[Kinetics and differentiation of leukemia cells].
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Biomedical subjects
Publications and source records attributed to D Hoelzer.
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A randomized and controlled study was undertaken to test whether substitution with factor XIII concentrates influences the clinical course in patients with acute leukaemia and acquired factor XIII deficiency (less than or equal to 60%). A control group of 31 patients was compared with a factor XIII-treated group of 29 patients. Partial factor XIII deficiency was successfully corrected by substitution. On the other hand, there was no statistically significant difference between the two patient groups in the frequency and severity of bleeding complications, transfusion requirements, and the number of remissions. Undesirable side-effects as a result of substitution treatment were not observed.
A patient with Philadelphia (Ph1) chromosome positive chronic myelocytic leukemia is described, who had in blast crisis in addition an abnormality of chromosome No. 3; ins(3; 3)(q26; q21q26). This abnormality might be connected with hyperplasia of megakaryocytes and thrombocythemia, as recently reported in patients with acute leukemia. In the initial phase of the disease our patient had also thrombocythemia, hyperplasia of megakaryocytes with morphological abnormalities. Furthermore, when blast cells were culture in diffusion chambers, differentiation into several cell lines occurred but not into megakaryopoiesis. It is, therefore, concluded that the involved band on chromosome No. 3 might contain the locus which controls megakaryocytic proliferation and platelet production but additional factors seem to be required for their expression.
The granulocyte production of two patients suffering from leukemia was studied extensively by means of the tritiated thymidine method of cellular kinetics. The data obtained (1-h labeling index, pattern of cell labeling, labeling intensity, as well as other conventional parameters of bone marrow and blood) were used to develop a computer model (GPSS-language) to fit the observations. From these models, it was concluded that patients with leukemia may have an abnormal granulopoiesis, characterized by a high degree of inefficiency (premature cell death, skipping of divisions with undisturbed maturation). However, the underlying mechanisms may be quite different. While it cannot be excluded that in acute myelocytic leukemia there is a stem and/or progenitor cell pool that is highly ineffective but still capable of feeding some cells into the granulocytic pathway, it is nevertheless possible, as shown in plasma cell leukemia, that the ineffective granulopoiesis may be the result of direct or indirect interaction between the "leukemic" and the "normal" cell clone.
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The efficiency of strict reverse isolation and antimicrobial decontamination in remission induction therapy of acute leukemia was studied retrospectively in 47 patients who were treated with a standardized aggressive chemotherapy of daunorubicin and cytosine arabinoside. Twenty-two patients were treated in strict reverse isolation with antimicrobial decontamination and 25 patients in the open ward without any measures against infections. In the patients in isolation the incidence of new infections per patient was 0.77 compared to 1.42 in the control group. The rate of complete remissions was 77% in the patients in isolation vs. 56% in the control patients.
This study reviews the experience of the Nutrition Support Service at the Children's Hospital of Philadelphia over a 13-mo period from 1977 to 1979. Parenteral nutrition was administered to 585 children, 385 by peripheral vein infusion and 200 by central vein infusion. Weight gain was seen in 63% of those patients receiving peripheral vein infusions and 82.5% of those receiving central vein nutrients, and this apparent difference is likely due to the longer duration of therapy in the central vein recipients (33.7 versus 11.4 mean days) and the greater caloric intake delivered to these same patients (128 Kcal/kg/day versus 63.2 Kcal/kg/day). The complication rates were calculated for the more than 11,000 patient days of therapy surveyed; 35 of the 385 peripheral vein patients developed complications, the primary type being solution administration soft tissue sloughs. This amounted to an incidence of 9.08%. Central vein patients in 40 circumstances likewise had complications, 21 being infectious and 12 being metabolic. This accounted for 20% of all central vein recipients, a difference from the peripheral vein group significant to a p value of less than .01. However, when total days of therapy are considered in this complication incidence, a per diem complication rate between these two groups is not different, and in fact, is somewhat worse for the peripheral vein nutrient recipients. Vascular access in this group of patients was via peripheral vein cannulation or via central venous catheter placement, the latter more recenty done exclusively by percutaneous subclavian vein catheter insertions. This technique was safe and allowed repeated access to the central venous system. These data suggest that the only legitimate determining factor for selecting proper nutritional support of the pediatric patient is the caloric need of the individual.
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Growth of mononuclear cells from human peripheral blood from 10 normal individuals was tested in diffusion chamber culture over a period up to 17 or 21 days. After an initial decrease during the first few days an increase of the total cell number was observed with maximal values on day 13. In all individuals growth of undifferentiated blast cells, lymphocytes, plasma cells, immature and mature granulopoietic cells, macrophages, and megakaryocytes occurred. In all individuals the different cell types had similar growth patterns in diffusion chamber culture. The considerable numerical variations which were seen in the granulopoietic cells were probably due to different stem cell concentrations in the peripheral blood of the investigated individuals. The results indicate that the diffusion chamber technique is a valuable method for the detection of haemopoietic stem cells and the culture of lymphocytic cells in man.
