[Polyneuropathy as a sole syndrome in malignant thymoma]. / Polyneuropathie als einziges paraneoplastisches Syndrom bei malignem Thymom.

Up to 40% of patients with malignant thymoma suffer from paraneoplastic symptoms (90% myasthenia, 10% other symptoms). A 55-year-old patient developed ascending symmetrical sensorimotor tetraparesis. A malignant thymoma without metastases was diagnosed 6 months later. Despite thymectomy followed by radiation and high-dose corticosteroid therapy, the polyneuropathy progressed. Six months after onset, the patient was bound to a wheelchair. Immunosuppressive therapy with cyclophosphamide was initiated, leading to marked remission. After ten cycles, the patient was able to walk independently with walking aids. After the sixth and tenth cycle, respectively, attempts to discontinue immunosuppression led to relapse. In several diagnostic workups, however, there was no tumour relapse. After 13 cycles, cyclophosphamide was replaced by immunoglobulins (0.4 g/kg per day i.v. for 5 days/month) due to progressive renal failure. The patient died just before the second course of this treatment. In conclusion, in the differential diagnosis of rapidly progressive polyneuropathy, a malignant thymoma should be considered, even in the absence of myasthenia. Immunosuppression with cyclophosphamide resulted in amelioration of symptoms in this patient.

Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship to macrophages and for a cytokine-related disorder.

AIMS: Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease is a rare histiocytic disorder of unknown origin. Immunophenotypically the histiocytes of SHML express intensively the S100 protein and in addition a panel of macrophage-associated antigens. Their exact relationship to either monocytes/macrophages or immune accessory dendritic cells is, however, still controversial. METHODS AND RESULTS: In this report recurrent nodal and extranodal manifestations of SHML of a 70-year-old patient were analysed by differential phenotyping using a panel of monoclonal and polyclonal antibodies to macrophage and immune accessory dendritic cell related antigens and by applying nonradioactive in-situ hybridization. CONCLUSIONS: We conclude that stimulation of monocytes/macrophages via macrophage colony stimulating factor (M-CSF) leading to immune suppressive macrophages represents a main mechanism for the pathogenesis of SHML. The study further provides evidence for the monocyte/macrophage but not dendritic cell differentiation of SHML histiocytes.

Advantages of isovolemic large-volume erythrocytapheresis as a rapidly effective and long-lasting treatment modality for red blood cell depletion in patients with polycythemia vera.

Long-term survival of patients with polycythemia vera (PV) is essentially determined by the ability to reduce the risk of thromboembolic complications resulting from the altered rheological conditions by the high red blood cell (RBC) mass of these patients. RBC depletion to normal hematocrit (Hct) values is the first line therapy and should be preferred to chemotherapy (or P32) because of the long-term risk of acute leukemia or other secondary malignancies. RBC depletion is accomplished much more effectively and rapidly by erythrocytapheresis (EA) than by repeated phlebotomies and has been shown to be well tolerated and accepted by the patients (8). The main indications for EA for a PV patient (often newly diagnosed) are high risk Hct values of >55-60% that can be reduced to the normal range within 1-2 h. The long-lasting effect (median interval between 2 EA treatments: ca. 6 months) is partially the result of the massive loss of iron, a growth factor for erythropoesis. This has been shown by in vitro studies in erythroid progenitor cells of PV patients before and after EA (11). The advantages and possible disadvantages of EA treatment are discussed.

Cryoglobulinemia in chronic hepatitis C virus infection: prevalence, clinical manifestations, response to interferon treatment and analysis of cryoprecipitates.

