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1.
Leuk Lymphoma ; : 1-10, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031030

RESUMO

Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2-10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (p<.001), unmutated IGHV (p<.001), and del(17p) (p<.001) were independently associated with risk of developing RT. Half of the patients with RT (49%) were treatment-naïve prior to transformation and demonstrated longer survival after RT compared to patients previously treated for CLL (6.1 vs. 2.8 years, p=.03). Whether this finding could be explained by a higher proportion of clonally unrelated RT among treatment-naïve patients, remain to be addressed.

2.
Nat Commun ; 11(1): 363, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953409

RESUMO

Infections have become the major cause of morbidity and mortality among patients with chronic lymphocytic leukemia (CLL) due to immune dysfunction and cytotoxic CLL treatment. Yet, predictive models for infection are missing. In this work, we develop the CLL Treatment-Infection Model (CLL-TIM) that identifies patients at risk of infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. CLL-TIM is an ensemble algorithm composed of 28 machine learning algorithms based on data from 4,149 patients with CLL. The model is capable of dealing with heterogeneous data, including the high rates of missing data to be expected in the real-world setting, with a precision of 72% and a recall of 75%. To address concerns regarding the use of complex machine learning algorithms in the clinic, for each patient with CLL, CLL-TIM provides explainable predictions through uncertainty estimates and personalized risk factors.

3.
Clin Cancer Res ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919133

RESUMO

PURPOSE: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. EXPERIMENTAL DESIGN: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. RESULTS: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. CONCLUSIONS: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

4.
BMJ Open ; 9(3): e023566, 2019 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833314

RESUMO

INTRODUCTION: Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma. Studies have shown that 2-10% of patients with CLL develop RT including diffuse large B-cell lymphoma (DLBCL) and less common Hodgkin lymphoma (HL). This study aims to assess the risk factors for RT of CLL in a nationwide cohort. Additionally, we want to examine prognostic factors in patients with RT. These findings may guide management of treated as well as untreated patients with CLL in the risk of RT. METHODS: Clinical data for patients diagnosed with CLL between 2008 and 2016 will be retrieved from the Danish National CLL registry (DCLLR). Using the Danish unique person identification number, clinical data will be merged with histologically verified DLBCL and/or HL diagnoses retrieved from the Danish National Pathology Data Bank. This will ensure complete follow-up for all patients.The DCLLR includes data from more than 4000 patients with CLL ensuring a median follow-up of 3 years. With the reported incidences (2-10%) of RT, we expect to identify 80-200 CLL patients with RT enabling analysis of overall survival following RT. From time of CLL diagnosis, estimates of cumulative incidence of RT will be calculated using the Aalen-Johansen estimator. From time of RT diagnosis, survival analysis will be performed by Kaplan-Meier method. Cox proportional hazards models will be used for multivariable survival analysis. ETHICS AND DISSEMINATION: Approvals for data collection and analysis was obtained from the Danish Data Protection Agency and the Danish Health Authorities. All data will be managed confidentially according to guidelines and legislation. The dissemination will include a publication of scientific papers and/or presentations of the study findings at international conferences.

5.
Haematologica ; 104(4): 789-796, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514802

RESUMO

In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15% have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted next-generation sequencing assay allowing for the detection of TP53 mutations as low as 0.2% variant allele frequency. Within a consecutive, single center cohort of 290 newly diagnosed patients with chronic lymphocytic leukemia, deletion of chromosome 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (variant allele frequency >10%) or low burden (variant allele frequency ≤10%), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10%) was only evident for patients with IGHV unmutated status; no impact of TP53 aberrations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 mutations over 1% variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as a clinical lower limit of detection.

7.
Eur J Haematol ; 98(4): 355-362, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27893172

RESUMO

OBJECTIVE: The impact of body mass index (BMI) and body surface area (BSA) on survival in diffuse large B-cell lymphoma (DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients. PATIENTS AND METHODS: A total of 653 R-CHOP(-like)-treated DLBCL patients were included in this retrospective cohort study. Patients, baseline clinicopathologic characteristics and treatment information were retrieved from the Danish Lymphoma Registry. Anthropometric measures were obtained from chemotherapy prescription charts. RESULTS: Underweight (BMI <18.5 kg/m2 ) was associated with significantly worse progression-free survival (PFS) for male patients only in sex-stratified analyses (HR 3.92, 95% CI: 1.57-9.75, P = 0.003, for males; HR 1.65, 95% CI: 0.90-3.02, P = 0.107, for females). In multivariate analyses, underweight was associated with worse PFS for both sexes (HR 5.34, 95% CI: 2.07-13.79, P = 0.001, for males; HR 2.14, 95% CI: 1.12-4.08, P = 0.021, for females). Similar results were obtained in analyses of overall survival. In crude analyses, BSA <1.8 m2 was associated with worse PFS for men and women (HR 1.65, 95% CI: 1.03-2.65, P = 0.039, for men; HR 1.62, 95% CI: 1.03-2.56, P = 0.037, for women). In multivariate analyses, however, these associations diminished. CONCLUSIONS: Our study demonstrates that underweight DLBCL patients have worse outcomes following R-CHOP as compared to normal as well as overweight patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Índice de Massa Corporal , Superfície Corporal , Linfoma Difuso de Grandes Células B , Sobrepeso , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Ciclofosfamida/administração & dosagem , Dinamarca , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Sistema de Registros , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida , Vincristina/administração & dosagem
8.
Hemoglobin ; 39(5): 346-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26114741

RESUMO

A previously unknown α(0) deletion, designated - -(DANE), was found in three generations of a Danish family of Palestinian origin. Six patients were heterozygous and three patients had deletional Hb H (ß4) disease with a compound heterozygosity for the common -α(3.7) (rightward) deletion. Multiplex ligation-dependent probe amplification (MLPA) supplemented by repeated polymerase chain reaction (PCR) amplification identified the 5' and 3' breakpoints in the α-globin gene cluster. This novel 31.2 kb deletion (NG_000006.1: g.8800_40007del31208) leads to the removal of the HBZ, HBA2 and HBA1 genes.


Assuntos
Árabes/genética , Deleção de Sequência , alfa-Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Criança , Pré-Escolar , Consanguinidade , Índices de Eritrócitos , Feminino , Ordem dos Genes , Loci Gênicos , Genótipo , Hemoglobina H/genética , Hemoglobina H/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/diagnóstico
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