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1.
Br J Haematol ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32012224

RESUMO

Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0·0001). Achievement of a subsequent remission impacted survival (P = <0·0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0·046) and donor choice (matched family vs. matched unrelated donor, P = 0·029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32029909

RESUMO

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

3.
J Clin Immunol ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863244

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections, inflammation, and autoimmunity with an impact on health-related quality of life (HRQoL). Few data are available for children, whereas no study has been conducted in adults. Here, we investigated HRQoL and emotional functioning of 19 children and 28 adults enrolled in Italian registry for CGD. PEDsQL and SDQ were used for children and their caregivers, and adults completed the SF-12 questionnaire. Mean scores were compared with norms and with patients affected by chronic diseases. Comparisons were made for CGD patients who underwent or not hematopoietic stem cell transplantation (HSCT). When compared with norms, CGD children exhibited higher difficulties in social/school areas, peer relationship, and conduct/emotional problems (< 5 years of age), as scored by proxies. Differently, CGD adults reported higher difficulties both in mental and physical area than norms. Only for children, clinical status had a damaging effect on psychosocial and school dimensions, whereas age had a negative impact on social areas. No significant difference was observed between patients treated or not with HSCT. When compared with patients affected by chronic diseases, CGD children and adults both displayed fewer physical disabilities. Differently, in mental scale adults scored lower than those with rheumatology diseases and had similar impairment in comparison with patients with diabetes mellitus and cancer. This study emphasized the impact of CGD on HRQoL since infancy and its decline in adulthood, with emotional difficulties occurring early. HRQoL impairment should be considered in clinical picture of CGD and pro-actively assessed and managed by clinicians.

4.
Front Immunol ; 10: 1342, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354695

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for a wide range of immune and hematologic malignant and non-malignant disorders. Once transplanted, allogeneic cells have to support myeloid repopulation and immunological reconstitution, but also need to become tolerant to the host via central or peripheral mechanisms to achieve the desired therapeutic effect. Peripheral tolerance after allogeneic HSCT may be achieved by several mechanisms, though blocking alloreactivity to the host human leukocyte antigens while preserving immune responses to pathogens and tumor antigens remains a challenge. Recently uncovered evidence on the mechanisms of post-HSCT immune reconstitution and tolerance in transplanted patients has allowed for the development of novel cell-based therapeutic approaches. These therapies are aimed at inducing long-term peripheral tolerance and reducing the risk of graft-vs-host disease (GvHD), while sparing the graft-vs-leukemia (GvL) effect. Thus, ensuring effective long term remission in hematologic malignancies. Today, haploidentical stem cell transplants have become a widely used treatment for patients with hematological malignancies. A myriad of ex vivo and in vivo T-cell depletion strategies have been adopted, with the goal of preventing GvHD while preserving GvL in the context of immunogenetic disparity. αß T-cell/CD19 B-cell depletion techniques, in particular, has gained significant momentum, because of the high rate of leukemia-free survival and the low risk of severe GvHD. Despite progress, better treatments are still needed in a portion of patients to further reduce the incidence of relapse and achieve long-term tolerance. Current post-HSCT cell therapy approaches designed to induce tolerance and minimizing GvHD occurrence include the use of (i) γδ T cells, (ii) regulatory Type 1 T (Tr1) cells, and (iii) engineered FOXP3+ regulatory T cells. Future protocols may include post-HSCT infusion of allogeneic effector or regulatory T cells engineered with a chimeric antigen receptor (CAR). In the present review, we describe the most recent advances in graft engineering and post-HSCT adoptive immunotherapy.

5.
Front Immunol ; 10: 1179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231370

RESUMO

Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early '90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy.

6.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

7.
Am J Transplant ; 19(6): 1798-1805, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30586230

RESUMO

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.

