Publications by authors named "Manuel Abecasis"

29 Publications

  • Page 1 of 1

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT.

Am J Hematol 2021 May 4;96(5):571-579. Epub 2021 Mar 4.

French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital and University Paris Diderot, Paris, France.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.
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http://dx.doi.org/10.1002/ajh.26135DOI Listing
May 2021

[Preparing For the COVID-19 Pandemic: The Perspective of a Department of Anesthesiology in a Tertiary Hospital in Portugal].

Acta Med Port 2020 Nov 21;33(11):768-774. Epub 2020 Jul 21.

Serviço de Anestesiologia. Centro Hospitalar Universitário Lisboa Norte. Lisboa. Portugal.

Since the detection of the first cases of COVID-19, reported by the People's Republic of China on the 31st December 2019, up to the confirmation of the first cases in Portugal, on the 2nd March, countries like Italy and Spain faced the collapse of their healthcare systems. Anticipating this possibility, the Portuguese National Health Service carried out measures to prepare for this reality. This paper describes the changes implemented in the Anesthesiology department of a tertiary hospital center in Portugal, aiming to ensure the safety of both patients and healthcare professionals. The measures implemented had to do mostly with scientific preparation and team reorganization; management of personal protective equipment; redesigning the department's clinical common areas, separation of patient circuits with creation of a designated COVID Operating Room, Post-Anesthetic Care Unit; rescheduling of elective surgery and testing all patients before anesthesia procedures and consulting other hospital departments. The reported data covers the period between the 2nd March and the 30th April of 2020. In this period, 64 cases with COVID-19 or with high clinical suspicion were approached. To date, there have been no cases of in-hospital spread to other patients or to professionals in this department. With this paper we intend to start a reflection that will end up with the optimization of strategies that allows health systems to deal better with COVID-19, keeping patients and health providers safe.
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http://dx.doi.org/10.20344/amp.14238DOI Listing
November 2020

Is cancer latency an outdated concept? Lessons from chronic myeloid leukemia.

Leukemia 2020 09 6;34(9):2279-2284. Epub 2020 Jul 6.

Department of Immunology and Inflammation, Haematology Research Centre, Imperial College London, London, UK.

Our concept of cancer latency, the interval from when a cancer starts until it is diagnosed, has changed dramatically. A prior widely-used definition was the interval between an exposure to a cancer-causing substance and cancer diagnosis. However, this definition does not accurately reflect current knowledge of how most cancers develop assuming, mostly incorrectly, one exposure is the sole cause of a cancer, ignoring the possibility the cancer being considered would have developed anyway but that the exposure accelerated cancer development and eliding the randomness in when a cancer is diagnosed. We show, using chronic myeloid leukaemia as a model, that defining cancer latency is not as simple as it once seemed. It is difficult or impossible to know at which event or mutation to start to clock to measure cancer latency. It is equally difficult to know when to stop the clock given the stochastic nature of when cancers are diagnosed. Importantly, even in genetically-identical twins with the same driver mutation intervals to develop cancer vary substantially. And we discuss other confonders. Clearly we need a new definition of cancer latency or we need to abandon the concept of cancer latency in the modern era of cancer biology.
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http://dx.doi.org/10.1038/s41375-020-0957-zDOI Listing
September 2020

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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http://dx.doi.org/10.1038/s41409-020-0854-0DOI Listing
August 2020

How Allogeneic Hematopoietic Stem Cell Transplantation has Evolved Over Time: 30-Years' Experience at a Single Institution.

Acta Med Port 2020 Feb 3;33(2):116-123. Epub 2020 Feb 3.

Clinical Research Unit. Instituto Português de Oncologia de Lisboa Francisco Gentil. Lisboa. Portugal.

Introduction: Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation.

Material And Methods: We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study.

Results: The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable.

Discussion: Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature.

Conclusion: Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.
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http://dx.doi.org/10.20344/amp.11768DOI Listing
February 2020

Atypical myeloproliferative neoplasm with concurrent BCR-ABL1 fusion and CALR mutation: A case report and literature review.

Medicine (Baltimore) 2020 Jan;99(5):e18811

Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China.

Rationale: Concurrent calreticulin (CALR) mutation and BCR-ABL1 fusion are extremely rare in chronic myelogenous leukemia; to date, only 12 cases have been reported.

