Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications.

Cardiac Events after Allo-HCT in Patients with Acute Myeloid Leukemia. Study Conducted con Behalf of the GETH-TC.

This multicenter study sponsored by GETH-TC aimed to investigate the incidence and predictors of early (within the first 100 days) and late cardiac events (CE) (ECE and LCE) following allo-HCT in AML patients treated with anthracyclines, focusing on exploring the impact of PTCY on cardiac complications and the impact of CE on overall survival (OS) and non-relapse mortality (NRM). 1020 AML patients were included. PTCY was given to 450 (44.1%) adults. Overall, 94 (9.2) patients experienced CE and being arrythmias, pericardial complications, and heart failure the most prevalent ones. ECE occurred in 49 (4.8%) patients in a median of 13 days after allo-HCT, while LCE were diagnosed in 45 (4.4%) patients in a median of 3.6 years after transplant. Using PTCY increased the risk for ECE in multivariate analysis (HR 2.86, P=0.007), but did not not significantly affect the risk for LCE (HR 1.06, P=0.892). The impact of variables on outcomes revealed was investigated using multivariate regression analyses and revealed that the diagnosis of CE significantly decreased the likelihood of OS (HR 1.66, P=0.005) and increased the likelihood of NRM (HR 2.88, P<0.001). Furthermore, despite using PTCY increased the risk for ECE, its administration was found to be beneficial for OS (HR 0.71, P=0.026). The study suggests that while the incidence of CE was relatively low, it significantly impacted mortality. Standard doses of PTCY increased ECE risk but were associated with improved OS. Therefore, implementing protocols to prevent cardiac complications is recommended, considering the widespread adoption of PTCY in allo-HCT.

Feasibility of allogeneic hematopoietic stem cell transplantation in advanced age.

Although it is known that increasing age is associated with increased morbidity and mortality in allogeneic transplantation (allo-HSCT), individualization of the process may allow to perform it in progressively older patients.This study analyzed the outcome of 97 patients older than 60 years with a first allo-HSCT performed at our institution between 2011 and 2019.Median age was 66 years (range 60-79) and 15.4% were older than 70 years. The most frequent diagnosis was acute leukemia (50.5%), and 58.8% received a myeloablative conditioning. With a median follow-up of 33.9 months (range 7.9-111.5), at 3-years overall survival (OS) was 50%; progression-free survival (PFS), 46%; cumulative incidence of relapse, 22%; and non-relapse mortality (NRM), 32%. There were no significant differences in OS (p = 0.415), PFS (p = 0.691), cumulative incidence of relapse (p = 0.357) or NRM (p = 0.658) between patients of 60-64 years (n = 37), 65-69 (n = 45) and ≥ 70 years (n = 15). No differences were observed either depending on the intensity of the conditioning regimen in terms of OS (p = 0.858), PFS (p = 0.729), cumulative incidence of relapse (p = 0.416) or NRM (p = 0.270).In conclusion, older adults can safely and effectively undergo allo-HSCT with proper patient selection and individualized transplantation procedures.

Strengths and Difficulties Questionnaire (SDQ): An update of the literature and instrumental study with schoolchildren

Introduction: Considering the current controversy regarding the factorial structure of the SDQ, this paper aimed to analyse the dimensionality and reliability of the parents' version for children from 4 to 16 years of age, and to present descriptive data according to sociodemographic variables. Method: The factor structure of the original five- and three-factor models, and the reliability of the SDQ were examined among a sample of 621 parents of Uruguayan children between 7 and 12 years of age (52% girls) from different socioeconomic levels. Results: Confirmatory factor analyses did not provide support for the five- and three-factor models. Data adjusted to three factors (prosociality, externalising symptoms, internalising symptoms) in an exploratory analysis with adequate reliability indices. Conclusions: The results of this study show the relevance of continued investigation of the SDQ internal structure, and further analysis of the behaviour of several of its items.

