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Torque Teno Virus (TTV) is a single-stranded circular DNA virus which has been identified as a surrogate marker of immune competence in transplantation. In this study we investigated the dynamics of plasma TTV DNAemia in 79 adult patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory large B-cell lymphoma, also evaluating the impact of TTV on immunotoxicities, response and survival outcomes. After lymphodepleting therapy, TTV DNA load decreases slightly until reaching nadir around day 10, after which it increased steadily until reaching maximum load around day 90. TTV DNA load

This is a multicenter prospective observational study which included a large cohort (n = 397) of allogeneic (allo-HSCT) (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3 to 6 weeks after complete SARS-CoV-2 vaccination from February 1st 2021 to July 20th 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopenia

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.

The SARS-COV-2 pandemic has led to strict and generalized transmission prevention measures that may have changed the epidemiological landscape of common seasonal respiratory virus (CSRV). Through a prospective CSRV survey program conducted from 2016 onwards in allogeneic stem cell transplant (allo-HSCT) recipients with respiratory symptoms, we aimed to analyze and compare the epidemiology and characteristics of CSRV over three consecutive periods [from February 1 to September 30 of 2018 (P1), 2019 (P2), and 2020 (P3)]. CSRV screening was performed through multiplex PCR assays during the study period. We identified 188 consecutive allo-HSCT recipients with 406 episodes screened for CSRV during the study period, of which 147 developed 300 CSRV. In P1 and P2 we diagnosed 115 (38.3%) and 145 (48.3%) CSRV episodes, respectively, whereas in P3 only 40 (13.3%) episodes were detected (p

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses., This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.

Background This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second‐line therapies for chronic graft‐vs‐host disease (cGvHD) in a tertiary Spanish institution. Methods Patients (≥18 years) diagnosed with steroid‐refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non‐ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA‐identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis‐related group (DRG) system: DRG 579 (€22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. Results Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25 319 (95% CI: €17 049–€33 590) across the two cohorts, with a slightly lower mean cost per ECP‐treated patient (€23 120) compared with the non‐ECP cohort (€27 519; P = .597). Twenty‐seven inpatient hospitalizations occurred among ECP‐treated patients, vs 33 in the non‐ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non‐ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). Conclusions ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.

Sirolimus has emerged as an alternative to calcineurin inhibitors-based (CNI) graft-versus-host disease (GVHD) prophylaxis. This retrospective study compares the outcome of 133 consecutive adult patients with haematological malignancies undergoing haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCy) and mycophenolate mofetil (MMF), combined with cyclosporine A (PTCy-CsA-MMF

There are many studies on the polymorphism of the HLA system in healthy donor populations, such as registries of unrelated bone marrow donors. Investigations on the characterization of the HLA complex in hematopoietic stem cell transplant (HSCT) patients, however, are scarce, at least in the Spanish population. This study presents a large-scale analysis of allelic diversity and HLA distribution at a high-resolution level in 2886 patients undergoing HSCT in Spanish centres of the "Grupo Español de Trasplante Hematopoyético y Terapia Celular" during a period of 11 years. Allelic diversity analysis identified 67 HLA-A, 133 HLA-B, 60 HLA-C, 63 HLA-DRB1, 24 HLA-DQB1 and 27 HLA-DPB1 different alleles. Rare alleles were detected among which 33 alleles had not been reported in the European catalog of common and well-documented HLA alleles. Regarding the distribution of five genes-haplotypes, it was observed that the five most frequent extended haplotypes found in our population were between the most common in other Spanish populations, both in patients and in healthy subjects. However, some particular haplotypes were also detected. Bilocus associations HLA-C ~ B and -DRB1 ~ DQB1 were analyzed in order to predict the probability of finding 10/10 matched donors in registries. We found HLA-B alleles showing a great diversity of combinations with HLA-C alleles and unusual associations involving a negative predicting factor. In the field of adoptive therapies, our work supports the necessity to expand further research of TCR-engineered cells, adoptive transfer of virus-specific T-cells and vaccines to target HLA alleles other than A*02:01. HLA alleles such as A*01:01, A*03:01, A*24:02, B*44:03, B*07:02 or B*51:01, might be considered new targets due to its high frequency in our population.