Patient Concerns: A 57-year-old male who had an 11-year history of essential thrombocytosis presented to our hospital with leukocytosis and marked splenomegaly for 3 months.

Diagnoses: Chronic myelogenous leukemia with myeloid fibrosis arising on the background of essential thrombocytosis harboring both BCR-ABL1 fusion and type-1 like CALR mutation.

Interventions: Imatinib was started at 300 mg daily and increased to 400 mg daily after 3 months; interferon was added after 12 months.

Outcomes: Partial cytogenetic response was achieved after 3 months of imatinib therapy and complete cytogenetic response was achieved after 1 year of treatment. However, CALR mutation was still present with a stable mutational allele burden.

Lessons: In this case report and review of additional 12 cases with simultaneous presence of CALR-mutation and BCR-ABL1 fusion, we highlighted the importance of integrating clinical, morphological, and molecular genetic data for classifying atypical myeloid neoplasms.
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http://dx.doi.org/10.1097/MD.0000000000018811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004640PMC
January 2020

Immunomodulatory effect of human bone marrow-derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients.

J Tissue Eng Regen Med 2020 01 11;14(1):16-28. Epub 2019 Nov 11.

Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal.

Rheumatoid arthritis (RA) is a Th1/Th17-mediated autoimmune disease whose current treatment, consisting in the blockage of inflammatory cytokines by disease-modifying antirheumatic drugs, is not effective for all patients. The therapeutic potential of mesenchymal stromal/stem cells' (MSCs) immunomodulatory properties is being explored in RA. Here, we investigate the effect of human bone marrow (BM)-MSCs on the expression of cytokines involved in RA physiopathology by the distinct functional compartments of CD4 and CD8 T cells from RA patients. Peripheral blood mononuclear cells from healthy individuals (n = 6) and RA patients (n = 12) were stimulated with phorbol myristate acetate plus ionomycin and cultured in the presence/absence of BM-MSCs. The expression of (interleukin) IL-2, tumor necrosis factor alpha (TNF-α), and interferon-gamma (IFN-γ) was evaluated in naive, central memory, effector memory, and effector CD4 and CD8 T cells, whereas IL-6, IL-9, and IL-17 expression was measured in total CD4 and CD8 T cells. mRNA expression of IL-4, IL-10, transforming growth factor beta (TGF-β), cytotoxic T-lymphocyte-associated antigen 4, and/or forkhead box P3 was quantified in fluorescence-activated cell sorting-purified CD4 T cells, CD8 T cells, and CD4 Treg. BM-MSCs inhibited the production of TNF-α, IL-17, IL-6, IL-2, IFN-γ, and IL-9 by T cells from RA patients, mainly by reducing the percentage of cells producing cytokines. This inhibitory effect was transversal to all T cell subsets analyzed. At mRNA level, BM-MSCs increased expression of IL-10 and TGF-β by CD4 and CD8 T cells. BM-MSCs displayed a striking inhibitory action over T cells from RA patients, reducing the expression of cytokines involved in RA physiopathology. Remarkably, BM-MSC-derived immunomodulation affected either naive, effector, and memory T cells.
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http://dx.doi.org/10.1002/term.2958DOI Listing
January 2020

Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey.

Am J Transplant 2019 06 25;19(6):1798-1805. Epub 2019 Jan 25.

Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt am Main, Germany.

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.
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http://dx.doi.org/10.1111/ajt.15240DOI Listing
June 2019

Refractory Severe Thrombocytopenia during Pregnancy: How to Manage.

Rev Bras Ginecol Obstet 2018 Dec 7;40(12):803-807. Epub 2018 Dec 7.

Department of Anaesthesiology, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.

