Successful treatment of IgM paraproteinaemic neuropathy with fludarabine. (1/496)

OBJECTIVES: To evaluate the response of four patients with IgM paraproteinaemic neuropathy to a novel therapy-pulsed intravenous fludarabine. BACKGROUND: The peripheral neuropathy associated with IgM paraproteinaemia usually runs a chronic, slowly progressive course which may eventually cause severe disability. Treatment with conventional immunosuppressive regimens has been unsatisfactory. Fludarabine is a novel purine analogue which has recently been shown to be effective in low grade lymphoid malignancies. METHODS: Four patients were treated with IgM paraproteinaemic neuropathy with intravenous pulses of fludarabine. Two of the four patients had antibodies to MAG and characteristic widely spaced myelin on nerve biopsy and a third had characteristic widely spaced myelin only. The fourth had an endoneurial lymphocytic infiltrate on nerve biopsy and a diagnosis of Waldenstrom's macroglobulinaemia. RESULTS: In all cases subjective and objective clinical improvement occurred associated with a significant fall in the IgM paraprotein concentration in three cases. Neurophysiological parameters improved in the three patients examined. The treatment was well tolerated. All patients developed mild, reversible lymphopenia and 50% mild generalised myelosuppression, but there were no febrile episodes. CONCLUSION: Fludarabine should be considered as a possible treatment for patients with IgM MGUS paraproteinaemic neuropathy.  (+info)

Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. (2/496)

To assess whether the progression of plasma cell tumors is accompanied by angiogenesis and secretion of matrix-degrading enzymes, bone marrow biopsy specimens from 20 patients with monoclonal gammopathy of undetermined significance (MGUS), 18 patients with nonactive multiple myeloma (MM), and 26 patients with active MM were evaluated for their angiogenic potential and matrix-metalloproteinase (MMP) production. A fivefold increase of the factor VIII+ microvessel area was measured by a planimetric method of point counting in the bone marrow of patients with active MM as compared with nonactive MM and MGUS patients (P <.01). When serum-free conditioned media (CM) of plasma cells isolated from the bone marrow of each patient were tested in vivo for their angiogenic activity in the chick embryo chorioallantoic membrane (CAM) assay, the incidence of angiogenic samples was significantly higher (P <. 01) in the active MM group (76%) compared with nonactive MM (33%) and MGUS (20%) groups. Moreover, a linear correlation (P <.01) was found between the extent of vascularization of the bone marrow of a given patient and the angiogenic activity exerted in the CAM assay by the plasma cells isolated from the same bone marrow. In vitro, a significantly higher fraction of the plasma cell CM samples from the active MM group stimulated human umbilical vein endothelial cell (HUVEC) proliferation (53%, P <.01), migration (42%, P <.05), and/or monocyte chemotaxis (38%, P <.05) when compared with nonactive MM and MGUS groups (ranging between 5% and 15% of the samples). Also, immunoassay of plasma cell extracts showed significantly higher (P <. 01) levels of the angiogenic basic fibroblast growth factor (FGF)-2 in the active MM patients than in nonactive MM and MGUS patients (153 +/- 59, 23 +/- 17, and 31 +/- 18 pg FGF-2/100 micrograms of protein, respectively). Accordingly, neutralizing anti-FGF-2 antibody caused a significant inhibition (ranging from 54% to 68%) of the biological activity exerted on cultured endothelial cells and in the CAM assay by plasma cell CM samples from active MM patients. Finally, in situ hybridization of bone marrow plasma cells and gelatin-zymography of their CM showed that active MM patients express significantly higher (P <.01) levels of MMP-2 mRNA and protein when compared with nonactive MM and MGUS patients, whereas MMP-9 expression was similar in all groups. Taken together, these findings indicate that the progression of plasma cell tumors is accompanied by an increase of bone marrow neovascularization. This is paralleled by an increased angiogenic and invasive potential of bone marrow plasma cells, which is dependent, at least in part, by FGF-2 and MMP-2 production. Induction of angiogenesis and secretion of MMPs by plasma cells in active disease may play a role in their medullary and extramedullary dissemination, raising the hypothesis that angiostatic/anti-MMP agents may be used for therapy of MM.  (+info)

