ABSTRACT
Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6-25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.
Subject(s)
Biomarkers, Tumor , Clonal Evolution/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , Adult , Aged , Aged, 80 and over , DNA Copy Number Variations , Disease Progression , Female , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Signal Transduction , Young AdultABSTRACT
Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
Subject(s)
Genetic Variation , Genomics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Signal Transduction , Adult , Aged , Antineoplastic Agents/pharmacology , Cell Line, Tumor , DNA Copy Number Variations , Female , Genomics/methods , High-Throughput Nucleotide Sequencing , Humans , Janus Kinases/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Mutation , Neoplasm Staging , Receptors, Notch/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental. OBJECTIVE: This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications. METHODS: Ninety-five patients were analysed during the first year after primary renal transplantation. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids + CsA; Group II (35 patients) received corticosteroids + CsA + Basiliximab; Group III (25 patients) received corticosteroids + Tacrolimus + Basiliximab. RESULTS: Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III. CONCLUSIONS: Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Cyclosporine/therapeutic use , Graft Rejection/epidemiology , Kidney Transplantation/immunology , Postoperative Complications/epidemiology , Recombinant Fusion Proteins , Tacrolimus/therapeutic use , Adult , Basiliximab , Drug Therapy, Combination , Herpes Labialis/epidemiology , Humans , Immunosuppressive Agents/therapeutic use , Middle AgedABSTRACT
Se realizó la caracterización clínica de 53 recién nacidos con Secuencia de Bridas Amnióticas. La localización más frecuente de las anomalias fue en las extremidades presentes en 52 pacientes, en la mitad de ellos estaban afectados tanto las extremidades superiores como las inferiores. Las anomalías presentes en las extremidades fueron; amputaciones congénitas en 34 pacientes (65.3 por ciento del total); anillos de constricción, 32 pacientes (61,5 por ciento), sindactilia, 16 pacientes (30,7 por ciento); defectos posturales, 15 pacientes (28,8 por ciento) y pseudosindactilia 8 pacientes (15,3 por ciento). Además se encontraron anomalías localizadas en región craneofacial en 3 pacientes, y en sistema nervioso central y orgános internos un paciente en cada caso. En 10 pacientes se encontró Bridas adheridas al recién nacido. (AU)
