High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia.

Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.

Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine.

Chromosomal translocations represent an important prognostic indicator in B-cell chronic lymphocytic leukemia (B-CLL). However, their value had been neither determined in homogeneously treated patients nor compared to that of IgV(H) mutational status. Sixty-five B-CLL patients were investigated using cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis of IgV(H) and of TP53 mutational status before treatment with 2-chloro-2'-deoxyadenosine (CdA). Translocations (n=45) were detected in 42% of the patients, including both balanced (n=12) and unbalanced (n=33) types. IgV(H) was mutated in 43% of the patients. Patients with translocations were more heavily pretreated (P=0.05), presented with more complex karyotypes (P<0.001), 17p abnormalities and TP53 mutations, and had a higher failure rate (59 vs 21% in patients without translocations, P=0.004). Patients with unbalanced translocations displayed a shorter median treatment-free survival (TFS, 6.9 vs 35.9 months, log rank 22.72, P<0.001) and overall survival (OS, 13.0 vs 68.0 months, log rank 16.51, P<0.001), as compared to patients without translocation. In multivariate analysis, unbalanced translocations were independently associated with therapeutic failure, short TFS and short OS. IgV(H) mutational status was independently associated with risk of failure and TFS, but not OS. In B-CLL patients treated with CdA, translocations are strong predictors of outcome.

A new disease categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification.

Multilineage dysplasia was advanced by the World Health Organization to increase prognostic accuracy in myelodysplastic syndromes (MDS) classification. We performed a structured cytomorphological examination of bone marrow (BM) in 221 low-grade MDS patients, this in conjunction with strict guidelines for cytopenias. A dysplasia scoring system was developed utilizing dysplastic changes, which were associated with worse outcome on univariate and multivariate analysis corrected for the International Prognostic Scoring System (IPSS). Dysplasia >or=10% in one BM lineage and one cytopenia constituted the low-risk category UCUD or Unilineage Cytopenia and Unilineage Dysplasia. The high-risk category comprised patients with cytopenia in >or=2 lineages and dysplasia in >or=2 BM lineages, namely MCMD or Multilineage Cytopenia and Multilineage Dysplasia. Intermediate-risk patients had one cytopenia and multilineage dysplasia, or cytopenia in >or=2 lineages and unilineage BM dysplasia, designated UCMD/MCUD or Unilineage Cytopenia and Multilineage Dysplasia/Multilineage Cytopenia and Unilineage Dysplasia. This system utilizing cytopenia-dysplasia scoring at diagnosis enabled comprehensive categorization of low-grade MDS cases that predicted for overall as well as leukemia-free survival. Cytopenia-dysplasia categorization added additional prognostic values to the lower risk IPSS categories. This suggests that a standardized dysplasia scoring system, used in conjunction with cytopenia, could improve diagnostic and prognostic sub-categorization of MDS patients.

Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRbeta-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique.

Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRbeta) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRbeta-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRbeta-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRbeta-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRbeta-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRbeta-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRbeta-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.

Diferencias de género en las funciones cognitivas e influencia de las hormonas sexuales / Gender differences in cognitive functions and influence of sex hormones

Objetivo. Revisar las evidencias científicas sobre las diferencias cognitivas en función del género y la posible influencia de las hormonas sexuales en el rendimiento cognitivo. Método. Se realizó una búsqueda sistemática de la bibliografía a través del sistema Medline sobre artículos relacionados con el tema. Resultados. Las mujeres presentan un mayor rendimiento con respecto a los hombres en fluencia verbal, velocidad perceptiva, habilidad motora fina, tareas de memoria verbal y aprendizaje verbal. Los hombres superan a las mujeres en tareas visuoespaciales, resolución de problemas matemáticos y memoria visual. No se encuentran diferencias en función del género en atención y memoria de trabajo. Los estudios que evalúan la influencia de factores hormonales se han realizado en diversos grupos: a) pacientes con trastornos hormonales; b) pacientes sometidos a neuroimagen tras la administración hormonal; c) en mujeres sanas en función del ciclo menstrual, y d) en pacientes sometidos a tratamiento hormonales (hipogonadismo hipogonadotrófico, mujeres posmenopáusicas y trastorno de la identidad de género). Estos estudios en su mayoría encuentran una influencia de los niveles hormonales en diversas capacidades cognitivas, aunque los resultados no son del todo concluyentes por las limitaciones y escasez de estos estudios. Conclusiones. Existen diferencias cognitivas en función del género y las hormonas sexuales parecen ejercer una influencia en estas funciones cognitivas

