Ilana Tatarsky

The role of interleukin-1 and tumour necrosis factor-α in human multiple myeloma

This study investigates the capacity of interleukin‐1α (IL‐1α), interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) to induce interleukin‐6 (IL‐6) production in freshly isolated myeloma cells (MC) and bone marrow‐derived stromal cells (MSC). Recombinant human (rh) IL‐1α, IL‐1β and TNF‐α augmented production of IL‐6 in human MC.IL‐6 was determined on a factor‐dependent Cess cell line. This activity was completely abrogated by anti‐IL‐6 antibodies. Prior incubation of IL‐1α, IL‐1β and TNF‐α with their respective antibodies inactivated the ability of recombinant cytokines to stimulate the release of IL‐6 from myeloma cells. IL‐1α, IL‐1β and TNF‐α enhanced 3H‐TdR uptake in myeloma cells through IL‐6, as antibodies to IL‐6 completely abolished the DNA synthesis induced by culture supernatants of MC exposed to these cytokines. rhIL‐6 reversed the inhibitory action of anti‐IL‐6 antibodies and reinduced DNA synthesis in MC. Next we found that IL‐lα, IL‐1β and TNF‐α induced MSC to produce IL‐6. In contrast, supernatants of unstimulated MSC did not contain detectable IL‐6 biologic activity. Further data demonstrated that human MC were able to induce IL‐6 production in MSC. The stimulatory activities of MC appeared to be mediated through endogenously released IL‐1, as the addition of antibodies towards IL‐1 at the initiation of cocultures completely abrogated the IL‐6 production. We conclude from our data that IL‐1 and TNF‐α may play an important role in the pathogenesis of human multiple myeloma.

Enhancement of erythropoiesis in vitro by human growth hormone is mediated by insulin-like growth factor I

Insulin‐like growth factor I (IGF‐I) is the presumed paracrine or autocrine growth‐promoting mediator of growth hormone in peripheral tissues. In order to evaluate the role of IGF‐I as mediator of human growth hormone (hGH) in erythropoiesis, we compared the effects of both peptides upon in vitro colony formation by primitive (BFU‐E) and relatively mature (CFU‐E) human erythroid precursors. Biosynthetic IGF‐I (2 ng/ml) and hGH (25 ng/ml) induced a significant increase in the growth of both BFU‐E and CFU‐E. BFU‐E growth was maximally enhanced by 6 ng/ml IGF‐I and by 50 ng/ml hGH, resulting in an increase in burst numbers of 62 ± 12% and 52 ± 12%, respectively. Maximal enhancement of CFU‐E growth was detected at higher concentrations of IGF‐I (20 ng/ml) and hGH (150 ng/ml), with respective increases of 121 ± 35% and 137 ± 18% in colony numbers. Enhancement of bone marrow and peripheral blood erythroid progenitor cell growth by hGH required the presence of monocytes and was abrogated by specific monoclonal antibodies directed against IGF‐I membrane receptors. The in vitro growth‐promoting effect of hGH upon human erythroid precursors thus appears to be mediated by paracrine IGF‐I.

Increased risk of cancer in patients with gaucher disease

Background. An increased incidence of cancer, especially hematopoietic in origin, has long been suspected but never established in patients with Gaucher disease.

Prognostic significance of plasma cell morphology in multiple myeloma.

The effect of bone marrow plasma cell morphology at diagnosis on survival time was evaluated in 139 patients with multiple myeloma. According to the morphological classification scheme the patients were categorized as mature (30 patients), immature (76 patients) or plasmablastic (33 patients). The plasmablastic group had an estimated median survival (Kaplan‐Meier method) of 10.9 months, compared with 32.2 months for immature and 60 months for mature types (P = 0.0000). The prognostic value of a morphologic classification in multiple myeloma was further demonstrated by means of a multivariate linear regression analysis of survival data. Expected survival was calculated using clinical features and morphologic subtypes. The estimated survival time for plasmablastic myeloma was shorter by 51.4 months and for immature myeloma patients by 35 months, compared with mature myeloma patients with similar clinical characteristics. Plasma cell morphology at diagnosis is an important predictor of survival duration in patients with multiple myeloma.

Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.

