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1.
Sci Rep ; 11(1): 209, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420222

RESUMO

In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.

3.
JIMD Rep ; 51(1): 53-61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32071839

RESUMO

Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next-generation sequencing-based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73-gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non-LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann-Pick disease B, Gaucher disease) and three with non-LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost-effective screening of LDs and disorders sharing with them early clinical signs.

4.
Cytometry B Clin Cytom ; 98(6): 525-528, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31873987

RESUMO

BACKGROUND: The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is uncertain. METHODS: We performed a 5-year retrospective single-center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB-/FC- (75.6%), BMB+/FC+ (13.4%), and BMB-/FC+ (11%). RESULTS: Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event-free survival (EFS) after 18 months was 82, 23, and 27% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p < .001). After 18 months of observation, OS was 87, 46, and 55% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p = .001). In multivariate analysis (BM infiltration vs. cell-of-origin according to Hans algorithm and standard IPI), BM infiltration was independently associated with EFS (HR: 1.94, 95% CI: 1.3-2.9) and overall survival (HR: 1.69, 95% CI: 1.1-2.7). CONCLUSION: In summary, minimal BM infiltration, detected by FC but not by BMB, has same prognostic implications than overt BM infiltration and should be considered as extranodal involvement regardless the infiltration quantity.

6.
J Clin Pathol ; 69(10): 912-20, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26915371

RESUMO

BACKGROUND: Haemoglobinopathies have spread owing to human migration, and the number of people needing diagnosis and management of these conditions is increasing. Clinicians need to accurately identify carriers and provide adequate genetic counselling in order to prevent the occurrence of homozygous or compound heterozygous offspring. OBJECTIVES: To identify red blood cell (RBC) laboratory parameters that discriminate between structural haemoglobinopathy carriers and healthy subjects, and to compare RBC laboratory indices between HbAS and HbAC individuals. METHODS: Samples of 500 variant Hb carriers (355 HbAS, 104 HbAC, 19 HbAD, 7 HbAE, 7 HbAO-Arab, 4 α-chain variants and 4 Hb Lepore) and 251 normal controls were run on an Advia 2120 analyser (Siemens). Classic haematological parameters and RBC populations were assessed in all subjects. A multivariable binary logistic regression model was created to predict the probability of a subject carrying any structural haemoglobinopathy. HbAS (n=355, 71%) and HbAC (n=104, 20.8%) subjects were compared. RESULTS: A clinical prediction rule was developed by assigning one point to each of the most efficient variables: mean corpuscular volume (MCV) <88.4 fL, RBC distribution width >13.4%, percentage of microcytic RBCs (%MICRO) >0.7% and the ratio of microcytic RBCs to hypochromic RBCs >0.8. A score of 0, 1, 2, 3 or 4, resulted in a probability of 9.6%, 36.3%, 66.7%, 85.2% or 98.3%, respectively. Among the most frequent variant Hb, HbAC subjects had lower values of parameters related to cell size (MCV, %MICRO) and higher values of parameters related to haemoglobin concentration (MCHC, %HYPER) than HbAS subjects. Coexistence of α-thalassaemia in both HbAS and HbAC individuals resulted in decreased Hb, MCV, MCH and MCHC. CONCLUSIONS: Structural haemoglobinopathy should be investigated in subjects belonging to ethnic groups with high prevalence of variant Hb and with a score of 3 or 4. Erythrocytes of HbAC subjects are smaller and denser than those of HbAS subjects.


Assuntos
Testes Hematológicos/instrumentação , Hemoglobina C/genética , Hemoglobina Falciforme/genética , Hemoglobinopatias/genética , Heterozigoto , Estudos de Casos e Controles , Índices de Eritrócitos , Eritrócitos/patologia , Predisposição Genética para Doença , Hemoglobinopatias/sangue , Humanos , Fenótipo , Controle de Qualidade , Curva ROC , Reprodutibilidade dos Testes , Talassemia alfa/sangue , Talassemia alfa/genética
7.
Cytometry B Clin Cytom ; 90(6): 543-545, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-25612555

