Primary Sjögren's syndrome and aplastic anaemia.
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Adult↗
Biomedical subjects
C Dresch
Publications and source records attributed to C Dresch.
Risk of leukaemia, carcinoma, and myelofibrosis in 32P- or chemotherapy-treated patients with polycythaemia vera: a prospective analysis of 682 cases. The "French Cooperative Group for the Study of Polycythaemias".
An analysis of the risk of progression towards leukemia, carcinoma and myelofibrosis was performed in 93 patients treated by 32P alone (PVSG protocols) since 1970-1979, 395 patients over the age of 65 years treated by 32P with or without maintenance therapy using hydroxyurea (French protocol) since 1980-1994, and 202 patients under the age of 65 treated by either hydroxyurea or pipobroman since 1980. The risk of leukemia, or myelodysplasia, or lymphoma in the 32P-treated patients was 10% at the 10th year, but increase after that time to reach a value of about 30% at the 20th year, in the surviving case. This risk was not dose-related. Despite a marked reduction of the cumulative 32P dose in the patients maintained by hydroxyurea, the actuarial risk was 19% at the 10th year. In the patients treated exclusively by non radio-mimetic agents (hydroxyurea or pipobroman) a risk of 10% at the 10th year was observed. The risk of carcinoma (excluding skin cancers) was about 15% at the 10th year in the 32P-treated cases, a value similar to that generally reported by the French statistics. There was no prevalence of digestive carcinomas. In contrast, the patients receiving 32P and hydroxyurea as maintenance had an excess risk: 29% at the 10th year. In the relatively young cases treated by non radio-mimetic agents, the risk was similar in both arms: 9% at the 10th year, similar to the expected incidence at this age. The risk of myelofibrosis with myeloid metaplasia was still relatively low at the 10th year, about 15% in all arms, but increased towards a value higher than 30% in the patients surviving at the 20th year. At the present time, but in only a few cases with long-term following, no myelo-fibrosis with splenic metaplasia has been observed in the pipobroman-treated cases. The present results, which need to be confirmed (the present analysis has been done in spring 95) suggest that:-the use of non radio-mimetic agents does not protect against leukemic transformation, which may be a consequence of the disease; rather than of the treatment,-maintenance therapy after initial use of 32P increases the risk of both leukemia and carcinoma,-and hydroxyurea does not delay the risk of developing myelo-fibrosis, in comparison with 32P alone.
Actuarial Analysis↗
The very-long-term course of polycythaemia: a complement to the previously published data of the Polycythaemia Vera Study Group.
The very-long-term follow-up of patients initially included in the PVSG protocols provides useful information. The excess risk of cancer after chlorambucil appears to persist for 5 years after stopping this treatment. The risk of leukaemia induced by marrow suppression (32P or chemotherapy) was marked before the 10th year, but low thereafter. Phlebotomy is unacceptable as permanent treatment because of the poor clinical tolerance and the frequency of vascular complications. This treatment is also associated with a risk of early progression towards myelofibrosis with myeloid splenomegaly. In the very long term, 15 years or more after the diagnosis, this complication is the major clinical risk, affecting almost 50% of our patients surviving at this time. The prevention of this type of complication could constitute one of the objectives of future protocols dealing with this disease.
Aged↗
[Treatment of neutropenia in Shwachman's syndrome with granulocyte growth factor (G-CSF)].
BACKGROUND: Patients with Shwachman syndrome have neutropenia and depressed neutrophil chemotaxis and are therefore susceptible to recurrent infections. The diversity of causative microbial agents makes prevention of infection difficult. Some may be life-threatening, despite antibiotic therapy and even leukocyte transfusion. PATIENT: A 15 day-old boy presented with a staphylococcal cutaneous abscess. Neutropenia was detected when he was 45 day-old and Shwachman syndrome was diagnosed at the age of 8 months. He was then suffering from pneumonia plus pancreatic insufficiency, metaphysical chondroplasia and short stature. Frequent infections continued through childhood, but became less frequent from the age of 11 years. At 17 years, he still had neutropenia (polymorphonuclear leukocytes less than 300/mm3) and profound depressed chemotaxis. He was given subcutaneous injections of recombinant human granulocytes colony stimulating factor (rhG-CSF), 1 microgram/kg/day, for 15 days. The polymorphonuclear count increased above 1000/mm3 during the second week of treatment, and this effect was seen again during a second course of rhG-CSF. The benefit was not sustained when treatment was discontinued. CONCLUSION: These results confirm earlier reports of the effect of 5 micrograms/kg/day of rhG-CSF but the responses were greater and earlier. While more precise information concerning the treatment of this disease is required, rhG-CSF can be useful in patients with severe infections.
Agranulocytosis↗
Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells.
In the new context of the use of retinoic acid (RA) therapy as an inducer of leukemic differentiation and a selective inhibitor of human myeloid leukemia cell growth, we undertook to explore the potential physiological role of retinoids on the proliferation and differentiation of normal bone marrow myeloid progenitors. The effects of continuous exposure of all-trans-RA, its naturally occurring isomer, 13-cis-RA, and its metabolite 4-oxo-all-trans-RA were studied on the growth of normal human bone marrow cells in soft agar, directly and after liquid culture. Retinoids enhanced the total number of granulocytic colony and macrocluster formation in the presence of exogenous colony-stimulating factor (n = 9). Dose-response curve were bell-shaped, with a maximal increment between concentration of 0.5 and 0.05 nM. In all cases, a concomitant decrease of macrophagic colonies was noted. The positive effect on granulocytic colony formation was observed with each of the retinoids tested (all-trans, 13-cis and 4-oxo-all-trans) (n = 5). On erythroid colony formation, all-trans-RA had the opposite effect. Constant suppression of CFU-E and BFU-E colony formation and coloring was observed in a dose-related fashion from 0.1 to 10 microM (n = 5). Thus, in granulocytic, as in erythroid colony formation, retinoids affected both proliferation and differentiation parameters. However, after short-term suspension culture in the presence of all-trans-RA, an increase of both CFU-GM and BFU-E colonies, was observed. These results suggest a specific effect of retinoids on late myeloid precursors and places retinoids as possible candidates for enhancement of normal granulocytic differentiation.
Bone Marrow Cells↗
Thiamine responsive anemia: report of a new case associated with a thiamine pyrophosphokinase deficiency.
We report a new case of thiamine responsive anemia in a three years old boy with the characteristic association of anemia, diabetes mellitus and deafness. Thiamine therapy corrected anemia as described. A thiamine pyrophosphokinase deficiency (TPK) was found which was not influenced by treatment. However normal levels of thiamine pyrophosphate (TPP) were obtained without correction of all symptoms particularly dyserythropoïesis. Thus, etiology of the syndrome is not only a thiamine pyrophosphokinase deficiency as previously suggested.
Abnormalities, Multiple↗
Intermediary analysis of a French protocol of treatment of polycythemias (1980-1990): 253 patients. The French Group for the Study of Polycythemias.
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Clinical Protocols↗
Acute leukemia and myelodysplasia in polycythemia vera. A clinical study with long-term follow-up.
The analysis of 288 cases of polycythemia vera (PV) with a minimal follow-up of 10 years enabled us to study the characteristics of acute leukemia as observed in 33 patients (11.4%). In 50% of the patients (16 of 33), the malignant transformation is of the refractory anemia with excess of blasts (RAEB) type. Half of these further transform to acute nonlymphocytic leukemia (ANLL). Their life expectancy is not better than patients who abruptly develop ANLL. Leukemic transformation shows a frequency peak in the eighth year after initial evaluation in PV treated with chemotherapy and in the 11th year in patients treated with radiotherapy. In 30% of the patients myelofibrosis, or the spent phase of PV, is present before the transformation to acute leukemia (AL). This complication is, however, part of the natural history of PV and is observed in 20% of PV patients at 10 years when leukemic transformation is absent. Marrow fibrosis can therefore not be considered as a preleukemic phase. It was also noted that the occurrence of myeloid metaplasia/myelofibrosis is more frequent and begins earlier in patients treated by phlebotomy alone, and who do not transform to leukemia. The clinical characteristics of these AL, including high frequency of partial marrow invasion, difficulties in cytologic classification, a peak incidence similar to that in patients treated by chemotherapy or radiotherapy for a prior malignancy, multiple chromosome abnormalities, and poor response to therapy are all highly suggestive of secondary leukemias.
Acute Disease↗
Use of liquid culture and cell cycle analysis to compare drug damage following in vitro treatment of normal human bone marrow cells with adriamycin, arabinosyl-cytosine, and etoposide.
The effects of adriamycin (ADM), arabinosyl-cytosine (ARA-C), and etoposide (VP16) were studied on human bone marrow mononucleated cells using colony formation in agar, a modified liquid culture system, and flow cytometry analysis of the cell cycle. Drug concentrations tested during a 1-h incubation ranged from 0.1 to 4 micrograms/ml for ADM, from 0.3 to 30 micrograms/ml for VP16, and from 10(-7) to 10(-3) M for ARA-C. Regression analysis of the dose-response curves was used to assess the drug concentration that inhibited 90% +/- 5% (LD90) of colony growth. LD90s were 0.4 microgram/ml for ADM, 20 micrograms/ml for VP16, and 10(-4) M for ARA-C. LD90-surviving cells were cultured in liquid medium for 3 weeks. Surviving cells over this time were 13% of the control for ADM, 22% for VP16, and 95.7% for ARA-C. Although cells decreased drastically in ADM- and VP16-treated samples, granulocyte-macrophage colony-forming units (CFU-GM) per 10(5) surviving cells rose to twice the control for ADM, to 60% for VP16, and to 150% for ARA-C. Flow cytometry analysis of the cell cycle was performed at day 0 and at day 4 after treatment with the LD90 dose. It showed a rapid and reversible effect of ARA-C on cells in the S-phase, whereas the action of VP16 concerned all cells, regardless of their cycle phase. We conclude that the direct effects of the three drugs on CFU-GM in agar are poorly predictive of hematopoietic reconstitution capacity, except for VP16. Liquid culture gives a much more accurate appraisal of the long-term damage and recovery due to anticancer drugs.
Bone Marrow Cells↗
Radio-iron kinetic studies in anaemia and the measurement of dyserythropoiesis.
Analysis of radioactive iron kinetics was performed using a multi-compartment model on a series of 300 patients having either a quantitative (aplasia, haemolysis, iron deficiency) or qualitative (dyserythropoiesis, agnogenic myeloid metaplasia) anomaly of iron metabolism. Calculations were performed using a mammillary model of iron metabolism. The study demonstrated that the flux of iron from the plasma to the exchangeable compartment was a constant fraction of the global iron flux, equal to 15%, in those cases without dyserythropoiesis. This suggested that a constant correction for calculations of iron flux from the slope of the initial portion of the radioactive iron elimination curve may be applied to calculations of haemoglobin production and to the movements of iron to its exchangeable pools. Contrary to previously published information, the exchange of iron between the plasma and the exchangeable pools was not related to circulating iron levels when the other parameters were held constant. In the patients with aplastic anaemia the iron flux was diminished, but never eliminated, demonstrating that the exchangeable compartment was not solely erythroblastic, but included non-erythroid transferrin receptors. In dyserythropoietic states and myelofibrosis, the iron flux from the plasma was elevated, indicating that an important fraction of radio-iron leaves the plasma and then returns, without participating in effective erythropoiesis as determined by the appearance in the circulation of labelled viable red blood cells. The determination of this movement permitted the measurement of ineffective erythropoiesis.
