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1.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
2.
Support Care Cancer ; 28(11): 5085-5097, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32621264

RESUMO

BACKGROUND: PEGylated granulocyte colony-stimulating factor (G-CSF) is a safe alternative to G-CSF to improve chemotherapy-induced neutropenia (CIN). This superiority has resulted in its increased use by physicians; however, the superiority of PEGylated G-CSF for CIN in breast cancer has not been conclusively determined. OBJECTIVES: To assess the superiority of PEGylated G-CSF for CIN in breast cancer in terms of effectiveness and safety via a systematic review and meta-analysis. METHODS: A literature search in PubMed, Embase, Cochrane Library, and Web of Science was performed for eligible studies published from database inception to December 2019. All studies comparing PEGylated G-CSF and G-CSF for CIN of breast cancer were reviewed. After literature selection, data extraction and quality assessment were performed by two reviewers independently. Meta-analysis was conducted using Revman, version 5.2. RESULTS: Nine randomized controlled trials were finally identified. The publication bias of these studies was acceptable. For the endpoint of effectiveness, analysis of the incidence/duration of grade ≥ 3 neutropenia, the duration of grade 4 neutropenia, the incidence of febrile neutropenia (FN), and the time to absolute neutrophil count recovery showed no advantage of PEGylated G-CSF over G-CSF for CIN of breast cancer (P > 0.05), with the premise of a sufficient dose of G-CSF according to the guidelines. No significant differences in grade 4 adverse events were observed between the groups (P = 0.29), and PEGylated G-CSF did not increase the incidence of skeletal and/or muscle pain compared with G-CSF (P = 0.32). CONCLUSION: PEGylated G-CSF was as effective and safe as G-CSF to reduce CIN in breast cancer but did not show an obvious superiority. However, in clinical practice, PEGylated G-CSF has an obvious advantage in terms of convenience, which could improve patient's quality of life.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neutropenia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Feminino , Humanos , Neutropenia/induzido quimicamente , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem
4.
Vet J ; 259-260: 105479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32553236

RESUMO

A randomised controlled trial was carried out in four dairy herds located in the UK to evaluate the effect of pegbovigrastim treatment on the incidence of antimicrobial treatments during the first 30 d of lactation (DIM). Medical treatment records were analysed, and treatments identified where an antibiotic product was used. Records were available for 1865 cows, 933 of which received two injections of pegbovigrastim given approximately 14 d prior to expected calving (IMR) and again within 24 h of calving. 932 cows received no treatment (CON). In total, 11.6% (n = 108/933) IMR cows and 13.2% (n = 123/932) CON cows received at least one antibiotic treatment during the first 30 DIM. Of the IMR cows 2.9% (n = 27/933) were treated with antibiotics for the reason of mastitis along with 3.4% (n = 32/932) of cows from the CON group. 8.9% (n = 83/933) of IMR cows and 10.3% (n = 96/932) of CON cows received antibiotic treatment for a condition other than mastitis, 0.2% (n = 2/933) and 0.8% cows (n = 7/932) from the IMR and CON groups, respectively, received an antibiotic treatment for both mastitis and a reason other than mastitis during the first 30 DIM. Data were analysed with the farm where each cow was located as a random effect and with fixed effects of treatment (IMR or CON), parity (categorised as cows in 1st, 2nd and 3rd or subsequent lactations) and season of calving (autumn [AUT], September through November; winter [WIN], December through February; spring [SPR], March through May; and summer [SUM], June through August), and all 2-way interactions with treatment. Treatment was associated with reduced risk of receiving antibiotic therapy in the first 30 DIM (odds ratio [OR], 0.51; 95% confidence interval [95% CI], 0.28 to 0.94), but a treatment × farm interaction was detected. Compared with IMR, CON cows were more likely to receive an antibiotic treatment on 3/4 farms during the first 30 DIM. However, CON cows on Farm 2 were less likely to do so (12.4% [n = 45/364] vs.15.5% [n = 36/232]). Cows in the third or subsequent lactation were also found to be at increased risk of receiving antibiotic therapy (OR = 1.54; 95% CI, 1.09 to 2.20) than cows in their first lactation. Pegbovigrastim treatment pre-calving may be useful in some herds for reducing the incidence of antimicrobial treatments during early lactation.


Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Lactação , Mastite Bovina/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Animais , Bovinos , Indústria de Laticínios , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Incidência , Injeções Intramusculares/veterinária , Período Pós-Parto , Gravidez , Proteínas Recombinantes/administração & dosagem , Estações do Ano , Reino Unido
5.
Exp Hematol ; 86: 15-20.e2, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32450206

RESUMO

Transplantable CD34+ hematopoietic stem/progenitor cells (HSPCs) are currently isolated mainly from peripheral blood after mobilization with granulocyte colony-stimulating factor (G-CSF). These mobilized CD34+ cells have the potential to generate all blood cell types. For autologous transplantation, the minimal number of mobilized CD34+ cells is 2 × 106 CD34+ cells/kg body weight. However, up to 30% of patients fail to mobilize enough peripheral CD34+ cells after G-CSF treatment. To overcome this limitation, a combination of G-CSF and Plerixafor, a CXCR4 chemokine receptor inhibitor, is proposed to enhance CD34+ cell mobilization in poor mobilizer patients. However, only limited data are available on quantification of the functional quality of such patients' mobilized hematopoietic stem cells. Here, for six poor mobilizer patients, a head-to-head comparison of their CD34+ cells mobilized without versus with Plerixafor was performed to assess their properties with respect to the reconstitution of human hematopoiesis in vivo in immune-deficient mice. Our results indicate that mobilized CD34+ cells recovered after the G-CSF + Plerixafor mobilization protocol have an enhanced intrinsic hematopoietic reconstitution potential compared with CD34+ cells mobilized with G-CSF alone.


Assuntos
Antígenos CD34/sangue , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Células-Tronco de Sangue Periférico/metabolismo , Animais , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico/patologia
6.
Medicine (Baltimore) ; 99(15): e19746, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282735

RESUMO

RATIONALE: Toxic shock syndrome (TSS) typically is an acute onset multi-organ infection caused by TSS toxin-1 producing Staphylococcus aureus. Herein we describe a highly unusual case report. PATIENT CONCERNS: A male patient self-referred to the University of Minnesota Hospital with a chronic history of S aureus infection with accompanying fever, hypotension, and nonhealing, football-sized lesion on his leg. DIAGNOSIS: An unusual case presentation of TSS/hyperimmunoglobulin E syndrome is described. The patient had a leg wound from which TSS toxin-1 S aureus was isolated. The patient exhibited characteristic skewing of T cells to those with variable region, ß-chain T cell receptor-2. Other patients have been seen with related presentations. INTERVENTIONS: The following therapeutic regimen was instituted: vigorous antibacterial scrubs several times daily plus intravenous Ancef 3 days each month; intravenous infusions of immunoglobulin G infusions (28 gm) every 3 weeks; and weekly subcutaneous injections of recombinant granulocyte colony-stimulating factor. OUTCOME: Improvement was obvious within 3 months: no further cellulitic episodes occurred; the patient regained 95 pounds in 9 months; blanching and cyanosis of fingers disappeared within 3 months as did intractable pain although mild hypesthesias continued for 2 years; erythroderma resolved, and repeat skin biopsies performed after 2 years no longer demonstrated T cell receptor skewing. Although IgE levels have not completely returned to normal, the patient remains in excellent health. LESSONS: We propose that staphylococcal TSST-1 was responsible for the serious problems suffered by this patient as suggested by the following features: rapid onset of chronic, life-threatening, disorder that began with an episode of staphylococcal sepsis; the extraordinary elevation of IgE levels in this previously non-atopic individual; the acquired severe granulocyte chemotactic defect that accompanied this hyperimmunoglobulinemia ("Job Syndrome") with its accompanying wound-healing defect; and the striking diffuse erythroderma, including palmar erythema ("Red Man Syndrome") with hypotension and fever that also characterizes TSS.


