Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium.

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4 rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4 rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2 rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2 rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2 rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2 rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Allogeneic stem-cell transplantation in HIV-1-infected patients with high-risk hematological disorders.

INTRODUCTION: Although a number of patients with HIV infection and hematological disease have successfully undergone allogeneic hematopoietic stem-cell transplantation (HSCT), short and long-term outcomes remain not well known. We report the largest Spanish experience treating HIV-infected adult patients with high-risk hematological malignancies with allogeneic HSCT. METHODS: We retrospectively reviewed 22 HIV-positive patients who received allogeneic HSCT in five centers in Spain. RESULTS: A total of 22 patients with high-risk hematological malignancies were transplanted between 1999 and 2018. Median age was 44 years. With a median follow-up of 65 months (8-112), overall survival and event-free survival were 46%. Nonrelapse mortality was 14% at 12 months and relapse was 24% at 24 months. Grade II-IV acute graft-versus-host disease (GVHD) rate was 44%, and moderate/severe chronic GVHD rate was 41% at 24 months. All patients received combination antiretroviral therapy. Two patients showed severe toxicity related to drug interaction with antiretroviral therapy. 68% of patients showed infectious complications with viral infections as the most frequent cause. Two patients had invasive aspergillosis and one patient presented disseminated tuberculosis. All survivors except one maintained undetectable HIV load at last follow-up after HSCT. CONCLUSION: Allogeneic HSCT is an effective therapy for high-risk hematological malignancies in patients with HIV infection, and long-term HIV suppression with combination antiretroviral therapy is feasible. However, drug interactions with antiretroviral agents, occurrence of GVHD, and frequent infectious complications account for a complex procedure in this population. Selected HIV-infected patients with hematologic malignancies should be considered for allo-HSCT when indicated, in experienced centers.

Psycho-oncological intervention in haematopoietic progenitor cell transplant (HPT): effects of emotional impact / Intervención psicooncológica en trasplante de progenitores hematopoyéticos (TPH): efectos en el impacto emocional

The aim of this work has been to determine the repercussions a psycho-oncological program has on patients who need to undergo a haematopoietic stem cell transplantation (HPT). We have studied two groups, an intervention group (n=21), formed with patients that have gone through the program of psycho-oncologic preparation previous to the transplant, and a control group (n=15), without psychological intervention. The program consists of four sessions: analysis and handling of the information, coping skills, management of stress, and preparation for the isolation. The results show that patients who receive the psychological intervention. appear to obtain minor levels in anxiety and depression and has a more adaptive perception of the passage of time and a more positive mood with more activity than the control group. However, such differences are not significant in the perception of the physical symptomatology as the amount of time in isolation increases.

El objetivo de este trabajo ha sido determinar las repercusión un programa de intervención psicooncológica sobre los pacientes candidatos a un Trasplante de Progenitores Hematopoyéticos (TPH). Participan dos grupos de pacientes, el grupo intervención (n=21), formado por los pacientes que han realizado el programa de intervención previo al trasplante, y un grupo de control (n=15), que no recibe la intervención pre-TPH. El programa consta de cuatro módulos: análisis y manejo de la información, habilidades de afrontamiento, control del estrés, y preparación familiar al aislamiento. Los resultados muestran que los pacientes que reciben la intervención psicológica obtienen niveles menores en ansiedad y depresión y tiene una percepción más adaptativa del paso del tiempo y un estado de ánimo más positivo, con más actividad que el grupo de control. Sin embargo, tales diferencias no son significativas en la percepción de la sintomatología física que aumenta con el paso del tiempo en aislamiento.

Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: A phase I/II study.

BACKGROUND AIMS: Despite the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the procedure is still associated with high toxicity in patients with refractory graft-versus-host disease (GvHD). Mesenchymal stromal cells (MSCs) are a new mode of therapy in the context of allo-HSCT. The objective of this study was to evaluate the safety and feasibility of the use of adipose tissue-derived MSCs (AT-MSCs) in patients with chronic GvHD. METHODS: Fourteen patients with moderate (n = 7) or severe (n = 7) chronic GvHD received 1 × 106/kg (group A, n = 9) or 3 × 106/kg (group B, n = 5) AT-MSCs with cyclosporine and prednisone as first-line therapy. RESULTS: Ten of the 14 patients were able to continue under the protocol: 80% were in complete remission, and 100% were off of steroids at week 56. The remaining 4 patients either worsened from chronic GvHD (n = 3) or abandoned the study (n = 1). At the end of the study, 11 of 14 patients are alive (overall survival 71.4%, median survival of 45.3 weeks). No suspected unexpected serious adverse reactions occurred during the trial. Neither relapse of underlying disease nor mortality due to infection was observed in this cohort. Biological studies showed increased CD19, CD4 and tumor necrosis factor-α with a temporary decrease in natural killer cells. DISCUSSION: AT-MSCs, in combination with immunosuppressive therapy, may be considered feasible and safe and likely would have an impact on the course of chronic GvHD. More studies are warranted to understand the potential benefits of AT-MSCs in these patients.

Early mortality in multiple myeloma: the time-dependent impact of comorbidity: A population-based study in 621 real-life patients.