Chronic hepatitis C virus infection can be associated with mixed cryoglobulinemia and systemic vasculitis. The pathogenesis remains poorly understood. 55 consecutive patients with chronic HCI infection (anti-HCV- and serum HCV RNA-positive) were studies prospectively. Cryoglobulinemia was detected in 28 patients (51%) with a mean cryocrit level of 2.2%. Clinical symptoms of vasculitis were encountered in six patients. Compared to those HCV-infected patients without cryoglobulinemia the following distinctive features were observed in the presence of cryoglobulinemia: increased age (p<0.02), female preponderance (p<0.002), longer-lasting HCV infection (mean of 10.7 vs. 4.7 yrs), higher prevalence of cirrhosis (42.8 vs. 0%), increased serum concentration of IgM and increased rheumatoid factor activity, decreased concentration of serum C4 (each p<0.05). The response to interferon treatment was similar in patients with and without cryoglobulinemia. When cryoprecipitates were analyzed by immunofixation, type II cryoglobulinemia was present in 1/3 and type III in 2/3 of patients. By SDS-PAGE four different proteins were demonstrable in cryoprecipitates each identified by immunoblotting as IgG and IgM heavy or light chains respectively. Cryoprecipitate IgGs were shown to react with HCV structural as well a non-structural proteins in a recombinant immunoblotting assay (RIBA). In contrast, cryoprecipitate IgMs reacted only to the HCV core protein c22-3. HCV RNA was detected in cryoprecipitates without a significant enrichment when compared to the corresponding serum or supernatant HCV RNA content. Given the monoclonality of some cryoprecipitate IgM and their reactivity to HCV core, a cross-reactivity to IgG was postulated. In fact, when performing a computer-assisted search for sequence homology, a motif within the core protein (EGLGWAGWL, conserved in HCV genotypes) was identified homologous to a sequence of IgG heavy chains. Thus, temperature-dependent affinity changes of IgM anti-HCV core (nonapeptide) and ensuing complex formation with IgG via binding to the homologous IgG sequence could be a mechanism of cryoprecipitate formation.

[Large volume, isovolemic erythrocytapheresis in treatment of polycythemia vera. Effect of massive iron depletion of proliferation behavior of erythroid precursor cells (BFU-E)]. / Grossvolumige, isovolämische Erythrozytapherese in der Behandlung der Polycythaemia vera. Einfluss des massiven Eisenentzugs auf das Proliferationsverhalten erythroider Vorläuferzellen (BFU-E).

BACKGROUND: Isovolemic large volume erythrocyte-apheresis (EA) is a rapid, effective and well-tolerated treatment modality for red blood cell (RBC) depletion in patients with polycythaemia vera (PV). According to clinical observations its long lasting effect (median interval from EA to EA about 6 months) may, at least in part, be due to the associated loss of iron. METHODS: Therefore we investigated the influence of EA on the proliferative capacity of erythroid (BFU-E) and granulocyte-macrophage (GM-CFU) progenitor cells and on the erythropoietin-(EPO-)independent, spontaneous in vitro growth of BFU-E in particular. In six patients RBC and iron parameters as well as the proliferative capacity of hematopoietic progenitor cells were determined before and after EA. RESULTS: RBC parameters (in median) were before/after EA: RBC 7.64/5.93 x 10(6)/microliter; Hct 53/40%; Hb 15.5/12.0 g/dl and remained at reduced levels for several months; serum iron and ferritin levels decreased, while transferrin levels and transferrin receptor expression on peripheral mononuclear cells were enhanced. Serum EPO-levels were temporarily but only slightly increased. In all patients there was a significant inhibition of the growth of BFU-E detectable after EA while the GM-CFU were less affected. Within 3 to 6 weeks, the inhibition of endogenous BFU-E ranged from 53% to 100% and of EPO-dependent BFU-E from 31% to 74%. The inhibition of EA associated BFU-E growth could be reduced by in vitro addition of FeCl3. On the other hand, in vitro exposure of progenitor cells to an equivalent concentration of the iron chelator DFO (deferoxamine mesylate) resulted in a total suppression of progenitor cell growth. CONCLUSION: Our data suggest that the long lasting effect of EA is not only due to the high volume removal of RBC itself, but also to the growth inhibition of EPO-independent and -dependent BFU-E which is obviously mediated by the considerable loss of iron by EA.

[The analysis of a severe side effect of a cartilage-protective agent by immunological studies]. / Analyse einer schweren Nebenwirkung auf ein Chondroprotektivum mit Hilfe immunologischer Untersuchungen.

