Valcarcel, D. (David)

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    Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group
    (2018) Gayoso, J. (Jorge); López-Guillermo, A. (Armando); Castro, N. (Nerea); Suárez-Lledó, M. (María); Briones, J. (Javier); Bello, J. I. (José I.); Rodríguez, M.J. (María José); López, A. (Andrés); Ramirez, M.J. (María Javier); Rifon, J. J. (Jose J.); Montes-Moreno, S. (Santiago); López-Jiménez, J. (Javier); Martin, A. (Alejandro); Caballero, D. (Dolores); Colorado, M. (Mercedes); Valcarcel, D. (David); Palomera, L. (Luis); Terol, M.J. (María José); Canales-Albendea, M. A. (Miguel Ángel); Sanchez, A. (Andrés); Campo, R. (Raquel) del; Redondo, A. M. (Alba M.); Jarque, I. (Isidro); Arranz, R. (Reyes); González-Rodriguez, A.P. (Ana Pilar)
    We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28–71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9–72) and 14 (4–53) days to achieve neutrophil and platelet counts of >0.5 × 109/l and >20 × 109/l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40–77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12–0.56]) and OS (RR, 0.40 [95% CI 0.17–0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
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    Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial
    (Ferrata Storti Foundation, 2011-07) Cañizo, C. (C.) del; Martinez, C. (Carmen); Perez-Simon, J.A. (José Antonio); Diez-Campelo, M. (M.); Rifon, J. J. (Jose J.); Andreu, E.J. (Enrique José); Valcarcel, D. (David); Muntion, S. (Sandra); Lopez-Villar, O. (Olga); Sanchez-Guijo, F.M. (Fermín M.)
    This trial evaluated the feasibility and efficacy of the infusion of mesenchymal stem cells expanded using human serum for the treatment of refractory acute or chronic graft-versus-host disease. Twenty-eight expansions were started. In 22, a minimum of more than 1 x 10⁶ mesenchymal stem cells/kg were obtained after a median of 26 days; this threshold was not obtained in the remaining cases. Ten patients received cells for the treatment of refractory or relapsed acute graft-versus-host disease and 8 for chronic disease. One patient treated for acute graft-versus-host disease obtained a complete response, 6 had a partial response and 3 did not respond. One of the chronic patients achieved complete remision, 3 a partial response, and 4 did not respond. The current study supports the use of this approach in less heavily treated patients for both acute and chronic graft-versus-host disease. The trial has been registered at ClinicalTrials.gov: identifier NCT00447460.
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    Spanish guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia
    (2019) Cedena, M.T. (María Teresa); Zamora, L. (Lurdes); Cervera, J. (Jose); Cigudosa, J.C. (Juan Cruz); Fernandez-Mercado, M. (Marta); Palomo, L. (Laura); Alvarez, S. (Sara); Sole, F. (Francesc); Hernandez, J.M. (J. M.); Ibáñez, M. (Mariam); Acha, P. (Pamela); Such, E. (Esperanza); Tazón-Vega, Bárbara; Valcarcel, D. (David); Benito, R. (Rocío); Rapado, I. (Inmaculada); Cabezón, Marta; Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Larrayoz, M.J. (María J.); Fuster-Tormo, F. (Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Sanz, G. (Guillermo); Abaigar, M. (María)
    The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
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    Uncovering perturbations in human hematopoiesis associated with healthy aging and myeloid malignancies at single-cell resolution
    (2023) Gomez-Cabrero, D. (David); Lasaga, M. (Miren); Diez-Campelo, M. (M.); Molero, A. (Antonieta); San-Martín-Uriz, P. (Patxi); Romero-Riojas, J.P. (Juan Pablo); Alfonso-Piérola, A. (Ana); San-Julian, M. (Mikel); Jimenez-Solas, T. (Tamara); Ezponda, T. (Teresa); Valcarcel, D. (David); Lopez, F. (Félix); Dupéré-Richer, D. (Daphné); NO USAR Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Montoro, J. (Julia); Mution, S. (Sandra); Hernaez, M. (Mikel); Serrano-Sanz, G. (Guillermo); Ainciburu-Fernández, M. (Marina); Prosper-Cardoso, F. (Felipe); Berastegui-Zufiaurre, N. (Nerea); Diaz-Mazquiaran, A. (Aintzane); Sanchez-Guijo, F.M. (Fermín M.)
    Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals. Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease. In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients
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    Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide
    (Nature Research, 2024) Serrano, G. (Guillermo); Berastegui-Zufiaurre, N. (Nerea); Díaz-Mazkiaran, A. (Aintzane); García-Olloqui, P. (Paula); Rodriguez-Res, C. (Carmen); Huerga-Dominguez, S. (Sofia); Ainciburu-Fernández, M. (Marina); Vilas-Zornoza, A. (Amaia); San-Martín-Uriz, P. (Patxi); Aguirre-Ruiz, P. (Paula); Ullate-Agote, A. (Asier); Ariceta, B. (Beñat); Lamo-Espinosa, J.M. (J. M.); Acha, P. (Pamela); Calvete, O. (Oriol); Jimenez-Solas, T. (Tamara); Molero, A. (Antonieta); Montoro, M.J. (Maria Julia); Diez-Campelo, M. (Maria); Valcarcel, D. (David); Sole, F. (Francisco); Alfonso-Piérola, A. (Ana); Prosper-Cardoso, F. (Felipe); Ezponda, T. (Teresa); Hernaez, M. (Mikel); Ochoa-Álvarez, I. (Idoia)
    While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.