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1.
FP Essent ; 485: 17-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31613564

RESUMO

Leukocytosis is defined as a white blood cell count greater than 11,000/mcL in nonpregnant adults. It is a common finding, and the differential diagnosis can be broadly divided into primary malignant diseases and secondary causes that are expected physiologic responses of the bone marrow. Infections and chronic inflammatory conditions are common causes of secondary leukocytosis. A thorough history, physical examination, and peripheral blood smear are the basis of the initial evaluation. Constitutional symptoms along with an abnormal peripheral blood smear result indicate the need for evaluation for malignancy. Patients with chronic leukemias usually present with less severe symptoms than patients with acute leukemias. Symptoms generally are gradual in onset. Acute leukemias should be recognized quickly because they may be associated with life-threatening complications. Urgent referral to a hematology subspecialist is indicated in cases of suspected acute leukemia.


Assuntos
Leucemia , Leucocitose , Adulto , Humanos , Leucemia/diagnóstico , Leucemia/terapia , Contagem de Leucócitos , Leucocitose/diagnóstico , Leucocitose/terapia
2.
Psychiatr Danub ; 31(Suppl 3): 231-236, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488732

RESUMO

BACKGROUND: Acute leukemia and hospitalization for hematopoietic stem cell transplantation (HCT) are the great psychological stressors. The aim of this study was to assess anxiety and depression associated with such conditions and their psychophysical predictors before and after HCT. SUBJECTS AND METHODS: We conducted a longitudinal study using self-descriptive tools. The questionnaires: LOT-R, AIS, Mini-Mac, CECS, RSCL and HADS were filled by 60 patients with acute leukaemia before and after HCT. RESULTS: Anxiety and depressive symptoms correlated positively with psychological symptom distress. The correlation with depressive symptoms was weak, however, with anxious symptoms was moderate. In both cases, the higher was a level of psychological symptom distress, the higher level of anxiety and depression was observed in patients. The results indicated the weak, positive correlation between onerousness of physical symptoms and a level of anxiety. The greater was the severity of physical symptoms, the higher was the level of anxiety. The negative predictor of anxious symptoms was control of anxiety but it was weakly associated with a lower level of the explained variable. The negative predictor of anxious symptoms was also dispositional optimism whose high level accompanied the lower severity of the explained variable. However, the positive predictor of anxious symptoms was the variable of onerousness of symptoms whose high level accompanied the higher severity of anxious symptoms in the examined group CONCLUSION: Patients with acute leukemia who are hospitalized for HCT require detailed monitoring of their psychological distress to introduce the proper psychological and pharmacological interventions that reduce anxiety as well as boost "dispositional optimism" and mechanisms of control.


Assuntos
Ansiedade/complicações , Depressão/complicações , Transplante de Células-Tronco Hematopoéticas , Leucemia/psicologia , Leucemia/terapia , Humanos , Leucemia/complicações , Estudos Longitudinais , Inquéritos e Questionários
3.
Internist (Berl) ; 60(10): 1032-1035, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31486861

RESUMO

Antibodies play an important role in the therapy of patients with hematological tumors and have become an established part of this therapy. By using the example of acute lymphoblastic leukemia (ALL), different antibodies with different mechanisms of action are described. The focus of this review is on the description of a bispecific antibody molecule and an immunoconjugate in the relapse of ALL. Although the antibodies have improved the treatment of patients with ALL, it still holds true that the therapy of patients can only be successfully carried out with a strategy that integrates different, mutually complementary schemes. The improvement of therapy can only be achieved through clinical studies with clearly defined protocols.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Leucemia/terapia , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Anticorpos Biespecíficos/uso terapêutico , Hematologia/tendências , Humanos , Rituximab/uso terapêutico
4.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 548-555, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484620

