Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Eur Arch Psychiatry Clin Neurosci ; 272(6): 1087-1096, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34842982

RESUMO

Advanced parental age at delivery and neurological soft signs (NSS) constitute risk factors for schizophrenia. The aim of the current study was to develop a neurobiological diagnostic index by combining them, and without the contribution of clinical symptomatology. The study sample included 133 patients suffering from schizophrenia according to DSM-IV-TR (77 males and 56 females; aged 33.55 ± 11.22 years old) and 122 normal controls (66 males and 56 females; aged 32.89 ± 9.91 years old). The assessment included the Neurological Evaluation Scale (NES), and a number of scales assessing the clinical symptoms and adverse effects. The statistical analysis included exploratory t-test, Pearson Correlation coefficient (R) and Discriminant Function Analysis (DFA). Exploratory t-tests and Pearson's R suggested that sex, parental age and NSS constitute independent components. On the basis of DFA results, the Psychotic Neurological Index was developed. At the cut-off PNI score of 8.5, sensitivity was equal to 94.74 and specificity to 93.44. The current is probably the first study to report on an easily obtainable diagnostic neurobiological marker with identifiable properties which is absolutely independent from the clinical manifestations and could serve in distinguishing between patients with schizophrenia and healthy controls with high efficacy.


Assuntos
Esquizofrenia , Adulto , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Exame Neurológico , Idade Paterna , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Adulto Jovem
2.
BMC Psychiatry ; 22(1): 548, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962369

RESUMO

BACKGROUND: Functional recovery is an important treatment goal in major depressive disorder (MDD). This study assessed the real-world effectiveness of vortioxetine in patients with MDD, with particular focus on functioning; dose-response was also assessed. METHODS: This was a non-interventional, prospective, multicenter study conducted in Greece. Adult outpatients with MDD (n = 336) initiating vortioxetine (5-20 mg/day flexible dosing) as treatment for a current major depressive episode were followed for 3 months. Analyses were stratified according to vortioxetine dosage at 3 months: 5-10 mg/day versus 15-20 mg/day. Functioning was assessed using the Sheehan Disability Scale (SDS). RESULTS: Mean ± standard error SDS total score decreased (improved) from 18.7 ± 0.3 at baseline to 12.9 ± 0.3 after 1 month of vortioxetine treatment and 7.8 ± 0.4 after 3 months (p < 0.001 vs. baseline for all comparisons). Functional recovery (SDS score ≤ 6) was achieved in 14.6% of patients after 1 month of treatment and 48.4% of patients after 3 months. Improvement from baseline in SDS total and domain scores at 3 months was more pronounced in patients receiving vortioxetine 15-20 mg/day than in those receiving vortioxetine 5-10 mg/day. The mean ± standard error change in SDS total score from baseline was 9.2 ± 0.8 in the 5-10 mg/day group and 12.1 ± 0.4 in the 15-20 mg/day group (p < 0.001). Limitations of this study include its non-interventional study design and lack of a control group or active comparator. CONCLUSIONS: Statistically significant and clinically relevant improvements in functioning were seen in patients with MDD treated with vortioxetine in a real-world setting. Higher doses of vortioxetine were associated with significantly greater improvements in functioning.


Assuntos
Transtorno Depressivo Maior , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Grécia , Humanos , Pacientes Ambulatoriais , Estudos Prospectivos , Resultado do Tratamento , Vortioxetina/uso terapêutico
3.
Br J Haematol ; 190(5): 736-740, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32236950

RESUMO

The Complement 1 trial investigated the efficacy and safety of ofatumumab + chlorambucil with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia (CLL). On long-term follow-up in the chemoimmunotherapy arm vs. the chemotherapy arm there was an estimated 12% (not significant) and 39% risk reduction in overall survival and progression-free survival, respectively. A high rate (61%) of treatment with next-line therapies in both the treatment arms may dilute any potential OS difference and confound the interpretation of the OS results. Addition of ofatumumab to chlorambucil demonstrated clinical benefit and tolerability as a frontline treatment option in patients unfit for fludarabine-containing therapy, with no new safety concerns.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Linfocítica Crônica de Células B , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Clorambucila/administração & dosagem , Clorambucila/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
4.
Haematologica ; 105(10): 2440-2447, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33054084

