The Role of Molecular or Cytogenetic Response as a Favorable Prognostic Factor Before Hematopoietic Stem Cell Transplantation for Chronic Myeloid Leukemia.

Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of this study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD. Median survival was 11 years, with a 1-year OS of 70% (57.8 to 79.3) and a 5-year OS of 57.7% (45.1 to 68.5). The estimated 5-year OS was not different for CP1 (60%) versus advanced stages (45%); P = .60. The degree of response immediately before transplantation was directly associated with worse outcomes [HR 5.89 (1.19-29.16); P = .03] for patients with only a hematological response compared with patients with a cytogenetic or molecular response. This study corroborates the potential of HSCT in the scenario of therapeutic failure and highlights the role of molecular or cytogenetic response as a potential target to be achieved before transplantation.

A Locus Identified on Chromosome18P11.31 is Associated with Hippocampal Abnormalities in a Family with Mesial Temporal Lobe Epilepsy.

We aimed to identify the region harboring a putative candidate gene associated with hippocampal abnormalities (HAb) in a family with mesial temporal lobe epilepsy (MTLE). Genome-wide scan was performed in one large kindred with MTLE using a total of 332 microsatellite markers at ∼12 cM intervals. An additional 13 markers were genotyped in the candidate region. Phenotypic classes were defined according to the presence of hippocampal atrophy and/or hyperintense hippocampal T2 signal detected on magnetic resonance imaging. We identified a significant positive LOD score on chromosome 18p11.31 with a Z(max) of 3.12 at D18S452. Multipoint LOD scores and haplotype analyses localized the candidate locus within a 6-cM interval flanked by D18S976 and D18S967. We present here evidence that HAb, which were previously related mainly to environmental risk factors, may be influenced by genetic predisposition. This finding may have major impact in the study of the mechanisms underlying abnormalities in mesial temporal lobe structures and their relationship with MTLE.

Expression profile and distribution of Efhc1 gene transcript during rodent brain development.

One of the putative causative genes for juvenile myoclonic epilepsy (JME) is EFHC1. We report here the expression profile and distribution of Efhc1 messenger RNA (mRNA) during mouse and rat brain development. Real-time polymerase chain reaction revealed that there is no difference in the expression of Efhc1 mRNA between right and left hemispheres in both species. In addition, the highest levels of Efhc1 mRNA were found at intra-uterine stages in mouse and in adulthood in rat. In common, there was a progressive decrease in Efhc1 expression from 1-day-old neonates to 14-day-old animals in both species. In situ hybridization studies showed that rat and mouse Efhc1 mRNAs are expressed in ependymal cells of ventricle walls. Our findings suggest that Efhc1 expression is more important during initial phases of brain development and that at this stage it could be involved in key developmental mechanisms underlying JME.

Linkage study of voltage-gated potassium channels in familial mesial temporal lobe epilepsy.

Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at theta=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.

Linkage study of voltage-gated potassium channels in familial mesial temporal lobe epilepsy

Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at theta=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.

Canais de potássio voltagem-dependentes (CPVD) desempenham importante papel na excitabilidade neuronal e estão associados a determinados tipos de epilepsia. Recentemente, um tipo de encefalite límbica autoimune (EL) foi associado com anticorpos contra CPVD. Além disso, há relatos de pacientes com EL e epilepsia parcial, além de hipersinal em regiões límbicas detectadas em imagens de ressonância magnética (IRM). Nós temos descrito a epilepsia de lobo temporal mesial familial (ELTMF) associada à atrofia hipocampal (AH) e outros sinais de esclerose mesial temporal observadas em IRM. Para investigar se os CPVD podem estar associados com a AH identificada na ELTMF, empregamos o estudo de ligação genética nesses genes candidatos. Setenta e três marcadores microssatélites foram genotipados e o LOD score de dois pontos mostrou Zmax variando de 0.11 a -9.53 para teta=0.00. No presente estudo, os dados obtidos com a análise de ligação mostram que os CPVD não estão envolvidos na determinação da AH na ELTMF.

THE SCN2A gene is not a likely candidate for familial mesial temporal lobe epilepsy.

A transgenic mouse model carrying a mutation in the Scn2a gene showed chronic focal seizures associated with extensive cell loss and gliosis in the hippocampus, a similar phenotype found in familial mesial temporal lobe epilepsy (FMTLE). Our objective was to test whether the human homolog of the Scn2a gene is responsible for hippocampal abnormalities in FMTLE by linkage analysis. We conclusively ruled out the SCN2A gene as candidate in FMTLE.