RESUMEN
Sickle cell disease is a rare, but complex multi-systemic disorder with high need of interdisciplinary and specialized care and new structural requirements. Besides care of those chronically sick patients, transition process is a vulnerable phase which highly influences further treatment. To make matters worse, patients often have migration background with subsequent communication problems. A national guidance for a standardized transition process is lacking in Germany. In context of a structured consensus process, the "transition initiative sickle cell disease" developed specific recommendations for a structured transition of sickle cell patients on the basis of the S3 transition guideline of the DGfTM. These recommendations should improve this vulnerable process in this complex disease to ensure adequate further treatment and to avoid acute and chronic complications but also mental, social or job-related issues. Besides improvement of quality of life, medical treatment and survival, health economic aspects arise. Documents were developed to support and facilitate the transition process and are available under www.sichelzellkrankheit.info/transition/.
Asunto(s)
Anemia de Células Falciformes , Humanos , Anemia de Células Falciformes/terapia , Alemania , Transición a la Atención de Adultos , Guías de Práctica Clínica como AsuntoRESUMEN
In this analysis, we examined the risk of secondary malignancies for tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients. We also collected data on specific risk factors for colorectal cancer. Ninety-one patients with CML and 76 controls were included and in total 4 (4.4%) secondary malignancies were found in patients and 8 (10.5%) in controls. The risk for secondary malignancies was not significantly elevated for CML patients (p = 0.141). Two (2.2%) CML patients developed colorectal cancer compared to 4 (5.3%) in the reference group. A higher risk for CML patients for colorectal cancer could not be found (p = 0.414).
RESUMEN
Sickle cell disease (SCD) is considered a rare disease in Germany. Due to the increasing prevalence, the acute and chronic morbidities associated with the disease and the sharp increase in the mortality rate of young adults, a need-based transition structure for patients with SCD in Germany is explicitly required. This is the first multicenter German consensus statement addressing the importance of implementing a standardized transition guideline that allows adolescents and young adults to safely transition from pediatric to adult care. Early identification of medical needs and intervention remains important in the context of chronic diseases. Effective measures can improve health care in general, as they lead to a reduction in disease and the consequential economic burden. It is noteworthy that improving structural barriers remains a key challenge even in highly developed countries such as Germany. Inclusion of these transition services for patients with SCD into the regular care of chronically ill adolescents and young adults should be ensured, as well as the coverage of costs associated with a structured transition process.
RESUMEN
In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, eventfree survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.
Asunto(s)
Andrógenos/farmacología , Disqueratosis Congénita/sangre , Homeostasis del Telómero/efectos de los fármacos , Telómero/metabolismo , Adulto , Recuento de Células Sanguíneas , Disqueratosis Congénita/tratamiento farmacológico , Disqueratosis Congénita/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , ARN/genética , ARN/metabolismo , Telomerasa/genética , Telomerasa/metabolismo , Telómero/genéticaRESUMEN
OBJECTIVE: In older adults with acute myeloid leukemia (AML), the overall outcome is still dismal and long-term data on survival are scarce, particularly outside of clinical trials. Here, we assess characteristics, prognostic factors and long-term survival in patients ≥60 years who were treated for AML at our center over the past 17 years. METHODS: 590 older adults with newly diagnosed AML were characterized according to Eastern Cooperative Oncology Group (ECOG) score, Charlson comorbidity index (CCI), European LeukemiaNet (ELN) risk, type of therapy, serum ferritin (SF) and further baseline characteristics. Survival analysis was performed accordingly. RESULTS: Median age was 68 years and most patients were in good general condition. Median follow-up was 55.8 months. Of all patients, 66% received intensive chemotherapy (IC) +/- allogeneic hematopoietic stem cell transplantation (allo-HSCT). The remaining cohort received palliative chemotherapy (PC, 26%) or best supportive care only (BSC, 8%). Enrollment rate for interventional clinical trials was 26%. 5-year overall survival (OS) and relapse-free survival (RFS) were 18% (median 12.5 months) and 11,5% (median 10.0 months). Long-term survival was independently influenced by ECOG score, ELN risk group, baseline SF, previous myocardial infarction, and choice of therapy, but not consistently by age or CCI. Considering therapeutic subgroups, the contribution of particular parameters in predicting OS was most compelling in IC patients, but less consistent with PC or BSC. CONCLUSION: Our results provide thorough insights into prognostication within therapeutic subgroups and emphasize the need for more detailed prognostic algorithms and routine geriatric assessment in the treatment of older adults with AML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Anciano , Humanos , Leucemia Mieloide Aguda/terapia , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Centros de Atención TerciariaRESUMEN
Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.