Thrombocytopenia is the most common hemostatic change in pregnancy, but severe thrombocytopenia is rare. One of the causes, immune thrombocytopenic purpura (ITP), is characterized by increased platelet destruction by immunoglobulin G (IgG) antibodies, presenting a high risk of hemorrhage for the patient, but also for the fetus, since antibodies may cross the placenta. We present the case of a 23-year-old pregnant woman with a history of Langerhans cell histiocytosis of the mandible submitted to surgery and chemotherapy when she was 10 years old, with diagnosis of ITP since then. At 28 weeks of gestation, she presented with petechiae, epistaxis, and gingival bleeding, with a platelet count of 3 × 10/L and positive IgG antiplatelet antibodies test. At a multidisciplinary discussion, it was decided to delay a cesarean section, due to the absence of fetal distress and to the high risk of morbidity for the patient. Many therapies were attempted without success. The IgG produced a slight and transient increase in the platelet count. On the 36 week of gestation, an elective cesarean section was performed. The perioperative period transfusions were guided by rotational thromboelastometry (ROTEM) monitoring. The procedure was performed under general anesthesia and videolaryngoscopy-assisted intubation. The patient was hemodynamically stable, without significant bleeding, and was transferred to the intensive care unit. The platelet count eventually decreased and a splenectomy was performed. Regional anesthesia may be contraindicated, and general anesthesia is associated with an increased risk of airway hemorrhage due to traumatic injury during the tracheal intubation and of hemorrhage associated with the surgical procedure. A multidisciplinary approach is essential in high-risk cases.
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http://dx.doi.org/10.1055/s-0038-1675186DOI Listing
December 2018

MonoMAC Syndrome Caused by a Novel GATA2 Mutation Successfully Treated by Allogeneic Hematopoietic Stem Cell Transplantation.

J Clin Immunol 2019 01 26;39(1):4-6. Epub 2018 Nov 26.

Serviço de Transplantação de Medula Óssea, Instituto Português de Oncologia, Lisbon, Portugal.

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http://dx.doi.org/10.1007/s10875-018-0576-xDOI Listing
January 2019

Outcomes of Advanced Hodgkin Lymphoma after Umbilical Cord Blood Transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy & Immunobiology Working Party Study.

Biol Blood Marrow Transplant 2018 11 19;24(11):2265-2270. Epub 2018 Jul 19.

Eurocord, Hôpital Saint Louis, Paris, France; Monacord, Centre Scientifique de Monaco, Monaco; Hematology Department, Ospedale Pediatrico Bambin Gesù, Dipartimento di Oncoematologia e Terapia Cellulare e Genica, Rome, Italy. Electronic address:

Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HR], 3.14 [95% CI, 1.41 to 7.00], P = .005) and NRM (HR, 3.61 [95% CI, 1.58 to 8.27], P = .002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P < .001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P = .001). Conditioning regimen with cyclophosphamide + fludarabine + 2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR, .26 [95% CI, .10 to .64], P = .004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR, .25 [95% CI, .12 to .50], P < .001) and PFS (HR, .51 [95% CI, .27 to .96], P = .04). UCBT is feasible in heavily pretreated patients with HL. The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.019DOI Listing
November 2018

Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis.

Biol Blood Marrow Transplant 2017 01 21;23(1):96-102. Epub 2016 Oct 21.

Service d'Hématologie, Hôpital Robert Debré, APHP, Paris, France.

Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.
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http://dx.doi.org/10.1016/j.bbmt.2016.10.014DOI Listing
January 2017

Outcomes after Unrelated Umbilical Cord Blood Transplantation for Children with Osteopetrosis.

Biol Blood Marrow Transplant 2016 11 25;22(11):1997-2002. Epub 2016 Jul 25.

Eurocord, Hopital Saint Louis, Paris, France; Centre Scientifique de Monaco, Principality of Monaco; Churchill Hospital, University of Oxford, NHS Blood and Transplant (NHSBT), Oxford, United Kingdom.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34 cells infused was 14 × 10/kg and 3.4 × 10/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.
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http://dx.doi.org/10.1016/j.bbmt.2016.07.015DOI Listing
November 2016

Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells.

Stem Cells Int 2015 28;2015:819084. Epub 2015 Apr 28.

Blood and Transplantation Center of Coimbra, Portuguese Institute of the Blood and Transplantation, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal.