Introducción: Considerando la controversia vigente respecto a la estructura factorial del SDQ, este trabajo tuvo como objetivo analizar la validez de constructo y fiabilidad de la versión para padres de niños de 4 a 16 años y presentar datos descriptivos según variables sociodemográficas. Método: Se examinó la estructura factorial de los modelos originales de cinco y tres factores y la fiabilidad del SDQ en una muestra de 621 padres de niños uruguayos entre 7 y 12 años (52 % niñas) de distintos niveles socioeconómicos. Resultados: Los análisis factoriales confirmatorios no pudieron dar apoyo a los modelos de cinco y tres factores. Los datos se ajustaron a tres factores (prosocialidad, síntomas externalizantes y síntomas internalizantes) en un análisis exploratorio con adecuados índices de fiabilidad. Conclusiones: Los resultados de este estudio muestran la pertinencia de continuar investigando la estructura interna del SDQ y analizar con mayor profundidad el comportamiento de algunos de sus ítems.

Polyphenols as NLRP3 inflammasome modulators in cardiometabolic diseases: a review of in vivo studies.

The nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) are components of the innate immune system, important in coordinating the inflammatory response. Among them, NLRP3 can form inflammasomes, multiprotein complexes activating the inflammatory caspase-1 and leading, through a cell death-mediated signaling cascade, to the release of several proinflammatory cytokines. Dietary polyphenols, plant secondary metabolites, have been reported to exhibit anti-inflammatory properties, although studies have focused most on their effect on the expression of the final circulating cytokines rather than on the upstream signals activating the NLRP3 inflammasome. The present review explores current knowledge on the potential of dietary polyphenols to regulate the whole NLRP3 inflammasome pathway, in the context of cardiometabolic pathologies (obesity, cardiovascular diseases, type 2 diabetes and non-alcoholic fatty liver disease), based on in vivo studies. A clear tendency towards a decrease in the expression of the whole NLRP3 inflammasome signaling pathway when several animal models were supplemented with polyphenols was observed, commonly showing a dose-response effect; these modifications were concomitant with clinical improvements in the pathologies. Nevertheless, the diversity of doses used, the disparity in polyphenol structures tested and, particularly, the scarce clinical trials and exploration of mechanisms of action show the need to develop further research on the topic.

Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis.

OBJECTIVE: In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. DESIGN: We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. RESULTS: VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. CONCLUSION: The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.

Caracterización de pacientes con mieloma múltiple y afectación de la columna vertebral atendidos en un hospital de tercer nivel de Medellín, Colombia / Characterization of patients with multiple myeloma and spinal cord involvement treated at a tertiary care center in Medellín, Colombia

Introducción: el mieloma múltiple (MM) es un tipo de cáncer que se genera en células plasmáticas y puede provocar la destrucción del tejido óseo. Aproximadamente el 50% de los pacientes con esta enfermedad experimentarán fracturas vertebrales secundarias. Objetivo: describir las características de pacientes con MM y afectación de la columna vertebral atendidos en un hospital de tercer nivel.Metodología: estudio descriptivo retrospectivo realizado con los datos de pacientes con MM y afectación de la columna vertebral atendidos entre 2014 y 2018 en un hospital de tercer nivel de atención de Medellín, Colombia. Se obtuvieron datos sociodemográficos y clínicos. Las variables cuantitativas se describen usando medias y desviaciones estándar, mientras que las cualitativas, frecuencias absolutas y porcentajes con su respectivo intervalo de confianza (IC95%).Resultados: la muestra consistió de 109 pacientes. La edad media fue 63 años, la distribución de sexo fue 1:1, el 78,9% de los participantes fue diagnosticado de novo y el síntoma más frecuente fue dolor lumbar (47%). Además, se encontró una media de 5 niveles (cuerpos vertebrales) afectados, el método de diagnóstico de estas lesiones más frecuente fue la tomografía (62%) y solo el 26% de los pacientes presentaron algún tipo de lesión neurológica. En lo que respecta al tratamiento, 95%, 46%, 55% y 13% fueron tratados con quimioterapia, radioterapia, bifosfonatos e intervención quirúrgica, respectivamente.Conclusiones: las características de la muestra son similares a las reportadas en otras investigaciones, a excepción de la distribución del sexo. Además, se identificó una baja frecuencia de tratamiento quirúrgico