RESUMO

Double-hit lymphoma (DHL) is a rare type of lymphoma with concurrent chromosomal translocations of C-MYC with BCL2 or BCL6, associated with unfavorable prognosis. We describe a case of DHL in a 79-year-old female patient previously diagnosed with diffuse large B-cell lymphoma (DLBCL) with an early relapse in the ascitic fluid. A seven-color multiparametric flow cytometry immunophenotyping study of the ascitic fluid was carried out, and revealed 99.78% of large in size and high cellular complexity B-cells positive for CD19, CD10 (64.27%), CD45 dim, CD22 dim, CD25 (60%), CD43 bright, CD38 bright, and IgM (18.53%); and negative for CD20, CD5, CD23, CD79b, CD103, CD200, CD11c, and FMC7, and 78.99% without light chain expression and 21% with Lambda chain restriction. Due to the expression of CD19 and CD10 with overexpression of BCL-2 protein and due to CD43 and CD38 positivity detected, those cells showed features between DLBCL and Burkitt lymphoma. Fluorescence in situ hybridization (FISH) confirmed both c-MYC/IGH and BCL2/IGH rearrangement. Our findings may help to identify cases requiring additional cytogenetic analysis. © 2015 International Clinical Cytometry Society.


Assuntos
Líquido Ascítico/patologia , Citometria de Fluxo/métodos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Idoso , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Feminino , Humanos , Imunofenotipagem/métodos
8.
J Clin Pathol ; 69(2): 149-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26265587

RESUMO

AIMS: To analyse the differences in reticulocyte indices between delta beta thalassaemia trait (δß-TT), beta thalassaemia trait (ß-TT) and iron deficiency anaemia (IDA), and to correlate those differences with the physiopathological features of these three types of microcytoses. METHODS: We performed a descriptive study of 428 samples (43 δß-TT, 179 ß-TT and 206 IDA) that were run on Advia 2120 analyser (Siemens). The following reticulocyte indices were assessed: absolute reticulocyte count (ARC), percentage of reticulocytes, mean corpuscular volume of reticulocytes (MCVr), haemoglobin content of reticulocytes (CHr), mean corpuscular haemoglobin concentration of reticulocytes, red blood cell distribution width of reticulocytes (RDWr), haemoglobin distribution width of reticulocytes (HDWr) and reticulocyte subpopulations based on their fluorescence according to mRNA (low (L-R), medium (M-R) and high (H-R)), MCV ratio and MCHC ratio. Correlation between fetal haemoglobin (HbF) and RDWr in patients with thalassaemia was evaluated. RESULTS: RDWr was significantly higher in δß-TT compared with ß-TT (15.03% vs 13.82%, p<0.001), and so were HDWr (3.65% vs 3.27%, p<0.001), CHr (23.68 vs 22.66 pg, p<0.001) and MCVr (88.3 vs 85.5 fL, p<0.001). A good correlation was observed between HbF and RDWr (r=0.551, p<0.001). IDA subjects have more immature reticulocytes, but less ARC than ß-TT, suggesting a certain degree of inefficient erythropoiesis in IDA in comparison with ß-TT. CONCLUSIONS: Previously described differences between δß-TT, ß-TT and IDA in the corpuscular indices of mature red blood cell can also be observed in reticulocytes. The degree of anisocytosis in reticulocytes from patients with thalassaemia is correlated with HbF.


Assuntos
Anemia Ferropriva/sangue , Reticulócitos , Talassemia beta/sangue , Talassemia delta/sangue , Anemia Ferropriva/diagnóstico , Biomarcadores/sangue , Contagem de Eritrócitos , Índices de Eritrócitos , Hemoglobinas/análise , Humanos , Valor Preditivo dos Testes , Reticulócitos/metabolismo , Reticulócitos/patologia , Talassemia beta/diagnóstico , Talassemia delta/diagnóstico
13.
Ann Hematol ; 94(4): 565-73, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25387664

