Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 755
Filtrar
1.
Lancet Haematol ; 8(2): e110-e121, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33513372

RESUMO

BACKGROUND: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Rituximab/administração & dosagem , Índice de Gravidade de Doença , Transplante Autólogo/efeitos adversos , Adulto Jovem
2.
Ann Hematol ; 99(10): 2329-2338, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32821971

RESUMO

Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Hematopoéticas/patologia , Células Mieloides/patologia , Mielopoese/genética , Neutropenia/congênito , Pré-Leucemia/genética , Receptores de Fator Estimulador de Colônias/genética , Animais , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Perfilação da Expressão Gênica , Imunidade Inata , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutropenia/genética , Neutropenia/patologia , Pré-Leucemia/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias/fisiologia , Proteínas Recombinantes/genética , Organismos Livres de Patógenos Específicos
3.
Lancet Haematol ; 7(9): e649-e659, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32758434

RESUMO

BACKGROUND: Avadomide (CC-122) is a novel oral cereblon-modulating agent with promising activity in non-Hodgkin lymphoma. We aimed to examine the safety and preliminary activity of avadomide plus obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma. METHODS: CC-122-NHL-001 was a phase 1b dose escalation and expansion study at eight sites in France, Italy, and the Netherlands. Eligible patients (aged ≥18 years) had histologically confirmed CD20-positive relapsed or refractory non-Hodgkin lymphoma, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received previous treatment. In the dose expansion phase, only patients with previously treated relapsed or refractory follicular lymphoma (grade 1, 2, or 3a) were included. Avadomide was administered in escalating doses and two formulations: active pharmaceutical ingredient in capsule in 1·0 mg, 2·0 mg, 3·0 mg, and 4·0 mg doses and as formulated capsules in 3·0 mg and 4·0 mg doses orally once daily on days 1-5 followed by 2 days off (5-7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was administered intravenously on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability, the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). All patients who received treatment were included in the safety analyses. Efficacy-evaluable patients completed at least one cycle of treatment and had baseline and at least one post-baseline assessment. The study is registered with ClinicalTrials.gov, NCT02417285 and EudraCT 2014-003333-26, and is ongoing. FINDINGS: Between June 24, 2015, and Dec 5, 2018, 73 patients were enrolled and treated; 19 had diffuse large B-cell lymphoma, 53 follicular lymphoma, and one marginal zone lymphoma. Median follow-up was 253 days (IQR 127-448). The median number of previous anticancer regimens was three (IQR 2-4). The maximum tolerated dose and non-tolerated dose were not reached in the dose escalation phase. On the basis of safety and pharmacokinetic-pharmacodynamic data, the avadomide RP2D was established as 3·0 mg as formulated capsules on a 5-7-day schedule in combination with 1000 mg of obinutuzumab. Patients enrolled in the expansion cohort received the established RP2D of avadomide. Across all doses, three patients had dose-limiting toxicities; one patient treated at the RP2D had dose-limiting toxicity (grade 3 sepsis). The most common adverse events of grade 3 and above were neutropenia (41 [56%] of 73) and thrombocytopenia (17 [23%] of 73). 34 (47%) patients had serious adverse events, which were considered to be avadomide-related in 23 (32%) of 73 patients and obinutuzumab-related in 20 (27%) of 73 patients. Two treatment-related deaths occurred, one owing to tumour flare and one from acute myeloid leukaemia after study discontinuation. INTERPRETATION: Avadomide plus obinutuzumab has a manageable toxicity, being a tolerable treatment option for most patients. Although the prespecified threshold for activity was not met in the trial, we believe that the preliminary antitumour activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated relapsed or refractory non-Hodgkin lymphoma warrants further investigation as a chemotherapy-free option in this setting. FUNDING: Celgene Corporation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Piperidonas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Meia-Vida , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Índice de Gravidade de Doença , Trombocitopenia/etiologia , Trombocitopenia/patologia , Resultado do Tratamento
4.
Nature ; 582(7810): 109-114, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494068

RESUMO

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.