Introduction: Multiple myeloma (MM) is a type of cancer that originates in plasma cells and can lead to the destruction of bone tissue. Approximately 50% of patients with this condition will experience secondary vertebral fractures. Objective: To characterize patients with MM and spine involvement treated at a tertiary care center.Methodology: Retrospective, descriptive study conducted using data from patients with MM and spinal involvement treated between 2014 and 2018 in a tertiary care center in Medellín, Colombia. Sociodemo-graphic and clinical data were obtained. Quantitative variables are described using means and standard deviations, while qualitative variables are presented as absolute frequencies and percentages with their respective confidence interval (CI95%).Results: The sample consisted of 109 patients, with a mean age of 63 years and a sex ratio of 1:1. In addition, 78.9% of the participants were newly diagnosed and the most frequent symptom was low back pain (47%). It was also found that an average of 5 sections (vertebral bodies) were affected, that the most frequent method of diagnosis of these lesions was tomography (62%), and that only 26% of the patients presented with some type of brain lesion. Regarding treatment, 95%, 46%, 55%, and 13% were treated with chemotherapy, radiotherapy, bisphosphonates, and surgery, respectively.Conclusions: The characteristics of the sample are similar to those reported in other studies, with the exception of sex ratio. Moreover, a low frequency of surgical treatment was observed

Diurnal Interplay between Epithelium Physiology and Gut Microbiota as a Metronome for Orchestrating Immune and Metabolic Homeostasis.

The behavior and physiology of most organisms are temporally coordinated and aligned with geophysical time by a complex interplay between the master and peripheral clocks. Disruption of such rhythmic physiological activities that are hierarchically organized has been linked to a greater risk of developing diseases ranging from cancer to metabolic syndrome. Herein, we summarize the molecular clockwork that is employed by intestinal epithelial cells to anticipate environmental changes such as rhythmic food intake and potentially dangerous environmental stress. We also discuss recent discoveries contributing to our understanding of how a proper rhythm of intestinal stem cells may achieve coherence for the maintenance of tissue integrity. Emerging evidence indicates that the circadian oscillations in the composition of the microbiota may operate as an important metronome for the proper preservation of intestinal physiology and more. Furthermore, in this review, we outline how epigenetic clocks that are based on DNA methylation levels may extensively rewire the clock-controlled functions of the intestinal epithelium that are believed to become arrhythmic during aging.

A Different View for an Old Disease: NEDDylation and Other Ubiquitin-Like Post-Translational Modifications in Chronic Lymphocytic Leukemia.

Despite the enormous amount of molecular data obtained over the years, the molecular etiology of chronic lymphocytic leukemia (CLL) is still largely unknown. All that information has enabled the development of new therapeutic approaches that have improved life expectancy of the patients but are still not curative. We must increase our knowledge of the molecular alterations responsible for the characteristics common to all CLL patients. One of such characteristics is the poor correlation between mRNA and protein expression, that suggests a role of post-translational mechanisms in CLL physiopathology. Drugs targeting these processes have indeed demonstrated an effect either alone or in combination with other aimed at specific pathways. A recent article unveiled an increment in ubiquitin-like modifications in CLL, with many protein members of relevant pathways affected. Interestingly, the inhibition of the NEDD8-activating protein NAE reverted a substantial number of those modifications. The present review gets the scarce data published about the role of NEDDylation in CLL together and establishes connections to what is known from other neoplasias, thus providing a new perspective to the underlying mechanisms in CLL.

Safety Profile of the Adjuvanted Recombinant Zoster Vaccine in Immunocompromised Populations: An Overview of Six Trials.

INTRODUCTION: The adjuvanted recombinant zoster vaccine (RZV) has demonstrated high efficacy against herpes zoster in older adults and immunocompromised populations. We present comprehensive safety data from six clinical trials in immunocompromised populations (autologous hematopoietic stem cell transplant and renal transplant recipients, patients with hematologic malignancies, patients with solid tumors, and human immunodeficiency virus-infected adults) who are at an increased risk of herpes zoster. METHODS: In all trials, immunocompromised adults ≥ 18 years of age were administered RZV or placebo. Safety was evaluated in the total vaccinated cohort. Solicited adverse events (AEs) were collected for 7 days and unsolicited AEs for 30 days after each dose. Serious AEs, fatal serious AEs, and potential immune-mediated diseases were collected from dose 1 until 12 months post-last dose or study end. Data were pooled for solicited AEs; unsolicited AEs, (fatal) serious AEs, and potential immune-mediated diseases were analyzed for each individual trial. All AEs were analyzed for sub-strata of adults 18-49 years of age and ≥ 50 years of age. RESULTS: In total, 1587 (RZV) and 1529 (placebo) adults were included in the pooled total vaccinated cohort. Solicited AEs were more common after RZV than placebo, were generally more common in the younger age stratum, and were mostly mild to moderate and resolved within 3 days (median duration). Unsolicited AEs and serious AEs were in line with underlying diseases and therapies. Across studies, the percentage of adults reporting one or more unsolicited AE was comparable between RZV and placebo, irrespective of age stratum. The percentage of adults reporting one or more serious AE, fatal serious AE, or potential immune-mediated diseases was generally similar for RZV and placebo, irrespective of age stratum. Overall, no safety concerns were identified. CONCLUSIONS: Recombinant zoster vaccine has a clinically acceptable safety profile. With the previously published vaccine efficacy and immunogenicity results, these data support a favorable benefit-risk profile of RZV vaccination in immunocompromised populations who are at an increased risk of herpes zoster.

