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Magnetic Resonance Imaging (MRI) allows the visualization of organs and tissues for medical diagnosis. This technique is non-invasive, does not require the use of radioactive agents or high-energy electromagnetic waves, and has a high spatial resolution and a great image depth. Despite these advantages, in order to increase the contrast in these images between the region of interest and its surroundings, it is often necessary to use contrast agents (CAs), which are composed of magnetically active substances that shorten T1 and T2 proton relaxation times. Although MRI is well established in clinics, several modifications of this technique are being currently addressed with the aim of improving diagnostic reliability. In particular, high-field MRI and T1-T2 dual mode MRI have been proposed. The first one improves image resolution by using higher magnetic fields than those involved in conventional scanners (? 3 T). T1-T2 dual mode MRI involves recording bright and dark images simultaneously. By so doing, cross-validation of both types of images can be carried out, so that false positives can be excluded, and complementary information can be also obtained. Both advantages allow to increase diagnostic sensitivity and accuracy. Unfortunately, the conventional CAs used in clinics are not suitable for these novel techniques, for which, it is imperative to develop new contrast agents. For the high-field MRI technique, several alternatives have been considered. The most promising candidates are compounds based on Dy3+, since this ion has a very high magnetic moment (10.6 ?B), which leads to high transverse relaxivity values. For T1-T2 dual mode MRI, compounds based on Dy3+ ions as T2 component are equally interesting, and as T1 component, Gd3+ ions are usually used, which have a high spin angular momentum (7/2) that allows high values of longitudinal relaxivity. Different CAs have been reported in the literature, both for high-field MRI and T1-T2 dual mode MRI, consisting of, La técnica de obtención de imágenes por Resonancia Magnética (MRI, siglas en inglés) permite la visualización de órganos y tejidos para el diagnóstico médico. Esta técnica destaca por ser no invasiva, no requerir el uso de agentes radiactivos u ondas electromagnéticas de alta energía, poseer una alta resolución espacial y una gran profundidad de imagen. A pesar de estas ventajas, a veces es necesario aumentar el contraste entre la región de interés y su entorno, empleando agentes de contraste (ACs) que están constituidos por sustancias magnéticamente activas que acortan los tiempos de relajación T1 y T2 del protón. Los ACs que acortan T2 oscurecen la región de interés, mientras que aquellos que disminuyen el valor de T1 dan lugar a un mayor brillo de dicha región. Entre los primeros destacan los óxidos superparamagnéticos basados en óxido de hierro, y entre los segundos, los compuestos de Gd3+ en los cuales están basados los agentes de contraste comerciales. Aunque la técnica MRI está muy bien establecida en el ámbito clínico, se están abordando en la actualidad diversas modificaciones de la misma con el objetivo de mejorar la fiabilidad del diagnóstico. En concreto, se han propuesto la técnica de MRI a alto campo y la técnica de MRI dual T1 - T2. La primera supone emplear campos magnéticos más altos que los implicados en los escáneres usados en clínica (≤ 3 T), con el objeto de mejorar la resolución. La segunda permite aumentar la sensibilidad y exactitud del diagnóstico registrando imágenes brillantes y oscuras de forma simultánea, ya que, mediante la validación cruzada de ambos tipos de imágenes, se pueden excluir falsos positivos y, además, obtener información complementaria. Desafortunadamente, los ACs convencionales que se usan en clínica no son adecuados para la obtención de imágenes mediante estas técnicas por lo que es imperativo desarrollar nuevos agentes de contraste. Para la técnica de MRI a alto campo, se han desarrollado diversas alternativas siendo lo

Studies comparing the efficacy of posttransplant cyclophosphamide (PTCy) to conventional calcineurin inhibitor (CNI)–based graft-versus-host disease (GVHD) prophylaxis regimens in patients with Hodgkin lymphoma (HL) are scarce. This study aimed to compare the outcomes of patients with HL undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched donors who received GVHD prophylaxis with either PTCy- or conventional CNI-based regimens, using data reported in the European Society for Blood and Marrow Transplantation database between January 2015 and December 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. Notably, PTCy prophylaxis was associated with delayed hematopoietic recovery but also with a lower risk of chronic (25% vs 43%; P < .001) and extensive chronic GVHD (13% vs 28%; P = .003) compared with the CNI-based cohort. The 2-year cumulative incidence of nonrelapse mortality and relapse was 11% vs 17% (P = .12) and 17% vs 30% (P = .007) for PTCy- and CNI-based, respectively. Moreover, the 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) were all significantly better in the PTCy group compared with the CNI-based group: 85% vs 72% (P = .005), 72% vs 53% (P < .001), and 59% vs 31% (P < .001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS than the CNI-based platform. Our findings suggest that PTCy as GVHD prophylaxis offers more favorable outcomes than conventional CNI-based prophylaxis in adult patients with HL undergoing HSCT from HLA-matched donors.