Objective. To review scientific evidence on gender differences in cognitive functions and influence of sex hormones on cognitive performance. Method. Systematical search of related studies identified in Medline. Results. Women outperform men on verbal fluency, perceptual speed tasks, fine motor skills, verbal memory and verbal learning. Men outperform women on visuospatial ability, mathematical problem solving and visual memory. No gender differences on attention and working memory are found. Researchers distinguish four methods to investigate hormonal influence on cognitive performance: a) patient with hormonal disorders; b) neuroimaging in individuals during hormone administration; c) in women during different phases of menstrual cycle, and d) in patients receiving hormonal treatment (idiopathic hypogonadotropic hypogonadism, postmenopausal women and transsexuals). The findings mostly suggest an influence of sex hormones on some cognitive functions, but they are not conclusive because of limitations and scarcity of the studies. Conclusions. There are gender differences on cognitive functions. Sex hormones seem to influence cognitive performance

[Estimation of prevalence, incidence and sex ratio of transsexualism in Catalonia according to health care demand]. / Estimación de la prevalencia, incidencia y razón de sexos del transexualismo en Cataluña según la demanda asistencial.

OBJECTIVE: To estimate the epidemiology of transsexualism in the autonomous community of Catalonia according to data gathered at the Hospital Clinic of Barcelona, the single public hospital providing specialized psychiatric and endocrinological care for transsexual patients in this community. PATIENTS AND METHODS: Prevalence was calculated on the basis of the total number of patients diagnosed of transsexualism (ICD-10, F64.0) at the Hospital Clinic and living in Catalonia, and the incidence by counting all new cases of transsexuals for the last 5 years, based on the population census between 15 and 65 years of age. RESULTS: During the period from 1996 through 2004 a total of 201 subjects were referred to this hospital with complaints of gender dysphoria. Transsexualism was diagnosed in 182 patients, 161 of whom were living in Catalonia. This yields a prevalence rate in Catalonia of 1:21,031 males and 1:48,096 females. The sex ratio was 2.6. Annual incidence in the last five years was 0.73/100,000/year. DISCUSSION: The low prevalence compared with recently published data from European Union countries may be due to the relatively few years of data collection and to the low clinical demand because surgical procedures costs are not covered by the public health insurance. In contrast, the high incidence may be due to the increasing demand since 2000, when a more benevolent and tolerant social climate in Spain started.

Estimación de la prevalencia, incidencia y razón de sexos del transexualismo en Cataluña según la demanda asistencial / Estimation of prevalence, incidence and sex ratio of transsexualism in Catalonia according to health care demand