RESUMO

Leukemia is a disease featured by the malignant proliferation of hematopoietic stem cells or progenitor cells in the blood system.While chemotherapy remains its mainstream treatment,disease relapse and drug resistance are still challenging problems.As one of the epigenetic mechanisms,histone methylation is involved in cell proliferation,differentiation,and apoptosis by regulating gene transcription.Recent studies have found that the histone demethylase lysine-specific demethylase 6A(KDM6A),also known as ubiquitously transcribed tetratricopeptide repeat on chromosome X(UTX),is closely related to the occurrence of a variety of tumors,especially leukemia.KDM6A activates gene expression by demethylating H3K27me3 to H3K27me2 or H3K27me1.Besides,KDM6A can regulate the activation of the target gene transcription through its non-demethylase functions.It can serve as the subunit of complex of proteins associated with Set1,thus getting involved in the regulation of H3K4me1.It can be combined with yeast mating type conversion/sucrose unfermented complex family to promote the formation of an open chromatin conformation.Finally,it can promote the production of H3K27ac.This article reviews the recent studies on the structure and biological activity of histone demethylase KDM6A(UTX)and its role in treating leukemia,thus providing a new research direction for targeted treatment of leukemia.


Assuntos
Epigênese Genética , Histona Desmetilases/metabolismo , Leucemia/enzimologia , Lisina , Proteínas Nucleares/metabolismo , Histonas , Humanos , Leucemia/terapia
5.
Ann Hematol ; 98(9): 2103-2110, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267177

RESUMO

Childhood leukaemia survivors (CLS) are known to have developed long-term impairment of lung function. The reasons for that complication are only partially known. The aims of this study were to assess pulmonary function in CLS and identify (1) risk factors and (2) clinical manifestations for the impairment of airflow and lung diffusion. The study group included 74 CLS: 46 treated with chemotherapy alone (HSCT-), 28 with chemotherapy and haematopoietic stem cell transplantation (HSCT+), and 84 healthy subjects (control group (CG)). Spirometry and diffusion limit of carbon monoxide (DLCO) tests were performed in all subjects. Ten (14%) survivors had restrictive, five (7%) had obstructive pattern, and 47 (66%) had reduced DLCO. The age at diagnosis, type of transplant, and type of conditioning regimen did not significantly affect the pulmonary function tests. The DLCO%pv were lower in CLS than in CG (p < 0.03) and in the HSCT+ than in the HSCT- survivors (p < 0.05). The pulmonary infection increased the risk of diffusion impairment (OR 5.1, CI 1.16-22.9, p = 0.019). DLCO was reduced in survivors who experienced CMV lung infection (p < 0.001). The main symptom of impaired lung diffusion was poor tolerance of exercise (p < 0.005). The lower lung diffusion capacity is the most frequent abnormality in CLS. HSCT and pulmonary infection, in particular with CMV infection, are strong risk factors for impairment of lung diffusion capacity in CLS. Clinical manifestation of DLCO impairment is poor exercise tolerance. A screening for respiratory abnormalities in CLS seems to be of significant importance.


Assuntos
Sobreviventes de Câncer , Transplante de Células-Tronco Hematopoéticas , Leucemia , Pulmão/fisiopatologia , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Seguimentos , Humanos , Leucemia/fisiopatologia , Leucemia/terapia , Masculino , Testes de Função Respiratória
6.
Eur J Oncol Nurs ; 41: 49-55, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31358257

RESUMO

PURPOSE: This study explores how newly diagnosed patients with acute leukemia (AL) experience the diagnosis and the initial treatment, and their need and preferences for social support. METHODS: Explorative semi-structured individual interviews were carried out in patients with AL (n = 18) four to sixteen weeks post diagnosis. Thematic analysis was used to analyze the qualitative interview data. RESULTS: Identified themes were 1) Jolted by the diagnosis, and subtheme Loss of personal autonomy; 2) Restoring normality in everyday life, and subtheme Facing a new social identity; and 3) A lifeline of hope. Being newly diagnosed with AL was experienced as traumatic, which negatively affected personal autonomy and everyday life. There was a pressing need to restore a sense of normality in everyday life while managing a new social identity as a cancer patient. Social support from family, friends and other patients were invaluable and experienced as an important lifeline. CONCLUSION: Receiving a life threatening diagnose and undergoing chemotherapeutic treatment had a negative impact on everyday life which required re-establishing daily life activities. This increased the need for social support which had a distinct role in facilitating the patients' coping strategy. CLINICAL IMPLICATIONS: It is important to support and strengthen the patient's social network from the time of diagnosis. Future studies should examine the feasibility and benefit of experienced-based social support from peers (former patients) to patients with AL.


