RESUMEN
As a promising alternative to bone marrow aspiration (BMA), mutational profiling on blood-derived circulating cell-free tumor DNA (cfDNA) is a harmless and simple technique to monitor molecular response and treatment resistance of patients with refractory/relapsed multiple myeloma (R/R MM). We evaluated the sensitivity and specificity of cfDNA compared to BMA CD138 positive myeloma plasma cells (PCs) in a series of 45 R/R MM patients using the 29-gene targeted panel (AmpliSeq) NGS. KRAS, NRAS, FAM46C, DIS3, and TP53 were the most frequently mutated genes. The average sensitivity and specificity of cfDNA detection were 65% and 97%, respectively. The concordance per gene between the two samples was good to excellent according to Cohen's κ coefficients interpretation. An increased number of mutations detected in cfDNA were associated with a decreased overall survival. In conclusion, we demonstrated cfDNA NGS analysis feasibility and accuracy in R/R MM patients who may benefit from early phase clinical trial.
Asunto(s)
Biomarcadores de Tumor , ADN Tumoral Circulante , Secuenciación de Nucleótidos de Alto Rendimiento , Mieloma Múltiple , Mutación , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Sensibilidad y Especificidad , Anciano de 80 o más Años , Adulto , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Resistencia a Antineoplásicos/genética , Análisis Mutacional de ADN/métodos , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Azacitidina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Estudios RetrospectivosAsunto(s)
Neoplasias Hematológicas/patología , Células Madre Hematopoyéticas/patología , Isocitrato Deshidrogenasa/genética , Linfocitos/patología , Mutación/genética , Células Mieloides/patología , Animales , Células Cultivadas , Neoplasias Hematológicas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Humanos , Linfocitos/metabolismo , Ratones , Células Mieloides/metabolismo , Retroviridae/genéticaRESUMEN
A chiral polymer easily obtained by treatment of a linear polyacrylamide with L-proline was adsorbed on a silica support treatment of a linear polyacrylamide with L-proline. After complexation with copper(II), and in spite of a rather low efficiency due to slow ligand exchange, such packing are very convenient for the resolution of amino acid enantiomers eluted in water (relative retention, k'L/k'D, higher than 2 may be observed). Other eluents may also be used. The chiral polymer was studied in solution by potentiometry and nuclear magnetic resonance spectroscopy (13C relaxation measurement). A model of the complex involved in the stereoselection is proposed which accounts for the chromatographic results obtained.