Assuntos
Síndrome de Job/microbiologia , Choque Séptico/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Administração Intravenosa , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Cefazolina/administração & dosagem , Cefazolina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/uso terapêutico , Infusões Intravenosas , Injeções Subcutâneas , Síndrome de Job/diagnóstico , Síndrome de Job/etiologia , Perna (Membro)/patologia , Masculino , Pessoa de Meia-Idade , Choque Séptico/diagnóstico , Choque Séptico/etiologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/patologia , Resultado do Tratamento , Ferimentos e Lesões/microbiologia
7.
Protein J ; 39(2): 160-173, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32172395

RESUMO

Previously we reported that site-specific modification of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) A3C analog with polyethylene glycol (PEG) dramatically improved the pharmacokinetic properties of the protein in rats. However, we could not evaluate the hematological properties of the PEG-A3C protein in rats because human GM-CSF is inactive in rodents. To study the biological effects of PEGylated GM-CSF analogs in rodents we created a homologous site-specific PEGylated murine (mu) GM-CSF (T3C) protein. muGM-CSF and the T3C protein were expressed in Escherichia coli and purified by column chromatography. The purified T3C protein was covalently modified with a linear 20 kDa- or a branched 40 kDa-maleimide-PEG, and the monoPEGylated proteins purified by column chromatography. muGM-CSF, T3C and the two PEG-T3C proteins had comparable in vitro biological activities, as measured by stimulation of proliferation of the murine FDC-P1 cell line. The PEG-T3C proteins had 10- to 25-fold longer circulating half-lives than muGM-CSF and stimulated greater and longer lasting increases in neutrophils and white blood cells than muGM-CSF following a single intravenous or subcutaneous administration to rats. Treatment of rats made neutropenic with cyclophosphamide with the PEG-T3C proteins shortened the time for recovery of neutrophils to normal levels from 9 or 10 days to 5 or 6 days, whereas muGM-CSF showed no benefit versus vehicle solution. Acceleration of neutrophil recovery in cyclophosphamide-treated rats required a minimum of three PEG-T3C treatments over five days. The PEG-T3C proteins should prove useful for evaluating the potential therapeutic benefits of GM-CSF and long-acting GM-CSF proteins in rodent disease models.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacocinética , Hematopoese/efeitos dos fármacos , Polietilenoglicóis/farmacocinética , Animais , Linhagem Celular , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Meia-Vida , Masculino , Neutropenia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
8.
PLoS One ; 15(3): e0228878, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134938

RESUMO

We studied a cohort of 367 healthy related donors who volunteered to donate their hematopoietic stem cells for allogeneic transplantation. All donors were homogeneously cared for at a single institution, and received rhG-CSF as a mobilization treatment prior to undergoing apheresis. Peripheral blood CD34+ cell counts were used as the main surrogate marker for rhG-CSF induced mobilization. We searched whether inter-individual variations in known genetic polymorphisms located in genes whose products are functionally important for mobilization, could affect the extent of CD34+ mobilization, either individually or in combination. We found little or no influence of individual SNPs or haplotypes for the SDF1, CXCR4, VCAM and VLA4 genes, whether using CD34+ cell counts as a continuous or a categorical variable. Simple clinical characteristics describing donors such as body mass index, age and possibly sex are more potent predictors of stem cell mobilization. The size of our cohort remains relatively small for genetic analyses, however compares favorably with cohorts analyzed in previously published reports suggesting associations of genetic traits to response to rhG-CSF; notwithstanding this limitation, our data do not support the use of genetic analyses when the choice exists of several potential donors for a given patient.