Assuntos
Modelos Animais de Doenças , Células Precursoras de Granulócitos/patologia , Mutação , Neutropenia/genética , Neutropenia/patologia , Neutrófilos/patologia , Animais , Candida albicans/imunologia , Candida albicans/patogenicidade , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Imunidade Inata , Masculino , Camundongos , Camundongos Transgênicos , Neutropenia/congênito , Neutropenia/imunologia , Neutrófilos/imunologia , Fatores de Transcrição/genética
5.
Tumori ; 106(4): 273-280, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32538316

RESUMO

Neutropenia is the most frequent side effect of commercially available myelosuppressive drugs and its most significant complication is febrile neutropenia. It is associated with increased hospital admissions and higher probability of death. Prophylaxis with the administration of granulocyte colony-stimulating factor can prevent neutropenia caused by anticancer drugs. The correct administration of these drugs and the management of febrile neutropenia are extremely important in the treatment of patients with cancer.


Assuntos
Antineoplásicos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/tratamento farmacológico , Neutropenia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Gerenciamento Clínico , Guias como Assunto , Humanos , Quimioterapia de Indução/efeitos adversos , Neoplasias/complicações , Neoplasias/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologia
6.
PLoS Pathog ; 16(5): e1008544, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32407390

RESUMO

Beyond their canonical roles in hemostasis and thrombosis, platelets function in the innate immune response by interacting directly with pathogens and by regulating the recruitment and activation of immune effector cells. Thrombocytopenia often coincides with neutropenia in patients with hematologic malignancies and in allogeneic hematopoietic cell transplant recipients, patient groups at high risk for invasive fungal infections. While neutropenia is well established as a major clinical risk factor for invasive fungal infections, the role of platelets in host defense against human fungal pathogens remains understudied. Here, we examined the role of platelets in murine Aspergillus fumigatus infection using two complementary approaches to induce thrombocytopenia without concurrent neutropenia. Thrombocytopenic mice were highly susceptible to A. fumigatus challenge and rapidly succumbed to infection. Although platelets regulated early conidial phagocytosis by neutrophils in a spleen tyrosine kinase (Syk)-dependent manner, platelet-regulated conidial phagocytosis was dispensable for host survival. Instead, our data indicated that platelets primarily function to maintain hemostasis and lung integrity in response to exposed fungal antigens, since thrombocytopenic mice exhibited severe hemorrhage into the airways in response to fungal challenge in the absence of overt angioinvasion. Challenge with swollen, heat-killed, conidia was lethal in thrombocytopenic hosts and could be reversed by platelet transfusion, consistent with the model that fungus-induced inflammation in platelet-depleted mice was sufficient to induce lethal hemorrhage. These data provide new insights into the role of platelets in the anti-Aspergillus host response and expand their role to host defense against filamentous molds.


Assuntos
Aspergillus fumigatus/imunologia , Plaquetas/imunologia , Transplante de Células-Tronco Hematopoéticas , Neutropenia/imunologia , Aspergilose Pulmonar/imunologia , Quimeras de Transplante/imunologia , Aloenxertos , Animais , Camundongos , Neutropenia/microbiologia , Neutropenia/patologia , Aspergilose Pulmonar/patologia , Quimeras de Transplante/microbiologia
7.
Lung Cancer ; 145: 213-215, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389426
8.
Pediatr Blood Cancer ; 67(6): e28237, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277798

RESUMO

BACKGROUND: The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature. METHODS: Two patients with neutropenia underwent hematological, immunological, and genetic work-up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole-exome sequencing, and in silico proteomic analysis. RESULTS: Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life-threatening infection requiring leg amputation. Immunological and hematological work-up showed isolated neutropenia with normal lymphocyte subpopulations, immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in-frame deletion in the SRP54 gene, c.342-344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability. CONCLUSIONS: We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene.


Assuntos
Mutação , Neutropenia/congênito , Neutropenia/patologia , Partícula de Reconhecimento de Sinal/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neutropenia/genética , Neutropenia/metabolismo , Linhagem , Prognóstico , Proteômica , Sequenciamento Completo do Exoma
10.
J Leukoc Biol ; 107(4): 635-647, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32057138