RESUMO

Next generation sequencing studies in Chronic lymphocytic leukemia (CLL) have revealed novel genetic variants that have been associated with disease characteristics and outcome. The aim of this study was to evaluate the prognostic value of recurrent molecular abnormalities in patients with CLL. Therefore, we assessed their incidences and associations with other clinical and genetic markers in the prospective multicenter COMPLEMENT1 trial (treatment naive patients not eligible for intensive treatment randomized to chlorambucil (CHL) vs. ofatumumab-CHL (O-CHL)). Baseline samples were available from 383 patients (85.6%) representative of the total trial cohort. Mutations were analyzed by amplicon-based targeted next generation sequencing (tNGS). In 52.2% of patients we found at least one mutation and the incidence was highest in NOTCH1 (17.0%), followed by SF3B1 (14.1%), ATM (11.7%), TP53 (10.2%), POT1 (7.0%), RPS15 (4.4%), FBXW7 (3.4%), MYD88 (2.6%) and BIRC3 (2.3%). While most mutations lacked prognostic significance, TP53 (HR2.02,p<0.01), SF3B1 (HR1.66,p=0.01) and NOTCH1 (HR1.39,p=0.03) were associated with inferior PFS in univariate analysis. Multivariate analysis confirmed the independent prognostic role of TP53 for PFS (HR1.71,p=0.04) and OS (HR2.78,p=0.02) and of SF3B1 for PFS only (HR1.52,p=0.02). Notably, NOTCH1 mutation status separates patients with a strong and a weak benefit from ofatumumab addition to CHL (NOTCH1wt:HR0.50,p<0.01, NOTCH1mut:HR0.81,p=0.45). In summary, TP53 and SF3B1 were confirmed as independent prognostic and NOTCH1 as a predictive factor for reduced ofatumumab efficacy in a randomized chemo (immune)therapy CLL trial. These results validate NGS-based mutation analysis in a multicenter trial and provide a basis for expanding molecular testing in the prognostic workup of patients with CLL. ClinicalTrials.gov registration number: NCT00748189.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Fosfoproteínas/genética , Prognóstico , Estudos Prospectivos , Fatores de Processamento de RNA/genética , Receptor Notch1/genética
5.
J Pathol ; 247(4): 416-421, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30484876

RESUMO

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Genes de Imunoglobulinas/genética , Linfoma de Zona Marginal Tipo Células B/genética , Regiões Determinantes de Complementaridade/genética , Rearranjo Gênico do Linfócito B/genética , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Região Variável de Imunoglobulina/genética , Mutação/genética , Receptores de Antígenos de Linfócitos B/genética , Microambiente Tumoral
6.
Hum Psychopharmacol ; 34(5): e2712, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31486169

RESUMO

INTRODUCTION: Recently, the usefulness of antipsychotics has been challenged. The aim of the study was to measure the real-life effect of antipsychotic treatment on remission and recovery rates in already stabilized patients with schizophrenia after 1 year. MATERIAL AND METHODS: The study included 133 stabilized patients with schizophrenia (77 males and 56 females; aged 33.55 ± 11.22 years). The assessment included testing at baseline and after 1 year with the Positive and Negative Syndrome Scale, Calgary Depression Scale, State-Trait Anxiety Inventory, UKU, Extrapyramidal Symptom Rating Scale, and General Assessment of Functioning. RESULTS: More patients were on antipsychotics after 1 year (increase by 16.45%). There was an increase in the remission by 75% and in the recovery rate by 66%. It was not possible to predict the outcome on the basis of baseline variables. DISCUSSION: There is an accumulating beneficial effect of antipsychotic treatment over a 12-month period; early lack of remission is not prognostic of a poor outcome. There might be different neurobiological mechanisms underlying acute and sustained response. Both remission and recovery are difficult to achieve for patients with schizophrenia and characterize only a minority of patients. Only a very small minority of patients (4.5%) that is impossible to identify a priori would do well without off antipsychotics.