Asunto(s)
Evolución Clonal , Mielofibrosis Primaria/genética , Anciano , Exoma , Femenino , Estudios de Seguimiento , Heterogeneidad Genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteína Oncogénica p21(ras)/genética , Estudios Prospectivos , Análisis de la Célula Individual , Células Madre/citologíaRESUMEN
AIMS: The aim of the presente study was to examine the effects of oral gallic acid (GA) administration on the brown adipose tissue of obese mice fed with high-fat diet. New mechanisms and interactions pathways in thermogenesis were accessed through bioinformatics analyses. MAIN METHODS: Swiss male mice were divided into four groups and fed during 60 days with: standard diet, standard diet combined with gallic acid, high-fat diet and high-fat diet combined with gallic acid. Body weight, food intake, and blood parameters (glucose tolerance test, total-cholesterol, high-density low-c, triglyceride and glucose levels) were evaluated. Brown and subcutaneous white adipose tissue histological analysis were performed. SIRT1 and PGC1-α mRNA expression in the brown adipose tissue were assessed. KEY FINDINGS: Our main findings showed that the gallic acid improved glucose tolerance and metabolic parameters. These results were accompanied by bioinformatics analyses that evidenced SIRT1 as main target in the thermogenesis process, confirmed as increased SIRT1 mRNA expression was evidenced in the brown adipose tissue. SIGNIFICANCE: Together, the data suggest that the gallic acid effect in brown adipose tissue may improve body metabolism, glucose homeostasis and increase thermogenesis.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Biología Computacional/métodos , Dieta Alta en Grasa/efectos adversos , Ácido Gálico/farmacología , Metaboloma/efectos de los fármacos , Obesidad/metabolismo , Sirtuina 1/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/patología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Sirtuina 1/genética , Termogénesis/efectos de los fármacosRESUMEN
Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23-60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.
Asunto(s)
Biomarcadores de Tumor/genética , Disqueratosis Congénita/genética , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Acortamiento del Telómero/genética , Adulto , Disqueratosis Congénita/complicaciones , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Incidencia , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Platelets are important for effective hemostasis and considered to be involved in pathophysiological processes, e.g. in cardiovascular diseases. Platelets provided for research or for therapeutic use are frequently separated from citrated whole blood (WB) stored for different periods of time. Although functionally intact platelets are required, the stability of platelet integrity, e.g. adenosine diphosphate (ADP) mediated responsiveness, has never been thoroughly investigated in citrated WB under ex vivo conditions. OBJECTIVES: Platelet integrity was evaluated at different time points in citrated WB units, collected from healthy donors and stored for 5 days at ambient temperature. The analysis included the measurement of activation markers, of induced light transmission aggregometry and of purinergic receptor expression or function. Inhibitory pathways were explored by determination of basal vasodilator-stimulated phosphoprotein (VASP)-phosphorylation, intracellular cyclic nucleotide levels and the content of phosphodiesterase 5A. Fresh peripheral blood (PB) samples served as controls. RESULTS: On day 5 of storage, thrombin receptor activating peptide-6 (TRAP-6) stimulated CD62P expression and fibrinogen binding were comparable to PB samples. ADP induced aggregation continuously decreased during storage. Purinergic receptor expression remained unchanged, whereas the P2Y1 activity progressively declined in contrast to preserved P2Y12 and P2X1 function. Inhibitory pathways were unaffected except for a slight elevation of VASP phosphorylation at Ser239 on day 5. CONCLUSION: After 5 days of storage in citrated WB, platelet responsiveness to TRAP-6 is sufficiently maintained. However, ADP-mediated platelet integrity is more sensitive to deterioration, especially after storage for more than 2 days. Decreasing ADP-induced aggregation is particularly caused by the impairment of the purinergic receptor P2Y1 activity. These characteristics should be considered in the use of platelets from stored citrated WB for experimental or therapeutic issues.