High Incidence of Myeloproliferative Disorders in Ashkenazi Jews in Northern Israel

We have analysed epidemiological parameters in 339 patients with myeloproliferative disorders (MPD) diagnosed in northern Israel between 1975 and 1989 as having polycythemia vera (191 patients), agnogenic myeloid metaplasia (AMM) (113) and essential thrombocythemia (ET) (36). Mean average annual incidence was 11.4 per 1 million residents for polycythemia vera, 6.5 for AMM and 2.1 for ET. For all three diseases the average annual incidence increased with age and was 10 times higher in patients over 65 years compared to those less under the age of 45 years. Four percent of all patients had relatives with MPD. Incidence of MPD in Jews was 10 fold higher than expected compared to Arabs and this difference was noted for all 3 diseases. The incidence in Ashkenazi Jews originating from eastern and central Europe, was 10 and 20 folds higher than in Sephardic Jews and Arabs respectively. Mean age at diagnosis of MPD in Arabs and Sephardic Jews was lower than in Ashkenazi Jews (52 and 56 years compared to 64 years P < 0.05). Likewise, mean age at diagnosis was lower in the 11.5% of MPD patients with prior exposure to biological or chemical hazards compared to unexposed individuals (58 years versus 63 years, P < 0.02). These data demonstrate a cluster of MPD in Ashkenazi Jews in northern Israel and emphasize the importance of genetic predisposition possibly interacting with acquired factors in the pathogenesis of these disorders.

Treatment of polycythemia vera with hydroxyurea

Thirty‐six patients with polycythemia vera were treated with hydroxyurea for 12 to 67 months. Nineteen patients were previously treated with other drugs. In the vast majority of patients, an average dose of 1 g/day was sufficient to control hematocrit value and platelet count. Half of the patients experienced relief of pruritus, and two thirds experienced regression of splenomegaly. None of the patients had either thrombotic complications or leukemia. Four patients suffered from mild side effects, which included fever, hyperbilirubinemia, and stomatitis, and were relieved of their symptoms when treatment was stopped. However, two patients experienced renal failure, a possible major complication not described previously.

The Physiopathological Significance of Benign Monoclonal Gammopathy: a Study of 64 Cases

Sixty‐four patients with monoclonal protein in serum but initially without evidence of multiple myeloma, macroglobulinaemia, amyloidosis or lymphoma, were studied. Fifty patients (78%) were observed for a period exceeding 3 years. Based on the follow‐up data the patients were classified into the following four groups: Group 1=patients with transient monoclonal gammopathy: 4.7%; Group 2 = patients without significant increase in monoclonal serum protein: 75%; Group 3 = patients with more than 50% increase in monoclonal serum protein: 14.1%; Group 4=patients in whom multiple myeloma developed: 6.2%. The mean interval from discovery of the serum monoclonal protein to evolution to multiple myeloma was 61 months. Retrospective analysis of age, sex, blood count, bone marrow picture, antigenic type and size of serum monoclonal proteins, presence of small amounts of homogeneous light chain in the urine, serum albumin level, levels of residual immunoglobulins, did not help to distinguish initially the patients in whom the monoclonal gammopathy evolved to multiple myeloma from patients in whom the disease remained benign and stable. The evolution to multiple myeloma had occurred abruptly after long periods of stable condition; and until this progression the follow‐up data were similar to the patients with benign disease. The possible physiopathology of occurrence and evolution of benign monoclonal gammopathy is discussed.

Autoimmune hemolytic anemia in the course of kaposts sarcoma—report of a case

A patient with Kaposis sarcoma and autoimmune hemolytic anemia is reported. Only two similar cases are yet on report. As in these previously reported cases, in our patient there was visceral involvement with Kaposis sarcoma. The autoimmune hemolytic anemia in our patient was detected at an advanced stage of the disorder, whereas in the remaining two, it preceded the Kaposis sarcoma by one to eight years.

Incidence, prognostic significance and therapeutic modalities of central nervous system involvement in multiple myeloma.

In 114 patients with systemic malignant gammopathies followed during a 10-year period in the hematology clinic of the Rambam Medical Center, 23 episodes of CNS involvement were recorded. 19 cases with spinal cord compression and 4 cases of intracranial plasmacytomas. Early diagnosis followed by prompt laminectomy and subsequent radiotherapy resulted in complete recovery in 50% and partial improvement in 30% of the patients with spinal cord involvement. In good responders. overall survival was not affected by the neurological complication. In the 4 patients with intracranial involvement, external plasmacytomas of the skull preceded the neurological symptoms. 3 of them were diagnosed late, which led to delay and failure of accurate treatment. Only 1 patient was immediately operated and continued to be well for the past 2 years.