The immunosuppressive properties of mesenchymal stromal/stem cells (MSC) rendered them an attractive therapeutic approach for immune disorders and an increasing body of evidence demonstrated their clinical value. However, the influence of MSC on the function of specific immune cell populations, namely, monocyte subpopulations, is not well elucidated. Here, we investigated the influence of human bone marrow MSC on the cytokine and chemokine expression by peripheral blood classical, intermediate and nonclassical monocytes, and myeloid dendritic cells (mDC), stimulated with lipopolysaccharide plus interferon (IFN)γ. We found that MSC effectively inhibit tumor necrosis factor- (TNF-) α and macrophage inflammatory protein- (MIP-) 1β protein expression in monocytes and mDC, without suppressing CCR7 and CD83 protein expression. Interestingly, mDC exhibited the highest degree of inhibition, for both TNF-α and MIP-1β, whereas the reduction of TNF-α expression was less marked for nonclassical monocytes. Similarly, MSC decreased mRNA levels of interleukin- (IL-) 1β and IL-6 in classical monocytes, CCL3, CCL5, CXCL9, and CXCL10 in classical and nonclassical monocytes, and IL-1β and CXCL10 in mDC. MSC do not impair the expression of maturation markers in monocytes and mDC under our experimental conditions; nevertheless, they hamper the proinflammatory function of monocytes and mDC, which may impede the development of inflammatory immune responses.
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http://dx.doi.org/10.1155/2015/819084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427776PMC
June 2015

Alternaria alternata invasive fungal infection in a patient with Fanconi's anemia after an unrelated bone marrow transplant.

Clin Drug Investig 2013 Feb;33 Suppl 1:S33-6

Alternaria spp. have emerged as opportunistic pathogens particularly in immunosuppressed patients, such as bone marrow transplant recipients. The authors present a case of Alternaria alternata in a patient with Fanconi's anemia, who received antifungal prophylaxis with posaconazole after an unrelated bone marrow transplantation, followed by empirical antifungal treatment with caspofungin when persistent fever emerged until cutaneous lesions eventually appeared. At that time there were clinical reasons to assume that the patient had an infection with an emerging fungus. This consideration triggered a change of the antifungal therapy from caspofungin to liposomal amphotericin B. After collecting sufficient evidence for the presence of an invasive fungal infection by A. alternata and given the severity of neutropenia and other immunosuppression, oral posaconazole was added to liposomal amphotericin B. The course of disease in this case suggests a possibly synergistic interaction between liposomal amphotericin B and posaconazole when administered simultaneously to treat an invasive systemic infection by Alternaria spp. in immunocompromised patients.
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http://dx.doi.org/10.1007/s40261-012-0018-0DOI Listing
February 2013

Widespread skin nodules as a manifestation of breakthrough invasive aspergillosis in a bone marrow transplant patient.

Clin Drug Investig 2013 Feb;33 Suppl 1:S15-7

Serviço de Transplantação de Medula Óssea, Instituto Portugues de Oncologia, Lisbon, Portugal.

Invasive aspergillosis (IA) is a life-threatening complication of bone marrow transplantation manifesting most often as a respiratory tract infection with potential hematogenous dissemination to any organ. The authors report an unusual case of IA manifesting as widespread subcutaneous nodules, with intact overlying skin, complicating pulmonary infection in a transplanted patient who received mold-active antifungal prophylaxis. The present case emphasizes the relevance of cellular immunity, in particular T lymphocytes, in the control of invasive fungal disease and highlights the potential role of positron emission tomography scan in assessing its dissemination.
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http://dx.doi.org/10.1007/s40261-012-0015-3DOI Listing
February 2013

Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells.

Stem Cell Res 2012 Nov 23;9(3):225-36. Epub 2012 Jul 23.

Department of Bioengineering and Institute for Biotechnology and Bioengineering, Instituto Superior Técnico (IST), Technical University of Lisbon, Lisboa, Portugal.

Recent studies have described the occurrence of chromosomal abnormalities and mitochondrial dysfunction in human stem/stromal cells (SCs), particularly after extensive passaging in vitro and/or expansion under low oxygen tensions. To deepen this knowledge we investigated the influence of hypoxia (2% O(2)) and prolonged passaging (>P10) of human bone marrow stromal cells (BMSCs) and adipose-derived stromal cells (ASCs) on the expression of genes involved in DNA repair and cell-cycle regulation pathways, as well as on the occurrence of microsatellite instability and changes in telomere length. Our results show that hypoxic conditions induce an immediate and concerted down-regulation of genes involved in DNA repair and damage response pathways (MLH1, RAD51, BRCA1, and Ku80), concomitantly with the occurrence of microsatellite instability while maintaining telomere length. We further searched for mutations occurring in the mitochondrial genome, and monitored changes in intracellular ATP content, membrane potential and mitochondrial DNA content. Hypoxia led to a simultaneous decrease in ATP content and in the number of mitochondrial genomes, whereas the opposite effect was observed after prolonged passaging. Moreover, we show that neither hypoxia nor prolonged passaging significantly affected the integrity of the mitochondrial genome. Ultimately, we present evidence on how hypoxia selectively impacts the cellular response of BMSCs and ASCs, thus pointing for the need to optimize oxygen tension according to the cell source.
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http://dx.doi.org/10.1016/j.scr.2012.07.001DOI Listing
November 2012

[High dose chemotherapy with autologous stem-cell support in germ cell tumors: The Instituto Português de Oncologia de Lisboa Francisco Gentil Series].