Assuntos
Doença Aguda/psicologia , Adaptação Psicológica , Leucemia/diagnóstico , Leucemia/psicologia , Leucemia/terapia , Determinação de Necessidades de Cuidados de Saúde , Pacientes/psicologia , Apoio Social , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto Jovem
7.
Ann Hematol ; 98(8): 1877-1883, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144019

RESUMO

Secondary poor graft function (sPGF) is defined as secondary cytopenia after initial engraftment of allogeneic stem cell transplantation (allo-SCT). It has been shown to be associated with poor prognosis; however, there are very few reports on the incidence, risk factors, and outcomes of sPGF. Between January 2015 and December 2015, 564 patients, who received transplantation at Peking University People's Hospital, were retrospectively reviewed. Among the 490 patients who achieved initial engraftment of both neutrophils and platelets, 28 patients developed sPGF. The cumulative incidence of sPGF on day 100 was 5.7%. The median time of sPGF was 54.5 (34-91) days after transplantation. Low (< median) CD34+ cell dose (p = 0.019, HR 3.07 (95% CI, 1.207-7.813)), Epstein-Barr Virus (EBV) reactivation (p = 0.009, HR 3.648 (95%CI, 1.382-9.629)), and cytomegalovirus (CMV) reactivation (p = 0.003, HR 7.827 (95%CI, 2.002-30.602)) were identified as independent risk factors for sPGF. There was no significant difference in PGF incidence between the matched sibling donor (MSD) group and haploidentical donor (HID) group (p = 0.44). The overall survival of patients with sPGF at 1 year after transplantation was significantly poorer than that of patients with good graft function (GGF) (50.5% versus 87.2%, p < 0.001). In conclusion, sPGF developed in 5.7% patients after allo-SCT, especially in patients with CMV, EBV reactivation, or infusion with a low dose of CD34+ cells. The prognosis of sPGF is still poor owing to a lack of standard treatment.


Assuntos
Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Ativação Viral/imunologia , Adolescente , Adulto , Idoso , Antígenos CD34/imunologia , Criança , Pré-Escolar , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/patologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Feminino , Sobrevivência de Enxerto/fisiologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/virologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Humanos , Leucemia/mortalidade , Leucemia/patologia , Leucemia/virologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/virologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Haploidêntico
8.
Tumour Biol ; 41(4): 1010428319846803, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31018830

RESUMO

Mesenchymal stem cells have therapeutic properties that are related to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, inhibitory effect on tumor proliferation, and induction of apoptosis. This study was performed to analyze the role of mesenchymal stem cells as an alternative for cellular signaling growth factors involved in the pathogenesis of leukemogenesis in rats. Treatment of rats with 7,12-dimethyl benz [a] anthracene induced leukemogenesis appeared as a significant decrease in hematological parameters with concomitant significant increase in bone marrow oxidative and inflammatory indices (transforming growth factor beta and interleukin-6) in comparison with normal groups. On the contrary, Western immunoblotting showed a significant increase in the signaling growth factors: PI3K, AKT, mTOR proteins and a significant decrease in PTEN in 7,12-dimethyl benz [a] anthracene-treated group. In addition, a significant increase in the transcript levels of B cell lymphoma-2 protein gene in the 7,12-dimethyl benz [a] anthracene group, while that of C-X-C motif chemokine receptor-4 and B cell lymphoma-2 protein associated x-protein were significantly downregulated compared to controls. Meanwhile, therapeutic mesenchymal stem cells treatment predict a significant improvement versus 7,12-dimethyl benz [a] anthracene group through the modulation of growth factors that confront bone marrow dysplasia. In the same direction treatment of 7,12-dimethyl benz [a] anthracene group with mesenchymal stem cells, it induced apoptosis and increased the homing efficacy to bone marrow. In conclusion, mesenchymal stem cells improve hematopoiesis and alleviate inflammation, and modulated PI3K/AKT signaling pathway contributed to experimental leukemogenesis.