Asunto(s)
Adenosina Difosfato/farmacología , Plaquetas/efectos de los fármacos , Ácido Cítrico/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Receptores Purinérgicos P2Y1/genética , Adulto , Plaquetas/citología , Plaquetas/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Supervivencia Celular/genética , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Femenino , Fibrinógeno/metabolismo , Regulación de la Expresión Génica , Humanos , Masculino , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Selectina-P/genética , Selectina-P/metabolismo , Fragmentos de Péptidos/farmacología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Unión Proteica/efectos de los fármacos , Receptores Purinérgicos P2X1/genética , Receptores Purinérgicos P2X1/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismoRESUMEN
BACKGROUND: This study aims to investigate the effects of a modified, balanced crystalloid including phosphate in a perioperative setting in order to maintain a stable electrolyte and acid-base homeostasis in the patient. METHODS/DESIGN: This is a single-centre, open-label, randomized controlled trial involving two parallel groups of female patients comparing a perioperative infusion regime with sodium glycerophosphate and Jonosteril® (treatment group) or Jonosteril® (comparator) alone. The primary endpoint is to maintain a stable concentration of weak acids [A-] according to the Stewart approach of acid-base balance. Secondary endpoints are measurement of serum phosphate levels, other acid-base parameters such as the strong ion difference (SID), the onset and severity of postoperative nausea and vomiting (PONV), electrolyte levels and their excretion in the urine, monitoring of renal function and glycocalyx components, haemodynamics, amounts of catecholamines and other vasopressors used and the safety of the infusion regime. DISCUSSION: Perioperative fluid replacement with the use of currently available crystalloid preparations still fail to maintain a stable acid-base balance and experts agree that common balanced solutions are still not ideal. This study aims to investigate the effectivity and safety of a new crystalloid solution by adding sodium glycerophosphate to a standardized crystalloid preparation in order to maintain a balanced perioperative acid-base homeostasis. TRIAL REGISTRATION: EudraCT number 201002422520 . Registered on 30 November 2010.
Asunto(s)
Equilibrio Ácido-Base , Acidosis/prevención & control , Fluidoterapia/métodos , Glicerofosfatos/administración & dosificación , Soluciones Isotónicas/administración & dosificación , Soluciones para Rehidratación/administración & dosificación , Acidosis/sangre , Acidosis/etiología , Acidosis/fisiopatología , Biomarcadores/sangre , Protocolos Clínicos , Soluciones Cristaloides , Femenino , Fluidoterapia/efectos adversos , Alemania , Glicerofosfatos/efectos adversos , Humanos , Infusiones Intravenosas , Soluciones Isotónicas/efectos adversos , Modelos Biológicos , Atención Perioperativa , Fosfatos/sangre , Proyectos Piloto , Náusea y Vómito Posoperatorios/etiología , Estudios Prospectivos , Soluciones para Rehidratación/efectos adversos , Proyectos de Investigación , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Anciano , Dasatinib/uso terapéutico , Progresión de la Enfermedad , Femenino , Proteínas de Fusión bcr-abl/metabolismo , Expresión Génica , Humanos , Mesilato de Imatinib/uso terapéutico , Interferones/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Pirimidinas/uso terapéutico , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: The use of artificial colloids is currently controversial, especially in Central Europe Several studies demonstrated a worse outcome in intensive care unit patients with the use of hydroxyethyl starch. This recently even led to a drug warning about use of hydroxyethyl starch products in patients admitted to the intensive care unit. The data on hydroxyethyl starch in non-critically ill patients are insufficient to support perioperative use. METHODS/DESIGN: We are conducting a single-center, open-label, randomized, comparative trial with two parallel patient groups to compare human albumin 5% (test drug) with hydroxyethyl starch 6% 130/0.4 (comparator). The primary endpoint is cystatin C ratio, calculated as the ratio of the cystatin value at day 90 after surgery relative to the preoperative value. Secondary objectives are inter alia the evaluation of the influence of human albumin and hydroxyethyl starch on further laboratory chemical and clinical parameters, glycocalyx shedding, intensive care unit and hospital stay and acute kidney injury as defined by RIFLE criteria (risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease) criteria. DISCUSSION: There is a general lack of evidence on the relative safety and effects of hydroxyethyl starch compared with human albumin for volume replacement in a perioperative setting. Previously conducted studies of surgical patients in which researchers have compared different hydroxyethyl starch products included too few patients to properly evaluate clinical important outcomes such as renal function. In the present study in a high-risk patient population undergoing a major surgical intervention, we will determine if perioperative fluid replacement with human albumin 5% will have a long-term advantage over a third-generation hydroxyethyl starch 130/0.4 on the progression of renal dysfunction until 90 days after surgery. TRIAL REGISTRATION: EudraCT number 2010-018343-34. Registered on 11 January 2010.