Varicella zoster virus leads to chickenpox after primary infection and herpes zoster upon reactivation of the latent virus. Older adults and immunocompromised people, whose immune system is impaired because of the age-related decline in immunity and their underlying disease and/or treatment, respectively, are at an increased risk of herpes zoster and its complications. Recombinant zoster vaccine has been approved to prevent herpes zoster and its complications in adults aged ≥ 50 years in over 30 countries. In Europe, the vaccine has recently received approval to expand its use in adults aged 18 years or older who are at an increased risk of herpes zoster. We present an overview of the safety data from six clinical trials in immunocompromised patients vaccinated with recombinant zoster vaccine. We found that solicited adverse events were more common after the vaccine than placebo but that these were mild to moderate in intensity. Furthermore, the frequency of unsolicited adverse events was similar between the vaccine and placebo, and most of the reported adverse events and severe adverse events (e.g., infections or tumors) could be attributed to the pre-existent diseases and/or therapies. As such, no safety concern was identified following the review of the available clinical data. This overview, together with the published efficacy data in the prevention of herpes zoster and the vaccine immunogenicity, provides useful medical information and supports the use of the recombinant zoster vaccine in an immunocompromised population at an increased risk of herpes zoster.

Prevalence and Associated Factors of Polypharmacy in Nursing Home Residents: A Cross-Sectional Study.

In Spain, there has been a progressive increase in aging. Specifically, Leon has been one of the Spanish provinces with the highest aging index. Polypharmacy is highly prevalent among the elderly, with significant consequences for safety. The aim of this study was to assess the consumption of drugs in a nursing home in the province of Leon and establish the relationship between polypharmacy and the most common comorbid diseases. A descriptive, observational, and cross-sectional study design was used. Residents' information and treatments were collected by reviewing on medical charts, completed with clinical information obtained from the physician of the nursing home. The mean age of residents was 86.8 years, and 63.8% were female. Mean medical consumption amounted to 7.02 prescriptions. Polypharmacy was observed in 54.9% of residents, and excessive polypharmacy in 22.1%. The most commonly used medications (ATC classification) were those acting on the cardiovascular system (84.4%) and the nervous system (82.8%). A high-level of drug consumption was observed in the nursing home. Interventions should focus on those residents hospitalized the last year and with recent contact with a general practitioner. There is a need to develop a comprehensive monitoring system to assess the quality of prescriptions for nursing home residents.

Multiplex Detection of Clinically Relevant Mutations in Liquid Biopsies of Cancer Patients Using a Hybridization-Based Platform.