RESUMO

Neutropenia and impaired functions were common manifestation in antiretroviral therapy (ART) in both naïve and experienced PLWHA. Granulopoiesis can be divided into two phases: lineage determination and committed granulopoiesis. However, stage-specific impairment of granulopoiesis in PLWHA with neutropenia remains unclear. A total of 48 ART-naïve and 49 ART-experienced PLWHA from 2016 to 2018 were recruited and divided into non-, mild-, and moderate-to-severe-neutropenia groups according to their neutrophil counts. The bone marrow aspirates and peripheral blood were collected and analyzed by multicolor flow cytometry for granulocyte subsets, hematopoietic stem/progenitor cells (HSPC), apoptosis, and emigration and retention of different subsets. Compared with healthy donors, the percentages of circulating segmented neutrophils were significantly decreased along with an increase of immature neutrophils in both groups. ART-naïve patients with moderate to severe neutropenia exhibited decreased proportion and accelerated apoptosis of relative mature segmented neutrophils. In contrast, ART-experienced patients with neutropenia displayed decreased proportion of granulocyte macrophage progenitors, indicating a defect at a stage of lineage determination. Meanwhile, ART-experienced patients with neutropenia also the expression of CXCR4 segmented neutrophils, suggesting an increased retention of segmented neutrophils inn the bone marrow. ART-naïve patients with neutropenia is caused by increased apoptosis of relatively differentiated neutrophils at committed granulopoiesis, whereas impaired lineage determination and enhanced retention of segmented neutrophils contribute to in ART-experienced patients.


Assuntos
Síndrome de Imunodeficiência Adquirida/patologia , Granulócitos/patologia , Neutropenia/patologia , Síndrome de Imunodeficiência Adquirida/sangue , Adulto , Medula Óssea/patologia , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Neutropenia/sangue , Neutrófilos/patologia , Receptores CXCR4/metabolismo , Receptores de Interleucina-8B/metabolismo
11.
Mol Cells ; 43(2): 139-144, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32041395

RESUMO

Somatic RUNX1 mutations are found in approximately 10% of patients with de novo acute myeloid leukemia (AML), but are more common in secondary forms of myelodysplastic syndrome (MDS) or AML. Particularly, this applies to MDS/AML developing from certain types of leukemia-prone inherited bone marrow failure syndromes. How these RUNX1 mutations contribute to the pathobiology of secondary MDS/AML is still unknown. This mini-review focusses on the role of RUNX1 mutations as the most common secondary leukemogenic hit in MDS/AML evolving from severe congenital neutropenia (SCN).


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/etiologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/complicações , Neutropenia/congênito , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Progressão da Doença , Humanos , Leucemia Mieloide Aguda/patologia , Mutação , Neutropenia/etiologia , Neutropenia/patologia
12.
Ann N Y Acad Sci ; 1466(1): 83-92, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32083314

RESUMO

Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Elastase de Leucócito/genética , Neutropenia/etiologia , Resposta a Proteínas não Dobradas/fisiologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Seguimentos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Elastase de Leucócito/fisiologia , Mutação , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Neutropenia/patologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genética
13.
J Clin Exp Hematop ; 59(4): 202-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866622

RESUMO

CD3+/CD57+ T-cell large granular lymphocyte leukemia (T-LGLL) is an indolent neoplasm, exhibiting mostly CD8+, less frequently CD4+ phenotypes, and T-LGLL consisting of 2 populations with CD8+ and CD4+ phenotypes is markedly rare. An 87-year-old female was admitted under a diagnosis of immune thrombocytopenia (ITP) with a platelet count of 5.0×109/L and increased number of LGL with unknown etiology. Her neutrophil count also decreased to 0.27×109/L and she was positive for antineutrophil antibody. The WBC count was 2.7×109/L with 34.7% LGL and flow cytometry (FCM) analysis revealed 16% CD3+/CD4+/CD8dim/CD57+ and 20.9% CD3+/CD8+/CD57+ populations. These populations also expressed granzyme B and perforin. Circulating mononuclear cells were found to be clonal by PCR analysis of T-cell receptor ß-chain gene. Serum immunofixation and bone marrow FCM analyses demonstrated 2 clonal B-cells producing IgG-λ and IgA-λ. Deep amplicon sequencing of STAT3 and STAT5B genes revealed a STAT3 R302G mutation with an allele burden of 2.6%. The thrombocytopenia and neutropenia were successfully treated by prednisolone and romiplostim with negative conversion of antineutrophil antibody. This is the first reported case of T-LGLL with dual components of CD4+/CD8dim and CD4-/CD8+ populations in terms of multiple comorbidities related to the respective CD8+ and CD4+ T-LGLLs.


