A Novel Digital Educational Strategy Improves Treatment Adherence and Quality of Life in Patients with Multiple Myeloma.

Multiple myeloma, the second most common hematologic malignancy worldwide, is an aggressive disease with high morbidity and mortality rates. Although myeloma remains incurable, new treatments have improved patients' life expectancy and quality of life. However, as these therapies are administered for prolonged and often indefinite periods, their success depends on high treatment adherence and significant patient engagement. This study aimed to evaluate the impact of a novel digital educational strategy on treatment adherence, quality of life, and the development of complications in patients with newly diagnosed myeloma. To this end, a two-arm, randomized, prospective, double-blind study was conducted to compare the conventional educational approach alone or combined with the novel digital strategy. This strategy was based on some principles of the Persuasive Systems Design model and incorporated the educational recommendations of patients and caregivers. Compared to the control group that only received information through the conventional educational approach, patients randomized to the digital strategy showed significantly higher treatment adherence and quality of life, associated with increased functionality and rapid reincorporation into daily routines. The digital strategy empowered patients and caregivers to understand the disease and therapeutic options and helped patients recall treatment information and implement healthy lifestyle habits. These results support that patient-targeted educational strategies can positively influence treatment adherence and thus improve their quality of life.

Impact of Memory T Cells on SARS-COV-2 Vaccine Response in Hematopoietic Stem Cell Transplant.

During the COVID-19 pandemic, hematopoietic stem cell transplant (HSCT) recipients faced an elevated mortality rate from SARS-CoV-2 infection, ranging between 10-40%. The SARS-CoV-2 mRNA vaccines are important tools in preventing severe disease, yet their efficacy in the post-transplant setting remains unclear, especially in patients subjected to myeloablative chemotherapy and immunosuppression. We evaluated the humoral and adaptive immune responses to the SARS-CoV-2 mRNA vaccination series in 42 HSCT recipients and 5 healthy controls. Peripheral blood mononuclear nuclear cells and serum were prospectively collected before and after each dose of the SARS-CoV-2 vaccine. Post-vaccination responses were assessed by measuring anti-spike IgG and nucleocapsid titers, and antigen specific T cell activity, before and after vaccination. In order to examine mechanisms behind a lack of response, pre-and post-vaccine samples were selected based on humoral and cellular responses for single-cell RNA sequencing with TCR and BCR sequencing. Our observations revealed that while all participants eventually mounted a humoral response, transplant recipients had defects in memory T cell populations that were associated with an absence of T cell response, some of which could be detected pre-vaccination.

SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.

The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth. RNA sequencing (RNA-seq) followed by gene set enrichment analysis indicated the presence of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) with enriched gene expression profiles of enhanced differentiation, activation and expression of immunostimulatory molecules. In mice with conditional targeting of PD-1 in myeloid cells, which also displayed diminished tumor growth, TAMs had gene expression profiles enriched for myeloid differentiation, activation and leukocyte-mediated immunity displaying >50% overlap with enriched profiles of SHP-2-deficient TAMs. In bone marrow, GM-CSF induced the phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Deletion of SHP-2 or PD-1 enhanced GM-CSF-mediated phosphorylation of the transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment, respectively. Thus, SHP-2 and PD-1-SHP-2 signaling restrained myelocyte differentiation resulting in a myeloid landscape that suppressed antitumor immunity.

Producción de leche materna y estado emocional en madres de recién nacidos de muy bajo peso / Breast milk production and emotional state in mothers of very low birth weight infants

Introducción. Existe poca evidencia de la influencia de variables emocionales en la lactancia de madres de recién nacidos de muy bajo peso al nacer (RNMBPN). El objetivo de este estudio fue medir la producción de leche materna (PLM) en dos momentos de la internación neonatal y su asociación con los niveles de ansiedad, depresión y autoeficacia en lactancia en madres de RNMBPN.Población y métodos. Estudio prospectivo, observacional, multicéntrico en madres de RNMBPN (500-1500 g), en 9 centros de la Red NEOCOSUR. La PLM se obtuvo midiendo lo extraído por cada madre. Se utilizaron las escalas STAI para ansiedad, BDI para depresión, y, la escala piloto ALMA para autoeficacia. Estas fueron aplicadas a los 14 días de vida y a las 36 semanas posmenstruales. Se registraron, además, las características biosociales de madres y neonatos. Resultados. Participaron 118 madres. La PLM media a los 14 días fue de 169 ml (desvío estándar ­DE­ ± 132,4) y de 285 ml (DE ± 266,9) a las 36 semanas, y se asoció significativamente con percepción de autoeficacia en lactancia (p < 0,001), que se mantuvo durante la hospitalización. Existió una tendencia a menor producción en madres con mayores índices de depresión a los 14 días de vida de su hijo, pero no a las 36 semanas. No se encontró asociación entre PLM y ansiedad. No se encontraron asociaciones consistentemente significativas con variables biosociales. Conclusión. La PLM se asoció positivamente con autoeficacia en lactancia; no se encontró asociación con ansiedad y depresión en madres de RNMBPN