Assuntos
Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Nord J Psychiatry ; 73(7): 451-461, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31393751

RESUMO

Objective: Neurological soft signs (NSS) are a group of minor non-localizable neurological abnormalities found more often in patients with schizophrenia. The aim of the current study was to investigate their temporal stability and relationship to the overall outcome over a 12-month period. Material and methods: The study sample included 133 stabilized patients suffering from schizophrenia (77 males and 56 females; aged 33.55 ± 11.22 years old). The assessment included the application at baseline and after 12 months of the Neurological Evaluation Scale (NES), and a number of scales assessing the clinical symptoms and adverse effects. The statistical analysis included ANOVA, exploratory t-test and Pearson correlation coefficients with Bonferroni correction. Results: In stabilized patients, NSS are stable over a 12-month period with only the subscale of NES-sensory integration manifesting a significant worsening, while, in contrast, most of the clinical variables improved significantly. There was no relationship of NES scores with the magnitude of improvement. The only significant negative correlation was between NES-motor coordination and Positive and Negative Syndrome Scale-GP change at 1 year. Discussion: The results of the current study suggest that after stabilization of patients with schizophrenia, there are probably two separate components, a 'trait' which is stable over a 12-month period, and a 'degenerative' component with a tendency to worsen probably in parallel with the progression of the illness and in correlation with the worsening of negative symptoms. However, the statistical support of the 'degenerative' component is weak. Significant outcomes Neurological softs signs are stable over a 12-month period, with the exception of 'sensory integration' which manifests significant improvement irrespective of treatment response. They do not respond to treatment with antipsychotics. They do not constitute a prognostic factor to predict improvement over a period of 1 year. Neurological soft signs constitute a trait symptom of schizophrenia which is stable though time. Limitations All the subjects have been previously hospitalized which may represent a more severe form of schizophrenia. Also, all patients were under antipsychotic and some also under benzodiazepine medications. Patients with comorbid somatic disorders were excluded which may decrease generalizability of results.


Assuntos
Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Exame Neurológico/tendências , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/psicologia , Exame Neurológico/psicologia , Escalas de Graduação Psiquiátrica , Esquizofrenia/tratamento farmacológico , Fatores de Tempo , Adulto Jovem
8.
Int J Psychiatry Clin Pract ; 23(2): 90-98, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30880518

RESUMO

Objective: Advanced parental age might constitute a risk factor for various disorders. We tested whether this concerns also mood disorder patients. Methods: The study included 314 subjects (42 bipolar-BD patients; 21 manics and 21 depressives, 68 unipolar-UD, and 204 normal controls-NC). Analysis of Covariance (ANCOVA) and the calculation of the Relative Risk (RR) and the Odds Ratio (OR) were used for the analysis. Results: Paternal age differed between NC and UD patients (29.42 ± 6.07 vs. 32.12 ± 5.54; p = .01) and manics (29.42 ± 6.07 vs. 35.00 ± 5.75; p = .001) and maternal age between NC and manics (25.46 ± 4.52 vs. 31.43 ± 4.75; p < .001) and manic and UD (31.43 ± 4.75 vs. 26.75 ± 6.03; p = .002). The RR and OR values suggested that advanced parental age constitutes a risk factor for the development of mood disorders. Conclusions: In a non-dose dependent and gender-independent, advanced parental age constitutes a risk factor for the development of BD with index episode of mania (probably manic predominant polarity); only advanced paternal age constitutes a risk factor for the development of UD and BD with index episode of depression (probably depressive predominant polarity). This is the first study suggesting differential effect of advanced parental age depending on predominant polarity of BD.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Depressivo/epidemiologia , Idade Materna , Idade Paterna , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
Blood ; 127(8): 1007-16, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26675346

