RESUMO
Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mieloma Múltiplo/genética , Plasmocitoma/genética , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Evolução Clonal , Progressão da Doença , Feminino , GTP Fosfo-Hidrolases/sangue , Transplante de Células-Tronco Hematopoéticas , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/terapia , Mutação , Plasmócitos/metabolismo , Plasmócitos/patologia , Plasmocitoma/sangue , Plasmocitoma/diagnóstico por imagem , Plasmocitoma/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sequenciamento do ExomaRESUMO
The chronic high-dose right ventricular apical (RVA) pacing may have deleterious effects on left ventricular (LV) systolic function. We hypothesized that the expression changes of genes regulating cardiomyocyte energy metabolism and contractility were associated with deterioration of LV function in patients who underwent chronic RVA pacing. Sixty patients with complete atrioventricular block and preserved ejection fraction (EF) who underwent pacemaker implantation were randomly assigned to either RVA pacing (n = 30) group or right ventricular outflow tract (RVOT) pacing (n = 30) group. The mRNA levels of OPA1 and SERCA2a were significantly lower in the RVA pacing group at 1 month's follow-up (both p < 0.001). Early changes in the expression of selected genes OPA1 and SERCA2a were associated with deterioration in global longitudinal strain (GLS) that became apparent months later (p = 0.002 and p = 0.026, resp.) The altered expressions of genes that regulate cardiomyocyte energy metabolism and contractility measured in the peripheral blood at one month following pacemaker implantation were associated with subsequent deterioration in LV dyssynchrony and function in patients with preserved LVEF, who underwent RVA pacing.