Introduction. There is little evidence regarding the influence of emotional variables on breastfeeding among mothers of very low birth weight infants (VLBWIs). The objective of this study was to measure breast milk production (BMP) at two points in time during neonatal hospitalization and its association with anxiety, depression, and breastfeeding self-efficacy levels among mothers of VLBWIs.Population and methods. Prospective, observational, and multicenter study in mothers of VLBWIs (500-1500 g) from 9 NEOCOSUR Network centers. BMP was obtained by measuring the amount extracted by each mother. The STAI scale was used for anxiety, the BDI scale for depression, and the ALMA pilot scale for self-efficacy. They were administered at 14 days of life and at 36 weeks of postmenstrual age. The biosocial characteristics of mothers and neonates were also recorded.Results. A total of 118 mothers participated. Mean BMP was 169 mL (standard deviation [SD]: ± 132.4) at 14 days and 285 mL (SD: ± 266.9) at 36 weeks, and it was significantly associated with the perception of breastfeeding self-efficacy (p < 0.001), which was maintained during hospitalization. There was a lower production trend among mothers with higher depression indices at 14 days of life, but not at 36 weeks. No association was observed between BMP and anxiety. No consistently significant associations were observed with biosocial variables.Conclusion. BMP was positively associated with breastfeeding self-efficacy; no association was observed with anxiety and depression among mothers of VLBWIs

Breast milk production and emotional state in mothers of very low birth weight infants. / Producción de leche materna y estado emocional en madres de recién nacidos de muy bajo peso.

INTRODUCTION: There is little evidence regarding the influence of emotional variables on breastfeeding among mothers of very low birth weight infants (VLBWIs). The objective of this study was to measure breast milk production (BMP) at two points in time during neonatal hospitalization and its association with anxiety, depression, and breastfeeding self-efficacy levels among mothers of VLBWIs. POPULATION AND METHOS: Prospective, observational, and multicenter study in mothers of VLBWIs (500-1500 g) from 9 NEOCOSUR Network centers. BMP was obtained by measuring the amount extracted by each mother. The STAI scale was used for anxiety, the BDI scale for depression, and the ALMA pilot scale for selfefficacy. They were administered at 14 days of life and at 36 weeks of postmenstrual age. The biosocial characteristics of mothers and neonates were also recorded. RESULTS: A total of 118 mothers participated. Mean BMP was 169 mL (standard deviation [SD]: ± 132.4) at 14 days and 285 mL (SD: ± 266.9) at 36 weeks, and it was significantly associated with the perception of breastfeeding self-efficacy (p < 0.001), which was maintained during hospitalization. There was a lower production trend among mothers with higher depression indices at 14 days of life, but not at 36 weeks. No association was observed between BMP and anxiety. No consistently significant associations were observed with biosocial variables. CONCLUSION: BMP was positively associated with breastfeeding self-efficacy; no association was observed with anxiety and depression among mothers of VLBWIs.