Introducción. Se realiza una estimación de la distribución epidemiológica del transexualismo en Cataluña según la demanda observada en el Hospital Clínic de Barcelona, que es el único hospital público que proporciona atención psiquiátrica y endocrinológica especializada a estos pacientes en esta comunidad autónoma. Pacientes y método. La prevalencia se calculó según el número total de pacientes diagnosticados de transexualismo (CIE-10, F64.0) en el Hospital Clínic residentes en Cataluña y la incidencia según el número de pacientes con nuevo diagnóstico durante los últimos 5 años en relación con los datos de población de edad entre 15 y 65 años. Resultados. Entre los años 1996 y 2004 solicitaron atención por disforia de género un total de 201 pacientes. Se diagnosticó transexualismo en 182 pacientes, de los cuales 161 vivían en Cataluña. La prevalencia estimada de transexualismo en Cataluña fue de 1:21.031 varones y 1:48.096 mujeres. La razón de sexos fue de 2,6 a favor del grupo de transexuales hombre a mujer. La incidencia media anual en los últimos 5 años fue de 0,72/100.000 habitantes/año. Discusión. La baja prevalencia observada, en comparación con los datos publicados por países de la Unión Europea, se puede atribuir al período corto de recogida de datos y a la baja demanda registrada al no estar financiado el tratamiento de reasignación de sexo por el Sistema Nacional de Salud. La elevada incidencia se puede atribuir al incremento de la demanda desde el año 2000, que coincide con un clima social de mayor aceptación y tolerancia

Objective. To estimate the epidemiology of transsexualism in the autonomous community of Catalonia according to data gathered at the Hospital Clinic of Barcelona, the single public hospital providing specialized psychiatric and endocrinological care for transsexual patients in this community. Patients and methods. Prevalence was calculated on the basis of the total number of patients diagnosed of transsexualism (ICD-10, F64.0) at the Hospital Clinic and living in Catalonia, and the incidence by counting all new cases of transsexuals for the last 5 years, based on the population census between 15 and 65 years of age. Results. During the period from 1996 through 2004 a total of 201 subjects were referred to this hospital with complaints of gender dysphoria. Transsexualism was diagnosed in 182 patients, 161 of whom were living in Catalonia. This yields a prevalence rate in Catalonia of 1:21,031 males and 1:48,096 females. The sex ratio was 2.6. Annual incidence in the last five years was 0.73/100,000/year. Discussion. The low prevalence compared with recently published data from European Union countries may be due to the relatively few years of data collection and to the low clinical demand because surgical procedures costs are not covered by the public health insurance. In contrast, the high incidence may be due to the increasing demand since 2000, when a more benevolent and tolerant social climate in Spain started

Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast.

For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.

[The practice guideline 'Diagnosis and pharmaceutical treatment of dementia']. / Richtlijn 'Diagnostiek en medicamenteuze behandeling van dementie'.

The practice guideline 'Diagnosis and pharmaceutical treatment of dementia' emphasizes that a nosological diagnosis should be made and that it is important to assess the extent of need for care. The guideline recommends the use of diagnostic criteria for the various conditions that can cause dementia. With respect to ancillary investigations, the burden to the patient should be weighed against the benefits of increasing diagnostic confidence. Observation of the course of the disease, laboratory and cerebrospinal-fluid investigations, neuropsychological and EEG examinations, and neuroimaging all increase diagnostic confidence. Treatment with a cholinesterase inhibitor or memantine should always be embedded in a comprehensive-treatment protocol that includes explicit discussion of treatment goals and expectations at baseline, in combination with criteria for starting and stopping treatment. Guidelines for evaluating the effects of treatment with cholinesterase inhibitors or memantine are specified. If psychosis, depression or behavioural disturbances occur in patients with dementia, antidepressants, antipsychotics or anticonvulsants may be indicated.

Molecular cytogenetic study of 126 unselected T-ALL cases reveals high incidence of TCRbeta locus rearrangements and putative new T-cell oncogenes.