Evaluation of a particle-enhanced turbidimetric immunoassay for the measurement of immunoglobulin E in an ILab 900 analyzer. (3/496)

BACKGROUND: The measurement of immunoglobulin E (IgE) in serum is widely used in the diagnosis of allergic reactions and parasitic infections. We describe here a fully automated assay for human IgE suitable for routine application in a general chemistry analyzer. METHODS: We used an ILab 900 analyzer. This instrument automates a particle-enhanced immunoturbidimetric assay with an analysis time of 9 min. RESULTS: The assay was linear in the range 4-1000 kIU/L (r = 0.9998). The intra- and interassay CVs at 57, 235, and 434 kIU/L were <3.5% and <7.4%, respectively. The detection limit was 4 kIU/L. Hemoglobin (+info)

14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. (4/496)

Clonal plasma cells in monoclonal gammopathy of undetermined significance (MGUS) have been shown to bear copy number chromosome changes. To extend our knowledge of MGUS to structural chromosomal abnormalities, we have performed fluorescence in situ hybridization experiments with probes directed to the 14q32 and 13q14 chromosomal regions in 100 patients with either MGUS or smoldering multiple myeloma (SMM). 14q32 abnormalities were observed in at least 46% of patients with MGUS/SMM, with these abnormalities being present in the majority of clonal plasma cells. Whereas t(11;14)(q13;q32) occurs in 15% of MGUS/SMM patients, an incidence similar to that of overt multiple myeloma (MM) patients, translocation t(4;14)(p16;q32) is observed in only 2% of these cases [P = 0.002 for difference with t(11;14)], as compared with 12% in MM patients (P = 0.013). Monoallelic deletions of the 13q14 region were found in 21% of patients, with two types of situations. In half of the evaluable patients, and especially in patients with SMM, the deletion is present in the majority of clonal plasma cells, as in MM, whereas in the other half of the evaluable patients (essentially in MGUS patients), it is observed in subclones only. These data enable us to elaborate a plasma cell oncogenesis model from MGUS to MM.  (+info)

Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. (5/496)

Chromosomal abnormalities are present in most (if not all) patients with multiple myeloma (MM) and primary plasma cell leukemia (PCL). Furthermore, recent data have shown that numerical chromosomal changes are present in most individuals with monoclonal gammopathy of undetermined significance (MGUS). Epidemiological studies have shown that up to one third of MM may emerge from pre-existing MGUS. To clarify further possible stepwise chromosomal aberrations on a pathway between MGUS and MM, we have analyzed 158 patients with either MM or primary PCL and 19 individuals with MGUS using fluorescence in situ hybridization (FISH). Our FISH analyses were designed to detect illegitimate IGH rearrangements at 14q32 or monosomy 13. Whereas translocations involving the 14q32 region were observed with a similar incidence (60%) in both conditions, a significant difference was found in the incidence of monosomy 13 in MGUS versus MM or primary PCL. It was present in 40% of MM/PCL patients, but in only 4 of 19 MGUS individuals. Moreover, whereas monosomy 13 was found in the majority of plasma cells in MM, it was observed only in cell subpopulations in MGUS. It is noteworthy that, in a group of 20 patients with MM and a previous MGUS history, incidence of monosomy 13 was 70% versus 31% in MM patients without a known history of MGUS (P =.002). Thus, this study highlights monosomy 13 as correlated with the transformation of MGUS to overt MM and may define 2 groups of MM with possible different natural history and outcome, ie, post-MGUS MM with a very high incidence of monosomy 13 and de novo MM in which other genetic events might be involved. Serial analyses of individuals with MGUS will be needed to validate this model.  (+info)

Monoclonal gammopathy may disturb oestradiol measurement in the treatment and monitoring of in-vitro fertilization: case report. (6/496)