Introducción. Existe poca evidencia de la influencia de variables emocionales en la lactancia de madres de recién nacidos de muy bajo peso al nacer (RNMBPN). El objetivo de este estudio fue medir la producción de leche materna (PLM) en dos momentos de la internación neonatal y su asociación con los niveles de ansiedad, depresión y autoeficacia en lactancia en madres de RNMBPN. Población y métodos. Estudio prospectivo, observacional, multicéntrico en madres de RNMBPN (500-1500 g), en 9 centros de la Red NEOCOSUR. La PLM se obtuvo midiendo lo extraído por cada madre. Se utilizaron las escalas STAI para ansiedad, BDI para depresión, y, la escala piloto ALMA para autoeficacia. Estas fueron aplicadas a los 14 días de vida y a las 36 semanas posmenstruales. Se registraron, además, las características biosociales de madres y neonatos. Resultados. Participaron 118 madres. La PLM media a los 14 días fue de 169 ml (desvío estándar ­DE­ ± 132,4) y de 285 ml (DE ± 266,9) a las 36 semanas, y se asoció significativamente con percepción de autoeficacia en lactancia (p < 0,001), que se mantuvo durante la hospitalización. Existió una tendencia a menor producción en madres con mayores índices de depresión a los 14 días de vida de su hijo, pero no a las 36 semanas. No se encontró asociación entre PLM y ansiedad. No se encontraron asociaciones consistentemente significativas con variables biosociales. Conclusión. La PLM se asoció positivamente con autoeficacia en lactancia; no se encontró asociación con ansiedad y depresión en madres de RNMBPN.

Commentary on: Combination of Metabolic Intervention and T Cell Therapy Enhances Solid Tumor Immunotherapy.

Metabolism is a common cellular feature. Cancer creates a suppressive microenvironment resulting in inactivation of antigen-specific T cells by metabolic reprogramming. Development of approaches that enhance and sustain physiologic properties of T cell metabolism to prevent T cell inactivation and promote effector function in the tumor microenvironment is an urgent need for improvement of cell-based cancer immunotherapies.

T Cell Metabolism in Cancer Immunotherapy.

Immune checkpoint therapies aiming to enhance T cell responses have revolutionized cancer immunotherapy. However, although a small fraction of patients develops durable anti-tumor responses, the majority of patients display only transient responses, underlying the need for finding auxiliary approaches. Tumor microenvironment poses a major metabolic barrier to efficient anti-tumor T cell activity. As it is now well accepted that metabolism regulates T cell fate and function, harnessing metabolism may be a new strategy to potentiate T cell-based immunotherapies.

Targeted deletion of PD-1 in myeloid cells induces antitumor immunity.

PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell-specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1-blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell-specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell-specific PD-1 ablation, myeloid cell-specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell-specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1-deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.

Reactivation of BK virus after double umbilical cord blood transplantation in adults correlates with impaired reconstitution of CD4+ and CD8+ T effector memory cells and increase of T regulatory cells.

BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

Metabolic Targets for Improvement of Allogeneic Hematopoietic Stem Cell Transplantation and Graft-vs.-Host Disease.

Utilization of the adaptive immune system against malignancies, both by immune-based therapies to activate T cells in vivo to attack cancer and by T-cell therapies to transfer effector cytolytic T lymphocytes (CTL) to the cancer patient, represent major novel therapeutic advancements in oncologic therapy. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is a form of cell-based therapy, which replaces the HSC in the patient's bone marrow but also serves as a T-cell therapy due to the Graft-vs.-leukemia (GVL) effect mediated by donor T cells transferred with the graft. Allogeneic HSCT provides one potentially curative option to patients with relapsed or refractory leukemia but Graft-vs.-Host-Disease (GVHD) is the main cause of non-relapse mortality and limits the therapeutic benefit of allogeneic HSCT. Metabolism is a common cellular feature and has a key role in the differentiation and function of T cells during the immune response. Naïve T cells and memory T cells that mediate GVHD and GVL, respectively, utilize distinct metabolic programs to obtain their immunological and functional specification. Thus, metabolic targets that mediate immunosuppression might differentially affect the functional program of GVHD-mediating or GVL-mediating T cells. Components of the innate immune system that are indispensable for the activation of alloreactive T cells are also subjected to metabolism-dependent regulation. Metabolic alterations have also been implicated in the resistance to chemotherapy and survival of malignant cells such as leukemia and lymphoma, which are targeted by GVL-mediating T cells. Development of novel approaches to inhibit the activation of GVHD-specific naïve T cell but maintain the function of GVL-specific memory T cells will have a major impact on the therapeutic benefit of HSCT. Here, we will highlight the importance of metabolism on the function of GVHD-inducing and GVL-inducing alloreactive T cells as well as on antigen presenting cells (APC), which are required for presentation of host antigens. We will also analyze the metabolic alterations involved in the leukemogenesis which could differentiate leukemia initiating cells from normal HSC, providing potential therapeutic opportunities. Finally, we will discuss the immuno-metabolic effects of key drugs that might be repurposed for metabolic management of GVHD without compromising GVL.