RESUMEN
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.
Asunto(s)
Encéfalo , Interferón Tipo I , Microglía , Animales , Ratones , Interferón Tipo I/metabolismo , Microglía/metabolismo , Neuronas/metabolismo , Pez Cebra , Encéfalo/citología , Encéfalo/crecimiento & desarrolloRESUMEN
Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
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Mielofibrosis Primaria , Humanos , Pronóstico , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Mutación , Janus Quinasa 2/genética , Frecuencia de los GenesRESUMEN
BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.
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Leucemia Mieloide Aguda , Neoplasias Primarias Secundarias , Policitemia Vera , Mielofibrosis Primaria , Trombosis , Hemorragia/inducido químicamente , Humanos , Hidroxiurea/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Nitrilos , Policitemia Vera/tratamiento farmacológico , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles , Pirimidinas , Estudios Retrospectivos , Trombosis/inducido químicamente , Trombosis/tratamiento farmacológico , Trombosis/prevención & controlRESUMEN
Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.
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Mielofibrosis Primaria , Trombocitemia Esencial , Trombosis , Humanos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Trombosis/epidemiología , Trombosis/etiología , Trombosis/diagnóstico , Hemorragia/diagnóstico , Sistema de Registros , Factores de RiesgoRESUMEN
Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.
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Leucemia Mieloide Aguda , Policitemia Vera , Mielofibrosis Primaria , Trombosis , Humanos , Leucemia Mieloide Aguda/complicaciones , Persona de Mediana Edad , Flebotomía/efectos adversos , Policitemia Vera/complicaciones , Policitemia Vera/diagnóstico , Policitemia Vera/cirugía , Mielofibrosis Primaria/diagnóstico , Sistema de Registros , Trombosis/complicaciones , Trombosis/etiologíaRESUMEN
The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.
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Calreticulina/genética , Genotipo , Hidroxiurea/administración & dosificación , Mutación Missense , Quinazolinas/administración & dosificación , Sistema de Registros , Trombocitemia Esencial , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Niño , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , España , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genéticaRESUMEN
Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.
Asunto(s)
Policitemia Vera/complicaciones , Circulación Esplácnica , Trombocitemia Esencial/complicaciones , Trombosis de la Vena/etiología , Adulto , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Hemorragia/epidemiología , Humanos , Estimación de Kaplan-Meier , Hepatopatías/epidemiología , Masculino , Venas Mesentéricas , Persona de Mediana Edad , Neoplasias Primarias Secundarias/epidemiología , Vena Porta , Mielofibrosis Primaria/etiología , Modelos de Riesgos Proporcionales , Sistema de Registros , Riesgo , España/epidemiología , Vena EsplénicaRESUMEN
BACKGROUND: We analyze the cost of an incorrect application, by the haematologist, of bridging anticoagulation in patients with low-risk atrial fibrillation (AF) needing interruption of treatment prior to a scheduled invasive procedure. Although not recommended, bridging therapy is widely used, resulting in avoidable costs and increased workload. METHODS: Observational retrospective study. We recorded demographic and clinical data including age, sex, type of procedure, use of bridging therapy with low molecular weight heparin (LMWH), and haemorrhagic complications within 30 days of acenocoumarol withdrawal. RESULTS: Acenocoumarol was stopped in 161 patients, 97 (60%) were male and 64 (40%) female. Average age was 76,11 ± 8,45 years. Procedures included: minor surgical intervention 58 (36%), colonoscopy 61 (38%), gastroscopy 11 (7%), breast biopsy 4 (2.5%), prostate biopsy 4 (2.5%), infiltration 5 (3%), and other 18 (11%). All patients received bridging anticoagulation with LMWH (40 mg enoxaparin per day) 3 days before and 3 days after the procedure (6 doses). We used a total of 966 doses, at 4.5 per unit, resulted in 4347 of total cost. No complications occurred in 156 patients (97%). Haemorrhage was observed in 5 cases: 1 major haemorrhage needing 6 days of hospital stay and transfusion, and 4 minor haemorrhages (2 patients needed emergency attendance and 2 required hospital admission for 3 and 2 days, respectively). The cost of emergency care was 237.36, and the cost of hospital stay was 6860.81 (623.71 per day, for 11 days). The total cost of the incorrect application of the protocol was 11,445.17. CONCLUSION: Guidelines about bridging anticoagulation in low risk AF patients undergoing scheduled invasive procedures were not followed. This practice increments the complications and supposes an increase in costs besides to an inadequate use of the human resources.
Asunto(s)
Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Adhesión a Directriz/estadística & datos numéricos , Heparina de Bajo-Peso-Molecular/administración & dosificación , Anciano , Anciano de 80 o más Años , Costos y Análisis de Costo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Guías de Práctica Clínica como Asunto , Estudios RetrospectivosRESUMEN
Prognostic models are widely used in clinical practice for transplant decision-making in myelofibrosis (MF). We have compared the performance of the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus in a series of 544 patients with primary or secondary MF aged ≤ 70 years at the time of diagnosis. The median projected survival of the overall series was 9.46 years (95% confidence interval 7.44-10.59). Median survival for the highest risk groups was less than 4 years in the three prognostic models. By contrast, the projected survival for patients in the intermediate-2 categories by the IPSS, DIPSS, and DIPSS-plus was 6.6, 5.6, and 6.5 years, respectively. The number of patients in the intermediate-2 and high-risk categories was smaller in the DIPSS than in the IPSS or the DIPSS-plus. The IPSS and DIPSS-plus were the best models to discriminate between the intermediate-1 and intermediate-2 risk categories, which is a critical cut-off point for patient selection to transplant. Among patients assigned at diagnosis to the intermediate-2 or high-risk groups by the IPSS, DIPSS, and DIPSS-plus, only 17, 21, and 20%, respectively, were subsequently transplanted. In conclusion, in our contemporary series of younger MF patients only the highest risk categories of the current prognostication systems have a median survival below the 5-year threshold recommended for considering transplantation. Patient selection for transplantation can significantly differ depending on which prognostication model is used for disease risk stratification.
