Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma

Purpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6µg/ml×40ml,9µg/ml×40ml,15µg/ml×40ml, or 9µug/ml×100ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6µug/ml×40ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.     

CoMFA and homology-based models of the glycine binding site of N-methyl-d-aspartate receptor

Homology modeling was used to build 3D models of the N-methyl-d-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.     

Complex chromosomal rearrangements in a secondary acute myeloblastic leukemia after chemotherapy in TRAPS

We report on the cytogenetic findings from a patient with a de novo TNF-receptor-associated periodic syndrome (TRAPS), who showed first symptoms at the age of four months. Thus, he obtained a long-term therapy with cortisone, chlorambucile, methotrexate and cyclophosphamide. At the age of 14 he developed a secondary acute myeloblastic leukemia. Highly complex chromosomal rearrangements were detected after banding analysis. The exact definition of karyotype and the involved breakpoints could only be resolved after application of sophisticated multicolor-FISH techniques: 44,XY,-5,der(6)t(6;7)(6pter right curved arrow 6q12::7p22.2 right curved arrow 7pter or 7pter right curved arrow 7p22.2), dic(7;19)t(6;19;6;7;19;7;19)(19qter right curved arrow 19q12::7p13 right curved arrow 7p11.1::19q12 right curved arrow 19p12 or 19p12 right curved arrow 19q12::7p11.1 right curved arrow 7q21.3::6q12 right curved arrow 6q26::19p13.3 right curved arrow 19p12::6q26-6qter),dic(12;13)(13qter right curved arrow 13p11.2::12p13.1 right curved arrow 12qter),ace(12;13)(13pter right curved arrow 13p11.2::12p13.1 right curved arrow 12pter), -19. The simultaneous presence of two dicentric chromosomes has not been reported previously and is striking, as such chromosomes are suggested to be instable. However, such chromosomes are observed frequently after chemo- or radiotherapy and in secondary, i.e. therapy related AML (tAML). Thus, AML in this case may result from a long-term therapy of TRAPS with methotrexate, cyclophosphamide, chlorambucile and cortisone.     

Effects of noise from functional magnetic resonance imaging on auditory event-related potentials in working memory task

The effects of functional magnetic resonance imaging (fMRI) acoustic noise were investigated on the parameters of event-related responses (ERPs) elicited during auditory matching-to-sample location and pitch working memory tasks. Stimuli were tones with varying location (left or right) and frequency (high or low). Subjects were instructed to memorize and compare either the locations or frequencies of the stimuli with each other. Tape-recorded fMRI acoustic noise was presented in half of the experimental blocks. The fMRI noise considerably enhanced the P1 component, reduced the amplitude and increased the latency of the N1, shortened the latency of the N2, and enhanced the amplitude of the P3 in both tasks. The N1 amplitude was higher in the location than pitch task in both noise and no-noise blocks, whereas the task-related N1 latency difference was present in the no-noise blocks only. Although the task-related differences between spatial and nonspatial auditory responses were partially preserved in noise, the finding that the acoustic gradient noise accompanying functional MR imaging modulated the auditory ERPs implies that the noise may confound the results of auditory fMRI experiments especially when studying higher cognitive processing.     

Cervical transforaminal injection of corticosteroids into a radicular artery: a possible mechanism for spinal cord injury

Spinal cord injury has been recognized as a complication of cervical transforaminal injections, but the mechanism of injury is uncertain. In the course of a transforaminal injection, an observation was made after the initial injection of contrast medium. The contrast medium filled a radicular artery that passed to the spinal cord. The procedure was summarily abandoned, and the patient suffered no ill effects. This case demonstrates that despite using careful and accurate technique, it is possible for material to be injected into a radicular artery. Consequently, inadvertent injection of corticosteroids into a radicular artery may be the mechanism for spinal cord injury following transforaminal injections. This observation warns operators to always perform a test injection of contrast medium, and carefully check for arterial filling using real-time fluoroscopy with digital subtraction.     

Assessment of the prompt radiation hazards of trapped antiprotons

Investigators at several laboratories are seriously considering the storage and transport, perhaps over long distances, of very low energy antiprotons as a part of basic physics research programs and perhaps even for practical applications. To do this will require proper attention to the prompt radiation hazards due to the release of energy in the annihilations of antiprotons with nuclei, under either planned or accidental circumstances. In this paper, the potential storage of very low energy antiprotons is discussed, and the major features of the radiation fields produced by their annihilations are reviewed both qualitatively and quantitatively. Detailed Monte Carlo shielding calculations for a conceptual source of annihilating antiprotons nearly at rest are presented. It is concluded that these radiation fields are readily understood and that the radiation hazards can be mitigated using conventional means.     

Brain Glioma and Human Leukocyte Antigens (HLA) – is There an Association

Expression of human leukocyte antigens (HLA) is important for the immune response against infectious agents and malignant cells. Association of single HLA antigens or HLA haplotypes with disease has been investigated previously, and positive correlations between HLA and some cancers, such as cervical or nasopharyngeal carcinomas have been reported. In the present study, HLA antigen frequencies of 65 adult Caucasian patients with low-grade, anaplastic, or malignant astrocytic glioma (WHO grades II–IV) were compared with 157 racially similar, asymptomatic control individuals. Both standard serologic and PCR techniques for HLA typing were employed for all patients and controls.Our results suggest a positive association between single HLA antigens and presence of symptomatic cerebral glioma. Compared with the control population, patients positive for HLA-A*25 had a 3.0-fold increased risk of glioma (p = 0.04), patients positive for HLA-B*27, a 2.7-fold risk (p = 0.03), and patients positive for HLA-DRB1*15, a 2.2-fold risk (p = 0.03), whereas HLA-DRB1*07 was associated with a 0.4-fold decreased risk of glioma (p = 0.02). Occurrence rate of some HLA antigen combinations and estimated haplotypes was also different in glioma patients. Thus, HLA-DRB1*15:DRB5*(51) occurrence in combination with HLA-DRB1*11 was associated with a 13.4-fold increased risk of glioma (p = 0.001), and the incidence of HLA-Cw*6:DRB1*07 with a 0.2-fold decreased risk of glioma (p = 0.03).In conclusion, single HLA antigens and their combinations and estimated haplotypes are possibly significantly more or less frequent in persons developing symptomatic cerebral glioma during their adult life, compared with asymptomatic individuals.     

Transgenic pigs as models for translational biomedical research

The translation of novel discoveries from basic research to clinical application is a long, often inefficient, and thus costly process. Accordingly, the process of drug development requires optimization both for economic and for ethical reasons, in order to provide patients with appropriate treatments in a reasonable time frame. Consequently, “Translational Medicine” became a top priority in national and international roadmaps of human health research. Appropriate animal models for the evaluation of efficacy and safety of new drugs or therapeutic concepts are critical for the success of translational research. In this context rodent models are most widely used. At present, transgenic pigs are increasingly being established as large animal models for selected human diseases. The first pig whole genome sequence and many other genomic resources will be available in the near future. Importantly, efficient and precise techniques for the genetic modification of pigs have been established, facilitating the generation of tailored disease models. This article provides an overview of the current techniques for genetic modification of pigs and the transgenic pig models established for neurodegenerative diseases, cardiovascular diseases, cystic fibrosis, and diabetes mellitus.     

Hardware Failures in Spinal Cord Stimulation for Failed Back Surgery Syndrome

Spinal cord stimulation (SCS) is an efficient means for treatment of the postsurgical lumbar spine condition known as failed back surgery syndrome (FBSS). Although the devices and the implantation techniques are well established and the technology is sophisticated, there are some complications caused by hardware failures. This study was aimed at identifying the most frequent types of hardware failures and their causes in FBSS patients treated with SCS. In a retrospective analysis, a group of 42 FBSS patients using single lead SCS for 6–74 months was evaluated. Only hardware failures were considered in the analysis, and parameters such as occurrence of failure after primary implantation of the device, frequency and site of failure, stimulation time to failure (TF), and overall time of SCS usage were recorded. In the patient group studied, 12 surgical corrections of the hardware were carried out in 10 patients. In eight patients there was a single corrective procedure, in two additional cases there were two surgically corrected hardware failures each. The most often encountered type of hardware failure was lead breakage or disruption of insulation (percutaneously placed Quad leads only) leading to short circuiting and dysfunction (n= 8). Second in frequency were receiver (model 3470) failures due to insulation leakage at the plug connection site (n= 2). In one case, extension cable breakage caused dysfunction of the system, and another dysfunction was caused by distal extension cable disconnection. In conclusion, SCS is a low‐complication procedure for treatment of benign low‐back pain, but seems to be prone to lead and insulation failures.     

Electrochemical recognition properties of 13- and 16-membered azo- and azoxycrowns in solution

The voltammetric reduction of 13- and 16-membered azo- and azoxycrowns is investigated in the presence of alkali metal cations (Na⁺ or K⁺ for 13- or 16-membered azocrowns, respectively). Two types of recognition behaviour have been observed. The first type consists in a positive shift of the redox potential (100–150 mV) upon addition of metal cation (single peak behaviour). The second type consists in the appearance of two separated redox peaks (150–320 mV more positive, two-wave situation). Better electrochemical recognition results were obtained using SW voltammetry with the peak potential for the complex up to 0.32 V (for the azoxycrown derivative) more positive of the original azocrown compound. For azo- and azoxycrowns exhibiting ‘two-wave’ behaviour, the binding enhancement (ratio of binding constants for reduced and neutral species) was 10²–10⁵ M^?1. For other azocrown compounds with single peak recognition behaviour the binding constants for reduced species were estimated to be 10⁴–10⁵ M^?1. In general, K⁺ binds to 16-membered neutral azocrowns more strongly than Na⁺ to 13-membered ones, whilst binding to the anion-radical has the opposite trend.