Hans P. Wagner

L1 (1,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with beta-thalassaemia major

Summary L1 was given to eight patients with beta‐thalassaemia major who had previously been treated with deferox‐amine (DF) for 4–10 years. The patients’ages ranged from 11 to 27 years. Serum ferritin values ranged from 1.3 to 11.5 ± 103 pg/l. L1 was given twice daily at a daily dose of 55–80 mg/kg body weight and was continued for 10 months in two patients, 9 months in three, 7 months in two patients and 4 months in one patient. As previously observed with DF, each patients urinary iron excretion (UIE) varied greatly from day to day. The mean UIE of the eight patients ranged from 11 to 49 mg/d (0.2–0.87 mmol/d) on subcutaneous DF and from 16 to 53 mg/d (0.28–0.95 mmol/d) on L1. Two patients excreted significantly more and one patient significantly less iron while on L1. If the UIE was calculated as mmol Fe/mmol creatinine there was no statistically significant difference. Serum ferritin values fluctuated widely in all, with a consistent downward trend in three, no change in four and an increase in one of two non‐splenectomized patients. This patients splenomegaly and need for transfusions continued to increase while on L1. No toxicities attributable to the drug were detected during the period of study and tolerance of the drug was excellent.

Persisting Renotubular Sequelae after Cisplatin in Children and Adolescents

UNLABELLED Information on persisting renal sequelae after cisplatin in children and adolescents is limited. Twelve patients aged 4-20 years had been treated with cisplatin and were healthy 4-43 months after stopping chemotherapy. Plasma creatinine, calcium, albumin and hydrogen ion concentration, plasma and urinary sodium, chloride, phosphate and urate, and urinary magnesium and potassium were comparable in patients and controls. However, mean calciuria, magnesemia and potassemia were significantly reduced and bicarbonatemia increased in the patients. Calciuria, magnesemia, potassemia and bicarbonatemia were normal in 3 patients only, calciuria was below -2 SD control in 9 patients, renal magnesium deficiency was demonstrated in 5 patients (all with hypocalciuria as well), and 4 patients presented with hypokalemic metabolic alkalosis (all with magnesium deficiency and hypocalciuria). CONCLUSIONS (1) Renotubular dysfunctions persist very often after cisplatin; (2) hypocalciuria is more frequent than hypomagnesemia; (3) the most severe tubulopathy after cisplatin includes hypocalciuria, renal magnesium deficiency and hypokalemic metabolic alkalosis.

Repression of nuclear lamin A and C gene expression in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells

The lamins A, B and C which are differentially expressed during ontogenesis and differentiation are karyoskeletal proteins forming a polymeric meshwork at the inner nuclear membrane. Using Northern blot analyses we investigated the steady state levels of the three lamin specific RNA transcripts in neoplastic cells derived from 16 untreated patients with acute lymphoblastic leukemia (ALL) or non-Hodgkins lymphoma (NHL) and in ALL and NHL established cell lines. Whereas lamin B mRNA was present in all, lamin A and C transcripts were observed in none of the malignant cell samples except one of a common-ALL patient (precursor B-ALL, cytoplasmic mu chain negative). All three lamin mRNAs were detected in normal peripheral blood lymphocytes, however, only after mitogenic stimulation with concanavalin A. Our results provide evidence that expression of lamin A and C is repressed in neoplastic blast cells derived from patients with ALL or NHL and suggest that lamin A and C gene repression is not related to cell proliferation but might be relevant to the differentiated stages of the lymphoid cells in vivo.

Intravenous immunoglobulin for idiopathic thrombocytopenic purpura (ITP) in childhood.

IgG-SRK (identical with Sandoglobulin) is a polyvalent IgG concentrate obtained by modified alcohol cryoprecipitation, including mild acidification at pH 4. This product was given in high doses intravenously for the treatment of six children with acute ITP, four children with intermittent ITP, and three children with severe chronic idiopathic thrombocytopenic purpura (ITP). An impressive initial response was observed in all patients, the extent of which may be of prognostic significance in acute ITP. Maintenance therapy was required in two of six patients with acute ITP, in three out of four patients with intermittent ITP, and in all of the patients with severe chronic ITP. In the cases of severe chronic ITP, the disease could not be adequately controlled over long periods of time, but bleeding episodes subsided or became considerably less frequent. Although little is known of the effects of IgG-SRK, possible mechanisms were discussed. It is emphasized that a new model has been discovered to study the interrelations between structure and function of human immunoglobulin molecules.

Evaluation of the Fresenius cell separator AS 104 for harvesting peripheral blood stem cells in pediatric patients

In a single institution trial we carried out 35 peripheral blood stem cell harvesting procedures in 12 children with advanced malignancies to evaluate the procedures safety and the collection efficiency of the Fresenius blood cell separator AS 104 in a pediatric population. Despite a significant mean decrease of 21% (+/-8%) in systolic blood pressure after starting the procedure, all children tolerated leukapheresis without any adverse reaction. After termination of leukapheresis there was a significant decrease of all determined hematological parameters, as compared with pre-harvest values. The mean mononuclear cell recovery was 64% (+/-26%), and in 25/35 (71%) harvesting procedures the minimum progenitor number required for safe autografting could be obtained by one single leukapheresis. We conclude that the Fresenius AS 104 blood cell separator provides a high cell yield and is a safe device for leukapheresis in pediatric patients.