Characteristics and risk factors (RFs) of community-acquired respiratory virus (CARV) infections after umbilical cord blood transplantation (UCBT) are lacking. We retrospectively analyzed CARV infections in 216 single-unit myeloablative UCBT recipients. One-hundred and fourteen episodes of CARV infections were diagnosed in 62 (29%) patients. Upper respiratory tract disease (URTD) occurred in 61 (54%) whereas lower respiratory tract disease (LRTD) in 53 (46%). The 5-year cumulative incidence of CARV infection was 29%. RFs for developing CARV infections were: prednisone-based graft-versus-host disease (GVHD) prophylaxis and grade II–IV acute GVHD. RFs analysis of CARV progression to LRTD identified 2007–2009 period and absolute lymphocyte count (ALC)

Highlights • Rapid detection methods used as first diagnostic test for CARVs may delayed the start of antiviral therapy in a significant number of influenza and RSV cases. • Syndromic multiplex RT-PCR-based prospective clinical CARV survey in allo-HCT recipients translates into a lower mortality rate as compared to standard clinical practice based on RSV and influenza virus rapid detection test. • We found that donor/recipient HLA mismatch, CARV LRTD and high-risk ISI were also associated with higher mortality., Background There is a lack of studies comparing clinical outcomes among retrospective versus prospective cohorts of allogeneic stem cell transplant (allo-HCT) recipients with community acquired respiratory virus (CARV) infections. Methods We compare outcomes in two consecutive cohorts of allo-HCT recipients with CARV infections. The retrospective cohort included 63 allo-HCT recipients with 108 CARV infections from January 2013 to April 2016 who were screened and managed following standard clinical practice based on influenza and respiratory syncytial virus rapid antigen detection methods. The prospective cohort was comprised of 144 consecutive recipients with 297 CARV episodes included in a prospective interventional clinical surveillance program (ProClinCarvSur-P) based on syndromic multiplex PCR as first-line test from May 2016 to December 2018 at a single transplant center. Results CARV infections in the retrospective cohort showed more severe clinical features at the time of diagnosis compared to the prospective cohort (fever 83% vs. 57%, hospital admission 69% vs. 28% and lower respiratory tract 58% vs. 31%, respectively, p ≤ 0.002 for all comparisons). Antiviral therapy was more commonly prescribed in the prospective cohort (69 vs. 43 treated CARV episodes), particularly at the upper respiratory tract disease stage (34 vs. 12 treated CARV episodes). Three-month all-cause mortality was significantly higher in the retrospective cohort (n = 23, 37% vs. n = 10, 7%, p

We analyzed the outcomes of 26 consecutive patients with acquired severe aplastic anemia (SAA) undergoing peripheral blood stem cell transplantation (PBSCT) with partial ex vivo T cell depletion with a targeted T cell dose from HLA-identical sibling donors. The median patient age was 37 years (range, 3 to 63 years). Four patients with uncontrolled pneumonia at the time of transplantation died, on days +1, +2, +21, and +26. All evaluable patients engrafted, with a median time to neutrophil recovery of 11 days (range, 10 to 14 days) and a median time to platelet recovery of 19 days (range, 8 to 53 days). Two patients had transient grade I acute graft-versus-host disease (GVHD) with skin involvement, but no patients developed grade II-IV acute GVHD. Two patients had mild skin chronic GVHD, and 1 patient had moderate chronic GVHD with ocular involvement. No relapse was observed after a median follow-up of 114 months (range, 4 to 233 months). The overall cumulative incidence of TRM at 10 years was 19%, whereas it was 5% for those with a Karnofsky Performance Status (MPS) score >60 at the time of transplantation. Disease-free survival, overall survival, and GVHD and relapse-free survival at 10 years were 81%, 81%, and 80%, respectively, for all patients and 95%, 95%, and 90%, respectively, for patients with a MPS score >60 at transplantation. Our data indicate that PBSCT with partial ex vivo T cell-depleted targeted cell dose grafts from an HLA-identical sibling donor is a feasible, safe, and effective approach to reduce GVHD and cure patients with SAA. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Post-transplant cyclophosphamide (PTCy) has emerged as a promising graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no studies have reported the efficacy of a GvHD prophylaxis based on PTCy with sirolimus (Sir-PTCy) in patients with acute myeloid leukemia (AML). In this retrospective study, we analyze the use of sirolimus in combination with PTCy, with or without mycophenolate mofetil (MMF), on 242 consecutive adult patients with AML undergoing a myeloablative first allo-HSCT from different donor types, in three European centers between January 2017 and December 2020. Seventy-seven (32%) patients received allo-HSCT from HLA-matched sibling donor, 101 (42%) from HLA-matched and mismatched unrelated donor, and 64 (26%) from haploidentical donor. Except for neutrophil and platelet engraftment, which was slower in the haploidentical cohort, no significant differences were observed in major transplant outcomes according to donor type in univariate and multivariate analysis. GvHD prophylaxis with Sir-PTCy, with or without MMF, is safe and effective in patients with AML undergoing myeloablative allo-HSCT, resulting in low rates of transplant-related mortality, relapse/progression, and acute and chronic GvHD in all donor settings.