Acta Med Port 2011 Jul-Aug;24(4):533-44. Epub 2011 Dec 12.

Serviço de Oncologia Médica, Centro de Transplantação, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal.

Background: High dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) has been administered to patients with high-risk germ cell tumours (GCT). The role of this treatment for GCT still remains unclear, including the identification of subgroups more likely to benefit from such strategy.

Methods: A retrospective review was conducted of all male patients with gonadal and extra gonadal GCT treated with HDCT-ASCT between 1996 and 2008 at the Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG).

Results: Twenty patients were treated with HDCT-ASCT, 17 with primary testicular tumours, two mediastinal and one retroperitoneal GCT. According to the International Germ Cell Cancer Consensus Group (IGCCCG) classification, at diagnosis three patients had good risk, four intermediate, eight poor but for the patients left the risk group could not be ascertained. In eight patients HDCT-ASCT was used upfront, after induction with first-line conventional chemotherapy, and in the remaining 12 for relapsed GCT. One patient had platinum-resistant and another platinum-refractory disease. Only two patients had Beyer score > 2. All but one patient were treated with ICE (Ifosfamide, Carboplatin, Etoposide). Six patients underwent a second HDCT-ASCT course. The 5-year overall survival and progression free survival were respectively 53% and 44%; both patients with mediastinal GCT are long term survivors.

Conclusion: Randomized studies to date have failed to indicate a survival advantage for HDCT-ASCT in GCT. This series is small and heterogeneous which prevents us from drawing conclusions regarding the benefit of this treatment for GCT. However, we could confirm the lack of benefit of HDCT-ASCT for platinum-resistant GCT and to question the absolute contraindication to this therapeutic modality in mediastinal GCT. HDCT-ASCT should therefore be performed exclusively in experienced centers and, preferably, in the setting of clinical trials.
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August 2012

Toward a clinical-grade expansion of mesenchymal stem cells from human sources: a microcarrier-based culture system under xeno-free conditions.

Tissue Eng Part C Methods 2011 Dec 6;17(12):1201-10. Epub 2011 Sep 6.

Department of Bioengineering, Instituto Superior Técnico-IST, Lisboa, Portugal.

The immunomodulatory properties of mesenchymal stem cells (MSCs) make them attractive therapeutic agents for a wide range of diseases. However, the highly demanding cell doses used in MSC clinical trials (up to millions of cells/kg patient) currently require labor intensive methods and incur high reagent costs. Moreover, the use of xenogenic (xeno) serum-containing media represents a risk of contamination and raises safety concerns. Bioreactor systems in combination with novel xeno-free medium formulations represent a viable alternative to reproducibly achieve a safe and reliable MSC doses relevant for cell therapy. The main goal of the present study was to develop a complete xeno-free microcarrier-based culture system for the efficient expansion of human MSC from two different sources, human bone marrow (BM), and adipose tissue. After 14 days of culture in spinner flasks, BM MSC reached a maximum cell density of (2.0±0.2)×10⁵ cells·mL⁻¹ (18±1-fold increase), whereas adipose tissue-derived stem cells expanded to (1.4±0.5)×10⁵ cells·mL⁻¹ (14±7-fold increase). After the expansion, MSC expressed the characteristic markers CD73, CD90, and CD105, whereas negative for CD80 and human leukocyte antigen (HLA)-DR. Expanded cells maintained the ability to differentiate robustly into osteoblast, adipocyte, and chondroblast lineages upon directed differentiation. These results demonstrated the feasibility of expanding human MSC in a scalable microcarrier-based stirred culture system under xeno-free conditions and represent an important step forward for the implementation of a Good Manufacturing Practices-compliant large-scale production system of MSC for cellular therapy.
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http://dx.doi.org/10.1089/ten.tec.2011.0255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226421PMC
December 2011

Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients.