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). This study compared the outcomes of patients with HL undergoing HSCT from HLA-matched donors, including matched sibling donors (MSDs) and matched unrelated donors (MUDs), and haploidentical donors, using PTCy as the GVHD prophylaxis approach in all cohorts. We retrospectively compared outcomes of allo-HSCT from 166 HLA-matched donors (96 sibling and 70 unrelated donors) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the European Society for Blood and Marrow Transplantation database from 2010 to 2020. Compared to HLA-matched HSCT, haploidentical donor HSCT was associated with a significantly lower rate of platelet engraftment (86% versus 94%; P < .001) and a higher rate of grade II-IV acute GVHD (34% versus 24%; P = .01). The 2-year cumulative incidence of nonrelapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to the haploidentical cohort (10% versus 18%; P = .02), resulting in a higher overall survival (OS) rate (82% versus 70%; P = .002). There were no significant differences between the 2 cohorts in terms of relapse, progression-free survival, or GVHD-free relapse-free survival. In multivariable analysis, haploidentical HSCT was associated with an increased risk of grade II-IV acute GVHD and NRM and worse OS compared to HLA-matched HSCT. Our findings suggest that in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical HSCT.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4)

Introduction: Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making., Methods: We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient., Results: 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence., Discussion: The clinical significance is limited by the retrospective study design and the current data can’t replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influ

Introduction: The association of polymorphisms in molecules involved in the immune response (checkpoint inhibitors) with the clinical outcome after allogeneic transplantation (alloHSCT) has been described. Lymphocyte Activation 3 (LAG3) is a surface protein that plays a regulatory role in immunity as an inhibitory immune checkpoint molecule., Methods: To determine its role in the alloHSCT setting, we analyzed 797 patients transplanted from HLA-identical sibling donors. The LAG3 rs870849 C>T polymorphism was genotyped in donors., Results: We detected a higher incidence of severe acute GVHD in patients transplanted from donors with TT genotype (p: 0.047, HR 1.64; 95% CI 1.01 – 2.67). Overall survival (OS) was worse for patients transplanted from donors with the rs870849 CT/TT genotype (0.020; HR, 1.44; 95% CI 1.06 – 1.96), as well as disease-free survival (DFS) (p: 0.002; HR 1.58, 95%CI: 1.18 – 2.14) and transplant-related mortality (TRM) (p< 0.001; HR: 1.88, 95% CI 1.29 – 2.74). When combining the LAG3 rs870849 and the PDCD1 rs36084323 genotypes of the donor, three genetic groups were well defined, allowing a good stratification of the risk of acute GVHD, TRM, OS and DFS., Discussion: We conclude that the LAG3 genotype of the donor may be considered in donors’ selection. As this selection may be limited in the HLA-identical sibling donor scenario, further studies exploring the impact of LAG3 genotype of the donor in unrelated transplantation are warranted.

Mariluz Escribano Pueo’s poetry stems from the noblest tradition both in substance and in form. Accustomed to the pain due to the fateful avatar of her child-hood, loneliness and silence have been in-separable and faithful companions on her journey. With a unique human motivation, reflected in her whole journalistic and liter-ary production, Escribano brings us closer to the love experience from the alienation. Forged in the reading, education will be an effective spring and an essential foundation for its positioning in the world. Starting from a deductive methodology, which is based on the Romanesque heritage, an ac-tive link is formed between the status quo of reality and the substantial distortion of the creative act, contributing from the ef-fective confrontation of a model that as-sumes tradition as an exercise of recogni-tion and leads us to recover for the canon the silenced word of a brave and fighter woman faced with the rigor of her destiny, La poesía de Mariluz Escribano Pueo parte de la tradición más noble tanto en el fondo como en la forma. Avezada al dolor por el aciago avatar de su infancia, la soledad y el silencio han sido inseparables y fieles compañeros de andadura. Con una señera motivación humana, reflejada en toda su producción periodística y literaria, Escribano nos acerca a la experiencia amorosa desde el desarraigo. Forjada en la lectura, la educación será resorte eficaz y fundamento imprescindible de su posicionamiento ante el mundo. Partiendo de una metodología deductiva, que se sustenta en la herencia románica, se conforma un vínculo activo entre el statu quo de la realidad y la distorsión sustancial del acto creador, aportando la confrontación efectiva de un modelo que asume la tradición como ejercicio de reconocimiento y nos conduce a recobrar para el canon la palabra silenciada de una mujer luchadora y valiente enfrentada al rigor de su destino.

During the past years, considerable efforts have been made to uncover the genetic component of chronic lymphocytic leukemia (CLL) susceptibility. To date, several genome-wide association studies (GWAS) and their meta-analysis have identified not only single-nucleotide polymorphisms (SNPs) associated with CLL risk [1] but also patient survival [2]. However, despite these noticeable results, it becomes evident that both validation and functional characterization of the genetic variations identified are still required before they can be used in a clinical setting. Hence, we decided to validate the association of 41 GWAS-identified hits for CLL in 1158 CLL cases and 1947 controls ascertained through the Consortium for Research in Chronic lymphocytIc Leukemia (CRuCIAL) and to investigate their impact on modulating host immune responses and their utility to predict disease onset. Study participants were of European ancestry and gave their written informed consent to participate in the study, which was approved by the ethical review committee of participant institutions. CLL patients had often Binet stage A and Rai stage I (67.00% and 79.83%) and, compared to controls, had a higher mean age (66.19 ± 12.66 vs. 55.60 ± 11.50) and an increased male/female ratio (1.54 vs. 0.91). SNPs selection was based on published GWAS, functionality according to HaploReg data, and linkage disequilibrium between the SNPs. Genotyping of genetic variants was performed using KASPTM and Taqman® assays. Hardy–Weinberg equilibrium was assessed in the controls (P > 0.001) and the association between CLL and SNPs was tested using a multivariate unconditional logistic regression analysis adjusted for age, sex, and country of origin. A meta-analysis of the CRuCIAL results with those from previous GWAS was conducted to validate genetic associations and the I [2] statistic was used to assess statistical heterogeneity between the studies (PHet > 0.01). The pooled OR was computed using the fixed-effect mo

Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7-66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years' survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.