60 adult patients with acute leukemia (AL) previously untreated or in relapse received induction chemotherapy with different types of supportive care. Group A was decontaminated by nonabsorbable antibiotics in strict reverse isolation, group B was isolated only and group C was treated under routine hospital conditions. There were less infections in group A and B compared with group C. 76% of patients in group A achieved remission, in contrast to 57% in group B and 59% in group C. Late evaluation three years after termination of the study showed that all patients were dead except four patients being in first remission after discontinuation of maintenance treatment. Three patients were treated in group A, one patient in group C. However, the differences of survival and remission rates were not significant. Failure to demonstrate significant advantage of isolation and decontamination in treatment of AL was caused by insufficient suppression of microbes by the applied antimicrobial measures. Thus, it is suggested to investigate better antimicrobial treatment before gnotobiotic care is accepted as routine supportive treatment in AL.
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In the experimental rat leukemia, L5222, the decrease of normal in vitro colony-forming cells (CFU-C) after chemotherapy with daunomycin is much less than in nonleukemic controls. The leukemia is therefore used here to test the hypothesis that in leukemia the CFU-C are expelled from the active cell cycle to a resting state and are thereby less sensitive to cycle-dependent chemotherapeutic agents. The L5222 leukemia has the advantage that the leukemic blast cells do not form colonies in agar culture so that normal CFU-C can be assessed under leukemic conditions. To compare the proportions of CFU-C in the S-phase in normal and leukemic rats, two S-phase-specific agents, 3H-thymidine and hydroxyurea, were used to kill proliferating bone marrow cells. Following treatment with 3H-thymidine in vitro, about 41% of the CFU-C were killed in normal and about 25% in leukemic bone marrow. Hydroxyurea administered in vivo resulted in the death of about 33% and 26%, respectively. The results indicate that fewer normal CFU-C are in S-phase in the L5222 leukemia, which might help to explain how enough normal stem cells survive chemotherapy to regenerate the bone marrow.
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The proliferative behaviour of leukaemic cells from the peripheral blood of 12 patients suffering from acute leukaemia was investigated in short term liquid culture. In 3 cases of AML an increase of the blast cell number was observed exceeding the initial value whereas in 9 other cases the cell number decreased more or less rapidly. In 9 of these patients the proliferation kinetics of the cultured leukaemic blast cells were studied with 3H-thymidine labelling. In all these cases the labelling index increased during the first days of culture, in 3 cases to values of 48%, 45% and 38% on day 3. Only in 5 cases, however, did an absolute increase of the blast cells incorporating 3H-thymidine occur. Here the doubling times of the proliferating leukaemic blast cells were estimated to be 12, 13, 14, 28 and 55 h. Since a doubling time of 12 to 14 h seems to be too short to be explained only by an exponential growth of the initially proliferating cells it is postulated that leukaemic blast cells in a G0- or long G1-phase were present in the peripheral blood of these patients and that these entered the cell cycle during liquid culture.
Peripheral blood cells of 21 patients with different forms of acute leukemia were cultured in diffusion chambers (5 x 10(5) cells/chamber) implanted intraperitoneally in 650 R preirradiated host mice over a period of up to 21 days. In patients with acute myeloid leukemia (AML), acute erythroleukemia (AEL), or acute myelomonocytic leukemia (AMMoL), the total number of cells which developed during this culture period exceeded the implanted value and also the values for normal peripheral blood cells from ten controls. In acute undifferentiated leukemia (AUL), two out of six patients showed considerable growth whereas the others, and also two patients with acute lymphoid leukemia (ALL), had poor growth. Differential counts revealed that the rise in total cells was due mainly to proliferation of blast cells and formation of granulopoietic cells. The latter exceeded the numbers from normal peripheral blood cells in 9 out of 13 patients with AML, AEL, or AMMoL and in 2 out of 6 patients with ALL. The production of granulopoiesis was not restricted to proliferating cells, but included mature cells which were of abnormal morphology in some cases. From the amount of granulopoiesis and the time of its development it was assumed that they were at least partly derived from leukemic blast cells. Chromosome analyses to decide whether the granulopoietic cells were of leukemic or normal cell origin are in progress.
The growth of granulopoietic progenitors (CFU-C) and morphologically identifiable haemopoietic cells from rat bone marrow was studied in intraperitoneal diffusion chambers over a 6-day period. The aim of this study was to investigate whether stem cells preceding the granulopoietic progenitors are able to restore and to maintain depleted compartments of CFU-C and immature granulopoietic cells under the conditions of diffusion chamber culture. After treatment of rats with repeated doses of hydroxyurea (HU) a bone marrow cell suspension could be obtained wherein proliferating haemopoietic cells were reduced to a very low level and CFU-C to undetectable levels. During culture in diffusion chambers, growth of CFU-C, immature granulopoietic cells and macrophages could be observed from this HU-treated bone marrow. It is concluded that in diffusion chamber culture stem cells preceding CFU-C are able to rebuild functioning compartments of granulopoietic progenitors and morphologically identifiable haemopoietic cells.
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