Assuntos
Quimiocina CXCL12/genética , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Integrina alfa4beta1/genética , Polimorfismo de Nucleotídeo Único , Receptores CXCR4/genética , Molécula 1 de Adesão de Célula Vascular/genética , Adulto , Idoso , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
9.
Prev Vet Med ; 176: 104931, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32135413

RESUMO

The aim of this study was to evaluate the effects of pegbovigrastim injection (Imrestor, Elanco Animal Health, Greenfield, IN) on production parameters and postpartum disease occurrence (retained placenta, metritis, displaced abomasum, and clinical mastitis) in dairy cows. Study cows (n = 270) were blocked by parity group (multiparous or primiparous) and randomly assigned to control (CON, n = 144) or pegbovigrastim treatment (IMR, n = 126). Ten ± 4 days before expected calving and again at calving, IMR cows received 2.7 mL of Imrestor and CON cows received 2.7 mL of 0.9 % saline. Milk yield, fat, protein, lactose, solids nonfat (SNF) percent, and somatic cell count (SCC), body condition, hygiene, and lameness were evaluated weekly. Animals were evaluated for metritis twice weekly through rectal temperature, palpation, and uterine discharge evaluation until 30 days in milk. Farm personnel recorded other postpartum diseases. The MIXED procedure of SAS was used to evaluate milk composition and milk yields were analyzed as repeated measures in time with block, treatment, calving month, and lactation week included in mixed models. The GLIMMIX procedure was used to evaluate mastitis and metritis occurrence. Variables entered a model if P ≤ 0.10 when screened individually. Variables with P ≤ 0.10 were kept in the final model. Milk yield, fat, protein, lactose, SNF, and log of SCC were not significantly affected by treatment. Clinical mastitis occurrence did not differ between treatments, but only 17 cases were detected. Compared to CON, IMR treated cows had increased clinical metritis incidence, and were 2.46 times more likely to develop the disease. No difference was observed on puerperal metritis ocurrence. Cows given pegbovigrastim injections had increased odds of developing clinical signs of metritis, but no negative effects on milk production or composition were observed.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Lactação , Mastite Bovina/tratamento farmacológico , Leite/metabolismo , Proteínas Recombinantes/administração & dosagem , Animais , Bovinos , Contagem de Células/veterinária , Indústria de Laticínios , Feminino , Incidência , Mastite Bovina/epidemiologia , Mississippi/epidemiologia , Paridade , Período Periparto
10.
Leuk Res ; 93: 106318, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32127177

RESUMO

The fludarabine, high dose cytarabine and G-CSF with or without idarubicin combination regimen, referred to as FLAG+/-Ida, is commonly used as a salvage regimen for relapsed/refractory AML but its use as initial induction therapy has been more limited. The impact of choice of induction regimen on post remission survival remains unclear. We retrospectively analyzed 304 consecutive AML patients, with non-favorable NCCN risk who received initial treatment at our center with either 7 + 3 (n = 86) or FLAG+/-Ida (n = 218). Patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74 % vs 62 %, p < 0.001) and had a faster time to achieve CR (30 days vs 37.5, p < 0.001) compared to 7 + 3. The time from diagnosis to transplant was shorter among CR patients after FLAG+/-Ida compared to 7 + 3 (115 vs. 151 days, p < 0.003). The 3-year post-remission OS and DFS was significantly better for patients receiving FLAG-Ida at 54 % and 49 % compared to 39 % and 32 % for 7 + 3 respectively (P = 0.01). Factors associated with post-remission survival included age at CR1, NCCN risk, induction regimen (FLAG+/-Ida vs 3 + 7 h 0.62, p = 0.01) and receipt of HCT. Our data, with the limitations inherent to a retrospective analysis, shows that achieving CR after FLAG+/-Ida has better post remission survival than 7 + 3.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Vidarabina/administração & dosagem
11.
Am J Clin Oncol ; 43(5): 334-339, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32000167