Asunto(s)
Lesión Renal Aguda/prevención & control , Cistectomía , Fluidoterapia/métodos , Derivados de Hidroxietil Almidón/administración & dosificación , Hipovolemia/prevención & control , Riñón/efectos de los fármacos , Sustitutos del Plasma/administración & dosificación , Albúmina Sérica/administración & dosificación , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Protocolos Clínicos , Cistatina C/metabolismo , Cistectomía/efectos adversos , Progresión de la Enfermedad , Femenino , Fluidoterapia/efectos adversos , Alemania , Humanos , Derivados de Hidroxietil Almidón/efectos adversos , Hipovolemia/diagnóstico , Hipovolemia/etiología , Hipovolemia/fisiopatología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Sustitutos del Plasma/efectos adversos , Proyectos de Investigación , Albúmina Sérica/efectos adversos , Albúmina Sérica Humana , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The presence of a Philadelphia chromosome with a corresponding BCR-ABL1 rearrangement is the hallmark of chronic myeloid leukemia, but is considered a very rare event in de novo acute myeloid leukemia (AML). Here, we report the first case in which a dominant Philadelphia chromosome-positive subclone was detected upon relapse in a formerly Philadelphia chromosome-negative MLL-AF6(+) AML. Due to refractory disease under salvage chemotherapy, the patient was started on nilotinib treatment. As a result, the Philadelphia chromosome-positive subclone was eradicated within 1 month; however, disease progressed and was again dominated by the Philadelphia chromosome-negative founding clone, demonstrating rapid clonal expansion under nilotinib-induced selection pressure.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pirimidinas/administración & dosificación , Anciano , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Cromosoma Filadelfia , Recurrencia , Terapia Recuperativa/métodosRESUMEN
A better understanding of events triggering chronic myeloid leukemia progression is critical for optimized clinical management of chronic myeloid leukemia (CML). We sought to validate that increased expression of Musashi 2 (MSI2), a post-transcription regulator, is associated with progression and prognosis. Screening of 152 patients with CML showed that MSI2 was significantly decreased among patients with CML in chronic phase (CP) at diagnosis (p < 0.0001), but found no significant difference between the normal control group and treated patients with CML in CP. Moreover MSI2 was significantly increased (p < 0.0001) in patients with advance disease (AD) CML. Furthermore, our human hematopoietic cell line data imply that MSI2 and BCR-ABL1 mRNA expression are correlated. However, these data cast a doubt on earlier reports that MSI2 effects HES1 expression via NUMB-NOTCH signaling.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Proteínas de Unión al ARN/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Células Madre Hematopoyéticas/patología , Humanos , Técnicas para Inmunoenzimas , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tasa de Supervivencia , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Quinolinic acid (QA) is thought to be one of the most important metabolites of the kynurenine pathway with the highest biological activity in apoptotic responses and neurodegenerative diseases. The determination of QA might be of clinical relevance in different patient groups, but currently, only a few laborious methods with high levels of sample volume consumption are available. METHODS: We developed and validated a simple liquid chromatography-tandem mass spectrometric (LC-tandem MS) method for the determination of QA in human serum with low sample volume requirements. RESULTS: The presented method provides high sample throughput with 25 µL aliquots and works in the positive electrospray ionization (ESI) mode. A commercially available QA-d3 was used as internal standard. Specific transitions for QA and QA-d3 were m/z 280âm/z 78 and m/z 283âm/z 81, respectively. The intra- and inter-assay coefficients of variation (CVs) were all below 10%. Applying this method, in 50 healthy humans a mean serum concentration of QA of 350±167 nmol/L (mean±SD) was determined. CONCLUSION: The described method is suitable for large clinical trials, which is of potential clinical importance to elucidate the function of QA and its relationship to different disease patterns and may be applicable for clinical laboratory routine.