Assuntos
Leucemia/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteína Oncogênica v-akt/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Apoptose/genética , Células da Medula Óssea/patologia , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Humanos , Leucemia/induzido quimicamente , Leucemia/genética , Leucemia/patologia , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/genética , Ratos , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Fator de Crescimento Transformador beta/genética
10.
Int J Mol Sci ; 20(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818762

RESUMO

The non-redundant histone methyltransferase SETD2 (SET domain containing 2; KMT3A) is responsible for tri-methylation of lysine 36 on histone H3 (H3K36me3). Presence of the H3K36me3 histone mark across the genome has been correlated with transcriptional activation and elongation, but also with the regulation of DNA mismatch repair, homologous recombination and alternative splicing. The role of SETD2 and the H3K36me3 histone mark in cancer is controversial. SETD2 is lost or mutated in various cancers, supporting a tumor suppressive role of the protein. Alterations in the SETD2 gene are also present in leukemia patients, where they are associated with aggressive disease and relapse. In line, heterozygous SETD2 loss caused chemotherapy resistance in leukemia cell lines and mouse models. In contrast, other studies indicate that SETD2 is critically required for the proliferation of leukemia cells. Thus, although studies of SETD2-dependent processes in cancer have contributed to a better understanding of the SETD2⁻H3K36me3 axis, many open questions remain regarding its specific role in leukemia. Here, we review the current literature about critical functions of SETD2 in the context of hematopoietic malignancies.


Assuntos
Dano ao DNA , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia/genética , Transcrição Genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Humanos , Leucemia/patologia , Leucemia/terapia , Mutação/genética
11.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897713

RESUMO

Immunotherapeutic approaches, including allogeneic stem cell transplantation and donor lymphocyte infusion, have significantly improved the prognosis of leukemia patients. Further efforts are now focusing on the development of immunotherapies that are able to target leukemic cells more specifically, comprising monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and dendritic cell- or peptide-based vaccination strategies. One main prerequisite for such antigen-specific approaches is the selection of suitable target structures on leukemic cells. In general, the targets for anti-cancer immunotherapies can be divided into two groups: (1) T-cell epitopes relying on the presentation of peptides via human leukocyte antigen (HLA) molecules and (2) surface structures, which are HLA-independently expressed on cancer cells. This review discusses the most promising tumor antigens as well as the underlying discovery and selection strategies for the development of anti-leukemia immunotherapies.


Assuntos
Antígenos/imunologia , Imunoterapia/métodos , Leucemia/terapia , Humanos , Leucemia/imunologia , Leucemia/metabolismo , Peptídeos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
Eur J Oncol Nurs ; 38: 70-75, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30717939

RESUMO

PURPOSE: The purpose of this study is to investigate the difficulties experienced by adolescent leukemia survivors upon their return to school using qualitative study methods. METHODS: Study participants include 14 adolescents who visited a hospital for follow-up care following treatment for leukemia at a university hospital in Seoul. We investigated difficulties in returning to school using in-depth interviews. Using a semi-structured questionnaire, the researchers investigated "difficulties after termination of leukemia treatment," "difficulties in school life," "difficulties in relationships with family," and "causes of stress." RESULTS: Through interviews, we identified five categories of difficulties among adolescent leukemia survivors including "feelings of alienation from friends," "difficulty in studying," "Stuck being different from others", "apologetic feelings for family," and "feelings of having an uncertain future." CONCLUSION: Most adolescent leukemia survivors in the study sample complained about difficulties in friendships and academic difficulties. Changes in appearance following treatment and the focus of others on their appearance following treatment hurt their feelings, and they felt apologetic toward members of their families. Worries about incomplete recovery following treatment and the fear of recurrence tended to interfere with the feelings of adolescent leukemia survivors about their future.