Multiple myeloma is a heterogeneous disease with variable survival; this variability cannot be fully explained by the current systems of risk stratification. Early mortality remains a serious obstacle to further improve the trend toward increased survival demonstrated in recent years. However, the definition of early mortality is not standardized yet. Importantly, no study has focused on the impact of comorbidity on early mortality in multiple myeloma to date. Therefore, we analyzed the role of baseline comorbidity in a large population-based cohort of 621 real-life myeloma patients over a 31-year period. To evaluate early mortality, a sequential multivariate regression model at 2, 6, and 12 months from diagnosis was performed. It was demonstrated that comorbidity had an independent impact on early mortality, which is differential and time-dependent. Besides renal failure, respiratory disease at 2 months, liver disease at 6 months, and hepatitis virus C infection at 12 months, were, respectively, associated with early mortality, adjusting for other well-established prognostic factors. On the other hand, the long-term monitoring in our study points out a modest downward trend in early mortality over time. This is the first single institution population-based study aiming to assess the impact of comorbidity on early mortality in multiple myeloma. It is suggested that early mortality should be analyzed at three key time points (2, 6, and 12 months), in order to allow comparisons between studies. Comorbidity plays a critical role in the outcome of myeloma patients in terms of early mortality. Am. J. Hematol. 91:700-704, 2016. © 2016 Wiley Periodicals, Inc.

Trends in survival of multiple myeloma: a thirty-year population-based study in a single institution.

BACKGROUND: Despite the progress made in recent years, multiple myeloma is still considered an incurable disease. Most survival data come from clinical trials. Little is known about the outcome in unselected real-life patients. METHODS: Overall survival was analyzed in a cohort of newly diagnosed symptomatic multiple myeloma patients, over the last three decades, in a single institution population-based study. RESULTS: 582 consecutive myeloma patients were included in the study. Survival increased over time in patients younger than 65 years but did not reach statistical significance in patients with 65 years or older. The prognostic factors associated with overall survival were the International Staging System, the serum lactate dehydrogenase level, the renal impairment, the realization of autologous stem cell transplantation, and the presence of concomitant amyloidosis. Overall survival shows a steady improvement over time. INTERPRETATION: The survival of myeloma is improving progressively in real-life patients, particularly after the widespread use of the novel agents. A comprehensive assessment of comorbidity can help to explain the huge heterogeneity of myeloma outcome. The optimization of current therapeutic resources as well as the incorporation of new drugs will allow further improvement of survival in the coming years.

Transplantation-Associated Thrombotic Microangiopathy in Patients Treated With Sirolimus and Cyclosporine as Salvage Therapy for Graft-Versus-Host Disease.

BACKGROUND: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation. Because sirolimus (SIR) and calcineurin inhibitor-either cyclosporine (CsA) or tacrolimus-have become more common as graft-versus-host disease (GVHD) prophylaxis, we are witnessing a higher frequency of this complication. OBJECTIVE: To analyze the incidence, timing, and management of TA-TMA in patients who received the combination of CsA and SIR as therapy for uncontrolled GVHD in one single center. METHODS: This was a retrospective analysis from February 2002 to June 2014 of the combination of SIR and CsA as salvage therapy in 61 patients with treatment-refractory or relapsed acute GVHD (n = 24) or chronic GVHD (n = 37) in a tertiary hospital. RESULTS: A total of 61 patients received CsA and SIR as salvage therapy for acute (n = 16), late acute (n = 8), overlap syndrome (n = 22), or classic chronic (n = 15) GVHD. We identified 13 patients with TA-TMA (21.3%), and the status of GVHD was active in 11 of 13 patients. Only 1 patient showed high CsA levels, and 6 of 13 patients had very high concentrations of SIR in blood. We used an enzyme inducer in 6 patients, which proved effective in 3. Overall survival for TA-TMA patients was inferior compared to that for non TA-TMA patients at 12 months (42.9% vs 51.9%) and 24 months (34.3% vs 49.1%), although this difference was not significant. CONCLUSION: Prompt identification and good management of TA-TMA, with better control of GVHD, may contribute to a decrease in patient mortality that would result from this complication.

Interleukin-10 promoter polymorphism as risk factor to develop invasive pulmonary aspergillosis.

This present study was undertaken to examine the role of the host response to Aspergillus fumigatus in the development of clinical symptoms of invasive pulmonary aspergillosis (IPA). The natural outcome and response to IPA infection varies between individuals. Whereas some variation may be attributable to fungi and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and is involved in various inflammatory diseases. IL-10 promoter carries a polymorphism that has been associated to production levels. Our aim was to investigate the role of this polymorphism in susceptibility to develop IPA infection. The study included 120 haematological patients and 124 age and sex-matched controls and bi-allelic IL-10 -1082(G/A) polymorphism was examined. Genotypic (p=0.385) and allelic frequencies (p=0.527, OR=0.89, 95% CI=0.78-1.60) were similar between patients and healthy controls. IPA was diagnosed in 59 of the 120 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG). Our results provide evidence that IL-10 -1082(AA) genotype is associated with resistance to develop IPA (p=0.001). Allele frequency of IL-10 -1082A allele was weakly associated with susceptibility to develop IPA infection (p=0.052). In conclusion, these results suggest that differential production of IL-10 may alter the risk for IPA in haematological patients.