RESUMO

Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0-2 % and >2- < 5 %. This distinction is critical for establishing prognosis, but the reproducibility of this threshold is still not demonstrated. The objectives of our study were to explore the reliability of the 2008 WHO classification, regarding unilineage vs. multilineage dysplasia, by reviewing 110 cases previously diagnosed with MDS, and to study whether the threshold of ≤2 % BM blasts is reproducible among different observers. We used the same methodology as in our previous paper [Font et al. (2013) Ann Hematol 92:19-24], by encouraging investigators to include patients with <5 % BM blasts. Samples were collected from 11 hospitals and were evaluated by 11 morphologists. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. Discordance was observed in 36/108 suitable cases (33 %, kappa test 0.503). Diagnosis of MDS with unilineage dysplasia (refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS) or unclassifiable MDS) was assessed in 33 patients, by either of the two observers. We combined this series with the cases with RCUD or RARS included in our 2013 paper, thus obtaining 50 cases with unilineage dysplasia by at least one of the observers. The whole series showed very low agreement regarding RCUD (5/23, 21 %) and RARS (5/28, 18 %). Regarding BM blast count, the threshold of ≤2 % was not reproducible (discordance rate 32/108 cases, kappa test 0.277). Our study shows that among MDS WHO 2008 categories, interobserver discordance seems to be high in cases with unilineage dysplasia. We also illustrate that the threshold of ≤2 % BM blasts as settled by the R-IPSS may be not easy to reproduce by morphologists in real practice.


Assuntos
Crise Blástica/patologia , Medula Óssea/patologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Contagem de Células/estatística & dados numéricos , Linhagem da Célula , Citodiagnóstico/estatística & dados numéricos , Feminino , Humanos , Masculino , Variações Dependentes do Observador , Prognóstico , Reprodutibilidade dos Testes
14.
Am J Clin Pathol ; 142(4): 567-73, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25239426

RESUMO

OBJECTIVES: To analyze the differences not only in classic hematologic parameters but also in RBC subpopulations among δß-thalassemia trait (δß-TT), ß-thalassemia trait (ß-TT), and iron deficiency anemia (IDA) and to evaluate the role of fetal hemoglobin (HbF) in elevated RBC distribution width (RDW). METHODS: Samples from 553 patients with microcytosis (74 δß-TT, 272 ß-TT, and 207 IDA) were run on an Advia 2120i analyzer (Siemens Medical Solutions Diagnostics, Tarrytown, NY). Classic hematologic parameters and RBC subpopulations were assessed. The correlation between HbF and RDW in patients with thalassemia (both ß and δß) was evaluated. An independent sample t test was used to compare classic hematologic parameters and RBC subpopulations among ß-TT, IDA, and δß-TT and receiver operating characteristic curves performed in the significant comparisons. RESULTS: RDW was significantly higher in δß-TT compared with ß-TT (18.79% vs 16.04%, P < .001), as was mean corpuscular volume (66.39 vs 64.82 fL, P < .001), mean corpuscular hemoglobin (20.73 vs 20.04 pg, P < .001), and mean corpuscular hemoglobin concentration (31.16 vs 30.66 g/dL, P = .03). Pearson coefficient showed a good correlation between HbF and RDW. The values obtained for all the parameters were significantly different (P < .001) between patients with thalassemia (ß and δß) and IDA. CONCLUSIONS: RDW is the best parameter to discriminate δß-TT from ß-TT. The degree of anisocytosis in patients with ß-TT and δß-TT is strongly correlated with HbF.


Assuntos
Anemia Ferropriva/diagnóstico , Talassemia/diagnóstico , Anemia Ferropriva/sangue , Diagnóstico Diferencial , Índices de Eritrócitos , Eritrócitos/patologia , Hemoglobina Fetal/metabolismo , Humanos , Talassemia/sangue , Talassemia beta/sangue , Talassemia beta/diagnóstico , Talassemia delta/sangue , Talassemia delta/diagnóstico
15.
Nat Rev Nephrol ; 10(10): 574-86, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25048549

RESUMO

In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Benzoatos/efeitos adversos , Taxa de Filtração Glomerular , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Triazóis/efeitos adversos , Deferasirox , Humanos , Sobrecarga de Ferro/etiologia , Reação Transfusional
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