Haematologica 2011 Aug 5;96(8):1231-5. Epub 2011 May 5.

Dept. of Haematology, Karolinska University Hospital, Stockholm, Sweden.

During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients.
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http://dx.doi.org/10.3324/haematol.2011.041913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148919PMC
August 2011

Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study.

Haematologica 2010 Oct 15;95(10):1762-8. Epub 2010 Jul 15.

Service d'Hématologie Clinique, Hôpital Henri Mondor, 51 Av. Maréchal de Lattre de Tassigny, Créteil, France.

Background: Recurrence of prior invasive fungal infection (relapse rate of 30-50%) limits the success of stem cell transplantation. Secondary prophylaxis could reduce disease burden and improve survival.

Design And Methods: A prospective, open-label, multicenter trial was conducted evaluating voriconazole (4 mg/kg/12 h intravenously or 200 mg/12 h orally) as secondary antifungal prophylaxis in allogeneic stem cell transplant recipients with previous proven or probable invasive fungal infection. Voriconazole was started 48 h or more after completion of conditioning chemotherapy and was planned to be continued for 100-150 days. Patients were followed for 12 months. The primary end-point of the study was the incidence of proven or probable invasive fungal infection.

Results: Forty-five patients were enrolled, 41 of whom had acute leukemia. Previous invasive fungal infections were proven or probable aspergillosis (n=31), proven candidiasis (n=5) and other proven or probable infections (n=6); prior infection could not be confirmed in three patients. The median duration of voriconazole prophylaxis was 94 days. Eleven patients (24%) died within 12 months of transplantation, but only one due to systemic fungal disease. Three invasive fungal infections occurred post-transplant: two relapses (one candidemia and one fatal scedosporiosis) and one new zygomycosis in a patient with previous aspergillosis. The 1-year cumulative incidence of invasive fungal disease was 6.7±3.6%. Two patients were withdrawn from the study due to treatment-related adverse events (i.e. liver toxicity).

Conclusions: Voriconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after allogeneic stem cell transplantation. The observed incidence of 6.7% (with one attributable death) is considerably lower than the relapse rate reported in historical controls, thus suggesting that voriconazole is a promising prophylactic agent in this population.
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http://dx.doi.org/10.3324/haematol.2009.020073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948103PMC
October 2010

Fertility recovery and pregnancy after allogeneic hematopoietic stem cell transplantation in Fanconi anemia patients.

Haematologica 2010 Oct 21;95(10):1783-7. Epub 2010 May 21.

Eurocord Hospital Saint Louis, 1 Avenue Claude Vellefaux, Paris, France.

Reduced fertility is one clinical manifestation among other well known Fanconi anemia features. Most recipients of allogeneic hematopoietic stem cell transplantation suffer from secondary infertility owing to gonadal damage from myeloablative conditioning. In order to evaluate the rate of pregnancy in Fanconi anemia transplanted patients, we performed a retrospective analysis of female patients transplanted in 15 centers from 1976 to 2008. Among 578 transplanted Fanconi anemia patients, we identified 285 transplanted females of whom 101 patients were aged 16 years or over. Ten became pregnant (4 twice). Before hematopoietic stem cell transplantation all had confirmed Fanconi anemia diagnosis. Median age at transplantation was 12 years (range 5-17 years). Conditioning regimen consisted of cyclophosphamide with or without irradiation. During follow up, 5 of 10 patients presented signs of ovarian failure. Among those, 2 patients spontaneously recovered regular menses, and 3 received hormonal replacement therapy. Pregnancy occurred from four to 17 years after hematopoietic stem cell transplantation. Three patients had preterm deliveries, one patient had a hysterectomy for bleeding. All 14 newborns had normal growth and development without congenital diseases. In conclusion, recovery of normal ovarian function and a viable pregnancy is a realistic but relatively rare possibility even in Fanconi anemia patients following hematopoietic stem cell transplantation. Mechanisms of fertility recovery are discussed.
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http://dx.doi.org/10.3324/haematol.2010.023929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948106PMC
October 2010

Maximizing the ex vivo expansion of human mesenchymal stem cells using a microcarrier-based stirred culture system.

J Biotechnol 2010 Apr 25;146(4):194-7. Epub 2010 Feb 25.

IBB - Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.