Os centros comerciais, como outros ativos, podem ser vistos como um investimento quer pela geração de resultados da sua exploração como pela evolução do seu valor imobiliário. A perspetiva do investimento está relacionada com as características e pretensões dos seus Investidores, ou seja, investidores centrados em negócios de maior risco, com prioridade na valorização do imóvel, ou investidores com risco reduzido que procuram estabilidade, conforme mencionado por Sarmento (2018) A avaliação dos centros comerciais por fundos de investimentos é um processo relevante cujo conhecimento poderá levar a decisões das entidades gestoras, ajuste da gestão e definição das suas áreas prioritárias de acordo com as características do Fundo de Investimento proprietário. Em Portugal, nos últimos 10 anos, tem se assistido a uma predominância de investimento estrangeiro no sector dos centros comerciais, revelando o aumento de atratividade de Portugal neste tipo de imóveis aos olhos do investimento internacional. Com a presente investigação pretende-se analisar como é percecionada a atratividade dos Centros Comerciais por parte dos Fundos de Investimento estrangeiros em Portugal, permitindo compreender a sua avaliação dos atos de gestão e na análise para a aquisição de novos ativos. O instrumento utilizado para esta análise foi o método STATIS Structuration des Tableaux à Trois Indices de la Statistique), proposto por L’Hermier des Plantes (1976) e desenvolvido por Lavit (1988a) e Lavit et al. (1994), tem as suas bases teóricas no trabalho de Escoufier (1973, 1976). Trata-se de um método exploratório, que tem por finalidade analisar as relações entre a estrutura de uma série de matrizes de dados, como um todo. Os resultados desta análise permitiram identificar três padrões de comportamento de centros comerciais, a convergência entre as perspetivas interna, externa e de desempenho e a divergência com a atratividade atribuída por cada fundo de investimento. Foi possível elencar um conjunto de ações de melhoria a ser desenvolvidas pela gestão dos centros comerciais e clarificar quais os fatores e relações mais importantes para os fundos de investimento em estudo. Shopping centers, like other assets, can be seen as an investment either by the operating results or by the evolution of the asset value. The investment perspective is related with the investors characteristics and intentions, like, investors focused on higher risk businesses, with priority on property valuation, or investors with reduced risk, looking for stability, as mentioned by Sarmento (2018). The evaluation of shopping centers by Investment Funds is a relevant process, the knowledge, may lead the Shopping Center Management entities for their decisions adjust the management and definition of the priority areas according to the characteristics of the Investment Fund that owns the property. In Portugal, in the last 10 years, there has been a predominance of foreign investment in the shopping center sector, revealing the increase of attractiveness from Portugal in this type of property in the eyes of international investment. With this research we intend to analyze how the attractiveness of Shopping Centers is perceived by foreign Investment Funds in Portugal, allowing to understand their evaluation of management acts and in the analysis for the acquisition of new assets. The instrument used for this analysis was the STATIS Structuration des Tableaux à Trois Indices de la Statistique method, proposed by L’Hermier des Plantes (1976) and developed by Lavit (1988a) and Lavit et al. (1994), has its theoretical bases in the work of Escoufier (1973, 1976). It is an exploratory method, which aims to analyze the relationships between the structure of a series of data matrices, as a whole. The results of this analysis allowed us to identify three patterns of behavior of shopping centers, the convergence between the internal, external and performance perspectives and the divergence with the attractiveness attributed by each investment fund. It was possible to list a set of improvement actions to be developed by the Shopping Center Management team and clarify which factors and relationships were more important for the investment funds under study

Objectives To describe current resistance to the β-lactams empirically recommended in the guidelines in bloodstream infection (BSI) episodes caused by Gram-negative bacilli (GNB). Methods Retrospective, multicentre cohort study of the last 50 BSI episodes in haematological patients across 14 university hospitals in Spain. Rates of inappropriate empirical antibiotic therapy (IEAT) and impact on mortality were evaluated. Results Of the 700 BSI episodes, 308 (44%) were caused by GNB, mainly Escherichia coli (141; 20.1%), Klebsiella spp. (56; 8%) and Pseudomonas aeruginosa (48; 6.9%). Among GNB BSI episodes, 80 (26%) were caused by MDR isolates. In those caused by Enterobacterales, 25.8% were ESBL producers and 3.5% were carbapenemase producers. Among P. aeruginosa BSI episodes, 18.8% were caused by MDR isolates. Overall, 34.7% of the isolated GNB were resistant to at least one of the three β-lactams recommended in febrile neutropenia guidelines (cefepime, piperacillin/tazobactam and meropenem). Despite extensive compliance with guideline recommendations (91.6%), 16.6% of BSI episodes caused by GNB received IEAT, which was more frequent among MDR GNB isolates (46.3% versus 6.1%; P Conclusions Current resistance to empirical β-lactams recommended in febrile neutropenia guidelines is exceedingly high and IEAT rates are greater than desired. There is an urgent need to adapt guidelines to current epidemiology and better identify patients with a high risk of developing MDR GNB infection.

