Natalia; Domínguez, Marina; Méndez, Miriam; Colomo, Luis; Salar, Antonio; Horcajo, Beatriz; Navarro, Marta; García-cosío, Mónica; Piris-villaespesa, Miguel; Llanos, Marta; F. García, Juan; Sequero, Silvia; Mercadal, Santiago; García-hernández, Sonia; Navarro, Belén; Mollejo, Manuela; Provencio, Mariano; Sánchez-beato, Margarita
Follicular lymphoma (FL) is the most frequent indolent lymphoma. Some patients (10%-15%) experience histologic transformation (HT) to a more aggressive lymphoma, usually diffuse large Bcell lymphoma (DLBCL). This study aimed to validate and improve a genetic risk model to predict HT at diagnosis.We collected mutational data from diagnosis biopsies of 64 FL patients. We combined them with the data from a previously published cohort (total n 1/4 104; 62 from nontransformed and 42 from patients who did transform to DLBCL). This combined cohort was used to develop a nomogram to estimate the risk of HT. Prognostic mutated genes and clinical variables were assessed using Cox regression analysis to generate a risk model. The model was internally validated by bootstrapping and externally validated in an independent cohort. Its performance was evaluated using a concordance index and a calibration curve. The clinicogenetic nomogram included the mutational status of 3 genes (HIST1HE1, KMT2D, and TNFSR14) and high-risk Follicular Lymphoma International Prognostic Index and predicted HT with a concordance index of 0.746. Patients were classified as being at low or high risk of transformation. The probability HT function at 24 months was 0.90 in the low-risk group vs 0.51 in the high-risk group and, at 60 months, 0.71 vs 0.15, respectively. In the external validation cohort, the probability HT function in the low-risk group was 0.86 vs 0.54 in the high-risk group at 24 months, and 0.71 vs 0.32 at 60 months. The concordance index in the external cohort was 0.552. In conclusion, we propose a clinicogenetic risk model to predict FL HT to DLBLC, combining genetic alterations in HIST1H1E, KMT2D, and TNFRSF14 genes and clinical features (Follicular Lymphoma International Prognostic Index) at diagnosis. This model could improve the management of FL patients and allow treatment strategies that would prevent or delay transformation. (c) 2024 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
One-year longitudinal changes of peripheral CD4+ T-lymphocyte counts, gut microbiome, and plaque vulnerability after an acute coronary syndrome
(Elsevier BV, 2024-06-04) Fernández-avila, Ana I; Gutiérrez-ibanes, Enrique; Martín De Miguel, Irene; Sanz-ruiz, Ricardo; Gabaldón, Álvaro; Fernández-avilés, Francisco; Gómez-lara, Josep; Fernández-castillo, Marta; Vázquez-cuesta, Silvia; Martínez-legazpi, Pablo; Lozano-garcia, Nuria; Blázquez-lópez, Elena; Yotti, Raquel; López-cade, Igor; Reigadas, Elena; Muñoz, Patricia; Elízaga, Jaime; Correa, Rafael; Bermejo, Javier
Background: Longitudinal changes in gut microbiome and inflammation may be involved in the evolution of atherosclerosis after an acute coronary syndrome (ACS). We aimed to characterize repeated profiles of gut microbiota and peripheral CD4 + T lymphocytes during the first year after an ACS, and to address their relationship with atherosclerotic plaque changes. Methods: Over one year we measured the microbiome, peripheral counts of CD4 + T populations and cytokines in 67 patients shortly after a first ACS. We compared baseline measurements to those of a matched population of 40 chronic patients. A subgroup of 20 ACS patients underwent repeated assessment of fibrous cap thickness (FCT) of a non-culprit lesion. Results: At admission, ACS patients showed gut dysbiosis compared with the chronic group, which was rapidly reduced and remained low at 1-year. Also, their Th1 and Th2 CD4 + T counts were increased but decreased over time. The CD4 + T counts were related to ongoing changes in gut microbiome. Unsupervised clustering of repeated CD4 + Th0, Th1, Th2, Th17 and Treg counts in ACS patients identified two different cell trajectory patterns, related to cytokines. The group of patients following a high-CD4 + T cell trajectory showed a one-year reduction in their FCT [net effect = -24.2 mu m; p = 0.016]. Conclusions: Patients suffering an ACS show altered profiles of microbiome and systemic inflammation that tend to mimic values of chronic patients after 1-year. However, in one-third of patients, this inflammatory state remains particularly dysregulated. This persistent inflammation is likely related to plaque vulnerability as evident by fibrous cap thinning (Clinical Trial NCT03434483).