BACKGROUND: With the advent of precision oncology, liquid biopsies are quickly gaining acceptance in the clinical setting. However, in some cases, the amount of DNA isolated is insufficient for Next-Generation Sequencing (NGS) analysis. The nCounter platform could be an alternative, but it has never been explored for detection of clinically relevant alterations in fluids. METHODS: Circulating-free DNA (cfDNA) was purified from blood, cerebrospinal fluid, and ascites of patients with cancer and analyzed with the nCounter 3 D Single Nucleotide Variant (SNV) Solid Tumor Panel, which allows for detection of 97 driver mutations in 24 genes. RESULTS: Validation experiments revealed that the nCounter SNV panel could detect mutations at allelic fractions of 0.02-2% in samples with ≥5 pg mutant DNA/µL. In a retrospective analysis of 70 cfDNAs from patients with cancer, the panel successfully detected EGFR, KRAS, BRAF, PIK3CA, and NRAS mutations when compared with previous genotyping in the same liquid biopsies and paired tumor tissues [Cohen kappa of 0.96 (CI = 0.92-1.00) and 0.90 (CI = 0.74-1.00), respectively]. In a prospective study including 91 liquid biopsies from patients with different malignancies, 90 yielded valid results with the SNV panel and mutations in EGFR, KRAS, BRAF, PIK3CA, TP53, NFE2L2, CTNNB1, ALK, FBXW7, and PTEN were found. Finally, serial liquid biopsies from a patient with NSCLC revealed that the semiquantitative results of the mutation analysis by the SNV panel correlated with the evolution of the disease. CONCLUSIONS: The nCounter platform requires less DNA than NGS and can be employed for routine mutation testing in liquid biopsies of patients with cancer.

Comparison of matched sibling, unrelated and haploidentical donors in hematopoietic stem cell transplantation. A real world experience from the Argentine Group For Bone Marrow Transplantation And Cell Therapy (GATMO-TC) / Comparación de donantes relacionados, no relacionados y haploidénticos en trasplante de progenitores hematopoyéticos. Experiencia del Grupo Argentino de Trasplante de Médula Ósea y Terapia Celular (GATMO-TC)

Abstract We retrospectively analyzed 570 adult patients who received allogeneic stem cell transplantation for malignant diseases. The outcomes were compared according to donor type. Most of the patients (60%) were transplanted for acute leukemia. Median follow-up was 1.6 years. Haploidentical allogeneic stem cell transplantation was more frequently performed for acute myeloid leukemia and in late stages than any other donor type. Non-relapse mortality at 100 days and one year for unrelated and haploidentical donors were similar, 19%-29% vs. 17%-28%, respectively. A significant better non-relapse mortality was observed for matched sibling donors (7%-15%; p < 0.001). Relapse rate was higher in haploidentical donors compared to matched sibling and unrelated donors (three year relapse rate 46%, 39%, 28%; respectively p < 0.001). Haploidentical donors resulted in lower three year progression-free survival and worse 3 year overall survival (32%; p < 0.001 and 42%; p < 0.001) compared with other donors (44% and 55% MSD, 40% and 42% UD, respectively). The incidence of grade II-IV acute graft-versus-host disease was higher in unrelated donors (51% unrelated, 35% haploidentical, 36% matched sibling; respectively; p = 0.001), with no difference in grades III-IV (p = 0.73) or in chronic graft-versus-host disease (p = 0.2) between groups. After multivariate analysis, haploidentical and unrelated donors remained negatively associated with non-relapse mortality (HR 1.95; 95% CI 1.10-3.20 and HR 2.70; 95% CI 1.63-4.46, respectively). Haploidentical donors were associated with a higher risk of relapse and worse overall survival. This analysis shows that haploidentical donors were associated with similar non-relpase mortality and higher relapse rates than unrelated donors. Better results in non-relapse mortality were observed for matched sibling donors.

Resumen Se efectuó un análisis retrospectivo de 570 pacientes adultos que recibieron un trasplante alogénico de precursores hematopoyéticos, comparando los resultados según el tipo de donante. La mediana de seguimiento fue de 1.6 años. El 60% de la población se trasplantó por leucemias agudas. Los trasplantes haploidénticos se hicieron en su mayoría en leucemia mieloide aguda y en estadios tardíos en comparación a otros donantes. La mortalidad libre de enfermedad al día +100 y a 1 año fue similar para los donantes no emparentados y haploidénticos (19% y 29% vs. 17% y 28%, respectivamente). Se obtuvieron mejores resultados con donantes relacionados idénticos (7% y 15%; p < 0.001). La recaída fue mayor en los donantes haploidénticos (tres años 46% haploidénticos, 39% relacionados idénticos, 28% no emparentados; p < 0.003). El trasplante con donante haploidéntico presentó una menor supervivencia libre de progresión y menor supervivencia global a tres años (32%; p < 0.001 y 42%; p < 0.001). La incidencia de enfermedad injerto contra huésped aguda fue mayor en no emparentados (51%, 35% haploidénticos, 36% relacionados idénticos; p = 0.001), sin diferencias en grados III-IV (p = 0.73) o en EICH crónica (p = 0.2). Los trasplantes con donante haploidéntico y no emparentado mantuvieron su asociación negativa con mortalidad libre de enfermedad (HR 1.95; 95%IC 1.10-3.20 y HR 2.70; 95%IC 1.63-4.46), en análisis multivariado. El trasplante haploidéntico se asoció a mayor recaída y a menor supervivencia global. Esta experiencia mostró similar mortalidad libre de enfermedad entre trasplantes con donantes haploidénticos y no emparentados. Los trasplantes relacionados idénticos mostraron menores tasas de mortalidad libre de enfermedad.