Assuntos
Sobreviventes de Câncer/psicologia , Leucemia/psicologia , Retorno ao Trabalho , Instituições Acadêmicas , Adolescente , Ansiedade , Medo , Feminino , Amigos , Humanos , Leucemia/complicações , Leucemia/terapia , Masculino , Pesquisa Qualitativa , Inquéritos e Questionários
14.
J Pediatr Hematol Oncol ; 41(2): 87-95, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30557170

RESUMO

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix components and hence play a crucial role in physiological and pathologic processes. The imbalance between the expression of MMPs and their inhibitors can be effective in leukemic cell processes such as migration, angiogenesis, survival, and apoptosis, playing a key role in the progression and prognosis of leukemia. In this review, we discuss the potential involvement of MMPs and their inhibitors in the pathogenesis and progression of leukemia by examining their role in the prognosis of leukemia. Inducing leukemic cell growth, migration, invasiveness, and angiogenesis are the main roles of MMPs in leukemia progression mediated by their degradative activity. Given the important role of MMPs in leukemia progression, further clinical trials are needed to confirm the link between MMPs' expressions and leukemia prognosis. It is hoped to use MMPs as therapeutic targets to improve patients' health by recognizing the prognostic value of MMPs in leukemia and their effect on the progression of these malignancies and their response to treatment.


Assuntos
Gelatinases/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia , Proteínas de Neoplasias/biossíntese , Humanos , Leucemia/diagnóstico , Leucemia/enzimologia , Leucemia/terapia , Prognóstico
15.
Genes Dev ; 33(1-2): 61-74, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573454

RESUMO

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.


Assuntos
Endopeptidases/metabolismo , Leucemia/terapia , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Cromatina/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Endopeptidases/genética , Inibidores Enzimáticos/farmacologia , Técnicas de Inativação de Genes , Células HCT116 , Células HEK293 , Humanos , Leucemia/enzimologia , Leucemia/genética , Células MCF-7 , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Estabilidade Proteica , Análise de Sobrevida
16.
Blood Adv ; 2(24): 3590-3601, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30563883

RESUMO

HLA disparity is traditionally measured at the antigen or allele level, and its impact on haploidentical hematopoietic cell transplantation (haplo-HCT) with high-dose posttransplant cyclophosphamide (PTCy) is unclear. To the best of our knowledge, the relationship between HLA eplet-derived epitope mismatch (EM) and clinical outcome has not been examined in haplo-HCT. We retrospectively analyzed 148 patients who received a peripheral blood, T-cell-replete haplo-HCT with PTCy at a single center. HLA EM was quantified using an HLAMatchmaker-based method and was stratified by class and vector. The primary outcome was incidence of relapse. The total number of mismatched epitopes (MEs) per patient-donor pair in our patient population ranged from 0 to 51 (median, 24) in the graft-versus-host (GVH) direction and 0 to 47 (median, 24) in the host-versus-graft (HVG) direction. Higher HLA class II EM in the GVH direction was associated with a significantly reduced risk of relapse (adjusted hazard ratio [HR], 0.952 per ME; P = .002) and improved relapse-free survival (adjusted HR, 0.974 per ME; P = .020). Higher HLA class II EM in the HVG direction was associated with longer time to neutrophil (adjusted HR, 0.974 per ME; P = .013) and platelet (adjusted HR, 0.961 per ME; P = .001) engraftment. In peripheral blood haplo-HCT patients, increased HLA EM was associated with a protective effect on the risk of relapse in the GVH direction but a negative effect on time to count recovery in the HVG direction. HLA EM based on the HLA Matchmaker represents a novel strategy to predict clinical outcome in haplo-HCT.