RESUMO

Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação de Sentido Incorreto , Recidiva Local de Neoplasia/genética , Proteínas Ribossômicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting , Separação Celular , Ciclofosfamida/administração & dosagem , Análise Mutacional de DNA , Exoma , Humanos , Imunoprecipitação , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Recidiva Local de Neoplasia/patologia , Rituximab/administração & dosagem , Transfecção , Proteína Supressora de Tumor p53/genética , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
10.
Haematologica ; 103(1): 69-79, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29122992

RESUMO

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.


Assuntos
Ferro/metabolismo , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Transfusão de Sangue/métodos , Eritropoetina/uso terapêutico , Feminino , Humanos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Prognóstico , Modelos de Riscos Proporcionais
11.
Acta Neuropsychiatr ; 30(2): 97-105, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29183417

RESUMO

OBJECTIVE: Neurological soft signs (NSS) are a group of minor non-localisable neurological abnormalities found more often in patients with schizophrenia. The aim of the current study was to test for the effect of gender, age, parental age, age at onset and clinical symptomatology on NSS.Material and methodsThe study sample included 133 patients suffering from schizophrenia according to DSM-IV-TR (77 males and 56 females; aged 33.55±11.22 years old) and 122 normal controls (66 males and 56 females; aged 32.89±9.91 years old). The assessment included the Neurological Evaluation Scale (NES), and a number of scales assessing the clinical symptoms and adverse effects especially extrapyramidal. The statistical analysis included exploratory t-test, simple linear regression analysis, analysis of covariance and the calculation of correlation coefficients. RESULTS: The results of the current study confirm that NSS are more frequent in patients with schizophrenia in comparison with normal controls (Wilks=0.622, p<0.0001), but do not support an effect of gender, age, age at onset, paternal or maternal age, education, medication status or clinical subtype of schizophrenia on NES scores.DiscussionOverall these results suggest that NSS constitute an independent (from the rest of symptoms), core (present in the vast majority of patients) and trait (unrelated to age and probably to the stage of schizophrenia) symptom of schizophrenia which could be of value in the clinical assessment and research of schizophrenia. Overall these results are not in full accord with the literature, but they could serve to fill in gaps and inconsistencies observed so far.


Assuntos
Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Adulto , Fatores Etários , Feminino , Humanos , Masculino , Exame Neurológico , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Fatores Sexuais
12.
Int J Psychiatry Clin Pract ; 22(3): 170-176, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29069946

RESUMO

OBJECTIVE: Advanced parental age might constitute a generic risk factor for mental and somatic disorders. The current study tested whether this concerns also patients with schizophrenia. METHODS: A total of 231 schizophrenic, 56 other severe mental disorders patients and 204 controls were diagnosed according to DSM-IV-TR. Data were tested with ANOVA models including relative risk and odds ratios. RESULTS: Patients with schizophrenia manifested higher paternal (32.55 ± 6.35 vs. 29.42 ± 6.07, p < .001) and maternal age (27.66 ± 5.57 vs. 25.46 ± 4.52, p < .001). Patients with other mental disorders had higher paternal (33.29 ± 8.35; p = .001) but not maternal age (26.69 ± 5.89; p = .296) compared to controls. There was no difference between the two patient groups concerning either paternal or maternal age (p > .05). There seems to be a higher risk for the development of schizophrenia in offspring with paternal age above 25 years and maternal age above 22 years at delivery. CONCLUSIONS: The current study provides further support for the suggestion that advanced paternal age constitutes a risk factor (in a non-dose dependent and gender-independent way) for the development of schizophrenia but also for other mental disorders. In contrast, advanced maternal age characterises schizophrenia specifically. The higher risk is evident after 25 years of paternal and 22 years of maternal age, respectively.