Assuntos
Linfócitos B , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Leucemia Linfocítica Granular Grande , Linfocitose , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Neutropenia , Púrpura Trombocitopênica Idiopática , Fator de Transcrição STAT3 , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Linfócitos B/metabolismo , Linfócitos B/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Cadeias lambda de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/metabolismo , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Linfocitose/genética , Linfocitose/metabolismo , Linfocitose/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , Púrpura Trombocitopênica Idiopática/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
14.
Sci Rep ; 9(1): 16868, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727989

RESUMO

Septic arthritis is one of the most aggressive joint diseases. Although caused predominantly by S. aureus, Gram-negative bacteria, Pseudomonas aeruginosa among them, account for a significant percentage of the causal agents of septic arthritis. However, septic arthritis caused by P. aeruginosa has not been studied thus far, due to lack of an animal model. NMRI mice were inoculated with different doses of P. aeruginosa. The clinical course of septic arthritis and radiological changes of joints were examined. Furthermore, the host molecular and cellular mechanisms involved in P. aeruginosa-induced septic arthritis were investigated. Inoculation of mice with P. aeruginosa caused septic arthritis in a dose-dependent manner. Neutrophil depletion led to higher mortality and more severe joint destruction (p < 0.01). In contrast, monocyte depletion resulted in higher mortality (p < 0.05) but similar arthritis severity compared to controls. Mice depleted of CD4+ T-cells inoculated with P. aeruginosa displayed less severe bone damage (p < 0.05). For the first time, a mouse model for P. aeruginosa septic arthritis is presented. Our data demonstrate that neutrophils play a protective role in P. aeruginosa septic arthritis. Monocytes/macrophages, on the other hand, are only essential in preventing P. aeruginosa-induced mortality. Finally, CD4+ T-cells are pathogenic in P. aeruginosa septic arthritis.


Assuntos
Artrite Infecciosa/patologia , Modelos Animais de Doenças , Articulações/patologia , Neutropenia/patologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/patogenicidade , Animais , Artrite Infecciosa/imunologia , Artrite Infecciosa/microbiologia , Artrite Infecciosa/mortalidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Articulações/imunologia , Articulações/microbiologia , Contagem de Leucócitos , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Neutropenia/imunologia , Neutropenia/microbiologia , Neutropenia/mortalidade , Neutrófilos/imunologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Especificidade de Órgãos , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida
15.
Hum Immunol ; 80(12): 990-998, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706743

RESUMO

Severe congenital neutropenia (SCN) is described by the absolute neutrophil counts less than 500 cells/mm3, bacterial infections, and an arrest of neutrophil differentiation. So, effective strategies for improving the function and lifespan of the existing neutrophils in these patients are necessary. Mesenchymal stem cells (MSCs) have supportive effects on neutrophils. Recently, it was determined that MSCs exert their effects, mostly by secreting soluble factors and exosomes. So, in this study, neutrophils were isolated from the bloodstream of healthy donors and SCN patients and cultured with medium, MSC-exosomes or MSC-conditioned media (MSC-CM). Then, the effects of the two treatments on neutrophil respiratory burst, apoptosis and phagocytosis percentage were assessed using nitro blue tetrazolium (NBT) assay, annexin V-propidium iodide (PI) and Giemsa staining, respectively. Both treatments could significantly augment respiratory burst of neutrophils from SCN patients and healthy donors. But, only CM could significantly enhance phagocytosis index. About the lifespan of neutrophils, only exosomes could significantly enhance it in both groups. Based on these results, both exosomes and CM derived from MSCs could be attractive candidates for rescuing SCN patients from serious infections.


Assuntos
Tecido Adiposo/patologia , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Exossomos/patologia , Células-Tronco Mesenquimais/patologia , Neutropenia/congênito , Neutrófilos/patologia , Adulto , Apoptose , Células Cultivadas , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Meios de Cultivo Condicionados/metabolismo , Humanos , Transplante de Células-Tronco Mesenquimais , Neutropenia/patologia , Neutropenia/terapia , Fagocitose
16.
Expert Rev Clin Immunol ; 15(11): 1225-1233, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31592698

RESUMO

Objectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p = 0.001 and p = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p = 0.04 and p = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, p = 0.004).Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.


Assuntos
Imunodeficiência de Variável Comum , Neutropenia , Adolescente , Adulto , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Feminino , Seguimentos , Humanos , Masculino , Neutropenia/epidemiologia , Neutropenia/imunologia , Neutropenia/patologia , Estudos Retrospectivos
17.
BMC Res Notes ; 12(1): 464, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362783

RESUMO

OBJECTIVE: The aim of this study was to determine the predominant bacterial species causing bacteremia among febrile cancer patients, and their antibacterial resistance profiles at the Uganda Cancer Institute. RESULTS: We enrolled in-patients with a documented fever (≥ 37.5 °C). Bacteria from positive blood cultures were identified using standard methods biochemically. Antibacterial susceptibility testing was performed with the Kirby-Bauer disc diffusion method. From a total of 170 febrile episodes, positive blood cultures were obtained from 24 (14.1%). A positive culture was more likely to be obtained from a patient with neutropenia (P = 0.017). Of 22 (66.7%) Gram-negative bacteria isolated, half were E. coli (n = 11). Gram-negative compared to Gram-positive bacteria were most likely to be isolated from patients with a hematologic malignancy (P = 0.02) or patients with neutropenia (P = 0.006). Of the isolated Enterobacteriaceae 85% (n = 20) were resistant to three or more classes of antibiotic and 41% (n = 7) had extended spectrum beta-lactamases. Of the 11 Gram-positive bacteria isolated, the S. aureus isolate was methicillin resistant but susceptible to vancomycin. Multidrug resistant Gram-negative bacteria are the main cause of bacteremia in febrile cancer patients at the Uganda Cancer Institute. There is need for ongoing microbial surveillance, infection prevention and control, and antibiotic stewardship programs.


Assuntos
Bacteriemia/microbiologia , Febre/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Neoplasias/microbiologia , Neutropenia/microbiologia , Adulto , Antibacterianos/uso terapêutico , Bacteriemia/complicações , Bacteriemia/tratamento farmacológico , Bacteriemia/patologia , Hemocultura , Criança , Estudos Transversais , Farmacorresistência Bacteriana Múltipla/genética , Feminino , Febre/complicações , Febre/tratamento farmacológico , Febre/patologia , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/patologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Neutropenia/patologia , Uganda , beta-Lactamases/genética , beta-Lactamases/metabolismo
18.
Pediatr Hematol Oncol ; 36(7): 432-437, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31411529

RESUMO

Monosomy 7 is an indicator of malignant transformation in patients with different subtypes of severe congenital neutropenias (SCNs). We present the case of a 5-year-old male diagnosed with SCN. Standard karyotype and fluorescent in situ hybridization (FISH) analyses for centromere of chromosome 7 (chromosome enumeration probe 7 [CEP7]) in bone marrow samples showed disomy for chromosome 7 and a single copy of CEP7. In all cells examined, karyotype analysis of peripheral PHA-stimulated blood samples revealed disomy for chromosome 7. Our results address the issue of centromeric heteromorphism in cytogenetic analysis. Herein, we report a case where FISH using CEP7 in the bone marrow sample showed the presence of only one signal suggesting monosomy seven due to an acquired heteromorphism, whereas extensive conventional karyotyping showed disomy of chromosome 7.


Assuntos
Aneuploidia , Centrômero , Cromossomos Humanos Par 7/genética , Síndrome Congênita de Insuficiência da Medula Óssea , Hibridização in Situ Fluorescente , Neutropenia/congênito , Centrômero/genética , Centrômero/patologia , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Humanos , Masculino , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/patologia
19.
Leuk Lymphoma ; 60(14): 3512-3520, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298598

RESUMO

Benefits of serial electrocardiographic (ECG) monitoring to detect QT prolongation in patients with hematological malignancies remain unclear. This retrospective, single-center, study evaluated 316 adult acute leukemia and high-risk MDS patients who received 11,775 patient-days of voriconazole prophylaxis during induction chemotherapy. Of these, 37 patients (16.2%) experienced QTc prolongation. Medications associated with QTc prolongation included furosemide, haloperidol, metronidazole, mirtazapine, prochlorperazine, and venlafaxine. Hypokalemia and hypomagnesemia were also significantly associated with QTc prolongation (HR 3.15; p = .003 and HR 6.47, p = .007, respectively). Management modifications due to QTc prolongation included discontinuation of QT prolonging medications (n = 25), more aggressive electrolyte repletion (n = 5), and enhanced ECG monitoring (n = 3). One patient with multiple QT prolonging factors experienced possible Torsades de Pointes. Overall mortality was 15% with no cardiac-related deaths. Serial ECG monitoring during induction chemotherapy can be tailored proportionally to QT-prolonging risk factors. Management should include aggressive electrolyte repletion and avoidance of concurrent QT prolonging medications.


Assuntos
Antifúngicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia/tratamento farmacológico , Síndrome do QT Longo/induzido quimicamente , Síndromes Mielodisplásicas/tratamento farmacológico , Neutropenia/tratamento farmacológico , Voriconazol/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Quimioterapia de Indução , Leucemia/patologia , Síndrome do QT Longo/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Neutropenia/induzido quimicamente , Neutropenia/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...