Cell cycle analysis in lymphoid neoplasia of childhood: differences among immunologic subtypes and similarities in the proliferation of normal and leukaemic precursor B cells

Summary. Cell proliferation in untreated lymphoid malignancies of children was investigated by an in vitro assessment of the 3H‐thymidine labelling index (LI), the growth fraction (GF) with the monoclonal antibody Ki‐67, and the duration of the DNA‐synthesis phase (ts) with a double labelling technique. Mean cell cycle time (tg) was similar in lymphoid malignancies of precursor B cell and T cell origin (115 h and 102 h, respectively), while B cell neoplasias had a mean tg of only 25 h. A positive correlation between the II and the GF (r = 0·892) and a negative correlation between the LI and tg (r = −0·908) could be detected in childhood lymphoid malignancies.

Immunogenotyping with antigen receptor gene probes as a diagnostic tool in childhood acute lymphoblastic leukaemia

Abstract: 13 cases of childhood acute lymphoblastic leukaemia (ALL) were studied combining cell surface marker analysis with immunogenotyping by Southern blot hybridisation with a panel of antigen receptor gene probes. The immunophenotypes were unequivocal: 7 patients had B‐phenotype and 6 patients T‐phenotype ALL. In several patients immunogenotypes were not fully consistent with the respective phenotypes. For example, 2 B‐cell precursor ALL had rearranged TCRβ chain genes and 2 T‐ALL rearrangement of Ig heavy‐chain genes. All cases showed clonal rearrangement or deletions within the TCRδ gene locus. TCRδ gene rearrangements might, therefore, serve as markers of clonality but not of B‐ or T‐lineage in immature lymphoid neoplasms. We conclude that in current diagnostic practice immunogenotyping is a supplement rather than an alternative to immunophenotyping by surface marker analysis.

Acute megakaryoblastic leukemia in children identified by immunological marker studies

Acute megakaryoblastic leukemia (AMkL), defined by the presence of the platelet-associated glycoprotein IIb/IIIa complex on malignant cells, was diagnosed in 4 (4%) of 103 consecutive children with untreated acute leukemia or 4 (21%) of 19 children with acute nonlymphoblastic leukemia (ANLL). Particular features in the four children with AMkL were an age below 12 months at diagnosis (two patients), the absence of a significant hepatosplenomegaly (three patients), a leukocyte count below 20 x 10(9)/L with only a few blast cells in the peripheral blood (four patients), a technically difficult bone marrow aspiration (three patients), the presence of many megakaryocytes in marrow particles (two patients), and an inconclusive cytochemistry (four patients). The four children with AMkL were treated according to protocols for ANLL and a complete remission was obtained in all patients. One patient died from relapse after 3 months, one patient is a long-term survivor (38+ months), and two patients still on chemotherapy are disease-free for 11+ and 13+ months.

Single Institution Experience with Mobilization, Harvesting, and Reinfusion of Peripheral Blood Stem Cells in Children with a Solid Tumor or Leukemia

The aim of our single center pilot study was to evaluate the feasibility of peripheral blood stem cell autotransplantation (PBSCT) in a pediatric population. Only children with solid and hematological malignancies and poor prognosis who were without a HLA-identical bone marrow donor were included in this study. Mobilization of PBSC was done by treatment with myelosuppressive chemotherapy followed by recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Circulating progenitor cells were harvested by a total of 24 leukaphereses on an AS 104 cell separator in eight patients. Seven patients had undergone conditioning with high-dose chemotherapy with or without irradiation prior to PBSCT. All patients showed a rapid hematological recovery, although reconstitution of thrombopoiesis was incomplete in three children. We conclude that PBSCT is feasible in childhood and that it results in a rapid hematologic recovery.

Cell cycle control and cancer

This review consists of two parts. In the first part normal mechanisms regulating the progression of cells through the cell cycle are briefly reviewed. Besides mitogenic stimulation, cyclin kinase inhibition, the G1 restriction point and the prb pathway, accuracy of DNA replication and DNA repair, the G2 to M transition, apoptosis and the p 53 pathway, proteolytic, in particular ubiquitindependent mechanisms involved in the initiation of DNA synthesis in the separation of sister chromatids and in the telophase to GO/G1 transition, are discussed. In the second part oncogene and tumor suppressor gene products are briefly characterized. Aberrations of cell cycle control mechanisms associated with cancer are grouped as follows : deregulation of protooncogenes by translocations juxtaposing protooncogenes to immunoglobulin — or T cell receptor genes; translocations producing chimeric proteins unique to cancer cells; inversions and amplifications resulting in over expression of regulator genes; and deletions and mutations of tumor suppressor genes. It is emphasized that cancer is the result of a multistep process and that uncontrolled cell production and other alterations are, as a rule, late phenomena.