Vários são os estudos e os alertas de todos os quadrantes da sociedade para o estado de emergência climática que nos encontramos, no entanto um dos momentos mais recentes que reforçam esta urgência ocorreu em 2015, durante a COP21 (Conferência das Nações Unidas sobre as Mudanças Climáticas) com a assinatura do Acordo de Paris. Este acordo tem por objectivo limitar o aumento da temperatura média do Planeta em menos de 2 graus, idealmente 1,5ºC, assim como a descarbonização da economia, durante a segunda metade do século. Para que tal seja possível a sociedade civil é parte integrante e fulcral da solução, pelo que descarbonizar é um processo que implica um investimento significativo (CE, COM2018/773, pág. 19), assim como um eficaz direcionamento desse investimento. Neste processo, são as intuições financeiros, em particular o sector da Banca, que podem assumir um papel decisivo enquanto financiadores e intermediários de capital, que exercem influência nos investimentos de toda a sociedade. O presente trabalho de pesquisa é um estudo de caso da instituição financeira “Crédito Agrícola” e visa analisar as acções que estão a ser tomadas por este Banco, e o seu alinhamento com os objectivos do Acordo de Paris; como são estes objectivos incorporados na operação bancária; qual o papel dos stakeholders nesta mudança; como se comunica a mudança; quais os risco e oportunidades que decorrem da implementação de processos pioneiros e desta forma avaliar se o Banco está a financiar a sustentabilidade e a contribuir para a transição energética. Para a realização deste trabalho foi desenvolvida uma pesquisa qualitativa de carácter exploratório, utilizando como técnicas auxiliares a pesquisa de dados secundários, recorrendo a literatura disponível sobre a temática e a consulta privilegiada de documentação do Banco (privilegiada, não confidencial). Utilizou-se também como técnica de recolha de informação, com produção de informação primária, entrevistas escritas com perguntas estruturadas, que, foram enviadas à responsável interna da sustentabilidade, à consultora externa responsável pela implementação do projecto de sustentabilidade no Grupo CA, ao Presidente do Conselho de Administração do Crédito Agrícola e a dezanove Colaboradores do Crédito Agrícola. Concluindo-se que as bases estão lançadas na instituição financeira em análise, e começam a ser tomadas medidas práticas no sentido de consubstanciar e materializar a política adoptada. There are several studies and warnings from all sides of society about the climate emergency that we are in, however one of the most recent moments that reinforce this urgency occurred in 2015, during COP21 (United Nations Conference on Climate Change ) with the signing of the Paris Agreement. This agreement aims to limit the increase in the planet's average temperature to less than 2 degrees, ideally 1.5°C, as well as the decarbonization of the economy, during the second half of the century. For this to be possible, civil society is an integral and central part of the solution, so decarbonizing is a process that implies a significant investment (EC, COM2018/773, page 19), as well as an effective targeting of this investment. In this process, it is the financial institutions, in particular the banking sector, which can play a decisive role as financers and capital intermediaries, which exert influence on the investments of the whole society. This research work is a case study of the financial institution “Crédito Agrícola” and aims to analyze the actions that are being taken by this Bank, and their alignment with the objectives of the Paris Agreement; how are these objectives incorporated in the banking operation; what is the role of stakeholders in this change; how change is communicated; what are the risks and opportunities that arise from the implementation of pioneering processes and, in this way, assess whether the Bank is financing sustainability and contributing to the energy transition. To carry out this work, a qualitative exploratory research was developed, using secondary data research as auxiliary techniques, using the available literature on the subject and privileged consultation of the Bank's documentation (privileged, non-confidential). It was also used as an information gathering technique, with the production of primary information, written interviews with structured questions, which were sent to the internal responsible for sustainability, to the external consultant responsible for the implementation of the sustainability project in the CA Group, to the President of Board of Directors of Crédito Agrícola and the nineteen Employees of Crédito Agrícola. It is concluded that the foundations have been laid on the financial institution under analysis and practical measures are being taken, to substantiate and materialize the adopted policy.