Assuntos
Antígenos HLA/imunologia , Leucemia/terapia , Adulto , Idoso , Epitopos/imunologia , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Transplante Haploidêntico/efeitos adversos , Adulto Jovem
17.
Front Immunol ; 9: 2887, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574153

RESUMO

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1ß, TGFß, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.


Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressão/métodos , Leucemia/terapia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Leucemia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Transplante de Pele , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Quimeras de Transplante , Transplante Homólogo/efeitos adversos , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Medicine (Baltimore) ; 97(51): e13673, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572489

RESUMO

RATIONALE: Facial paralysis as the initial clinical presentation of infant leukemia (IL) is rare, and the rate of its misdiagnosis is high. Identifying the clinical characteristics of IL with facial paralysis as the initial symptom is necessary to improve the understanding of the causes of facial paralysis and IL. PATIENT CONCERNS: A 10-month-old infant had facial paralysis and recurrent fever. He was misdiagnosed as having bacterial meningitis for >2 months. DIAGNOSES: The infant was diagnosed as having acute monocytic leukemia (M5) with central infiltration based on examinations of the bone marrow and cerebrospinal fluid by flow cytometry. INTERVENTIONS: Before the diagnosis of leukemia, the patient was given meropenem, ceftriaxone, vancomycin, and ampicillin successively for anti-infective treatment for 2 months, and dexamethasone for several days. But he gave up further treatment after confirmed diagnosis. OUTCOMES: Our patient discontinued treatment and discharged. From literature review, there were 6 cases (including this case) of IL with facial paralysis as the initial symptom. 80% of patients were misdiagnosis and treated with a corticosteroid in the early stage, and the mortality was 33.3%. LESSONS: The clinical symptoms of IL with facial paralysis are not typical, with a high rate of misdiagnosis. When the cause of facial paralysis is unknown or the advance treatment effect is poor, tumor diseases should be considered. Corticosteroids should be carefully administered to children with facial paralysis.


Assuntos
Paralisia Facial/diagnóstico , Paralisia Facial/etiologia , Leucemia/complicações , Leucemia/diagnóstico , Diagnóstico Diferencial , Erros de Diagnóstico , Paralisia Facial/patologia , Paralisia Facial/terapia , Humanos , Lactente , Leucemia/patologia , Leucemia/terapia , Masculino , Suspensão de Tratamento
19.
Indian Pediatr ; 55(11): 962-965, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30587644

RESUMO

OBJECTIVE: To find out prevalence of iron overload in children with leukemia at the end of treatment, and to identify factors affecting iron overload. METHODS: Children (age-1-14 y) treated for Leukemia of our center who completed treatment between January and August 2016 were included in the study. Serum ferritin and iron were measured at completion of treatment and total blood transfusion received throughout treatment was quantified. Serum ferritin >1000 ng/mL was considered as marker of transfusional iron overload. RESULTS: Out of 66 participants, 55 (83.3%) received red cell transfusions. Average transfused volume was 48 mL/kg, and patients with high-risk leukemia received more transfusions than standard-risk patients. 16 patients (24.2%) demonstrated transfusional iron overload. Total transfused volume and treatment intensity were significant factors associated with iron overload, and total transfused volume of >100 mL/kg (approximately 10 transfusions) was the most important determinant of transfusional iron burden. CONCLUSIONS: One-fourth of pediatric leukemia patients demonstrated iron overload at the end of treatment. These patients need to be monitored and followed-up after treatment to assess need for later chelation therapy.


Assuntos
Transfusão de Eritrócitos/efeitos adversos , Sobrecarga de Ferro/epidemiologia , Leucemia/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Humanos , Lactente , Ferro/sangue , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Masculino , Prevalência , Estudos Prospectivos , Fatores de Risco
20.
Am Soc Clin Oncol Educ Book ; (38): 616-625, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30231346

RESUMO

Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.


Assuntos
Leucemia/diagnóstico , Leucemia/terapia , Humanos , Pessoa de Meia-Idade
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