Comparison of matched sibling, unrelated and haploidentical donors in hematopoietic stem cell transplantation. A real-world experience from the Argentine Group for Bone Marrow Transplantation and Cell Therapy (GATMO-TC).

We retrospectively analyzed 570 adult patients who received allogeneic stem cell transplantation for malignant diseases. The outcomes were compared according to donor type. Most of the patients (60%) were transplanted for acute leukemia. Median follow-up was 1.6 years. Haploidentical allogeneic stem cell transplantation was more frequently performed for acute myeloid leukemia and in late stages than any other donor type. Non-relapse mortality at 100 days and one year for unrelated and haploidentical donors were similar, 19%-29% vs. 17%-28%, respectively. A significant better non-relapse mortality was observed for matched sibling donors (7%-15%; p < 0.001). Relapse rate was higher in haploidentical donors compared to matched sibling and unrelated donors (three year relapse rate 46%, 39%, 28%; respectively p < 0.001). Haploidentical donors resulted in lower three year progression-free survival and worse 3 year overall survival (32%; p < 0.001 and 42%; p < 0.001) compared with other donors (44% and 55% MSD, 40% and 42% UD, respectively). The incidence of grade II-IV acute graft-versus-host disease was higher in unrelated donors (51% unrelated, 35% haploidentical, 36% matched sibling; respectively; p = 0.001), with no difference in grades III-IV (p = 0.73) or in chronic graft-versus-host disease (p = 0.2) between groups. After multivariate analysis, haploidentical and unrelated donors remained negatively associated with non-relapse mortality (HR 1.95; 95% CI 1.10-3.20 and HR 2.70; 95% CI 1.63-4.46, respectively). Haploidentical donors were associated with a higher risk of relapse and worse overall survival. This analysis shows that haploidentical donors were associated with similar non-relpase mortality and higher relapse rates than unrelated donors. Better results in non-relapse mortality were observed for matched sibling donors.

Se efectuó un análisis retrospectivo de 570 pacientes adultos que recibieron un trasplante alogénico de precursores hematopoyéticos, comparando los resultados según el tipo de donante. La mediana de seguimiento fue de 1.6 años. El 60% de la población se trasplantó por leucemias agudas. Los trasplantes haploidénticos se hicieron en su mayoría en leucemia mieloide aguda y en estadios tardíos en comparación a otros donantes. La mortalidad libre de enfermedad al día +100 y a 1 año fue similar para los donantes no emparentados y haploidénticos (19% y 29% vs. 17% y 28%, respectivamente). Se obtuvieron mejores resultados con donantes relacionados idénticos (7% y 15%; p < 0.001). La recaída fue mayor en los donantes haploidénticos (tres años 46% haploidénticos, 39% relacionados idénticos, 28% no emparentados; p < 0.003). El trasplante con donante haploidéntico presentó una menor supervivencia libre de progresión y menor supervivencia global a tres años (32%; p < 0.001 y 42%; p < 0.001). La incidencia de enfermedad injerto contra huésped aguda fue mayor en no emparentados (51%, 35% haploidénticos, 36% relacionados idénticos; p = 0.001), sin diferencias en grados III-IV (p = 0.73) o en EICH crónica (p = 0.2). Los trasplantes con donante haploidéntico y no emparentado mantuvieron su asociación negativa con mortalidad libre de enfermedad (HR 1.95; 95%IC 1.10-3.20 y HR 2.70; 95%IC 1.63-4.46), en análisis multivariado. El trasplante haploidéntico se asoció a mayor recaída y a menor supervivencia global. Esta experiencia mostró similar mortalidad libre de enfermedad entre trasplantes con donantes haploidénticos y no emparentados. Los trasplantes relacionados idénticos mostraron menores tasas de mortalidad libre de enfermedad.