Assuntos
Idade Materna , Idade Paterna , Esquizofrenia/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
13.
Blood ; 125(5): 856-9, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25634617

RESUMO

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.


Assuntos
Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico de Cadeia Pesada de Linfócito B/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Heterogeneidade Genética , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Hipermutação Somática de Imunoglobulina , Análise de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento
14.
Lancet ; 385(9980): 1873-83, 2015 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-25882396

RESUMO

BACKGROUND: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. METHODS: We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. FINDINGS: We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. INTERPRETATION: Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. FUNDING: GlaxoSmithKline, Genmab A/S.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Clorambucila/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Clorambucila/administração & dosagem , Clorambucila/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Distribuição por Sexo , Resultado do Tratamento
15.
Haematologica ; 101(8): 959-67, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27198719

RESUMO

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).


Assuntos
Biomarcadores Tumorais , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Mutação , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Regiões Determinantes de Complementaridade/genética , Análise Citogenética , Feminino , Frequência do Gene , Rearranjo Gênico do Linfócito B , Genes de Imunoglobulinas , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região de Junção de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico
16.
Immunogenetics ; 67(1): 61-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25388851

RESUMO

Νext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.


Assuntos
Regiões Determinantes de Complementaridade/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Prognóstico , Alelos , Sequência de Aminoácidos/genética , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Mutação , Alinhamento de Sequência
18.
Haematologica ; 100(3): 370-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25480502

RESUMO

Next-generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re-sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features (unmutated IGHV, n=137; IGHV3-21 subset #2, n=51) were sequenced on the HiSeq 2000 and data were analyzed using well-established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/180 (63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/177 (84%) of all mutations. We selected 155 mutations for Sanger validation (variant allele frequency, 10-99%) and 93% (144/155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11-27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/82 (94%) mutations. In summary, this study demonstrates that targeted next-generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand-alone test without the need for confirmation by Sanger sequencing.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Linfocítica Crônica de Células B/diagnóstico , Mutação , Proteínas de Neoplasias/genética , Alelos , Expressão Gênica , Frequência do Gene , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Prognóstico , Fatores de Processamento de RNA , Receptor Notch1/genética , Receptor Notch1/metabolismo , Ribonucleoproteína Nuclear Pequena U2/genética , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
Ann Gen Psychiatry ; 13(1): 36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25505930

RESUMO

BACKGROUND: The revised NEO Personality Inventory (NEO-PI-3) includes 240 items corresponding to the Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) and subordinate dimensions (facets). It is suitable for use with adolescents and adults (12 years or older). The aim of the current study was to validate the Greek translation of the NEO-PI-3 in the general Greek population. MATERIAL AND METHODS: The study sample included 734 subjects from the general Greek population of whom 59.4% were females and 40.6% males aged 40.80 ± 11.48. The NEO-PI-3 was translated into Greek and back-translated into English, and the accuracy of the translation was confirmed and established. The statistical analysis included descriptive statistics, confirmatory factorial analysis (CFA), the calculation of Cronbach's alpha, and the calculation of Pearson product-moment correlations. Sociodemographics groups were compared by ANOVA. RESULTS: Most facets had Cronbach's alpha above 0.60. Confirmatory factor analysis showed acceptable loading of the facets on their own hypothesized factors and very good estimations of Cronbach's alphas for the hypothesized factors, so it was partially supportive of the five-factor structure of the NEO-PI-3.The factors extracted with Procrustes rotation analysis can be considered reasonably homologous to the factors of the American normative sample. Correlations between dimensions were as expected and similar to those reported in the literature. DISCUSSION: The literature suggests that overall, the psychometric properties of NEO-PI-3 scales have been found to generalize across ages, cultures, and methods of measurement. In accord with this, the results of the current study confirm the reliability of the Greek translation and adaptation of the NEO-PI-3. The inventory has comparable psychometric properties in its Greek version in comparison to the original and other national translations, and it is suitable for clinical as well as research use.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA