[Consequences of splenectomy].
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Biomedical subjects
Publications and source records attributed to A Najman.
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Twelve patients with non-Hodgkin malignant lymphoma of poor prognosis were treated with heavy chemotherapy of the TACC type (cyclophosphamide 45 mg/kg/day i.v. X 4; cytosine arabinoside 200 mg/m2/12 hours i.v. X 7; 6-thioguanidine 100 mg/m2/12-hourly p.o X 7 and CCNU 200 or 250 mg/m2 p.o. single dose) followed by autologus bone marrow transplantation (853 to 20.000 CFUc/kg). The patients were divided into 2 groups depending on whether they received an induction treatment for large visible tumoral mass (group I: 3 initial presentations, 3 relapses) or a consolidation treatment for small residual tumour (group II: 6 complete and 1 partial remissions). The results show that autologous bone marrow transplantation shortens the duration of the therapeutic aplasia. White cell (greater than 10(9)/l) and platelet (greater than 50.10(9)/l) recovery was observed on days 12 (range 9-19) and 14 (range 8-27) respectively. In group I, 1 patient died of myocardial TACC toxity and acute renal failure on tumoral kidney; there were 2 failures and 3 complete remissions (8, 21, 45 + months). Remissions occurred in patients treated initially; the overall survival since diagnosis was 48+, 48+ and 60+ months. In group II patients there were 1 failure and 5 complete remissions persisting after a 2+ months to 30+ months follow-up; the overall survival was 23+, 24+, 27+, 42+ and 70+ months. The 3 failures in the series occurred in circumstances suggesting contamination of the cryopreserved bone marrow by tumoral cells. The toxicity, largely due to infection, of the TACC-bone marrow transplantation combination was tolerable. It was clearly lower in group II (6 patients, no septicaemia) than in group I (5/6 patients with septicaemia). These preliminary results confirm that there is room for autologous bone marrow transplantation in highly malignant non-Hodgkin lymphomas, particularly during complete remissions to facilitate the use of an aggressive consolidation chemotherapy.
Thirty-five patients were treated by intensive chemotherapy and/or whole-body irradiation followed by reinjection of cryopreserved autologous bone marrow. In 8 patients the kinetics of recovery of haemopoiesis was delayed (recovery to 10(9) leucocytes/litre beyond day 27 and recovery to 50 X 10(9) platelets/litre beyond day 25). This delay was directly responsible for the death of 3 patients and contributed to a fatal outcome in 2 others (mortality rate 9-14%). Retrospective analysis of these 8 cases revealed that failure of autologous transplantation was associated with poor recovery of CFUc, which was in turn related to an excessively rapid freezing rate after the release of fusion heat. Recovery of CFUc to 50% or more was achieved in 100% of cases when the freezing rate was less than 5 degrees C/min, 45% for freezing rates between 5 and 10 degrees C/min and 22% when the freezing rate exceeded 10 degrees C/min (n = 71, P less than 0.001). There was an inverse linear or logarithmic relationship between CFUc recovery and freezing rate after the transition phase (r = -0.46, r = -0.43, P less than 0.001). The quantity of nitrogen introduced into the freezing chamber to annul the fusion heat must therefore be calibrated with accuracy so that the desired shortening of the transition phase will not be accompanied by an overly marked increase in the freezing rate, which would result in the destruction of stem cells. To ensure an adequate freezing rate, it is crucial to monitor the temperature continuously in each sample of bone marrow during the freezing process. This study also suggested that other factors may have interfered with the kinetics of recovery after autologous bone-marrow transplantation. These factors include myelofibrosis, the presence of an Australia antigen and administration of compounds that are toxic for the bone marrow after reinjection of cryopreserved marrow. However, the responsibility of these factors cannot be stated with certainty.