Introduction Tisagenlecleucel (tisa-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). The pivotal phase 2 trial JULIET included 93 patients and reported an overall response rate (ORR) of 52% and a complete response rate of 40% among treated patients. However, very little is known regarding its safety and efficacy in the commercial or real-world setting as well as from an intention-to-treat perspective. In our study, we report clinical outcomes of patients with R/R LBCL treated with commercial tisa-cel in 10 Spanish institutions. Methods Data were collected retrospectively from all consecutive patients with R/R LBCL who underwent apheresis for tisa-cel at a Spanish site from December 2018 until June 2020. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to the Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for tisa-cel (intention-to-treat). Results During the study period 91 patients with R/R LBCL underwent apheresis for tisa-cel. At the study cutoff, 69 (76%) patients had received a CAR T-cell infusion whereas 22 (24%) had not due to progressive disease (n=10, 45%), pending manufacturing process (n=7, 32%), out of specification (OOS) or manufacturing failure (n=4, 18%), or others (n=1, 5%). Sixty-one patients had at least the first disease response evaluation at 1-month post-infusion. Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 57 years (range 24-77) and 65% were male. Most of the patients had a high-risk International Prognostic Index score (62%), an advanced stage at diagnosis (91%) and were refractory to the previous therapy (80%). Median follow-up after CAR T-cell infusion was 4 months (1-16). Fifty-six patients (81%) received bridging therapy before infusion, including chemotherapy in most cases (n=51, 91%). All patients received fludarabine and cyclophosphamide as lymphodepleting chemotherapy. Median time from apheresis to infusion was 53 days (range 29-225). Median infused cell dose was 2.2 x 108 CAR positive viable T-cells (range 0.4-4.2 x 108). Eleven (16%) products were considered OOS although 45% of them were infused. Among the infused patients, 47 (68%) and 9 (13%) developed any grade of cytokine release syndrome (CRS) and neurotoxicity, respectively. Grade >2 CRS and neurotoxicity events occurred in 3 (4%) and 0 patients, respectively. Tocilizumab was administered to 21 (30%) patients and steroids to 13 (19%) patients. Nine (13%) patients required admission to the Intensive Care Unit. By day 100, 2 (3%) patients experienced non-relapse mortality. Other adverse events including infections and tumor lysis syndrome are summarized in table 2. Best response achieved among the infused patients included complete remission in 17 (28%) patients and partial remission in 22 (36%) patients, with an ORR of 64%. Stable disease and progressive disease were the best response in 4 (7%) and 18 (29%) patients, respectively. Considering all patients who underwent apheresis, CR and PR were obtained in 19% and 24% (ORR 43%), respectively. Median progression-free survival (PFS) and overall survival (OS) for infused patients were 3 months (95%CI 2.1-3.4) and 8 months (95%CI 5.7-10.8), respectively. In the univariate analysis, patients with ECOG score >1 (HR 4.3 95%CI 1.5 - 40.9) (p < 0.001) and IPI score >2 (HR 4.8 95%CI 1.6 - 14.4) (p = 0.002) were associated with lower PFS while an ECOG score >1 was also associated with lower OS (HR 3.4 95%CI 1.15 - 34.4) (p = 0.04). In the intention-to-treat analysis for all patients who underwent apheresis, median PFS and OS from apheresis were 4 months (95%CI 2.8-5.8) and 9 months (95%CI 5.8-11.8), respectively. Conclusions Treatment with tisa-cel was able to induce disease response with a good toxicity profile in a population of patients with LBCL treated in a European country. Poor performance status at the time of CAR T-cell infusion was associated with lower PFS and OS. Disclosures Iacoboni: Novartis, Gilead, Celgene, Roche: Honoraria. Guerreiro:Novartis: Honoraria. Mussetti:Novartis, Gilead: Honoraria, Research Funding. Sancho:Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Mundipharma y Takeda; Advisory y/o consultor para Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Celltrion y Kern-Pharma.: Honoraria. Hernani:Gilead: Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria. Martin Garcia-Sancho:Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy; Roche, Celgene, Janssen, Servier, Gilead: Honoraria. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Reguera:Celgene, Novartis: Consultancy; Novartis, Gilead: Honoraria. Barba:Novartis, Celgene, Gilead, Pfizer, Amgen, Roche: Honoraria.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be associated with neurologic complications, data on noninfectious etiologies are scanty. Therefore, we analyzed the incidence, clinical characteristics, risk factors, and influence on outcomes of noninfectious neurologic complications (NCs) in 971 consecutive patients with hematologic malignancies undergoing allo-HSCT at our center between January 2000 and December 2016. We evaluated NCs affecting the central nervous system (CNS) and peripheral nervous system (PNS). The median duration of follow-up of survivors was 71 months (range, 11 to 213 months). A total of 467 patients received a matched sibling donor (MSD) transplant, 381 received umbilical cord blood (UCB), 74 received a haploidentical transplant, and 49 received a matched unrelated donor (MUD) transplant. One hundred forty-nine (15.3%) NCs were documented at a median of 78 days after transplantation (range, 5 days before to 3722 days after). The cumulative incidence risk of developing NC was 7.5% (95% confidence interval, 6% to 8.2%) at day +90 and 13% at 5 years. The 5 -year cumulative incidence of NCs was 10.8% after MSD alto-HSCT and 15.3% after alternative donor (UCB, MUD, haploidentical) allo-HSCT (P=.004). There were 101 (68%) CNS complications, including encephalopathy, n = 46 (31%); headache, n = 20 (13%); stroke, n = 15 (10%); seizures, n = 9 (6%), posterior reversible encephalopathy syndrome, n = 6 (4%), and myelopathy, n = 5 (3%). PNS complications (32%) included neuropathies, n = 25 (17%), and myopathies and neuromuscular junction disorders, n = 23 (17%), with 17% of the total PNS complications being immune-related. In multivariable analysis, donor type other than MSD, age >= 40 years, development of acute graft-versus-host disease (GVHD) grade II-IV (hazard ratio [HR], 3.3; P < .00001), and extensive chronic GVHD (HR, 3.2; P=.0002) were independently associated with increased risk of NCs. The 5 -year overall survival (OS) was 21% in patients who developed NCs and 41% for those who did not (P < .0001). This difference in OS was observed in patients developing CNS NCs, but not in those developing PNS complications. In conclusion, our study reveals NCs as a frequent and heterogeneous complication that, when affecting CNS, is associated with poor prognosis following allo-HSCT. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Objectives Umbilical cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) modalities have been developed to offset the lack of matched donors. In this study, we compare the transfusion requirements of patients undergoing UCBT and haplo-HSCT in a single institution with the aim of providing additional information for clinicians to choose the most adequate alternative graft for HSCT. Methods The study reviewed 67 and 46 patients undergoing UCBT and haplo-HSCT, respectively. Results There were no significant differences for RBC and PLT requirements according to the transplantation modality. Median time to RBC transfusion independence was 35 and 25.5 days in patients who received an UCBT and haplo-HSCT, respectively (P = 0.38), while median time to platelet transfusion independence was 31 days for UCBT patients and 23 for haplo-HSCT patients (P < 0.001). Days until neutrophils > 0.5 x 10(9)/L were the only variable that significantly influenced RBC and PLT requirements for both transplantation modalities. Cumulative incidence of RBC and PLT transfusion independence at 90 days after transplantation was similar for both UCBT and haplo-HSCT. Conclusions Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy.