RESUMO

BACKGROUND: Preoperative chemotherapy is important in the management of women with breast cancer, with the ability to downstage the breast primary tumor and axillary lymph nodes. Long-term studies are needed to identify late toxicities, recurrence patterns, and equivalency with postoperative chemotherapy for recurrence-free survival (RFS) and overall survival (OS). PATIENTS AND METHODS: We conducted a single-institution prospective randomized control trial comparing preoperative or postoperative fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor chemotherapy for women with untreated clinical stage II (T1N1, T2N0, and T2N1) breast cancer. Long-term follow-up was conducted to define toxicities, recurrence patterns and RFS and OS. RESULTS: Fifty-three women with clinical stage II breast cancer were randomized, 26 patients to receive preoperative chemotherapy and 27 to receive postoperative chemotherapy. Long-term follow-up, with a median of 25.3 years, was obtained. Local or systemic recurrence occurred in 8 women in the preoperative group and in 10 women in the postoperative group, and recurrences were predominantly within 10 years of treatment. Late toxicities included local upper extremity paresthesia's, upper extremity edema and congestive heart failure in 1 patient each. Analysis revealed no difference in RFS (20-year RFS probabilities; preoperative: 61.3%, postoperative: 54.7%, P=0.42), or in OS between the 2 treatment groups (20-year probabilities, preoperative: 64.6%, postoperative: 62.2%, P=0.44). Twenty-five of 53 patients (47%) were alive and without disease at this follow-up. CONCLUSION: Twenty-five-year follow-up for this prospective randomized trial confirms the equivalency of preoperative versus postoperative chemotherapy with fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor for stage II breast cancer for both RFS and OS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Radioterapia Adjuvante/métodos , Resultado do Tratamento
12.
Nat Commun ; 11(1): 400, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964864

RESUMO

Circulating cell-free mRNA (cf-mRNA) holds great promise as a non-invasive diagnostic biomarker. However, cf-mRNA composition and its potential clinical applications remain largely unexplored. Here we show, using Next Generation Sequencing-based profiling, that cf-mRNA is enriched in transcripts derived from the bone marrow compared to circulating cells. Further, longitudinal studies involving bone marrow ablation followed by hematopoietic stem cell transplantation in multiple myeloma and acute myeloid leukemia patients indicate that cf-mRNA levels reflect the transcriptional activity of bone marrow-resident hematopoietic lineages during bone marrow reconstitution. Mechanistically, stimulation of specific bone marrow cell populations in vivo using growth factor pharmacotherapy show that cf-mRNA reflects dynamic functional changes over time associated with cellular activity. Our results shed light on the biology of the circulating transcriptome and highlight the potential utility of cf-mRNA to non-invasively monitor bone marrow involved pathologies.


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Medula Óssea/patologia , Ácidos Nucleicos Livres/isolamento & purificação , Leucemia Mieloide Aguda/diagnóstico , Mieloma Múltiplo/diagnóstico , RNA Mensageiro/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Medula Óssea/efeitos dos fármacos , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Estudos de Viabilidade , Perfilação da Expressão Gênica/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Estudos Longitudinais , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , RNA Mensageiro/sangue , RNA Mensageiro/genética , Análise de Sequência de RNA/métodos , Resultado do Tratamento , Adulto Jovem
13.
Am J Hematol ; 95(2): 198-204, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31691333

RESUMO

Impact of Plerixafor (P) mobilized stem cells on immune reconstitution, such as absolute lymphocyte count at day 30 (ALC30), and on long-term outcomes of Multiple Myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) has not been well established. We evaluated total of 469 patients mobilized with G-CSF (G) alone, and 141 patients mobilized with G-CSF plus plerixafor (G+ P). Patients only received plerixafor if they had peripheral blood CD34+ blood count <20/µL on first planned day of collection. Primary endpoint, ALC30, was 1.3 K/µL (range, 0.1-4.5) and 1.2 K/µL (range, 0.1-5.1) for G and G + P, respectively (P =. 61). The median PFS was 2.5 years (95% CI, 2.1-3.2) and 2.8 years (95% CI, 2.0-3.3) for G and G + P, respectively (HR: 1.13; 95% CI, 0.84-1.50; P = .42). The median OS was 6.1 years (95% CI, 4.6-NR) for G group compared to 3.7 years (95% CI, 3.2-NR) for the G + P group (HR: 1.64; 95% CI, 1.12-2.40; P = .01). The median follow-up time for OS was 2.53 years (95% CI, 2.13-2.99) and 1.59 years (95% CI, 1.17-2.02) for G and G+ P group, respectively. In this large retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery or PFS. There was an overall survival difference in patients who were poor mobilizers and could not be mobilized with G-CSF alone.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Mieloma Múltiplo/terapia , Recuperação de Função Fisiológica , Adulto , Idoso , Autoenxertos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade
15.
Cells ; 9(1)2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861319

RESUMO

Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb-/-) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb-/- mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb-/- mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb-/- mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Albumina Sérica Humana/genética , Animais , Disponibilidade Biológica , Feminino , Técnicas de Inativação de Genes , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/farmacocinética , Masculino , Camundongos
16.
Bratisl Lek Listy ; 120(9): 668-672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475551

RESUMO

Restrospective study to evaluate the efficacy of early vs. delayed initiation of G-CSF after autologous hematopoietic stem cell transplantation (AHSCT) in patients with lymphoid malignancies. BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is commonly used after AHSCT to accelerate stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal timing of G-CSF after HSCT. METHODS: A total of 117 patients with lymphoid malignancies who underwent AHSCT were included. All patients received G-CSF (filgrastim 5 µg/kg s.c.) daily after AHSCT (43 patients on day 6-8 and 74 patients on day 3 or 4). All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. RESULTS: The incidence of severe neutropenia was 81 % vs 17 %, and very severe neutropenia 61 % vs 4 % in the delayed and early G-CSF groups, respectively (p < 0.0001). The rate of fungal infection was higher in the group of patients who received delayed G-CSF (p < 0.005). CONCLUSION: An early administration of G-CSF after AHSCT (on day 3 or 4) accelerates neutophil engraftment; decreases the incidence of severe neutropenia and the risk of infectious complications (especially fungal infections) (Tab. 1, Fig. 3, Ref. 22).


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Filgrastim/administração & dosagem , Humanos , Neutropenia/terapia , Neutrófilos/citologia , Proteínas Recombinantes/administração & dosagem , Condicionamento Pré-Transplante , Transplante Autólogo
17.
Future Oncol ; 15(31): 3555-3563, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495201

RESUMO

Effective hematopoietic cell transplantation relies upon collecting adequate numbers of CD34+ hematopoietic stem cells, typically from peripheral blood. A minimum of ≥2 × 106 CD34+ cells/kg are necessary, while transplants of ≥5-6 × 106 CD34+ cells/kg are associated with improved hematopoietic recovery. Granulocyte colony stimulating factor (G-CSF) remains the gold standard for hematopoietic stem cell mobilization. However, in randomized trials for autologous-hematopoietic cell transplantation in multiple myeloma, approximately 45% of patients remain unable to optimally mobilize with G-CSF alone despite multiple injections and apheresis days. Therefore, reducing mobilization failures remains an unmet need. The study objective is to evaluate the superiority of one dose of BL-8040 plus G-CSF over placebo plus G-CSF to mobilize ≥6.0 × 106 CD34+ cells/kg in up to two apheresis days. ClinicalTrials.gov: NCT03246529.


Assuntos
Protocolos Clínicos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Peptídeos/uso terapêutico , Quimioterapia Combinada , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/metabolismo , Peptídeos/administração & dosagem , Projetos de Pesquisa , Transplante Autólogo
18.
Rinsho Ketsueki ; 60(6): 565-569, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281145

RESUMO

Sweet syndrome is a rare inflammatory disease with rapid onset of painful, edematous skin eruptions, and neutrophilia. Concerning hematological disorders, Sweet syndrome often presents in patients with myeloid diseases, but it is rarely observed in patients with lymphoid diseases. Here we describe a 72-year-old male with Philadelphia chromosome-positive acute lymphoblastic leukemia who suffered recurring Sweet syndrome. Following induction chemotherapy, granulocyte colony-stimulating factors (G-CSFs) were administered due to febrile neutropenia. A few weeks thereafter, skin eruption emerged on the palmar and dorsal surfaces of his hands, and skin biopsy confirmed Sweet syndrome. His symptoms improved with the short-term use of prednisolone. After recovering from the neutropenia, the patient received percutaneous coronary intervention (PCI) due to unstable angina that developed after the induction chemotherapy. During PCI, coronary artery dissection caused cardiopulmonary arrest. The patient recovered with intensive care. However, blood tests on the following day revealed marked neutrophilia. The skin eruption re-emerged on both hands, which was consistent with Sweet syndrome. Sweet syndrome repeatedly occurred after the recovery of neutropenia due to chemotherapy. We suggest that the intrinsic increase in G-CSF in response to inflammation might have caused recurring Sweet syndrome in this patient.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Síndrome de Sweet/diagnóstico , Idoso , Angina Instável , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Neutropenia/tratamento farmacológico , Intervenção Coronária Percutânea , Cromossomo Filadélfia , Prednisolona/uso terapêutico , Síndrome de Sweet/tratamento farmacológico
19.
Hematology ; 24(1): 552-558, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31315553

RESUMO

Objectives: To analyze the efficacy and safety of decitabine combined with low/reduced-dose chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive therapy and to investigate the early prognostic indicators for these patients. Methods: The eligible patients treated with decitabine-based chemotherapy were retrospectively analyzed. Responses and long-term survival were calculated and their correlation with clinical characteristics was analyzed. Minimal residual disease (MRD) detected by flow cytometry (FCM) after the induction therapy was measured, and the association with prognosis was explored. Results: Fifty-five newly diagnosed AML patients were enrolled. The overall response rate (ORR) was 80.0%, with a complete remission (CR) rate of 63.64% and partial remission (PR) rate of 16.36%. Grade 4 hematological toxicity was common, and the incidence of infections was 83.64%, with 18.18% of patients suffered from severe infections. No serious bleeding or non-hematological adverse events occurred. Treatment-related mortality was 3.64%. The median overall survival (OS) and disease-free survival (DFS) were 17.0 (13.7-20.3) months and 17.0 (10.2-23.8) months, respectively. Multivariate analysis showed that an advanced age (≥ 60 years) and higher MRD (≥ 1.34%) after induction therapy were adverse prognostic factors for patients who had achieved CR. Conclusions: Decitabine-based chemotherapy may be a suitable therapeutic alternative for newly diagnosed AML patients who are unfit for intensive chemotherapy. An advanced age (≥ 60 years) and higher MRD (≥ 1.34%) were considered adverse prognostic factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/patologia , Aclarubicina/administração & dosagem , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Mepesuccinato de Omacetaxina/administração & dosagem , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
20.
Methods Mol Biol ; 2017: 165-175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31197776

RESUMO

It has been shown that the complement cascade is involved in the process of mobilization of hematopoietic stem cells, from their niche in the bone marrow to the peripheral blood. Based on this knowledge modulation of complement, cascade activation may enable the development of better mobilization strategies for poorly mobilizing patients. Herein we present a mobilization protocol in mice model, useful for studying the effect of the complement activation in the mobilization process.


Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Animais , Ativação do Complemento , Técnicas de Inativação de Genes , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Modelos Animais , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco
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