RESUMEN
ABSTRACT: Among 281 patients with essential thrombocythemia and calreticulin (CALR) mutation, we found a variant allele frequency of ≥60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.
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Mielofibrosis Primaria , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/complicaciones , Calreticulina/genética , Mielofibrosis Primaria/complicaciones , Mutación , Janus Quinasa 2/genéticaAsunto(s)
Policitemia Vera/complicaciones , Policitemia/complicaciones , Trombosis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Policitemia/diagnóstico , Policitemia Vera/diagnóstico , Estudios Retrospectivos , Trombosis/diagnóstico , Adulto JovenAsunto(s)
COVID-19/etiología , Enfermedades Transmisibles/etiología , Trastornos Mieloproliferativos/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Policitemia Vera/complicaciones , Mielofibrosis Primaria/complicaciones , Estudios Prospectivos , Quebec/epidemiología , Factores de Riesgo , Trombocitemia Esencial/complicacionesAsunto(s)
Antineoplásicos/uso terapéutico , Medicamentos Genéricos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: In the current study, the authors determined whether adhering to molecular monitoring guidelines in patients with chronic myeloid leukemia (CML) is associated with major molecular response (MMR) and assessed barriers to adherent monitoring. METHODS: Newly treated patients with CML from the Quebec province-wide CML registry from 2005 to 2016 were included. Timely polymerase chain reaction (tPCR) was defined as the molecular assessment of BCR-ABL1 at the 3-month, 12-month, and 18-month time points from the initiation of tyrosine kinase inhibitor (TKI) therapy. The cohort was analyzed as a nested case-control study. Cases with a first-ever MMR (BCR-ABL1 ≤0.1%, assessed at any time during follow-up) were matched to up to 5 controls by duration of TKI therapy, volume of patients with CML at the treatment center, year of cohort entry, and age. Odds ratios (ORs) for the performance of tPCR and MMR were adjusted for sex, comorbidities, type of TKI, and other important covariates. RESULTS: The cohort included 496 patients. Of 392 MMR events, 67.9% occurred before 18 months. The performance of tPCR was associated with a doubling of the MMR rate (OR, 2.23; 95% confidence interval [95% CI], 1.56-3.21) and was similar with 1 to 3 tPCRs performed (P = .67). Furthermore, tPCRs at 3 months (OR, 2.77; 95% CI, 1.81-4.23) and 12 months (OR, 3.00; 95% CI, 1.64-5.49) were associated with achieving early MMR, whereas tPCRs at 18 months were not (OR, 1.23; 95% CI, 0.80-1.89). Low-volume centers were found to have lower adherence to tPCR (OR, 0.60; 95% CI, 0.40-0.89). CONCLUSIONS: Timely molecular assessment at 3 months and 12 months appears to benefit patients with CML. Adherence to timely monitoring should be encouraged, especially in low-volume treatment centers.
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Monitoreo de Drogas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Espera Vigilante/normas , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/metabolismoAsunto(s)
Proteínas de Fusión bcr-abl , Dosificación de Gen , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas/administración & dosificación , Sistema de Registros , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MasculinoRESUMEN
Plasmacytoid dendritic cells (pDCs) initiate both innate and adaptive immune responses, making them attractive targets for post-transplantation immunotherapy, particularly after cord blood transplantation (CBT). Toll-like receptor (TLR) agonists are currently studied for pDC stimulation in various clinical settings. Their efficacy depends on pDC number and functionality, which are unknown after CBT. We performed a longitudinal study of pDC reconstitution in children who underwent bone marrow transplantation (BMT) and single-unit CBT. Both CBT and unrelated BMT patients received antithymocyte globulin as part of their graft-versus-host disease prophylaxis regimen. pDC blood counts were higher in CBT patients than in healthy volunteers from 2 to 9 months after transplantation, whereas they remained lower in BMT patients. We showed that cord blood progenitors gave rise in vitro to a 500-fold increase in functional pDCs over bone marrow counterparts. Upon stimulation with a TLR agonist, pDCs from both CBT and BMT recipients upregulated T cell costimulatory molecules, whereas interferon-alpha (IFN-α) production was impaired for 9 months after CBT. TLR agonist treatment is thus not expected to induce IFN-α production by pDCs after CBT, limiting its immunotherapeutic potential. Fortunately, in vitro production of large amounts of functional pDCs from cord blood progenitors paves the way for the post-transplantation adoptive transfer of pDCs.
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Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre del Cordón Umbilical , Células Dendríticas/inmunología , Inmunoterapia , Leucemia/terapia , Oligodesoxirribonucleótidos/uso terapéutico , Receptor Toll-Like 9/agonistas , Adolescente , Antígenos CD/genética , Antígenos CD/inmunología , Suero Antilinfocítico/uso terapéutico , Recuento de Células , Proliferación Celular , Niño , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Femenino , Expresión Génica , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/biosíntesis , Leucemia/genética , Leucemia/inmunología , Leucemia/patología , Estudios Longitudinales , Masculino , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Plasmacytoid dendritic cells (PDCs) from human umbilical cord blood (UCB) produce lower amounts of IFN-α upon TLR stimulation compared with adult counterparts. This difference may play a role in the low graft-versus-host disease rate after UCB transplantation and in the impaired immune response of the neonate to pathogens. Comparing UCB PDC to their adults counterparts, we found that they exhibited a mature surface phenotype and a normal antigen uptake. They upregulated costimulatory molecules upon activation, although with delayed kinetics. Protein, but not ARN, levels of TLR-9, MyD88, IRAK1 and IRF-7, involved in the TLR-9 signaling pathway were reduced. The expression levels of miR-146a and miR-155, known to be involved in the post-transcriptional down-regulation of immune responses, were higher. These data point out a post-transcriptional down-regulation of the TLR-9/IRF-7 signaling pathway in UCB PDC.
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Células Dendríticas/inmunología , Sangre Fetal/inmunología , MicroARNs/genética , Interferencia de ARN , Transducción de Señal , Receptores Toll-Like/inmunología , Diferenciación Celular , Células Dendríticas/citología , Regulación hacia Abajo , Sangre Fetal/citología , Humanos , FenotipoRESUMEN
Physiological modulation of the immune system is required for foetal tolerance during pregnancy. However, this immune regulation might lead to impaired self-defence against pathogens. Indeed, pregnant women are more susceptible to newly encountered viruses comparing to non-pregnant women, as exemplified by the prevalence of severe complications in pregnant women infected with the pandemic influenza virus in 2009. Plasmacytoid dendritic cells (pDCs) are specialized dendritic cells that recognise viral antigens and initiate both innate and adaptive immune responses. We therefore sought to determine whether the number and/or the functions of peripheral blood pDCs are regulated during pregnancy. pDC maturation and interferon (IFN)-α production were analysed in response to Toll-like receptor (TLR) stimulation of peripheral blood mononuclear cells from pregnant and non-pregnant women. Our results reveal that pDC frequency is slightly decreased, while the IFN-α production in response to TLR stimulation increases during pregnancy. Interestingly, the up-regulation of the co-stimulatory receptors CD54 (ICAM1) and CD86 is significantly decreased in pDCs from pregnant women as compared to controls, suggesting a possible impact on T-cell responses. In conclusion, we propose that the modulation of CD54 and CD86 expression on peripheral blood pDCs during pregnancy might decrease the initiation of adaptive antiviral immune responses.