RESUMO
BACKGROUND: Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE: The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. STUDY DESIGN: We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. RESULTS: A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50-0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01-5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). CONCLUSION: Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Interleucina-2 , Polimorfismo de Nucleotídeo Único , Humanos , Interleucina-2/genética , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Estudos Retrospectivos , Adulto Jovem , Resultado do Tratamento , Genótipo , Idoso , Adolescente , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Imunossupressores/uso terapêutico , Leucemia Mieloide/terapia , Adolescente , Adulto , Feminino , Humanos , Leucemia Mieloide/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Irradiação Corporal Total , Adulto JovemRESUMO
Mucosal-associated invariant T (MAIT) cells are a type of innate lymphocyte and recognize riboflavin (vitamin B2) synthesis products presented by MHC-related protein 1. We investigated long-term reconstitution of MAIT cells and its association with chronic graft-versus-host disease (cGVHD) in a cross-sectional cohort of 173 adult patients after allogeneic hematopoietic cell transplantation. According to donor source, the number of MAIT cells significantly correlated with time after cord blood transplantation (CBT) but not with time after bone marrow transplantation or peripheral blood stem cell transplantation. The number of MAIT cells was significantly lower in patients with cGVHD compared with patients without cGVHD. We also examined the association between MAIT cell reconstitution and gut microbiota as evaluated by 16S ribosomal sequencing of stool samples 1 mo post-CBT in 27 adult patients undergoing CBT. The diversity of gut microbiota was positively correlated with better MAIT cell reconstitution after CBT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis indicated that amounts of ribB and ribA genes were significantly higher in the microbiomes of patients with subsequent MAIT cell reconstitution after CBT. In conclusion, long-term MAIT cell reconstitution is dependent on the type of donor source. Our data also unveiled an important role for the interaction of circulating MAIT cells with gut microbiota in humans.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células T Invariantes Associadas à Mucosa/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Vias Biossintéticas/imunologia , Estudos Transversais , DNA Bacteriano/isolamento & purificação , Fezes/microbiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Voluntários Saudáveis , Doenças Hematológicas/terapia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Ribossômico 16S/genética , Estudos Retrospectivos , Riboflavina/biossíntese , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.
Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , Humanos , RNA Viral , Vacinas Sintéticas , Vacinas de mRNARESUMO
This study was performed to assess the utility of tumor-derived fragmentary DNA, or circulating tumor DNA (ctDNA), for identifying high-risk patients for relapse of acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively collected tumor and available matched serum samples at diagnosis and 1 and 3 months post-alloSCT from 53 patients with AML/MDS. After identifying driver mutations in 51 patients using next-generation sequencing, we designed at least 1 personalized digital polymerase chain reaction assay per case. Diagnostic ctDNA and matched tumor DNA exhibited excellent correlations with variant allele frequencies. Sixteen patients relapsed after a median of 7 months post-alloSCT. Both mutation persistence (MP) in bone marrow (BM) at 1 and 3 months post-alloSCT and corresponding ctDNA persistence (CP) in the matched serum (MP1 and MP3; CP1 and CP3, respectively) were comparably associated with higher 3-year cumulative incidence of relapse (CIR) rates (MP1 vs non-MP1, 72.9% vs 13.8% [P = .0012]; CP1 vs non-CP1, 65.6% vs 9.0% [P = .0002]; MP3 vs non-MP3, 80% vs 11.6% [P = .0002]; CP3 vs non-CP3, 71.4% vs 8.4% [P < .0001]). We subsequently evaluated whether subset analysis of patients with 3 genes associated with clonal hematopoiesis, DNMT3A, TET2, and ASXL1 (DTA), could also be helpful in relapse prediction. As a result, CP based on DTA gene mutations also had the prognostic effect on CIR. These results, for the first time, support the utility of ctDNA as a noninvasive prognostic biomarker in patients with AML/MDS undergoing alloSCT.
Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/análise , Leucemia Mieloide Aguda/sangue , Síndromes Mielodisplásicas/sangue , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)-based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil-based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Incidência , Japão/epidemiologia , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Condicionamento Pré-Transplante/métodos , Resultado do TratamentoRESUMO
Mast cells (MCs) are key effector cells in allergic reactions. However, the inhibitory mechanism that prevents excessive activation of MCs remains elusive. Here we show that leukocyte mono-immunoglobulin-like receptor 3 (LMIR3; also called CD300f) is a negative regulator of MC activation in vivo. LMIR3 deficiency exacerbated MC-dependent allergic responses in mice, including anaphylaxis, airway inflammation, and dermatitis. Both physical binding and functional reporter assays via an extracellular domain of LMIR3 showed that several extracellular lipids (including ceramide) and lipoproteins were possible ligands for LMIR3. Importantly, MCs were frequently surrounded by extracellular ceramide in vivo. Upon engagement of high-affinity immunoglobulin E receptor, extracellular ceramide-LMIR3 binding inhibited MC activation via immunoreceptor tyrosine-based inhibitory and switch motifs of LMIR3. Moreover, pretreatment with LMIR3-Fc fusion protein or antibody against either ceramide or LMIR3 interfered with this binding in vivo, thereby exacerbating passive cutaneous anaphylaxis. Thus, the interaction between extracellular ceramide and LMIR3 suppressed MC-dependent allergic responses.
Assuntos
Ceramidas/imunologia , Ceramidas/metabolismo , Hipersensibilidade/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Anafilaxia/imunologia , Anafilaxia/metabolismo , Animais , Células Cultivadas , Dermatite/imunologia , Dermatite/metabolismo , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Lipoproteínas/imunologia , Lipoproteínas/metabolismo , Mastócitos/patologia , Camundongos , Ligação Proteica/imunologia , Estrutura Terciária de Proteína , Receptores de IgE/imunologia , Receptores de IgE/metabolismo , Tirosina/imunologia , Tirosina/metabolismoRESUMO
A prior history of cancer was associated with higher non-relapse mortality or overall mortality in patients undergoing allogeneic haematopoietic cell transplantation. Because it is unclear whether the outcomes after cord blood transplantation are influenced by a prior history of cancer, we retrospectively assessed the prevalence and prognostic impact of a prior history of cancer in adult patients undergoing myeloablative single-unit cord blood transplantation in our institute between 2004 and 2020. The univariate analysis showed that a prior history of cancer did not affect the probability of overall survival; the cumulative incidence of relapse; or non-relapse mortality. In the multivariate analysis, prior history of cancer was not associated with overall mortality, relapse or non-relapse mortality. No patients with a prior history of cancer had experienced prior cancer relapse. A prior history of cancer was not associated with non-relapse mortality or overall mortality following single-unit cord blood transplantation.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Neoplasias/patologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The intestinal microbiota plays a fundamental role in the development of host innate immune cells, such as monocytes, dendritic cells (DCs), and natural killer (NK) cells. We examined the association between intestinal microbiota and subsequent immune reconstitution of circulating monocyte, DC, and NK cell subsets in 38 adult patients undergoing single-unit cord blood transplantation (CBT). A higher diversity of intestinal microbiota at 1 month was significantly associated with higher counts of plasmacytoid DCs at 7 months after CBT, as measured by the Chao1 index. Principal coordinate analysis of unweighted UniFrac distances showed significant differences between higher and lower classical monocyte reconstitution at 7 months post-CBT. The families Neisseriaceae, Burkholderiaceae, Propionibacteriaceae, and Coriobacteriaceae were increased in higher classical monocyte reconstitution at 7 months post-CBT, whereas the family Bacteroidaceae was increased in lower classical monocyte reconstitution at 7 months post-CBT. These data show that intestinal microbiota composition affects immune reconstitution of classical monocyte and plasmacytoid DCs following single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Microbioma Gastrointestinal , Adulto , Células Dendríticas , Humanos , Células Matadoras Naturais , MonócitosRESUMO
CD300 molecules (CD300s) belong to paired activating and inhibitory receptor families, which mediate immune responses. Human CD300e (hCD300e) is expressed in monocytes and myeloid dendritic cells and transmits an immune-activating signal by interacting with DNAX-activating protein 12 (DAP12). However, the CD300e ortholog in mice (mCD300e) is poorly characterized. Here, we found that mCD300e is also an immune-activating receptor. We found that mCD300e engagement triggers cytokine production in mCD300e-transduced bone marrow-derived mast cells (BMMCs). Loss of DAP12 and another signaling protein, FcRγ, did not affect surface expression of transduced mCD300e, but abrogated mCD300e-mediated cytokine production in the BMMCs. Co-immunoprecipitation experiments revealed that mCD300e physically interacts with both FcRγ and DAP12, suggesting that mCD300e delivers an activating signal via these two proteins. Binding and reporter assays with the mCD300e extracellular domain identified sphingomyelin as a ligand of both mCD300e and hCD300e. Notably, the binding of sphingomyelin to mCD300e stimulated cytokine production in the transduced BMMCs in an FcRγ- and DAP12-dependent manner. Flow cytometric analysis with an mCD300e-specific Ab disclosed that mCD300e expression is highly restricted to CD115+Ly-6Clow/int peripheral blood monocytes, corresponding to CD14dim/+CD16+ human nonclassical and intermediate monocytes. Loss of FcRγ or DAP12 lowered the surface expression of endogenous mCD300e in the CD115+Ly-6Clow/int monocytes. Stimulation with sphingomyelin failed to activate the CD115+Ly-6Clow/int mouse monocytes, but induced hCD300e-mediated cytokine production in the CD14dimCD16+ human monocytes. Taken together, these observations indicate that mCD300e recognizes sphingomyelin and thereby regulates nonclassical and intermediate monocyte functions through FcRγ and DAP12.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Mastócitos/metabolismo , Monócitos/metabolismo , Processamento de Proteína Pós-Traducional , Receptores de IgG/metabolismo , Receptores Imunológicos/agonistas , Esfingomielinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Substituição de Aminoácidos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linhagem Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligantes , Mastócitos/citologia , Mastócitos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/imunologia , Mutação , Fragmentos de Peptídeos/agonistas , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Receptores de IgG/química , Receptores de IgG/genética , Receptores Imunológicos/química , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismoRESUMO
The optimal intensity of a conditioning regimen might be dependent on not only age and comorbidities but also disease activity and the type of graft source. We evaluated the outcome of unrelated single cord blood transplantation (CBT) using a conditioning regimen of fludarabine 180 mg/m2, i.v. busulfan 9.6 mg/kg, 4 Gy total body irradiation, granulocyte colony-stimulating factor-combined high-dose cytarabine (12 g/m2) in 23 elderly patients (median, 64 years) with nonremission myeloid malignancies between 2013 and 2018 in our institution. All but 1 patient achieved neutrophil engraftment at a median of 23.5 days (range, 18 to 50). With a median follow-up of 28 months, the probabilities of overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse at 2 years were 62%, 52%, and 26%, respectively. The cumulative incidences of nonrelapse mortality at 100 days and 2 years were 9% and 22%, respectively. In the univariable analysis a higher proportion of blasts in bone marrow and in peripheral blood and a monosomal or complex karyotype were significantly associated with inferior OS and DFS. Poor cytogenetics were significantly associated with inferior DFS and increased relapse incidence. These data demonstrate that this reduced-toxicity myeloablative conditioning regimen was tolerable and effective in terms of engraftment, relapse, and survival in single CBT for elderly patients with nonremission myeloid malignancies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/terapia , Vidarabina/análogos & derivados , Irradiação Corporal Total/métodos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bussulfano/farmacologia , Citarabina/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/farmacologia , Síndromes Mielodisplásicas/patologia , Vidarabina/farmacologia , Vidarabina/uso terapêuticoRESUMO
Markers of inflammatory and nutritional status, such as the Controlling Nutritional Status (CONUT) score, Prognostic Nutritional Index, Glasgow Prognostic Score, and C-reactive protein-albumin ratio (CAR) has been demonstrated to be associated with poor prognosis in patients with various cancers. Although the relatively low cell dose of a single cord blood unit restricts the indication for cord blood transplantation (CBT) to pediatric and relatively smaller and lighter adult patients, the impact of malnutrition on outcomes after CBT is unclear. We retrospectively analyzed 165 adult patients who underwent myeloablative single-unit CBT in our institute. In multivariate analysis, a higher CONUT score, which is indicative of poor inflammatory and nutritional status, was significantly associated with poor outcomes, including low neutrophil engraftment and development of extensive chronic graft-versus-host disease. A higher CAR, which is also suggestive of poor inflammatory and nutritional status, was significantly associated with poor neutrophil engraftment and higher overall mortality. Body mass index (BMI) was not associated with transplantation outcomes. These data suggest that poor pretransplantation inflammatory and nutritional status might be a more practical parameter than lower BMI, for predicting transplantation outcomes after single CBT for adults.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Inflamação/diagnóstico , Neoplasias/diagnóstico , Estado Nutricional , Adulto , Biomarcadores/análise , Índice de Massa Corporal , Proteína C-Reativa/análise , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Humanos , Agonistas Mieloablativos/uso terapêutico , Neoplasias/terapia , Prognóstico , Estudos Retrospectivos , Albumina Sérica Humana/análise , Adulto JovemRESUMO
The different effects of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on outcomes after cord blood transplantation (CBT) are unclear. We retrospectively evaluated the impact of PES and aGVHD on relapse and survival after single-unit CBT in 138 adult patients with hematologic malignancies at our institution between 2004 and 2016. Multivariate analysis demonstrated that development of grade III-IV aGVHD, particularly with gut or liver involvement, significantly contributed to higher nonrelapse mortality (P < .001), but PES and grade II-IV aGVHD did not. In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (Pâ¯=â¯.032) and better disease-free survival (DFS) (Pâ¯=â¯.046) in patients with acute myelogenous leukemia (AML). These data suggest that PES is associated with a reduced relapse rate and better DFS in AML, indicating that the early immune reaction before neutrophil engraftment may provide a unique graft-versus-leukemia effect after single-unit CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
T memory stem cells (TSCMs) are a subset of primitive T cells capable of both self-renewal and differentiation into all subsets of memory and effector T cells. Therefore, TSCMs may play a role in immune reconstitution and graft-versus-host disease (GVHD) in patients receiving allogeneic haematopoietic cell transplantation (HCT). We conducted a cross-sectional study to evaluate the proportions, absolute counts, phenotypes and functions of TSCMs in 152 adult patients without disease recurrence at least 12 months after undergoing HCT. CD4+ TSCMs were negatively correlated with number of months after transplantation in HCT patients that received cord blood transplantation, but not in patients that received bone marrow transplantation or peripheral blood stem cell transplantation. The proportions and absolute counts of CD4+ TSCMs and expression levels of inducible co-stimulator (ICOS) in CD8+ TSCMs were significantly higher in patients with mild and moderate/severe cGVHD compared to patients without cGVHD. These data suggested that, more than 12 months after allogeneic HCT, the kinetics of CD4+ TSCMs were dependent on the type of donor source, and further that CD4+ TSCMs and ICOS levels in CD8+ TSCMs were associated with cGVHD.
Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica , Doadores não Relacionados , Adulto , Idoso , Aloenxertos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Cinética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Neutropenia Febril/tratamento farmacológico , Micoses/prevenção & controle , Doadores não Relacionados , Adolescente , Adulto , Idoso , Aloenxertos , Neutropenia Febril/sangue , Neutropenia Febril/etiologia , Feminino , Humanos , Masculino , Micafungina/administração & dosagem , Micafungina/farmacocinética , Pessoa de Meia-Idade , Micoses/sangue , Micoses/etiologia , Estudos RetrospectivosRESUMO
The introduction of the prophylactic use of antifungal drugs caused the increased occurrence of invasive fungal infections due to previously rare molds, such as fusariosis, after allogeneic hematopoietic stem cell transplantation. We herein report the case of a patient with diffuse large B-cell lymphoma who developed fungemia due to Fusarium solani during liposormal amphotericin B on day 25 after cord blood transplantation (CBT). Because Fusarium species might differ in virulence and drug susceptibility, the sequencing of the internal transcribed spacer region of the ribosomal RNA gene accurately identified Fusarium solani to be the cause of fungemia at the species level. This case highlights Fusarium solani as the cause of fungemia in a patient under liposormal amphotericin B treatment after CBT.
Assuntos
Anfotericina B/efeitos adversos , Fungemia/microbiologia , Fusarium/patogenicidade , Idoso , Antifúngicos/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Fungemia/tratamento farmacológico , Humanos , MasculinoRESUMO
LPS triggers inflammatory responses; however, the negative regulation of LPS responses in vivo remains poorly understood. CD300f is an inhibitory receptor among the CD300 family of paired activating and inhibitory receptors. We have previously identified ceramide as a ligand for CD300f and shown that the binding of ceramide to CD300f inhibits IgE-mediated mast cell activation and allergic responses in mouse models. Here we identify the critical role of CD300f in inhibiting LPS-induced skin inflammation. CD300f deficiency remarkably enhanced LPS-induced skin edema and neutrophil recruitment in mice. Higher levels of factors that increase vascular permeability and of factors that induce neutrophil recruitment were detected in LPS-injected skin pouch exudates of CD300f-/- mice as compared with wild-type mice. CD300f was highly expressed in mast cells and recruited neutrophils, but not in macrophages, among skin myeloid cells. CD300f deficiency failed to influence the intrinsic migratory ability of neutrophils. Ceramide-CD300f binding suppressed the release of chemical mediators from mast cells and from neutrophils in response to LPS. Adoptive transfer experiments indicated that mast cells mediated enhanced edema in LPS-stimulated skin of CD300f-/- mice, whereas mast cells together with recruited neutrophils mediated robust neutrophil accumulation. Importantly, administering a ceramide antibody or ceramide-containing vesicles enhanced or suppressed LPS-induced skin inflammation of wild-type mice, respectively. Thus, ceramide-CD300f binding inhibits LPS-induced skin inflammation, implicating CD300f as a negative regulator of Toll-like receptor 4 (TLR4) signaling in vivo.
Assuntos
Ceramidas/metabolismo , Dermatite/prevenção & controle , Lipopolissacarídeos/toxicidade , Receptores Imunológicos/metabolismo , Animais , Quimiotaxia de Leucócito , Dermatite/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Receptores Imunológicos/genéticaRESUMO
Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5 × 109/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34+ cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10 mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transfusão de Plaquetas/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute. Within the entire cohort, 42 patients (88%) received L-AMB as empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62 to 2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7 to 241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1 to 313 days). A documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 patients (90%) survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patient developed an increase in serum creatinine levels of grade 3 or higher. In univariate analyses using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB of more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.
Assuntos
Anfotericina B/efeitos adversos , Anfotericina B/farmacologia , Antifúngicos/efeitos adversos , Antifúngicos/farmacologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Micoses/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome-positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute. Except for a negative association between the number of classical monocytes and imatinib treatment, the proportions and numbers of monocyte subsets were not significantly associated with TKI treatment. However, chemokine receptors, CCR2, CX3CR1 on classical monocytes, and scavenger receptor, CD204, on intermediate and non-classical monocytes were significantly associated with TKIs. These data demonstrated the relationships between alterations of chemokine and scavenger receptors on different monocyte subsets and the TKI treatments.