The influence of various lipoprotein fractions on the proliferation of normal human hematopoietic progenitors, CFUC and CFUE, was studied in vitro. The lipoprotein fractions, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), high density lipoproteins (HDL2 and HDL3), were isolated by sequential ultracentrifugation. The addition of each subfraction to lipoprotein deficient medium allowed us to distinguish two categories of lipoproteins: firstly, those with density d greater than 1.030, LDL, HDL2 and HDL3 which showed a marked inhibitory activity on CFUC and CFUE proliferation and, secondly, those with density d less than 1.030, VLDL and IDL which did not show any inhibitory activity. The regulatory role of lipoproteins on progenitor cell proliferation is discussed.
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From 1971 to 1980, 86 patients with polycythaemia (vera 69, undetermined 15 and respiratory 2) were treated with pipobroman (N,N' bis bromopropionyl piperazine). The initial treatment in doses of 75 mg/day resulted, within 45 days, in complete remission in 46/49 new patients (93.9%), and in 17/20 previously treated patients with polycythaemia vera (85%) and in 14/15 patients with apparently primary polycythaemia. The main duration of the first remission was 17.5 months. Relapses occurred in 30% of the cases but responded to pipobroman at the initial high dosage level. Low-dose maintenance treatment appears to be necessary. Adverse effects on the blood were rare; they included leucopenia (8%) and moderate thrombocytopenia (7%); macrocytosis was noted in 20% of the patients. Acute leukaemia (3 cases) and osteomyelofibrosis (3 cases) were only observed in patients previously treated with 32 P or busulfan. Pipobroman therefore appears to be much less toxic than other alkylating agents. Its is as effective as 32 P but acts more rapidly. It seems to have little oncogenic power, but a more prolonged study is required to ascertain this point.
Between January 1973 and January 1979, 131 patients with malignant non-Hodgkin's lymphomas (107 lymphocytic lymphomas, 24 histiocytic lymphomas) were treated with cyclophosphamide-vincristin-prednisone (CVP) either alone or combined with Adriamycin (CVP-A). Stage I and II lymphocytic lymphomas were all treated by CVP combined with radiotherapy. The survival curve for this group of patients plateaued at 89% from the 12th to the 60th month, which was the endpoint of the study. For Stage III and IV nodular lymphocytic lymphomas, actuarial survival was 69% at five years in the CVP-treated group as compared to 54% at three years in the group treated with CVP-A. For Stage III and IV diffuse lymphocytic lymphomas, the complete response rate and median survival were respectively 25% and 24 months in patients treated with CVP, as compared to 67% (P less than 0.01) and 26 months in the group treated with CVP-A. For histiocytic lymphomas, the complete response rate was 50% in the CVP-treated group as compared to 83% in the group treated with CVP-A. Most remarkable was the fact that while in the CVP treated group median survival was only 17 months, the small group of patients treated with CVP-A exhibited considerably improved survival with a horizontal survival curve at 90% after 36 months (12 patients). These results show that the CVP protocol remains an excellent treatment for nodular lymphocytic lymphomas. The addition of Adriamycin (CVP-A) as well as its inclusion in other drugs combination, has raised hopes for remissions of long duration and even for cures in patients with histiocytic lymphomas. Finally, in diffuse lymphocytic lymphomas, efforts will have to be pursued to improve the prognosis which remains poor despite the increased complete response rate achieved by the addition of Adriamycin.
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Repopulation of the bone marrow after heavy chemotherapy and autologous transplantation was monitored by means of biopsies and bone marrow cultures on agar carried out simultaneously from the 2nd to the 33rd days after transplantation. A parallelism was observed between the reappearance of cell clusters on biopsy material and the growth of colonies in cultures, both being the centres from which the corresponding series proliferated. The clusters were almost invariably formed of one series. Repopulation began 3 to 5 days after transplantation and was complete between the 10th and 20th days. Oedematous dissociation persisted long after the clusters reappeared. Bone marrow repair was virtually always accompanied by plasmocytosis.