Mitochondrial methylcytosines as blood-based biomarkers for Alzheimer's disease dementia prognosis
(Elsevier, 2025-08-21) Gascón-Bayarri, Jordi; Mosquera Mayo, José Luís; Blanch Lozano, Marta; Martí Benaiges, Pau; Fontal Aina, Beatriz; Trapero Candela, Carla; Rojo Fité, Nuria; Rico, Inma; Campdelacreu i Fumadó, Jaume; Fowler, Cristopher; Laws, Simon M.; Tort Merino, Adrià; Sánchez del Valle Díaz, Raquel; Bello, Joan; Fortea Ormaechea, Juan; Lleó Bisa, Alberto; Mehanian, Courosh; Swerdlow, Russell H.; Reñé Ramírez, Ramon; Barrachina, Marta
Alzheimer's Disease Dementia (ADD) prognosis is an unmet medical need. Mitochondrial dysfunction is an early AD etiopathogenic factor. The present study analyzed mitochondrial DNA (mtDNA) methylation patterns in blood samples from patients with mild cognitive impairment (MCI) who progressed to ADD (P), MCI remained stable (NP), and Cognitively Normal (CN) individuals. Differentially methylated sites were identified in the D-loop region in both CN vs. NP and NP vs. P comparisons, even before β-amyloid positivity. A Random Forest model was developed using mtDNA methylation data combined with cognitive and risk factor features. Model's performance was assessed by cross-validation and tested on an independent set, achieving 84.4% accuracy in training and 83.2% (95% CI: 75.2%-89.4%) in testing. For identifying P patients, sensitivity and specificity were 95.1% and 70.7%, respectively. The AUC-ROC was 90.3%. The developed model demonstrates predictive capacity in distinguishing cognitive decline and stability in MCI individuals, independently of their β-amyloid status.
Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1–High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial
(Elsevier BV, 2023-08-18) Chul Cho, Byoung; Seok Lee, Jong; Wu, Yi-long; Cicin, Irfan; Cobo Dols, Manuel; Ahn, Myung-ju; Cuppens, Kristof; Veillon, Rémi; Nadal, Ernest; Mourão Dias, Josiane; Martin, Claudio; Reck, Martin; B. Garon, Edward; Felip, Enriqueta; Paz-ares, Luis; Mornex, Francoise; E. Vokes, Everett; A. Adjei, Alex; Robinson, Clifford; Sato, Masashi; Vugmeyster, Yulia; Machl, Andreas; Audhuy, Francois; Chaudhary, Surendra; Barlesi, Fabrice
Introduction: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-bRII (a TGF-b trap) fused to a human immuno-globulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1-high advanced NSCLC. Methods: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 per independent review committee and overall survival. Results: Patients (N = 304) were randomized one-to-one to receive either bintrafusp alfa or pembrolizumab (n = 152 each). The median follow-up was 14.3 months (95% confidence interval [CI]: 13.1-16.0 mo) for bintrafusp alfa and 14.5 months (95% CI: 13.1-15.9 mo) for pem-brolizumab. Progression-free survival by independent re-view committee was not significantly different between bintrafusp alfa and pembrolizumab arms (median = 7.0 mo [95% CI: 4.2 mo-not reached (NR)] versus 11.1 mo [95% CI: 8.1 mo-NR]; hazard ratio = 1.232 [95% CI: 0.885- 1.714]). The median overall survival was 21.1 months (95% CI: 21.1 mo-NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 mo-NR) for pembrolizumab (hazard ratio = 1.201 [95% CI: 0.796-1.811]). Treatment-related adverse events were higher with bintrafusp alfa versus pembrolizumab; grade 3-4 treatment-related adverse events occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary end point. Conclusions: First-line treatment with bintrafusp alfa did not exhibit superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC.(c) 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).