Chromosomal aberrations of T-cell receptor (TCR) gene loci often involve the TCRalphadelta (14q11) locus and affect various known T-cell oncogenes. A systematic fluorescent in situ hybridization (FISH) screening for the detection of chromosomal aberrations involving the TCR loci, TCRalphadelta (14q11), TCRbeta (7q34) and TCRgamma (7p14), has not been conducted so far. Therefore, we initiated a screening of 126 T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma cases and 19 T-ALL cell lines using FISH break-apart assays for the different TCR loci. Genomic rearrangements of the TCRbeta locus were detected in 24/126 cases (19%), most of which (58.3%) were not detected upon banding analysis. Breakpoints in the TCRalphadelta locus were detected in 22/126 cases (17.4%), whereas standard cytogenetics only detected 14 of these 22 cases. Cryptic TCRalphadelta/TCRbeta chromosome aberrations were thus observed in 22 of 126 cases (17.4%). Some of these chromosome aberrations target new putative T-cell oncogenes at chromosome 11q24, 20p12 and 6q22. Five patients and one cell line carried chromosomal rearrangements affecting both TCRbeta and TCRalphadelta loci. In conclusion, this study presents the first inventory of chromosomal rearrangements of TCR loci in T-ALL, revealing an unexpected high number of cryptic chromosomal rearrangements of the TCRbeta locus and further broadening the spectrum of genes putatively implicated in T-cell oncogenesis.

Coexistence of light chain disease and chronic lymphocytic leukaemia, a complex karyotype with a rapid fatal outcome.

We report on a 48-year-old man with concomitantly diagnosed kappa expressing chronic lymphocytic leukaemia (CLL) and lambda light chain disease with highly complex chromosomal aberrations. The clinical course of the disease was very aggressive with survival of only 1 month. We demonstrate the distinct clonal origin by cytogenetic data and immunoglobulin rearrangement studies. To our knowledge this is the first report of a light chain disease associated with CLL.

FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations.

The transcription factor Forkhead box protein P1 (FOXP1) is highly expressed in a proportion of diffuse large B-cell lymphoma (DLBCL). In this report, we provide cytogenetic and fluorescence in situ hybridization (FISH) data showing that FOXP1 (3p13) is recurrently targeted by chromosome translocations. The genomic rearrangement of FOXP1 was identified by FISH in three cases with a t(3;14)(p13;q32) involving the immunoglobulin heavy chain (IGH) locus, and in one case with a variant t(2;3) affecting sequences at 2q36. These aberrations were associated with strong expression of FOXP1 protein in tumor cells, as demonstrated by immunohistochemistry (IHC). The cases with t(3p13) were diagnosed as DLBCL ( x 1), gastric MALT lymphoma ( x 1) and B-cell non-Hodgkin's lymphoma, not otherwise specified ( x 2). Further IHC and FISH studies performed on 98 cases of DLBCL and 93 cases of extranodal marginal zone lymphoma showed a high expression of FOXP1 in approximately 13 and 12% of cases, respectively. None of these cases showed, however, FOXP1 rearrangements by FISH. However, over-representation of the FOXP1 locus found in one additional case of DLBCL may represent another potential mechanism underlying an increased expression of this gene.

A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias.

Chromosomal translocations with breakpoints in T-cell receptor (TCR) genes are recurrent in T-cell malignancies. These translocations involve the TCRalphadelta gene (14q11), the TCRbeta gene (7q34) and to a lesser extent the TCRgamma gene at chromosomal band 7p14 and juxtapose T-cell oncogenes next to TCR regulatory sequences leading to deregulated expression of those oncogenes. Here, we describe a new recurrent chromosomal inversion of chromosome 7, inv(7)(p15q34), in a subset of patients with T-cell acute lymphoblastic leukemia characterized by CD2 negative and CD4 positive, CD8 negative blasts. This rearrangement juxtaposes the distal part of the HOXA gene cluster on 7p15 to the TCRbeta locus on 7q34. Real time quantitative PCR analysis for all HOXA genes revealed high levels of HOXA10 and HOXA11 expression in all inv(7) positive cases. This is the first report of a recurrent chromosome rearrangement targeting the HOXA gene cluster in T-cell malignancies resulting in deregulated HOXA gene expression (particularly HOXA10 and HOXA11) and is in keeping with a previous report suggesting HOXA deregulation in MLL-rearranged T- and B cell lymphoblastic leukemia as the key factor in leukaemic transformation. Finally, our observation also supports the previous suggested role of HOXA10 and HOXA11 in normal thymocyte development.