Asunto(s)
Toma de Decisiones Clínicas/métodos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/terapia , Trasplante de Células Madre/métodos , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/epidemiología , Pronóstico , Sistema de Registros , Factores de Riesgo , España/epidemiología , Trasplante Homólogo/métodosAsunto(s)
Violencia de Género , Maltrato Conyugal , Humanos , Femenino , Violencia , Instituciones de Salud , Atención Primaria de SaludRESUMEN
Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0-2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5-6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3-9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis.
Asunto(s)
Hidroxiurea/uso terapéutico , Flebotomía , Policitemia Vera/complicaciones , Policitemia Vera/terapia , Trombosis/epidemiología , Trombosis/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células Sanguíneas , Terapia Combinada , Resistencia a Medicamentos , Femenino , Hematócrito , Humanos , Hidroxiurea/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , Policitemia Vera/diagnóstico , Sistema de Registros , Riesgo , España/epidemiología , Trombosis/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.
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Hidroxiurea/uso terapéutico , Inhibidores de la Síntesis del Ácido Nucleico/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Medicamentos , Tolerancia a Medicamentos , Femenino , Humanos , Hidroxiurea/efectos adversos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Inhibidores de la Síntesis del Ácido Nucleico/efectos adversos , Policitemia Vera/sangre , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Studies comparing rabbit antithymocyte globulin (rATG) and horse ATG (hATG) in patients with aplastic anemia (AA) have shown conflicting results. These studies included fewer than 60 subjects in the rATG arm with relatively short follow-up. A total of 169 patients treated with rATG and 62 treated with hATG were included in this retrospective analysis, across 33 centers. Patients were treated with rATG or hATG plus cyclosporine A. Over half were classified, as having severe AA (SAA) or very severe AA (VSAA), and the mean follow-up was 45 months. There was no significant difference detected in cumulative response to treatment or survival between the rATG and hATG groups. The response to treatment was 63 % in the rATG group versus 66 % in the hATG group at 3 months. By 12 months, this pattern had reversed, and 84 % of rATG patients had responded to treatment versus 76 % in the hATG group (n.s.). Early mortality due to infection tended to be higher with rATG compared to hATG (n.s). rATG and hATG would seem to be therapeutically equivalent in SAA and VSAA. However, patients treated with rATG may take longer to respond than those treated with hATG and may also require more active prevention of early infections.
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Anemia Aplásica/sangre , Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico/administración & dosificación , Adulto , Anciano , Anemia Aplásica/diagnóstico , Animales , Femenino , Estudios de Seguimiento , Caballos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Conejos , Estudios Retrospectivos , Especificidad de la Especie , Resultado del Tratamiento , Adulto JovenRESUMEN
The role of bosutinib as rescue treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth-line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression-free survival was 73%. Grade 3-4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.
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Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Ensayos de Uso Compasivo , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Adulto , Anciano , Benzamidas/uso terapéutico , Dasatinib , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crónica/enzimología , Leucemia Mieloide de Fase Crónica/mortalidad , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/uso terapéutico , Estudios Retrospectivos , España , Análisis de Supervivencia , Tiazoles/uso terapéuticoRESUMEN
BACKGROUND: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. METHODS: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. RESULTS: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. CONCLUSION: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Proteínas de Unión al ADN , Dioxigenasas , Mutación , Policitemia Vera , Proteínas Proto-Oncogénicas , Proteínas Represoras , Trombosis , Humanos , Masculino , Femenino , Persona de Mediana Edad , Trombosis/genética , Factores de Riesgo , Anciano , Policitemia Vera/genética , Policitemia Vera/complicaciones , Proteínas Represoras/genética , Factores de Edad , Proteínas Proto-Oncogénicas/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Proteínas de Unión al ADN/genética , Estudios de Casos y Controles , Adulto , Europa (Continente)/epidemiología , Incidencia , Predisposición Genética a la Enfermedad , Medición de Riesgo , Estimación de Kaplan-Meier , Anciano de 80 o más AñosAsunto(s)
Mielofibrosis Primaria , Sistema de Registros , Trombocitopenia , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/sangre , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , España/epidemiología , Tasa de Supervivencia , Trombocitopenia/sangre , Trombocitopenia/diagnóstico , Trombocitopenia/mortalidad , Trombocitopenia/terapiaRESUMEN
Multiple myeloma (MM) is a hematological neoplasm for which different chemotherapy treatments are used with several drugs in combination. One of the most frequently used drugs for the treatment of MM is the proteasome inhibitor bortezomib. Patients treated with bortezomib are at increased risk for thrombocytopenia, neutropenia, gastrointestinal toxicities, peripheral neuropathy, infection, and fatigue. This drug is almost entirely metabolized by cytochrome CYP450 isoenzymes and transported by the efflux pump P-glycoprotein. Genes encoding both enzymes and transporters involved in the bortezomib pharmacokinetic pathway are highly polymorphic. The response to bortezomib and the incidence of adverse drug reactions (ADRs) vary among patients, which could be due to interindividual variations in these possible pharmacogenetic biomarkers. In this review, we compiled all pharmacogenetic information relevant to the treatment of MM with bortezomib. In addition, we discuss possible future perspectives and the analysis of potential pharmacogenetic markers that could influence the incidence of ADR and the toxicity of bortezomib. It would be a milestone in the field of targeted therapy for MM to relate potential biomarkers to the various effects of bortezomib on patients.
RESUMEN
Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.