Current challenges in cell and gene therapy: a joint view from the European Committee of the International Society for Cell & Gene Therapy (ISCT) and the European Society for Blood and Marrow Transplantation (EBMT)
(Elsevier BV, 2024-02-17) Sanchez-guijo, Fermin; Vives, Joaquim; Ruggeri, Annalisa; Chabannon, Christian; Corbacioglu, Selim; Dolstra, Harry; Farge, Dominique; Gagelmann, Nico; Horgan, Claire; Kuball, Jurgen; Neven, Benedicte; Rintala, Tuula; Rocha, Vanderson; Sanchez-ortega, Isabel; A. Snowden, John; Jan Zwaginga, Jaap; Gnecchi, Massimiliano; Sureda, Anna
Cell and gene therapy poses evolving challenges. The current article summarizes the discussions held by European Regional Committee of the International Society for Cell & Gene Therapy and the European Society for Blood and Marrow Transplantation (EBMT) on the current challenges in this field, focusing on the European setting. This article emphasizes the imperative assessment of real -world cell and gene therapy activity, advocating for expanded registries beyond hematopoietic transplantation and chimeric antigen receptor -Tcell therapy. Accreditation 's role in ensuring standardized procedures, as exemplified by JACIE (The Joint Accreditation Committee of ISCT-Europe and EBMT), is crucial for safety. Access to commercial products and reimbursement variations among countries underscore the need for uniform access to advanced therapy medical products (ATMPs). Academic product development and point -of -care manufacturing face barriers to patient access. Hospital Exemption 's potential, demonstrated by some initial experiences, may increase patient accessibility in individual situations. Regulatory challenges, including the ongoing European ATMPs legislation review, necessitate standardized criteria for Hospital Exemption and mandatory reporting within registries. Efforts to combat unproven therapies and fraud involve collaboration between scientific societies, regulatory bodies and patient groups. Finally, is important to highlight the vital role of education and work- force development in meeting the escalating demand for specialized professionals in the ATMP field. Collabo- ration among scientific societies, academic institutions, industry, regulatory bodies and patient groups is crucial for overcoming all these challenges to increase gene and cell therapy activity in Europe. (c) 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Insulin and disorders of behavioural flexibility
(Elsevier, 2023-04-27) Scholtz, Samantha; Glennon, Jeffrey C.; Sullivan, Mairead; Fernández Aranda, Fernando; Camacho Barcia, Lucía; Harkin, Andrew; Macrì, Simone; Mora Maltas, Bernat; Jiménez-Murcia, Susana; O'Leary, Aet; Ottomana, Angela Maria; Presta, Martina; Slattery, David
Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.
A novel technique for computer-assisted dental autotransplantation: A case report with 42 months of follow-up
(Tabriz University of Medical Sciences (TUOMS), 2025-04-13) Chegeni, Ehsan; Marques, José; Barbosa de Figueiredo, Rui Pedro; Valmaseda Castellón, Eduardo; Kadkhodazadeh, Mahdi
Dental autotransplantation (DAT) is an effective technique for replacing missing teeth. This case report presents a novel computer-assisted approach using cone-beam computed tomography (CBCT) for 3D planning. A 15-year-old female with a hopeless molar due to failed endodontic treatment underwent DAT. Following 3D planning, the donor tooth was surgically extracted and transplanted into the prepared socket, followed by semi-rigid splinting. A meticulous 42-month clinical and radiographic follow-up demonstrated the success and stability of the procedure. This innovative method emphasizes the role of advanced computer technology and 3D imaging in enhancing surgical precision and treatment outcomes. Within the limitations of this case report, DAT, combined with computer-assisted planning, proved a reliable and predictable treatment option for replacing hopeless teeth, particularly in young patients. This approach showed the potential of DAT to transform tooth replacement strategies with better accuracy and decision-making.
Gene-Specific Detection Rate of Adenomas and Advanced Adenomas in Lynch Syndrome
(Elsevier, 2025-09-01) Sánchez Brualla, Alicia; Castillo Iturra, Joaquín; Balmaña, Judith; Brunet, Joan; Castells Sánchez, Alba; Capellá, G. (Gabriel); Ladabaum, Uri; Dekker, Evelien; Moreira, Luciana; Pellisé, M.; Balaguer Prunés, Francesc; López Fernández, Adrià; Salces, Inmaculada; Picó, María Dolores; Rivas, Laura; Bujanda, Luis; Garzon, Marta; Pizarro, Angeles; Martinez de Castro, Eva; Roos, V.H.; Dueñas, Nuria; Pineda Riu, Marta; Moreno Calle, Lorena; Rodríguez Alonso, Lorena; Ramon y Cajal, Teresa; Llort, Gemma; Piñol, Virginia; López Arias, María .Jesús; Poves, Carmen; Garau, Catalina; Rodríguez Alcalde, Daniel; Herraiz, Maite; Álvarez Urrutia, Cristina; Dacal, Andrés; Carrillo Palau, Marta; Cid, Lucía; Ponce, Marta; Barreiro Alonso, Eva; Saperas, Esteban; Aguirre, Elena; Bastiaansen, B.; Ocaña, Teresa; Carballal, Sabela; Rivero Sánchez, Liseth; Ortiz, Oswaldo; Daca Álvarez, María; Prat Galito, Ricard; Bessa, Xavier; Cubiella, Joaquin; Jover, Rodrigo; Rodríguez Moranta, Francisco