After 18 intramuscular injections of Arumalon, a 62-year-old woman with degenerative hip-joint changes developed a severe illness with fever up to 39 degrees C, swellings of the finger, hand and knee joints, as well as a local skin rash and changes in the blood (WBC 1900/microliters, platelets 113,000/microliters), and increase in liver enzymes (GOT 83 U/l, GPT 93 U/l, lactate dehydrogenase 693 U/l). Arumalon, a glucosaminoglycan-peptide complex containing a watery extract of bovine cartilage and bone marrow, is used as a cartilage-protecting medication. The close temporal relationship between the injections and the symptoms suggested that the illness was drug-induced. This view was supported by a positive lymphocyte transformation test with Arumalon and its constituents, as well as by the demonstration of Arumalon-specific antibodies in the cultured lymphocyte fluid while the serum was negative for the antibodies. The illness took a protracted course. The patient became completely free of symptoms only after a year on a maintenance dose of prednisone, 15 mg daily. As a local inflammatory reaction was noted at the very start of the Arumalon injections, presensitization against the foreign proteins in Arumalon cannot be excluded. This is also supported by the fact that the specific lymphocyte proliferation was essentially unchanged even after nine months. This case illustrates the importance of careful assessment of increased and repeated manifestations of local reaction during Arumalon treatment, in particular in view of the risk of systemic side effects.

IgA producing primary intracerebral lymphoma.

The first case of a primary and solitary IgA (lambda) producing tumour (possibly a non-Hodgkin's lymphoma) in the CNS is reported. Clinical and neuroimaging findings are described. Early diagnosis without brain biopsy and successful therapy were possible by CSF and serum immunoglobulin analysis which proved local paraprotein production restricted to the CNS.

Treatment of polycythemia vera by isovolemic large-volume erythrocytapheresis.

Excess red blood cells (RBC) in patients with polycythemia vera (PV) are usually removed by repeated phlebotomy. In order to improve the efficacy of this treatment, we used isovolemic large-volume erythrocytapheresis (EA) by a cell separator. A retrospective analysis of our experience with 69 PV patients (206 EA procedures) is reported. EA induced a rapid, well-tolerated, and long-lasting reduction of Hct, Hb, and RBC counts, as well as an immediate disappearance or reduction of clinical symptoms of PV, while tissue oxygen tension - as measured in 8 patients - increased. Hct was reduced by EA from 56.8% +/- 5.6% to 41.9% +/- 6.6%, Hb from 17.5 +/- 2.3 to 12.7 +/- 2.4 g%, RBC counts from 7.4 +/- 0.9 to 5.4 +/- 0.9 x 10(6)/mm3. The mean volume of the apherisate was 1410 +/- 418 ml, (mean Hct 79.7% +/- 9.3%), and the actual RBC volume removed 1113 +/- 367 ml. The isovolemic procedure was well tolerated and the acceptance by patients seemed to be better than with repeated phlebotomy. In 21 patients whose Hct values (Hct before and after EA 58% +/- 5.7% and 41.5% +/- 4.9%) were regularly followed after EA the mean period with Hct less than 50% after a single EA procedure was 6.1 +/- 4.1 months (median, 6); in 14 out of these 21 patients a Hct of less than 43% after EA was reached and their mean period with Hct less than 50% after EA was 7.6 +/- 4.0 months (median, 7.5). For three patients this period was 11, 13, and 15 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Microheterogeneity of paraproteins. I. Diagnostic value of isoelectric focusing followed by immunoblotting.

Isoelectric focusing (IEF) in thin-layer polyacrylamide gels followed by immunoblotting on nitrocellulose membranes is presently the most sensitive method in the routine detection of IgG paraproteins. With this technique, immunoglobulin class and light chain composition can be as reliably identified as in immunoelectrophoresis. The problem of firm adherence between IEF polyacrylamide gels and nitrocellulose membranes can be overcome by brief incubation in sodium dodecyl sulfate. After isoelectric focusing, IgG paraproteins display a characteristic pattern of limited electrophoretic heterogeneity. This pattern is easily recognized even in the few cases with a constant tendency to aggregate under IEF conditions and in the surprisingly high percentage of paraproteins with very alkaline isoelectric points in which it is altered due to a cathodal collection effect. It is independent of the total amount of IgG in serum and remains stable intraindividually over extended observation periods. On the other hand, there is a very high degree of interindividual variability while common paraprotein characteristics still remain recognizable.