Asunto(s)
Análisis Químico de la Sangre/métodos , Cromatografía Liquida/métodos , Neurotoxinas/sangre , Ácido Quinolínico/sangre , Espectrometría de Masas en Tándem/métodos , Adulto , Métodos Analíticos de la Preparación de la Muestra , Femenino , Humanos , Límite de Detección , Masculino , Neurotoxinas/química , Control de Calidad , Ácido Quinolínico/químicaRESUMEN
Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/genética , Fosforilación/efectos de los fármacos , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Factor de Transcripción STAT5/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVES: One third of CML patients treated with first line imatinib have suboptimal responses or treatment failures with increased risk for disease progression. Imatinib is actively transported into cells by the SLC22A1 transporter (hOCT1) and its genetic variants may affect intracellular drug import. We studied the effect of SLC22A1 genetic variants on long-term outcomes of imatinib treated patients. METHODS: A total of 167 patients, 94% in chronic phase, were analyzed for rs41267797, rs683369, rs12208357, and rs628031 variants using the Sequenom MassARRAY platform. RESULTS: Rates of CHR, MCyR, CCyR, and MMolR were not significantly different according to allelic variants. However, patients with AA or GA rs628031 genotypes had a higher incidence of poor response to imatinib compared to the GG genotype (47% compared to 29%, P = 0.06), and a higher rate of KD mutation discovery (8/16 vs. 5/27, P = 0.04), suggesting that secondary resistance was more common in these genotypes. Median EFS was shorter for rs628031 genotype AA/AG compared with the GG genotype (61 months and not reached, respectively, P = 0.05), and 5 yr OS rates were lower for patients with the rs628031 genotypes AA/AG compared with the GG genotype (88% and 97%, respectively, P = 0.03). Patients with AA/GA rs628031 and additional rare genotypes had worse EFS and OS compared to patients with only AA/GA rs628031 (P = 0.02 for EFS and 0.01 for OS). There was no difference in pretreatment SLC22A1 mRNA expression levels in patients with rs628031 genotypes GG/AA or GA. CONCLUSIONS: Studying SLC22A1 genetic variants prior to TKI initiation could influence treatment decisions.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Variación Genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Transportador 1 de Catión Orgánico/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Expresión Génica , Frecuencia de los Genes , Genotipo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
Alpha-ketoglutaric acid (KG) and hydroxymethylfurfural (HMF) are currently being investigated in clinical trials as an approach in targeted cancer therapy. Hence, a method for the simultaneous determination of KG and HMF in plasma has been developed. Due to the strongly discriminative chemical properties of KG and HMF, SPE purification is performed using an ion-exchange cartridge to separate KG, and a hydrophobic polymeric cartridge to separate HMF. The cartridges are connected together for several steps, thus resulting in a quicker approach for the purification of plasma samples. The derivatization step is based on the reaction of the carbonyl groups of KG and HMF with dansylhydrazine (DNSH) catalyzed by trifluoroacetic acid. The formed derivatives could be separated by reversed-phase LC on a C8-column, and analyzed by UV and fluorescence detection in a single run using a gradient program. The obtained results show good reproducibility, specificity, and detection limits down to the low picomole range.