A phase I-II trial of 4'-deoxydoxorubicin (esorubicin) in refractory or relapsed acute leukemia

In a phase I-II study, 21 patients with relapsed or refractory acute leukemia were treated with 4'-deoxydoxorubicin (esorubicin), the 4'-deoxy derivative of doxorubicin. Four of 14 evaluable patients with acute nonlymphocytic leukemia (ANLL) in relapse or refractory to other anthracyclines achieved partial response (28.5%). Pharmacokinetics were similar to those of the parent compound, doxorubicin. Esorubicin has activity in ANLL and has pharmacologic properties comparable to those of other anthracyclines. Dose-limiting toxicity occurs in the form of mucositis, which may limit its use in combination with other antileukemic drugs.     

Presence of lysine at aa 335 of the hemagglutinin-neuraminidase protein of mumps virus vaccine strain Urabe AM9 is not a requirement for neurovirulence

The recent global resurgence of mumps has drawn attention to the continued need for robust mumps immunization programs. Unfortunately, some vaccines derived from inadequately attenuated vaccine strains of mumps virus have caused meningitis in vaccinees, leading to withdrawal of certain vaccine strains from the market, public resistance to vaccination, or in some cases, cessation of national mumps vaccination programs. The most widely implicated mumps vaccine in cases of postvaccination meningitis is derived from the Urabe AM9 strain, which remains in use in some countries. The Urabe AM9 vaccine virus has been shown to exhibit a considerable degree of nucleotide and amino acid heterogeneity. Some studies have specifically implicated variants containing a lysine residue at amino acid position 335 in the hemagglutinin-neuraminidase (HN) protein with neurotoxicity, whereas a glutamic acid residue at this position was associated with attenuation. To test this hypothesis we generated two modified Urabe AM9 cDNA clones coding either for a lysine or a glutamic acid at position 335 in the HN gene. The two viruses were rescued by reverse genetics and characterized in vitro and in vivo. Both viruses exhibited similar growth kinetics in neuronal and non-neuronal cell lines and were of similar neurotoxicity when tested in rats, suggesting that amino acid 335 is not a crucial determinant of Urabe AM9 growth or neurovirulence.     

Stimulation der Granulopoese mit hämatopoetischen Wachstumsfaktoren

Die therapieinduzierte Neutropenie kann mit den Kolonie stimulierenden Faktoren (CSF) der Granulopoese (G-CSF und GM-CSF) vermieden,abgemildert oder in ihrer Zeitdauer verkürzt werden. Die CSF erm?glichen die Mobilisation h?matopoetischer Stammzellen in das Blut und deren Sammlung für die Transplantation nach Hochdosistherapie.Diese Faktoren sind daher essenziell in der Supportivtherapie maligner Erkranklungen. Der Arbeitskreis Supportivma?nahmen in der Onkologie (ASO) der Deutschen Krebsgesellschaft hat Richtlinien zur Therapie mit den Kolonie stimulierenden Faktoren entwickelt, die unterschiedlichen klinischen Situationen angepasst sind. Der vollst?ndige Text wurde 12/2001 in “Der Onkologe” publiziert [23], er ist auch auf der Homepage des ASO unter http://www.onkosupport.de zu finden [24]. Prof.Dr. H. Link H?matologie, Internistische Onkologie, Endokrinologie, Medizinische Klinik I, Westpfalz-Klinikum Kaiserslautern, Akademisches Lehrkrankenhaus der Johannes-Gutenberg-Universit?t Mainz, 67653 Kaiserslautern, E-Mail: hlink@westpfalz-klinikum.de     

Improved Performance of Hip DXA Using a Novel Region of Interest in the Upper Part of the Femoral Neck: In Vitro Study Using Bone Strength as a Standard of Reference

We tested the hypothesis that bone mineral density (BMD) and bone mineral content (BMC) in proximal human femur specimens in the upper neck region of interest (ROI) and femoral neck axis length (FNAL) provide a significantly better prediction of femoral bone strength than standard ROIs in vitro. BMD and BMC were measured in 110 proximal femur specimens using a standard dual-energy X-ray absorptiometry (DXA) scanner. The analysis included a new ROI in the upper neck as well as the standard ROIs. FNAL was obtained from the scan images. The specimens' failure-load was measured in a mechanical loading device, simulating a fall on the greater trochanter. For the standard ROIs, correlations between failure-load and BMD ranged from R2 = 0.64 (shaft ROI) to R2 = 0.70, p < 0.001 (femoral neck). Prediction of strength by BMD did not significantly differ from those of BMC (R2 ranging from 0.65 to 0.75, p < 0.001). In the upper neck ROI, for both BMD and BMC correlations with failure-load were higher (R2 = 0.76 and 0.81, respectively; p < 0.001). A lower, yet still significant, correlation was found between FNAL and bone strength (R2 = 0.23, p < 0.001). Normalization of failure-load with respect to FNAL did not significantly increase the correlations with densitometric measures. This study provides in vitro evidence indicating that among the ROIs of the proximal femur the newly defined upper neck ROI provides the best prediction of bone strength. Only a weak association was observed between failure load and FNAL.     

Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH 1 and TH 2 cytokines

Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the amino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline. NO is important in the bactericidal and cytotoxic activities of macrophages. An equivalent functional role of arginase and its products is not known. We tested the induction of arginase in bone marrow-derived macrophages by endogenous mediators that are known to induce NO synthase, such as interferon-γ (IFN-γ), or suppress the induction of this enzyme, such as interleukin (IL)-4, IL-10, and prostaglandin E₂ (PGE₂). We find that PGE₂ and the TH2 cytokines IL-4 and IL-10 are potent inducers of arginase. In contrast, the TH 1 cytokine IFN-γ does not induce arginase. Simultaneous application of both types of mediators leads to reduced induction of both arginase and NO synthase. Exposure of macrophage cultures to inducers of NO synthase exhausts their ability to respond subsequently to inducers of arginase. Conversely, exposure of the cells to inducers of arginase exhausts their ability to respond subsequently to inducers of NO synthase. The results are consistent with a competition of both enzymes for their substrate, L-arginine, with a reciprocal inhibition in the induction of both enzymes, or a combination of both phenomena. The enzymes NO synthase and arginase appear to define two alternate functional states of macrophages, induced by TH 1 and TH 2 cytokines, respectively.     

Sex differences of human trabecular bone microstructure in aging are site-dependent.

In this study, we characterize bone microstructure, specifically sex differences, at multiple skeletal sites in 165 subjects >52 yr of age, using microCT technology in vitro. Significant sex differences are observed at the distal radius, femoral neck, and femoral trochanter, but not at the iliac crest, calcaneus, and lumbar vertebral body. Correlations in BV/TV between sites ranged from r = 0.13 to 0.56. INTRODUCTION: The goals of this study were (1) to assess potential sex differences of bone microstructure and their difference between skeletal sites and (2) to explore the relationship of trabecular microstructural properties between relevant skeletal sites. MATERIALS AND METHODS: Trabecular bone microstructural properties were measured in vitro in 165 subjects 52-99 yr of age using microCT. Defined volumes of interest (cylinders with 6 mm diameter and 6 mm length) were scanned at a resolution of 26 microm (isotropic) in six different anatomical sites: distal radius, femoral neck and trochanter, iliac crest, calcaneus, and second lumbar vertebral body. RESULTS: At the radius and femoral neck, trabecular bone displayed a more plate-like structure, thicker trabeculae, smaller separation/higher trabecular number, higher connectivity, and a higher degree of anisotropy in men than in women (p < 0.05). At the trochanter, men displayed more plate-like structure and thicker trabeculae (p < 0.05), but no differences in trabecular separation or other parameters compared with the women. At the calcaneus, iliac crest, and second lumbar vertebra none of the bone parameters displayed significant differences between sexes. The BV/TV at one site explained a range of only 2-32% of the variability at other sites. CONCLUSIONS: These results suggest that trabecular bone microstructural properties are remarkably heterogeneous throughout the skeleton. Significant differences between men and women are observed at some, but not at all, sites. The magnitude of sex differences in trabecular microstructure coincides with that of fracture incidence observed for some of the sites in epidemiological studies.     

Transarticular invasion of iliopelvic sarcomas into the sacrum: Radiological analysis of 47 cases

Joint cartilage functions as a barrier against the extension of bone tumors. However, transarticular invasion by iliopelvic sarcomas across the sacroiliac (SI) joints into the sacrum sometimes occurs. We made a radiological analysis (CT and/or MRI) of 47 bone sarcomas which originated in the ilium and extended nearly to the SI joint. 8 of 17 chondrosarcomas and 3 of 30 other sarcomas (2 of 23 Ewing's sarcomas and 1 of 7 osteosarcomas) invaded the sacrum through the SI joint.     

Multiple sclerosis: myelin basic protein induced mRNA expression of proinflammatory cytokines in mononuclear cells is suppressed by interferon-β 1b in vitro

Beta-interferon (IFN-β) is a promising treatment in multiple sclerosis (MS), reducing the exacerbation rate and MRI lesion burden, as well as the disease progression in relapsing-remitting MS. IFN-β was originally defined by its antiviral effects, but the interest has recently been focused on its immunomodulatory properties. Myelin basic protein (MBP) is one of several autoantigens considered to be the target for autoaggressive immune responses, which eventually might lead to the development of MS. To study in-vitro effects of IFN-β1b on MBP induced cytokine expression, mRNA for the Th1 cytokines IFN-γ and TNF-α, the Th2 related IL-4 and IL-6, the cytolytic perforin and the immune response downregulating TGF-β was measured with in situ hybridization after culture of blood mononuclear cells (MNC) in the presence and absence of MBP. Numbers of cells expressing IFN-γ, TNF-α, perforin and IL-4 mRNA were significantly suppressed after culture with 10 U/ml IFN-β1b. No such effect was seen on MBP induced IL-6 or TGF-β mRNA expression. These observations suggest that one of the major effects of IFN-β1b is the induction of a shift in the cytokine mRNA profile towards a more immunosuppressive pattern. In parallel in vitro tests, the control substance dexametasone (40 μg/ml) reduced the numbers of cells expressing mRNA for all cytokines under study with the exception of TGF-β, to an extent equal to or even more pronounced than IFN-β1b.