A 31 year old woman had her treatment for infertility by in-vitro fertilization (IVF) cancelled because a highly elevated serum concentration of oestradiol was detected, contrary to the clinical picture and that observed by vaginal ultrasound. The immunoassay for measuring oestradiol had been affected by circulating heterophilic antibodies in the form of an elevated immunoglobulin (Ig) G-kappa M component. This may often be associated with a haematological malignancy of lymphoid origin, but this patient had a benign monoclonal gammopathy. Monoclonal gammopathy has not been described in IVF patients previously, nor has monoclonal gammopathy been reported as a cause of erroneously elevated oestradiol concentration. This sort of interference in oestradiol analysis is probably very rare, but may lead to unnecessary cancellation of the treatment. A highly elevated oestradiol that is not in accordance with the clinical course may indicate heterophilic antibody interference, and the cause should always be investigated.  (+info)

Somatic mutations of the L12a gene in V-kappa(1) light chain deposition disease: potential effects on aberrant protein conformation and deposition. (7/496)

Light chain deposition disease (LCDD) and light chain amyloidosis (AL) are disorders of monoclonal immunoglobulin deposition in which normally soluble serum precursors form insoluble deposits in tissues. A common feature in both is the clonal proliferation of B-cells that produce pathogenic light chains. However, the deposits in LCDD differ from those in AL in that they are ultrastructurally granular rather than fibrillar and do not bind Congo red or colocalize with amyloid P component or apolipoprotein E. The reason(s) for their differences are unknown but are likely multifactorial and related to their protein conformation and their interaction with other molecules and tissue factors in the microenvironment. Knowledge of the primary structure of the light chains in LCDD is very limited. In the present study two new kappa(1) light chains from patients with LCDD are described and compared to seven other reported kappa-LCDD proteins. The N-terminal amino acid sequences of light chain GLA extracted from the renal biopsy and light chain CHO from myocardial tissue were each identical to the respective light chains isolated from the urines and to the V-region amino acid sequences translated from the cloned cDNAs obtained from bone marrow cells. The germline V-region sequences, determined from the genomic DNA in both and in MCM, a previously reported kappa(1) LCDD light chain, were identical and related to the L12a germline gene. The expressed light chains in all three exhibit amino acid substitutions that arise from somatic mutation and result in increased hydrophobicity with the potential for protein destabilization and disordered conformation.  (+info)

Blood dyscrasias in clozapine-treated patients in Italy. (8/496)

BACKGROUND AND OBJECTIVE: Clozapine is a dibenzodiazepine derivative that is more effective than standard neuroleptic drugs in refractory schizophrenic patients, but its introduction in some countries was delayed by its propensity to cause blood dyscrasias. However, over the last ten years, different reports have clearly demonstrated that agranulocytosis and neutropenia can be easily prevented by means of strict hematologic surveillance. This article reviews the results of the first five years of the Italian Clozapine Monitoring System (ICLOS). DESIGN AND METHODS: The hematologic parameters of 2,404 patients registered between 1995 and 1999 were collected in a central database, before the patients began clozapine-treatment, weekly for the first 18 weeks, and then monthly throughout the duration of therapy. On the basis of conventional criteria, different risk levels have been identified with total leukocyte <3. 0x10(9)/L and/or an absolute neutrophil count <1.5x10(9)/L leading to immediate discontinuation of the drug. RESULTS: The analysis shows that 0.9% of the patients developed neutropenia and 0.7% agranulocytosis, mainly during the first 18 weeks of clozapine treatment. Drug discontinuation led to the normalization of hematologic parameters in all cases, and the use of growth factors reduced the risk of infectious complications. Transient leukocytosis and eosinophilia were also observed but these did not have any serious clinical effects. INTERPRETATION AND CONCLUSIONS: The ICLOS study confirms that regular hematologic monitoring is highly effective in minimizing the incidence of clozapine-associated blood dyscrasias. The lower than initially expected rates of agranulocytosis and associated deaths are encouraging in view of the benefits of this drug in treatment-resistant schizophrenia and other neurologic disorders.  (+info)

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