OBJECTIVE Characteristics and risk factors (RFs) of invasive fungal disease (IFD) have been little studied in the setting of umbilical cord blood transplantation (UCBT). METHOD We retrospectively included 205 single-unit myeloablative UCBT recipients with a median follow-up of 64 months. RESULTS Fifty-six episodes of IFD were observed in 48 patients (23%) at a median time of 123 days after stem cell infusion. Invasive mold disease (IMD) occurred in 42 cases, 38 of them (90%) caused by invasive aspergillosis whereas invasive yeast disease (IYD) occurred in 14 cases, most of them due to candidemia (n = 12, 86%). The 5-year cumulative incidence of IFD, IMDs, and IYDs was 24% 19%, and 7%, respectively. In multivariate analysis, three RFs for IMDs were identified: age >30 years (HR 3.5, P = 0.017), acute grade II-IV graft-versus-host disease (HR 2.3, P = 0.011), and ≥1 previous transplant (HR 3.1, P = 0.012). The probability of IMDs was 2.5%, 14%, and 33% for recipients with none, 1, or 2-3 RFs, respectively (P

It is uncertain whether gastrointestinal (GI) infection caused by viral and bacterial pathogens may predispose to gastrointestinal acute Graft-versus-host disease (aGvHD-GI) in allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). We investigated the potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of aGvHD-GI in a cohort of 121 allo-HSCT patients. Eighty-six out of 121 patients (71%) had acute diarrhea and underwent screening for primary GI pathogens by molecular diagnostic methods. One or more GI pathogens were detected in 27 out of the 86 patients with diarrhea (31.3%). Specifically, Clostridioides difficile was found in 16 patients (18.6%), enteropathogenic viruses in 11 patients (12.7%) (Astrovirus, n=4; Norovirus, n=2; Sapovirus, n=2; Adenovirus, n=2, and Rotavirus, n=1), and Campylobacter spp. in 2 patients (2.3%). Thirty patients were diagnosed with all grade aGvHD-GI by histopathology. Detection of primary GI pathogens was achieved in 12 of the 30 patients (Clostridium difficile, n=5; enteric viruses, n=8; Campylobacter spp., n=1) who either subsequently developed (n=9) or previously had (n=3) grade I-IV IaGvHD (n=9). Neither the detection of these microorganisms (all combined), enteric viruses nor Clostridioides difficile was significantly associated with subsequent aGvHD-GI development in Cox models (HR, 1.11, P=0.80; HR, 1.64, P=0.62; HR, 0.75, P=0.64, respectively). Analogous results were obtained when grade II-IV aGvHD-GI was selected as the clinical outcome. In summary, data in the current study did not support an association between GI infection and subsequent occurrence of aGvHD-GI in an unselected cohort of allo-HSCT recipients. This article is protected by copyright. All rights reserved.

Cellular and humoral response to acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections is on focus of research. We evaluate herein the feasibility of expanding virus‐specific T cells (VST) against SARS‐CoV‐2 ex vivo through a standard protocol proven effective for other viruses. The experiment was performed in three different donors' scenarios: (a) SARS‐CoV‐2 asymptomatic infection/negative serology, (b) SARS‐CoV‐2 symptomatic infection/positive serology, and (c) no history of SARS‐CoV‐2 infection/negative serology. We were able to obtain an expanded VST product from donors 1 and 2 (1.6x and 1.8x increase of baseline VST count, respectively) consisting in CD3 + cells (80.3% and 62.7%, respectively) with CD4 + dominance (60% in both donors). Higher numbers of VST were obtained from the donor 2 as compared to donor 1. T‐cell clonality test showed oligoclonal reproducible peaks on a polyclonal background for both donors. In contrast, VST could be neither expanded nor primed in a donor without evidence of prior infection. This proof‐of‐concept study supports the feasibility of expanding ex vivo SARS‐CoV‐2‐specific VST from blood of convalescent donors. The results raise the question of whether the selection of seropositive donors may be a strategy to obtain cell lines enriched in their SARS‐CoV‐2‐specificity for future adoptive transfer to immunosuppressed patients., The neutralization antibody assay was supported by Valencian government grant Covid_19-SCI as well as the Spanish National Research Council grants CSIC-COV19-082 and CSIC-COV-19-104 to RG.

BACKGROUND: Defibrotide is approved in European Union for the treatment of severe sinusoidal obstruction syndrome (SOS) after HSCT. However, it has also been used for SOS prophylaxis, moderate SOS and in other complications such as transplant-associated thrombotic microangiopathy (TAM). The objective of this study was to evaluate current uses, effectiveness and safety of defibrotide in patients with HSCT. METHODS: This multicenter, retrospective study included patients treated with defibrotide for any indication at 28 HSCT centers of the Grupo Español de Trasplante Hematopoyetico (GETH) including the pediatric subgroup Grupo Español de Trasplante de Medula en Niños (GETMON). RESULTS: Three hundred and eighty eight patients treated with defibrotide between January 2011 and December 2018 were included. 253 patients were children, and 135 patients were adults. In total, 332 transplants were allogeneic, and the remainder were autologous. Main indications for defibrotide use were severe/very severe SOS in 173 patients, SOS prophylaxis in 135 patients, moderate SOS in 41 patients, TAM in six patients and suspected SOS in 33 patients. Overall survival (OS) at day +100 in the SOS prophylaxis group was 89% (95% CI, 87%-91%). In the group of patients with moderate and severe/very severe SOS, the OS at day +100 was 80% (95% CI, 74%-86%) and 62% (95% CI, 59%-65%), respectively (P = .0015). With a longer follow-up, median of 2 years (4 months-7 years), OS was 63% (95% CI, 59%-67%) in the SOS prophylaxis patients. OS for patients with moderate and severe/very severe SOS groups was 53% (95% CI, 47%-61%) and 26% (95% CI, 22%-30%), respectively (P = .006). 191 patients died, and SOS was the main cause of death in 23 patients (12%). CONCLUSIONS: Defibrotide has an acceptable safety profile with an improved response in severe/very severe SOS compared with historical controls, mainly in pediatric patients. Use of defibrotide for prophylaxis may improve prognosis of patients at high risk of complications due to endothelial damage such as those who receive a second transplant. SOS has an important impact on the HSCT long-term survival, as can be concluded from our study.