Bioreactor systems have been developed as alternatives to standard culture flasks due to their homogeneous nature, easiness of monitoring and increased cell production. Here we investigated the in vitro expansion of bone marrow (BM) mesenchymal stem cells (MSC) in spinner flasks, using gelatin microcarriers (Cultispher S) to support cell adhesion and proliferation. MSC expansion was performed using a low-serum containing medium (2% of fetal bovine serum, FBS). A strategy was defined for the maximization of cell expansion: microcarriers were pre-coated with FBS in order to increase cell seeding efficiency and an adequate feeding regime was established (25% medium exchange everyday). The maximum cell density, 4.2 x 10(5)cells/mL, was obtained at day 8, corresponding to a fold increase in total cell number of 8.4+/-0.8. Expanded MSC retained their differentiation potential into adipogenic and osteogenic lineages, as well as their clonogenic ability. Harvested cells expressed >90% of CD73, CD90 and CD105 markers. These results demonstrated that a microcarrier-based stirred culture system is adequate for human MSC expansion, using a low-serum containing medium, allowing the generation of significant cell numbers for potential applications in regenerative medicine.
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http://dx.doi.org/10.1016/j.jbiotec.2010.02.015DOI Listing
April 2010

Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia.

J Cell Physiol 2010 Apr;223(1):27-35

Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Lisboa, Portugal.

The low bone marrow (BM) MSC titers demand a fast ex vivo expansion process to meet the clinically relevant cell dosage. Attending to the low oxygen tension of BM in vivo, we studied the influence of hypoxia on human BM MSC proliferation kinetics and metabolism. Human BM MSC cultured under 2% (hypoxia) and 20% O(2) (normoxia) were characterized in terms of proliferation, cell division kinetics and metabolic patterns. BM MSC cultures under hypoxia displayed an early start of the exponential growth phase, and cell numbers obtained at each time point throughout culture were consistently higher under low O(2), resulting in a higher fold increase after 12 days under hypoxia (40 +/- 10 vs. 30 +/- 6). Cell labeling with PKH26 allowed us to determine that after 2 days of culture, a significant higher cell number was already actively dividing under 2% compared to 20% O(2) and BM MSC expanded under low oxygen tension displayed consistently higher percentages of cells in the latest generations (generations 4-6) until the 5th day of culture. Cells under low O(2) presented higher specific consumption of nutrients, especially early in culture, but with lower specific production of inhibitory metabolites. Moreover, 2% O(2) favored CFU-F expansion, while maintaining BM MSC characteristic immunophenotype and differentiative potential. Our results demonstrated a more efficient BM MSC expansion at 2% O(2), compared to normoxic conditions, associated to an earlier start of cellular division and supported by an increase in cellular metabolism efficiency towards the maximization of cell yield for application in clinical settings.
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http://dx.doi.org/10.1002/jcp.21987DOI Listing
April 2010

Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness.

Nat Genet 2009 Jan 30;41(1):106-11. Epub 2008 Nov 30.

Research Laboratory on Normal and Pathologic Development of the Immune System, U768, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France.

Reticular dysgenesis is an autosomal recessive form of human severe combined immunodeficiency characterized by an early differentiation arrest in the myeloid lineage and impaired lymphoid maturation. In addition, affected newborns have bilateral sensorineural deafness. Here we identify biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis. These mutations result in absent or strongly decreased protein expression. We then demonstrate that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Last, we establish that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation of the sensorineural deafness in these individuals. These results identify a previously unknown mechanism involved in regulation of hematopoietic cell differentiation and in one of the most severe human immunodeficiency syndromes.
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http://dx.doi.org/10.1038/ng.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612090PMC
January 2009

Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia.

Blood 2008 Oct 29;112(8):3500-7. Epub 2008 Jul 29.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.
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http://dx.doi.org/10.1182/blood-2008-02-141689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954751PMC
October 2008

Long-term follow-up of lymphocyte populations and cellular cytokine production in patients with chronic graft-versus-host disease treated with extracorporeal photopheresis.

Haematologica 2005 Apr;90(4):565-7

We studied lymphocyte populations and cytokine-expression profiles of ten patients with chronic graft-versus-host disease who at least transiently responded to photoimmunotherapy. The numbers of lymphocytes, monocytes and dendritic cells rose in most cases. Th1 cells always increased during therapy, supporting the hypothesis that a more favorable immune balance contributes to clinical responses.
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April 2005