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The paper describes the case of a 38 year's old alcoholic patient. The investigation of his severe asthenia led to the discovery of an isolated ACTH deficiency: plasma cortisol was less than 1 microgram 100 ml reactivable by tetracosa-peptide beta 1-24. Plasma ACTH was low and remained so after LVD and metyrapone. Persistent leuconeutropenia without myelogram and agar cultures abnormalities was noted. Etiocholanolone test was negative and epinephrine induced a significant rise in blood leucocytes. The authors review the mechanisms of corticoid action on leucopoiesis. After 10 months corticoid treatment, leuconeutropenia improved but was still present suggesting an other underlying mechanism than cortisol insufficiency per se.
Between 1971 and 1981, 74 patients with polycythemia vera were treated with pipobroman using a high-dose induction, low-dose maintenance regimen. Complete remission was achieved in 51 of 54 previously untreated patients (94.4%) and in 17 of 20 patients (85%) previously treated wih radioactive phosphorus (32 p) and busulfan. The earliest modifications were noted on day 16, and on the average, blood counts were normal by day 45. Thirty percent of the patients relapsed, the mean duration of the remission being 17.5 mo. Following recurrence pipobroman was consistently effective in the same doses but the mean duration of the next remissions was 10 mo. Transient leukopenia and thrombocytopenia occurred in 8% and 7% of patients, respectively, during initial phase, and anemia was noted in 3 patients. Macrocytosis was noted in 20% of patients during maintenance phase. Three cases of acute leukemia and 3 cases of osteomyelosclerosis were recorded, all occurring in patients who had previously received 32 p and/or busulfan. No hematologic malignancies were seen among patients treated with pipobroman alone; follow-up exceeded 6 yr for 20 patients and the median follow-up period was 3.6 yr. Pipobroman appears safer than other alkylating agents; it is as effective as 32 p and works more quickly. Longer follow-up will be required to evaluate the drug's oncogenic potential, which is still not known.
Storage of human hematopoietic stem cells has been made possible through effective preservation of viability by freezing technique. We have studied the quantitative and qualitative aspects of granulocyte-macrophage precursor (CFUc) recovery from 29 bags of frozen bone marrow stored at - 160 degree C in the gas phase of liquid nitrogen for several months or years. it has been shown that with the freezing and preservation technique used, over 75% of the proliferative capacity of the cryopreserved CFUc was recovered. The influence of various factors on the quality of bone marrow preservation was studied and showed that dimethylsulfoxide (DMSO) appeared to cause substantial loss of CFUc at 4 degree C. Evaluation of CFUc in vitro is essential for determining the quality and richness of cryopreserved bone marrow with a view to using such marrow for autologous grafting intensive chemotherapy or total body irradiation in patients with hematological malignancies or solid tumors. No correlation was found between the number of nucleated bone marrow cells and CFUc content.
A 56-year-old man with diffuse cutaneous xanthomatosis had neither mucosal lesions nor diabetes insipidus. Cutaneous lesions were characterised by dermal histiocytic infiltration, without X bodies, associated with Touton's cells and abundant iron deposits. Plasma lipid levels were normal. A lambda G monoclonal dysglobulinemia was present without Bence-Jones proteinuria or myeloma, except for a moderate increase in medullary plasmocytic cell elements. The diagnosis of disseminated xanthomatosis was established, the differential diagnosis from other histiocytic proliferations, particularly diffuse plane xanthoma, being sometimes difficult. The relation between normolipaemic xanthomatosis and dysglobulinemia certainly exists, but no satisfactory pathogenic explanation was possible in this case, in the absence of cryoglobulin, paraprotein antilipoprotein activity, and cutaneous deposits of lipoprotein-paraprotein complexes.
In a series of 154 patients with acute leukaemia (AL), 31 had myelofibrosis. The authors report in detail on 9 of these and demonstrate the distinctive features of this form of AL: pancytopenia is severe, circulating blast cells are rare, myelograms are difficult to read, and bone-marrow biopsies are necessary to the diagnosis, severity assessment and prognosis of the disease. Owing to the small number of cells, it is uneasy to distinguish these AL from acute myelofibrosis (a nosological entity which needs to be more precisely defined) and from megakaryoblastic leukaemias, recently individualized.
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