8.
Biol Blood Marrow Transplant ; 25(2): 313-320, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30266674

RESUMO

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P = .0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Polidesoxirribonucleotídeos/administração & dosagem , Sistema de Registros , Aloenxertos , Autoenxertos , Pré-Escolar , Intervalo Livre de Doença , Feminino , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/mortalidade , Humanos , Incidência , Lactente , Itália , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
9.
Bone Marrow Transplant ; 54(2): 275-283, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29899572

RESUMO

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

10.
Blood ; 132(24): 2594-2607, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30348653

RESUMO

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αß T-cell/B-cell depletion (αßhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αßhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αßhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αßhaplo-HSCT recipients (P < .001). Children treated with αßhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αßhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αßhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αßhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.


Assuntos
Linfócitos B , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia , Depleção Linfocítica , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Doadores não Relacionados , Doença Aguda , Adolescente , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Leucemia/mortalidade , Leucemia/terapia , Masculino , Estudos Retrospectivos
11.
J Immunol ; 201(5): 1460-1467, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068594

RESUMO

Four killer cell Ig-like receptor (KIR) genes, collectively referred to as framework genes, characterize almost all KIR haplotypes. In particular, KIR3DL3 and KIR3DL2 mark the ends of the locus, whereas KIR3DP1 and KIR2DL4 are located in the central part. A recombination hot spot, mapped between KIR3DP1 and KIR2DL4, splits the haplotypes into two regions: a centromeric (Cen) region (spanning from KIR3DL3 to KIR3DP1) and a telomeric region (from KIR2DL4 to KIR3DL2), both varying in KIR gene content. In this study, we analyzed KIR3DP1 polymorphism in a cohort of 316 healthy, unrelated individuals. To this aim, we divided KIR3DP1 alleles into two groups by the use of a sequence-specific primer- PCR approach. Our data clearly indicated that KIR3DP1 alleles present on haplotypes carrying Cen-A or Cen-B1 regions differ from those having Cen-B2 motifs. Few donors (∼3%) made exceptions, and they were all, except one, characterized by uncommon haplotypes, including either KIR deletions or KIR duplications. Consequently, as KIR2DL1 is present in Cen-A and Cen-B1 regions but absent in Cen-B2 regions, we demonstrated that KIR3DP1 polymorphism might represent a suitable marker for KIR2DL1 gene copy number analysis. Moreover, because Cen-B1 and Cen-B2 regions are characterized by different KIR3DP1 alleles, we showed that KIR3DP1 polymorphism analysis also provides information to dissect between Cen-B1/Cen-B1 and Cen-B1/Cen-B2 donors. Taken together, our data suggest that the analysis of KIR3DP1 polymorphism should be included in KIR repertoire evaluation.


Assuntos
Alelos , Centrômero/genética , Haplótipos , Polimorfismo Genético , Receptores KIR2DL4/genética , Receptores KIR3DS1/genética , Centrômero/imunologia , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Masculino , Receptores KIR2DL4/imunologia , Receptores KIR3DS1/imunologia
12.
J Immunol Res ; 2018: 1586905, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29850617

RESUMO

Natural killer (NK) cells are a population of cytotoxic innate lymphocytes that evolved prior to their adaptive counterparts and constitute one of the first lines of defense against infected/mutated cells. Several studies have shown that in patients with acute leukemia given haploidentical hematopoietic stem cell transplantation, donor-derived NK cells play a key role in the eradication of cancer cells. The antileukemic effect is mostly related to the presence of "alloreactive" NK cells, that is, mature KIR+ NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient. A genotypic analysis detecting KIR B haplotype and the relative B content is an additional donor selection criterion. These data provided the rationale for implementing phase I/II clinical trials of adoptive infusion of either selected or ex vivo-activated NK cells, often from an HLA-mismatched donor. In this review, we provide a historical perspective on the role played by NK cells in patients with acute leukemia, focusing also on the various approaches to adoptive NK cell therapy and the unresolved issues therein. In addition, we outline new methods to enhance NK activity, including anti-KIR monoclonal antibody, bi-/trispecific antibodies linking NK cells to cytokines and/or target antigens, and CAR-engineered NK cells.