Anemia↗
[Polyglobulia vera. Difficulties and complications of treatment by phlebotomy].
The authors report the results of phlebotomy for polyglobulia vera in a series of 73 patients eligible for inclusion in an international co-operative study. Previous studies usually gave actuarial survival curves but failed to mention the complications and discomfort associated with phlebotomy, although these are of importance in clinical practice. Most of the 73 patients were excluded on account of discomfort (20%), vascular thrombosis (almost 50%) or transformation into myelofibrosis within a mean period of 4 years (20%). Only 10% were treated with long-term phlebotomy. Although phlebotomies avoid the long-term risk of leukaemia attached to radiophosphorus or chemotherapy (20% on average after a mean delay of 12 years), they have practical limitations and their own, important risks. In patients over 65 and in those at high vascular risk, the best treatment is myelosuppression. However, younger subjects with polyglobulia vera but no vascular risk and/or thrombocytosis may benefit, at least temporarily, from phlebotomy.
Adult↗
Polycythaemia vera in young people: an analysis of 58 cases diagnosed before 40 years.
Over 20 years, 58 cases of PV in young people (46 meeting the full PVSG criteria, 12 with elevated red cell volume and leucocytosis or thrombocytosis, without splenomegaly) were studied and have been followed for periods of 3-24 years. These cases represent approximately 5% of the cases of PV referred to the Department of Nuclear Medicine of St Louis Hospital during this period. They differ from older patients in the initial clinical severity, the short interval between the first symptoms and the diagnosis, frequent presentation with a life-threatening complication (two cases of hepatic vein thrombosis, six thrombotic or haemorrhagic events, six splenectomies, two abortions) and a very enlarged spleen in half the cases. However, after the initial complications, the overall survival is very long (exceeding 70%, even when including the initial complications, at 15 years). The vascular accidents occur exclusively in the phlebotomized patients, the main risk factor being the poor stability of the haematocrit. Only one acute leukaemia was observed among the 14 cases treated by radioactive phosphorus and/or alkylating chemotherapy. The most frequent late complication was evolution towards myelofibrosis. This spent phase seemed to occur earlier in patients treated by phlebotomy. On the basis of this data, we would advise the following therapeutic strategy: phlebotomies, as soon as the diagnosis is established, and a systematic long-term treatment by hydroxyurea with the hope of reducing the number of vascular complications and of delaying the evolution towards the spent phase and the myelofibrosis.
Adult↗
Growth fraction of myelocytes in normal human granulopoiesis.
The labelling index (LI) of myelocytes (M) after flash labelling of normal human bone marrow cells with [3H]-thymidine ([3H]TdR) is always lower that the LI obtained for myeloblasts (MB) and for promyelocytes (PM). This fact can be interpreted in two ways: it may mean that the duration of the G1 phase of the cell cycle is longer in M than in MB or PM, or it may mean that the proportion of cells in cycle, i.e., the growth fraction (GF), is lower in the M population than in MB or PM. The evolution of the LI and of the mean number of grains per cell was monitored in [3H]TdR-labelled normal bone marrow during in vitro incubation for 50 hr. The generation time, measured by the halving time of the mean number of grains per cell after flash labelling, was similar for M to that for MB and PM. During continuous labelling, the LI of MB and PM reached 1 and the LI value for M never rose to more than 50% of the values recorded for MB and PM after 30 hr. These findings give support to the second hypothesis, i.e., a lower GF in the M population. Good correlation was found between the LI of M and the proportion of mature polymorphonuclear cells in the bone marrow of normal subjects and of patients with chronic benign neutropenia or hyperleucocytosis. Variations in the M growth fraction could be a medium-term (2-3 days) regulatory factor in granulocyte production.
Bone Marrow↗
The choice of treatment in polycythaemia vera.