Predicting Mortality after Autologous Transplant: Development of a Novel Risk Score.

There have been several efforts to predict mortality after autologous stem cell transplantation (ASCT), such as the hematopoietic cell transplant-comorbidity index (HCT-CI), described for allogeneic stem cell transplantation and validated for ASCT, but there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics. Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on nonrelapse mortality (NRM), overall survival (OS), and early morbidity endpoints (mechanical ventilation, shock or dialysis) after ASCT. For the training cohort, we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina (October 2002 to June 2017) for multiple myeloma or lymphoma. For the validation cohort, we analyzed 2168 ASCTs performed in the Medical College of Wisconsin and Spanish stem cell transplant group (Grupo Español de Trasplante Hematopoyético (GETH)) (January 2012 to December 2018). We first performed a multivariate analysis for NRM in order to select and assign weight to the risk factors included in the score (male patients, aged 55 to 64 and ≥65 years, HCT-CI ≥3, Hodgkin lymphoma and non-Hodgkin lymphoma). The hazard ratio for NRM increased proportionally with the score. Patients were grouped as low risk (LR) with a score of 0 to 1 (686, 33%), intermediate risk (IR) with a score of 2 to 3 (1109, 53%), high risk (HR) with a score of 4 (198, 10%), and very high risk (VHR) with a score of ≥5 (75, 4%). The score was associated with a progressive increase in all the early morbidity endpoints. Moreover, the score was significantly associated with early NRM (day 100: 1.5% versus 2.4% versus 7.6% versus 17.6%) as well as long term (1 to 3 years; 1.8% to 2.3% versus 3.8% to 4.9% versus 11.7% to 14.5% versus 25.0% to 27.4%, respectively; P< .0001) and OS (1 to 5 years; 94% to 73% versus 89% to 75% versus 76% to 47% versus 65% to 52% respectively; P < .0001). The score was validated in an independent cohort (N = 2168) and was significantly associated with early and late events. In conclusion, we developed and validated a novel score predicting NRM and OS in 2 large cohorts of more than 2000 autologous transplant patients. This tool can be useful for tailoring conditioning regimens or defining risk for transplant program decision making.

Assessment of Cell Adhesion After Purinoceptor Activation.

Cell adhesion is a characteristic feature of phagocytic myeloid cells, which is important for several inflammatory processes, such as migration, invasion, and proliferation. Purinergic signaling in macrophages plays an important role in cell adhesion of this cell type to different extracellular substrates. This protocol describes the use of two different detection methods to quantify cell adhesion upon P2X7 receptor activation by extracellular ATP.

Allogeneic stem cell transplantation improves survival in relapsed Hodgkin lymphoma patients achieving complete remission after salvage treatment.

Allogeneic stem cell transplant (alloSCT) is a current treatment option for patients with refractory/relapsed classic Hodgkin lymphoma (CHL), including those who have failed an autologous transplantation. We performed a retrospective multicenter analysis of 113 patients (median age 28 years; range 14-56; 54% males) with refractory/relapsed (R/R) CHL who had undergone alloSCT in Argentina. Kaplan-Meier was used to estimate overall (OS) and progression-free survival (PFS). Relapse rate (RR) and non-relapse mortality (NRM) were estimated with cumulative incidence analysis. Disease status at transplant was complete remission (CR) in 39%, partial remission (PR) in 44%, and stable/progressed disease (S/PD) in 17% of the patients. Donor type was matched related (MRD) in 60%, unrelated (URD) in 19%, and haploidentical (HID) in 21% of the patients. OS and PFS at 2 years were 43% and 27%, respectively, for all the cohort. In the univariate analysis, patients in CR showed better OS (p ≤ 0.001) and PFS (p ≤ 0.001), and lower NRM (p = 0.04). HID had better PFS (p = 0.04) and lower RR (p = 0.02). In the multivariate analysis, CR showed a significant impact on OS and PFS, and HID on PFS. AlloSCT is a feasible procedure in patients with CHL. Those in CR at the time of the transplant had better outcomes. Haploidentical transplantation is associated with better PFS in these patients with poor prognosis.

Real-world data on T-DM1 efficacy - results of a single-center retrospective study of HER2-positive breast cancer patients.

T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.

P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis.

Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.