Assuntos
Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Animais , Ensaios Clínicos como Assunto , Engenharia Genética , Humanos , Imunidade Inata , Isoantígenos/imunologia , Células Matadoras Naturais/transplante , Leucemia/terapia , Receptores KIR/genética , Receptores KIR/metabolismo
13.
Front Immunol ; 9: 1050, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868012

RESUMO

In human natural killer (NK) cells, human cytomegalovirus (HCMV) has been shown to be a driving force capable of inducing the expansion of a highly differentiated NKG2C+CD57+ subset, persisting over time in both HCMV+ healthy subjects and umbilical cord blood transplantation (UCBT) recipients experiencing HCMV viral reactivation. In HCMV+ healthy subjects, such expanded NK-cells are characterized by epigenetic modifications that modulate their phenotypic and functional characteristics. In particular, an enhanced ADCC activity is detectable in NK cells lacking the signaling protein FcεRγ. Timing and mechanisms involved in the acquisition of HCMV-induced, adaptive-like features by NK cells are currently unknown. In this study, we investigated the de novo acquisition of several adaptive features in NK cells developing after UCBT by monitoring NK-cell differentiation for at least 2 years after transplant. In UCBT recipients experiencing HCMV reactivation, a rapid phenotypic reconfiguration occurred resulting in the expected expansion of CD56dim NKG2C+CD57+ NK cells. However, while certain HCMV-driven adaptive hallmarks, including high KIR, LILRB1, CD2 and low/negative NKG2A, Siglec-7, and CD161 expression, were acquired early after UCBT (namely by month 6), downregulation of the signaling protein FcεRγ was detected at a later time interval (i.e., by month 12). This feature characterized only a minor fraction of the HCMV-imprinted NKG2C+CD57+ CD56dim NK cell subset, while it was detectable in higher proportions of CD57+ NK cells lacking NKG2C. Interestingly, in patients developing a hyporesponsive CD56-CD16bright NK-cell subset, FcεRγ downregulation occurred in these cells earlier than in CD56dim NK cells. Our data suggest that the acquisition of a fully "adaptive" profile requires signals that may lack in UCBT recipients and/or longer time is needed to obtain a stable epigenetic reprogramming. On the other hand, we found that both HCMV-induced FcεRγneg and FcεRγ+ NK cells from these patients, display similar CD107a degranulation and IFN-γ production capabilities in response to different stimuli, thus indicating that the acquisition of specialized effector functions can be achieved before the "adaptation" to HCMV is completed. Our study provides new insights in the process leading to the generation of different adaptive NK-cell subsets and may contribute to develop new approaches for their employment as novel immunotherapeutic tools.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Infecções por Citomegalovirus/imunologia , Células Matadoras Naturais/imunologia , Receptores de IgE/imunologia , Ativação Viral , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Citomegalovirus , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Lactente , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptores de IgE/genética , Transplantados , Adulto Jovem
14.
Int J Mol Sci ; 19(2)2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29470425

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) represents a curative treatment for many patients with hematological malignant or non-malignant disorders. Evaluation of potential donors for HSCT includes a rigorous assessment of the human leukocyte antigens (HLA) match status of family members, and the identification of suitable unrelated donors. Genes encoding transplantation antigens are placed both within and outside the major histocompatibility complex (MHC). The human MHC is located on the short arm of chromosome 6 and contains a series of genes encoding two distinct types of highly polymorphic cell surface glycoproteins. Donors for HSCT are routinely selected based on the level of matching for HLA-A, -B, -C, -DRB1, and -DQB1 loci. However, disease relapse, graft-versus-host-disease, and infection remain significant risk factors of morbidity and mortality. In the same breath, in high-risk patients, graft-versus-leukemia effects inherent in HLA mismatching play a substantial immunological role to limit the recurrence of post-transplant disease. The definition of a suitable donor is ever changing, shaped not only by current typing technology, but also by the specific transplant procedure. Indeed, a more complete understanding of permissible HLA mismatches and the role of Killer Immunoglobulin-like receptors' genes increases the availability of HLA-haploidentical and unrelated donors.