Tese de mestrado, Medicina Dentária, Universidade de Lisboa, Faculdade de Medicina Dentária, 2020 Submitted by Luiza Baptista (luiza.baptista@fmd.ulisboa.pt) on 2021-03-08T16:22:45Z No. of bitstreams: 1 Dissertação_MIMD_Rodrigo-Silva_2019-2020.pdf: 5244736 bytes, checksum: 5ad7299a6890ebb016a9613498eeec67 (MD5) Made available in DSpace on 2021-03-08T16:23:07Z (GMT). No. of bitstreams: 1 Dissertação_MIMD_Rodrigo-Silva_2019-2020.pdf: 5244736 bytes, checksum: 5ad7299a6890ebb016a9613498eeec67 (MD5) Previous issue date: 2020-12-09

Torque Teno virus (TTV) DNA load in blood may act as a marker of immune competence after allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). Conflicting data have been reported as to the value of this biomarker for anticipating acute Graft-versus-host disease (aGvHD) occurrence. Here, we hypothesized that quantitation of TTV DNA load in stool specimens early after allo-HSCT could be used to identify patients at high risk of acute intestinal graft-versus-host disease (aIGvHD). In this prospective two-center study we recruited a total of 83 non-consecutive adult patients undergoing allo-HSCT. The study period comprised the first 120 days after allo-HSCT. TTV DNA was quantitated in paired stool samples collected at a median of 2 days prior to cell infusion and at a median of 14 days after allo-HSCT by real-time PCR. Thirty-seven patients developed aGVHD, of whom 25 had aIGVHD (diagnosed at a median of 42 days after allo-HSCT). Median TTV DNA load values in post-transplant stools specimens were comparable (P=0.34) in patients with or without subsequent aIGvHD; nevertheless, a falling trajectory (decrease in TTV DNA load >0.5 log10 copies/0.1 g) in paired pre-transplant and pos-transplant specimens was independently associated with the occurrence of aIGvHD (OR, 5.2; 95% CI, 1.3-21.3; P = 0.02). Notably, displaying a rising trajectory had a negative predictive value of 87.5% for aIGvHD. In summary, in this hypothesis-generating study we suggest that the decrease in TTV DNA load from baseline in stool specimens may identify patients at risk of aIGVHD.

Objective To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis. Methods We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91). Results Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution. Conclusions PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.

Background Data have been published suggesting a bidirectional interaction between cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we hypothesized that prospective CMV DNA monitoring in stool specimens may be useful for predicting subsequent occurrence of intestinal aGvHD (IaGvHD). Methods This two-center study enrolled 121 consecutive adult patients undergoing any modality of allo-HSCT. A total of 1,009 stool specimens were collected (a median of 7 specimens/patient; range, 1-18). CMV DNA monitoring in stools and plasma was performed using real-time PCR assays. Results CMV DNA was detected in stools in 20 patients (cumulative incidence, 16.9%; 95% CI, 6.3%-31.8%). Median CMV DNA level in stool specimens was 1,258 IU/0.1g (range, 210-4,087 IU/0.1 g). All these patients and their donors were CMV seropositive, and 16 of the 20 patients also had CMV DNAemia, while 4 patients had CMV DNA detected in stools without CMV DNAemia. No correlation was found between CMV DNA loads in plasma and stools (P = .40). Prior CMV DNAemia, aGvHD, or IaGvHD were not associated with presence of CMV DNA in feces. IaGvHD was present in 30 patients, in 5 of whom CMV DNA was detected in stools. Neither detection of CMV DNA in feces nor in plasma was associated with subsequent IaGvHD (OR, 0.67; 95% CI, 0.18-2.52; P = .55 and OR, 0.86; 95% CI, 0.38-1.96; P = .71, respectively). No patient in this cohort had CMV end-organ disease within the study period. Conclusion Our study failed to provide evidence pointing to a reciprocal interaction between GI CMV infection and IaGvHD. CMV DNA monitoring in stools seems of no value to anticipate occurrence of IaGvHD.

After an in-depth analysis of EAP’s current situation, it was founda need to implementaction that, ,represent significant operation algains. The seinitiatives have as hort-termim pact, how ever ,they are meant to be a firsts tepfor the introduction of more profound changes. The analysis’ results proved that itis crucial to improve the network efficiency byre- structuring critical zones and excluding low-performing providers. Additionally, to guarantee that EA Pinternal systems runsmoothly, action sare recommended regarding the TASK and RoS systems. Finally, providers ’performance can be enhanced bylinking KPIsto SLAs