Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up

BACKGROUND: The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods. METHODS: The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years. RESULTS: In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients. CONCLUSIONS: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy.     

Suramin has adjuvant properties and promotes expansion of antigen-specific Th1 and Th2 cells in vivo

Aluminum hydroxide and incomplete Freund's adjuvant (IFA) are the only adjuvants approved for human use. Both are T helper 2 (Th2) adjuvants, however, T helper 1 (Th1) immunity is induced if microbial products such as mycobacteria, CpG's, or bacterial toxins are included in the adjuvant preparation. The usefulness of bacterial toxins, such as Pertussis toxin (PT) or Cholera toxin (CT), as adjuvants for human vaccination is limited by toxic side effects and high immunogenicity. Hence, we asked whether or not the adjuvant activity of bacterial toxins on Th1 and Th2 immunity could be mimicked by chemical compounds of small molecular weight and less immunogenicity. In the present study, we show that Suramin, a small molecular weight naphthylurea, which mainly acts on G-proteins and on P2X/P2Y receptors, promotes expansion of hen eggwhite lysozyme (HEL)-specific Th1 and Th2 cells upon immunization of BALB/c mice with HEL in aluminum hydroxide (alum). The results indicated that the adjuvant effects of Suramin on T cell responses were mediated by enhancing the expression of MHC class II and costimulatory molecules on antigen presenting cells (APCs), and by increasing their pro-inflammatory cytokine production. Together, the results suggest that small molecular weight compounds such as Suramin could be used as alternative vaccine adjuvants.     

Longitudinal results of mandibular distraction osteogenesis in hemifacial microsomia

The aim of this study was to evaluate mandibular distraction therapy by three-dimensional (3-D) computed tomography (CT) imaging so as to be able to improve the treatment results. The study group consisted of eight children (3 male and 5 female) with hemifacial microsomia. For each child, CT scans of the head were available (Pro Speed S Fast Spiral scanner; General Electric). Longitudinal measurements of the mandible, bony and soft tissue 3-D reconstructions, and masticatory muscles were demonstrated. Three-dimensional CT scans provide important data concerning the results of mandibular distraction therapy and should be used in treatment evaluation. In some patients and for some muscles only, a small increase in the volume of the affected side of the masticatory muscles in comparison to the normal side was found 3 years after mandibular distraction. In around 50% of the cases, there seems to be a relapse occurring 1 year after distraction osteogenesis, and this relapse has a progressive character when seen 3 years after distraction osteogenesis in comparison to 15 weeks after distraction osteogenesis.     

Dopaminergic sensitization of rats with and without early prefrontal lesions: implications for the pathogenesis of schizophrenia

To study whether an early lesion of prefrontal cortex (PFC) would influence mesolimbic dopaminergic sensitization induced by intermittent electrical stimulation (IES) of the ventral tegmental area (VTA) or change social interactions in animals exposed to both electrical sensitization and prefrontal lesions, we examined the behaviour of rats with or without early prefrontal lesions following repeated electrical stimulation of the VTA. Additionally, we wanted to study the influence of immobilization stress on rats exposed to a combination of prefrontal lesion and daily restraint in Plexiglas tubes prior to IES. Neither early lesion of PFC nor repeated restraint influenced development of sensitization. However, the combination of early prefrontal lesion and IES resulted in changes in social interactions neither seen following IES nor in lesioned rats. The changes were most pronounced in the group exposed to both IES, prefrontal lesions and restraint. Furthermore, repeated restraint caused a significant increase in the threshold current for provocation of the behavioural response related to VTA stimulation (head stereotypies/sniffing). The implications of the findings for sensitization of the mesolimbic dopaminergic system as a model for development of schizophrenia are discussed.     

Binding and distribution of Na2B12H11SH on cellular and subcellular level in tumor tissue of glioma patients in boron neutron capture therapy

To determine binding and distribution of Na2B12H11SH (BSH)in glioma tissue in case of boron neutroncapture therapy, an antibody to this compound wasproduced and used in immunohistochemical investigations. It ispossible to trace BSH in immunohistochemistry, because BSHis firmly bound to the glioma tissue. Theantibody against BSH is specific for that antigen,as tumor tissue from patients without BSH administrationdid not stain. In areas of healthy brainfrom BSH infused patients, no staining of tissuewas detectable. In tumor tissues, BSH is presentingas a strong staining in cytoplasm and nucleusareas.     

Fibroblast growth on surface-modified dental implants: an in vitro study

A major consideration in designing dental implants is the creation of a surface that provides strong attachment between the implant and bone, connective tissue, or epithelium. In addition, it is important to inhibit the adherence of oral bacteria on titanium surfaces exposed to the oral cavity to maintain plaque-free implants. Previous in vitro studies have shown that titanium implant surfaces coated with titanium nitride (TiN) reduced bacterial colonization compared to other clinically used implant surfaces. The aim of the present study was to examine the support of fibroblast growth by a TiN surface that has antimicrobial characteristics. Mouse fibroblasts were cultured on smooth titanium discs that were either magnetron-sputtered with a thin layer of titanium nitride, thermal oxidized, or modified with laser radiation (using a Nd-YAG laser). The resulting surface topography was examined by scanning electron microscopy (SEM), and surface roughness was estimated using a two-dimensional contact stylus profilometer. A protein assay (BCA assay) and a colorimetric assay to examine fibroblast metabolism (MTT) were used. Cellular morphology and cell spreading were analyzed using SEM and fluorescence microscopy. Fibroblasts on oxidized titanium surfaces showed a more spherical shape, whereas cells on laser-treated titanium and on TiN appeared intimately adherent to the surface. The MTT activity and total protein were significantly increased in fibroblasts cultured on titanium surfaces coated with TiN compared to all other surface modifications tested. This study suggests that a titanium nitride coating might be suitable to support tissue growth on implant surfaces.     

Increasing propensity to mind‐wander by transcranial direct current stimulation? A registered report

Transcranial direct current stimulation (tDCS) has been proposed to be able to modulate different cognitive functions. However, recent meta‐analyses conclude that its efficacy is still in question. Recently, an increase in subjects’ propensity to mind‐wander has been reported as a consequence of anodal stimulation of the left dorsolateral prefrontal cortex (Axelrod et al., Proceedings of the National Academy of Sciences of the United States of America, 112 , 2015). In addition, an independent group found a decrease in mind wandering after cathodal stimulation of the same region. These findings seem to indicate that high‐level cognitive processes such as mind wandering can reliably be influenced by non‐invasive brain stimulation. However, these previous studies used low sample sizes and are as such subject to concerns regarding the replicability of their findings. In this registered report, we implement a high‐powered replication of Axelrod et al. (2015) finding that mind‐wandering propensity can be increased by anodal tDCS. We used Bayesian statistics and a preregistered sequential‐sampling design resulting in a total sample size of N = 192 participants collected across three different laboratories. Our findings show support against a stimulation effect on self‐reported mind‐wandering scores. The effect was small, in the opposite direction as predicted and not reliably different from zero. Using a Bayes Factor specifically designed to test for replication success, we found strong evidence against a successful replication of the original study. Finally, even when combining data from both the original and replication studies, we could not find evidence for an effect of anodal stimulation. Our results underline the importance of designing studies with sufficient power to detect evidence for or against behavioural effects of non‐invasive brain stimulation techniques, preferentially using robust Bayesian statistics in preregistered reports.