Assuntos
Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Complexo Principal de Histocompatibilidade/genética , Polimorfismo Genético , Anticorpos/imunologia , Humanos
15.
Radiol Med ; 123(6): 469-473, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29374857

RESUMO

In the last few years, several scientific papers and reports have demonstrated magnetic resonance (MR) signal intensity (SI) changes on pre-contrast T1-weighted images following multiple gadolinium-based contrast agents (GBCA) administrations, particularly following the exposure to linear GBCAs. Pathological animal and human post-mortem studies have confirmed the relationship between this radiological finding and the presence of gadolinium accumulation in vulnerable brain regions in patients with normal renal function. In this short communication, we report the case of a 15-year-old patient affected by b-cell acute lymphoblastic leukemia (bALL) who developed a hyperintense signal in the dentate nuclei following multiple administrations of a macrocyclic GBCA. The purpose of this report is to discuss possible differential diagnoses of this radiological finding with special focus on the differentiation between iron or manganese accumulation, post-irradiation changes and GBCA-related Gd deposition, highlighting the importance of the acquisition of accurate clinical data to improve our scientific knowledge.


Assuntos
Núcleos Cerebelares/diagnóstico por imagem , Meios de Contraste/farmacocinética , Imagem por Ressonância Magnética , Meglumina/farmacocinética , Compostos Organometálicos/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Adolescente , Linfócitos B , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino
16.
Med Mycol ; 56(3): 263-278, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28992093

RESUMO

Indication and timing of trough plasma-voriconazole (VCZ)-concentration (t-PVC) measurement during VCZ treatment is a debated issue. Patterns of t-PVC were prospectively evaluated in pediatric (50 courses) and adult (95 courses) hematologic patients. Efficacy patterns were defined: adequate, t-PVC always ≥1 mcg/ml; borderline, at least one t-PVC measurement <1 mcg/ml but median value of the measurements ≥1 mcg/ml; inadequate, median value of the measurements <1 mcg/ml. Toxicity patterns were defined: favorable, t-PVC always ≤5 mcg/ml; borderline, one or more t-PVC measurements >5 mcg/ml but median value of the measurements ≤5 mcg/ml; unfavorable, median value of the measurements >5 mcg/ml. In children and adults the mean t-PVCs were higher during intravenous treatments. The t-PVC efficacy pattern was adequate, borderline and inadequate in 48%, 12%, and 40% of courses, respectively, in children, and in 66.3%, 16.8%, and 16.8% of courses, respectively, in adults. Adequate efficacy pattern was more frequent in children with body weight above the median (≥25 kg) (OR 4.8; P = .011) and in adults with active hematological disease receiving intravenous therapy (OR 3.93; P = .006). Favorable toxicity pattern was more frequent in children receiving VCZ daily dosage below the median (<14 mg/kg) (OR 4.18; P = .027) and in adults with body weight below the median (<68 kg) (OR 0.22; P = .004). T-PVC measurement is generally needed, however, a non t-PVC guided approach may be considered in heavier adults receiving intravenous VCZ. The risk of supratherapeutic levels does not seem an absolute indication for t-PVC monitoring.


Assuntos
Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Doenças Hematológicas/complicações , Micoses/complicações , Micoses/tratamento farmacológico , Voriconazol/farmacocinética , Voriconazol/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Antifúngicos/sangue , Antifúngicos/toxicidade , Peso Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Resultado do Tratamento , Voriconazol/sangue , Voriconazol/toxicidade , Adulto Jovem
17.
J Allergy Clin Immunol ; 141(1): 322-328.e10, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28392333

RESUMO

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.


Assuntos
Quebras de DNA de Cadeia Dupla , Distúrbios no Reparo do DNA/genética , Distúrbios no Reparo do DNA/terapia , Reparo do DNA , Transplante de Células-Tronco Hematopoéticas , Adolescente , Alelos , Criança , Pré-Escolar , Distúrbios no Reparo do DNA/diagnóstico , Distúrbios no Reparo do DNA/mortalidade , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mutação , Prognóstico , Resultado do Tratamento , Viroses , Adulto Jovem
18.
J Cell Physiol ; 233(3): 1796-1811, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28777460

RESUMO

Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Criança , Pré-Escolar , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Isoquinolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Purinas/farmacologia , Quinazolinonas/farmacologia , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia , Triazinas/farmacologia
20.
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