Notch signaling in leukemias and lymphomas

Aberrant Notch activation is linked to cancer since 1991 when mammalian Notch1 was first identified as part of the translocation t(7;9) in a subset of human T-cell acute lymphoblastic leukemias (T-ALL). Since then oncogenic Notch signaling has been found in many solid and hematopoietic neoplasms. Depending on tumor type Notch interferes with differentiation, proliferation, survival, cell-cycle progression, angiogenesis, and possibly self-renewal. In hematopoietic neoplasms, recent findings indicate an important role of Notch for T-ALL induction and progression and the pathogenesis of human T- and B-cell-derived lymphomas. Notch signaling has been identified as a potential new therapeutic target in these hematopoietic neoplasms. This review will focus on the most recent findings on Notch signaling in leukemias and lymphomas and its potential role in the maintenance of malignant stem cells.     

Neoplastic meningosis in immature cell leukemias and malignant lymphomas

162 patients with acute leukemias or malignant non-Hodgkin lymphomas were examined for meningeal and cerebral manifestations of their disease. A clinically manifest disease could be found in 13 patients, meningosis was additionally detected by autopsy in 32 patients. The highest frequency was found in acute lymphatic leukemia followed by lymphoblastic lymphomas and acute myeloic leukemias. Less frequently there was a meningeal involvement in low-grade malignant lymphomas which becomes clinically manifest only in some rare cases. In this respect, non-lymphoblastic, high grade-malignant lymphomas take an intermediate position. On principle, meningosis prophylaxis is imperative for acute lymphoblastic leukemias and advanced lymphoblastic lymphomas.     

Plasmodium falciparum: drug-resistant malaria complicating leukemias and lymphomas in children.

The present communication deals with drug-resistant Plasmodium falciparum malaria complicating hematologic malignancies (leukemias, n = 24, and lymphomas, n = 7) in children. Of 50 cases of hematologic malignancies, 31 patients were microscopically diagnosed as having P. falciparum infection (MP +). Initially, all the patients were treated with chloroquine. The results of primary treatment showed chloroquine resistance in 16 (51. 62%) cases. Of these 16 chloroquine-resistant cases, 13 were secondarily treated with a combination of pyrimethamine plus sulfamethopyrazine. The results of secondary treatment also revealed resistance to pyrimethamine plus sulfamethopyrazine in 6 of 13 (46. 10%) cases. The 6 pyrimethamine plus sulfamethopyrazine-resistant P. falciparum cases were finally cured by quinine therapy, against which no resistance was encountered. Conversely, in the control group comprising 38 cases of P. falciparum without malignancy, the incidence of chloroquine resistance was found in only 9 cases, which is rather low (23.70%). Of these 7 chloroquine-resistant cases, 5 were found to be sensitive to pyrimethamine plus sulfamethopyrazine treatment, while the 2 nonresponders were finally cured with quinine. The overall results of this study show a high prevalence of chloroquine resistance among clinical cases of falciparum malaria (25/69; 30.6%). Among the nonresponders (n = 20) 40% of cases were also resistant to the pyrimethamine plus sulfamethopyrazine combination. There was no resistance to quinine.     

Evaluation of circulating immune complexes in lymphomas and leukemias using two different assays

Summary Circulating immune complexes (CICs) have been detected in the sera of patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease, chronic myeloid leukemia, and acute lymphoblastic leukemia by using C1q-binding and L1210-binding assays. Both assays gave broadly similar patterns of reactivity in terms of frequency and magnitude, though there are some differences. Significantly elevated CIC levels were observed in all pathologic groups. However, sera from NHL patients with an unfavorable prognosis consistently exhibited the highest frequency of positive values and mean CIC levels in both these assays.The two tests showed concordance in 66.6% of the NHL patients' sera and were significantly correlated. Of the sera from NHL patients 12.7% were positive in the C1q-binding assay only and 15.9% in the L1210-binding assay only. Both the assays gave positive results in some patients, and a degree of overlap indicates the presence of different types of CIC in cancer patients' sera. The combined use of two methods for detecting CICs may be useful for evaluation of the activity, the extent, and the prognosis of the malignant disease.     

The generation of monoclonal anti-idiotype antibodies to human B cell-derived leukemias and lymphomas

We developed murine anti-idiotype monoclonal antibodies for each of four patients with B cell-derived leukemias and lymphomas. Idiotypic immunoglobulin was isolated from mouse X human tumor-cell hybridomas or from patients' serum and was used to immunize mice for the development of murine anti-idiotype monoclonal antibodies. Each patient's anti-idiotype antibodies demonstrated reactivity restricted to the immunizing immunoglobulin, thereby limiting their therapeutic utility to a single individual. In addition, we isolated isotype switch variants of hybridomas producing monoclonal anti-idiotypic antibody. The restricted specificity of these antibodies was found to be of value for the analysis of the extent of malignant B cell infiltration in a variety of tissues from several patients. Large populations of idiotype-bearing cells were detectable in biopsy specimens from patients K.T. and L.H. In contrast, although bone marrow specimens from patient G.D. were apparently devoid of morphologically abnormal cells, a small, highly fluorescent population of cells was demonstrable underscoring the potential utility of these antibodies for posttreatment evaluation as well as for therapy. In a fourth patient, H.M., anti-idiotype antibodies developed against the circulating macroglobulin isolated from his plasma failed to react with either his circulating or bone marrow hairy cell leukemia cells. However, examination of an enlarged inguinal lymph node revealed the presence of a large number of idiotype-bearing cells. Thus, the presence of two distinct malignant B cell clones were discovered in this individual through the use of anti-idiotype monoclonal antibodies. Anti-idiotype antibodies, therefore, represent a highly specific tool for the evaluation and potential therapy of B cell malignancies in individual patients.     

Monocytes in children with leukemias and lymphomas -- down-regulation of HLA and costimulatory molecules

The aim of the study was to evaluate the function of monocytes in children with leukemias and lymphomas based on the expression of critical costimulatory, activatory and adhesion molecules (CD80, CD86, HLA-DR and CD54 = ICAM-1), estimated with tricolor flow cytometry. In comparison to the control group we found a lower percentage of monocytes with costimulatory molecules (CD80 before and CD86 after lipopolysaccharide stimulation) at the time of diagnosis and of monocytes with HLA-DR molecules after remission induction. We also noted a lower percentage of monocytes with HLA-DR expression in the group with severe or therapy resistant infections. The results of our investigation suggest some defect in costimulation and antigen presentation in lymphoproliferative diseases in children.     

Newer drug treatment in dermatology

In a study of 58 patients with various diseases of muscle or of the neuromuscular system, the serum activity of various enzymes was measured. Abnormal elevation of serum activities of aldolase, lactic dehydrogenase and, to a lesser extent, glutamic-oxalacetic transaminase and phosphohexose isomerase, was an almost constant feature in patients with progressive muscular dystrophy. These elevations were very frequent in dermatomyositis, common in acute cerebral vascular accidents, and rarely seen in other neurological disorders. Abnormal serum activity of iso-citric dehydrogenase was not observed in the course of the present study. Supplementary protein feeding of patients with muscular dystrophy had no effect on serum enzyme activity, no consistent effect on urinary creatine excretion and no effect on the strength of the patient or the course of the disease. Dystrophic muscles from a dystrophic strain of mice showed a decrease in activity of lactic dehydrogenase and aldolase below that of control muscle and an increase of iso-citric dehydrogenase activity. These findings, taken with the differences in serum activities of lactic dehydrogenase, aldolase and isocitric dehydrogenase in the dystrophic animals, support the conclusion that dystrophic animals handle these soluble enzymes in quite different ways.