Background & Aims Colonoscopy is expected to reduce colorectal cancer (CRC) incidence in Lynch syndrome (LS) by detecting and removing adenomas. The existence of gene-specific differences in adenoma detection has been proposed yet remains insufficiently explored. This study aims to elucidate gene-specific adenoma detection rates and their association with post-colonoscopy CRC (PCCRC), which stands as an important issue in LS surveillance. Methods In this multicenter study, we analyzed 1072 LS carriers without prior CRC undergoing surveillance colonoscopy, evaluating adenoma and advanced adenoma (AA) detection rates by gene. The primary outcome was to compare adenoma detection rates in individuals without prior CRC carrying pathogenic variants in MLH1/MSH2 vs MSH6/PMS2. Subgroup analysis was performed to assess the intermediate risk profile in MSH6 carriers relative to MLH1/MSH2 and PMS2 carriers. We compared overall adenoma detection rates, adenoma burden, age at first adenoma occurrence, and 10-year cumulative detection rates. Risk factors for AA and PCCRC were also identified. Multiple testing and multivariate analyses were performed. Results The adenoma detection rates were similar across the 4 genes. However, MLH1/MSH2 carriers had a higher overall AA detection rate compared with MSH6/PMS2 carriers (14.5% vs 11.9%; P = .04) and showed higher cumulative AA detection rates over 10 years (21.6% vs 19.7%; P = .04). Subgroup analysis indicated that MSH6 carriers had an intermediate AA detection rate positioned between MLH1/MSH2 carriers and PMS2 carriers. Multivariate analysis indicated that AAs (odds ratio, 2.12; 95% confidence interval, 1.08–4.17; P=.03) and repeated AA detection (odds ratio, 4.62; 95% confidence interval, 1.70–12.57; P < .01) were independent risk factors for PCCRC. Conclusions Carriers of MLH1/MSH2 pathogenic variants are at a higher risk of developing AAs compared with those with MSH6/PMS2 mutations, with MSH6 carriers exhibiting an intermediate risk profile. AAs are an independent risk factor for PCCRC. LS patients with AAs should be identified as high risk and undergo enhanced colonoscopy surveillance.
Early anticoagulation may improve preprocedural patency of the infarct-related artery in primary percutaneous coronary intervention.
(Elsevier España, 2013-02-01) Ariza Solé, Albert; Ferreiro Gutiérrez, José Luis; Sánchez Salado, Jose Carlos; Lorente, Victòria; Gómez Hospital, Joan Antoni; Cequier Fillat, Àngel R.
The aim of this study was to evaluate the impact of early administration of anticoagulation therapy (at diagnosis) compared with its application in the cardiac catheterization laboratory at the start of the procedure on the initial patency of the infarct-related artery (IRA) in patients undergoing pPCI as a reperfusion strategy.
Time from symptoms onset to remdesivir is associated with the risk of ICU admission: a multicentric analyses
(BioMed Central, 2023-05-04) Alonso Navarro, Rodrigo; Ramírez, Margarita; Masiá, Mar; Paredes, Roger; Montejano, Rocío; Povar Echeverria, Marina; Carratalà, Jordi; Salavert, Miguel; Bernal, Enrique; Dueñas, Carlos; Flores, Juan; Fanjul, Francisco; Gutiérrez, Isabel; Rico, Verónica; Mateu, Lourdes; Cadiñanos, Julen; Berenguer Berenguer, Juan; Soriano, Alex
Background Shorter duration of symptoms before remdesivir has been associated with better outcomes. Our goal was to evaluate variables associated with the need of ICU admission in a cohort of hospitalized patients for COVID-19 under remdesivir including the period from symptoms onset to remdesivir. Methods We conducted a retrospective multicentric study analysing all patients admitted with COVID-19 in 9 Spanish hospitals who received treatment with remdesivir in October 2020. The main outcome was the need of ICU admission after 24 h of the first dose of remdesivir. Results In our cohort of 497 patients, the median of days from symptom onset to remdesivir was 5 days, and 70 of them (14.1%) were later admitted into ICU. The clinical outcomes associated with ICU admission were days from symptoms onset (5 vs. 6; p = 0.023), clinical signs of severe disease (respiratory rate, neutrophil count, ferritin levels and very-high mortality rate in SEIMC-Score) and the use of corticosteroids and anti-inflammatory drugs before ICU. The only variable significatively associated with risk reduction in the Cox-regression analyses was ≤ 5 days from symptoms onset to RDV (HR: 0.54, CI95%: 0.31–0.92; p = 0.024). Conclusion For patients admitted to the hospital with COVID-19, the prescription of remdesivir within 5 days from symptoms onset diminishes the need of ICU admission.

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