The current results of prospective protocols initiated by the Polycythaemia Vera Study Group are presented. These results help to define the best choice of treatment in accordance with the risk factors.
Bloodletting↗
Differentiation of mixed colony-forming cells in normal human bone marrow and blood.
In blood and marrow samples from ten normal adults, mixed colonies were found in agar cultures at concentrations of 4.1 +/- 3.4/10(5) mononuclear bone marrow cells, and of 4.7 +/- 4/5 X 10(5) mononuclear blood cells. Reseeding of five- to seven-day clusters of immature cells in fresh medium with 5% PHA leukocyte-conditioned medium (PHA-LCM) and 2 U erythropoietin (Epo) showed that 10(5) mononuclear cells contained as many as 42 +/- 12 CFU-mix in bone marrow and 12 +/- 7 CFU-mix in blood, i.e., ten times more than in the primary cultures. Attempts were made to discover why these potentially mixed colonies failed to develop in primary cultures. For this purpose five- to seven-day clusters of immature cells from cultures of 5 X 10(4) bone marrow cells grown with PHA-LCM, Epo, or both were reseeded in medium containing one or both stimulants. The presence of both in secondary culture gave the best CFU-mix growth, whatever the primary stimulation, i.e., more than one-third of the immature clusters gave rise to colonies of red cells and granulocyte lineages. The addition of one or both stimulants between days 7 and 14 of primary culture, however, did not increase the number of mixed colonies or give rise to late developing ones. Reseeding of colonies and clusters of 14-day primary cultures showed that at least one-third of erythroid bursts or of late-developing granulocyte colonies contained CFU-mix, but that less than 10% of 14-day clusters developed into mixed colonies. Cultures of nonadherent cells, mononuclear cells of less than 1.065/g density or with a velocity sedimentation rate of less than 6 mm/h gave the same results as the culture of total mononuclear cells; i.e., at least ten times more multipotent progenitors were found by reseeding after five to seven days than in primary cultures. We conclude that in human bone marrow and blood the physical and kinetic properties of pluripotent stem cells are similar to those of 14-day erythroid bursts and GM colonies. Under normal culture conditions, most of these cell types differentiate into one cell lineage only, and plurilineage differentiation is inhibited.
Blood Cell Count↗
An analysis of prognostic factors in preleukemia: interest of bone marrow scintigraphy.
Simultaneous bone marrow scintigraphy with 99m Technetium colloids and 111 Indium transferrin was performed on 34 cases of preleukemic anemias and was shown to be of good prognostic value. Groups of different outcome were defined: for a normal and parallel uptake of the two markers, 90% of the patients died of acute leukemia; for a low Indium and high Technetium uptake, only 1 patient out of 15 died of leukemia (P less than 0.001). Standard clinical and hematological data were of no predictive value. Iron kinetic data and CFU/GM colony growth were correlated to the scintigraphic results. Taken together, these three kinetic parameters have a good sensitivity and specificity for the prognosis of preleukemic states.
Aged↗
Cytogenetic studies on acute nonlymphocytic leukemias following polycythemia vera.
Chromosome studies were performed on 15 patients suffering from acute nonlymphocytic leukemia (ANLL) and in one patient in a preleukemic state following polycythemia vera (PV). Clonal chromosome abnormalities that were present in all cases were clearly nonrandom and involved chromosomes #1, #5, #7, #8, #9, #11, and #21. A subdivision of ANLL into two categories occurring in the course of PV is proposed from the clinical, hematologic, and cytogenetic data: one resembling de novo ANLL with rapid initial evolution, easy classification into one group of the FAB nomenclature, and simple chromosome abnormalities; the other resembling induced leukemia, often with more progressive initial evolution, difficulty or impossibility of classification into one group of the FAB nomenclature, and complex chromosome abnormalities. The consequences for the commitment level of progenitor cell from which the leukemic clones originate are discussed.
Acute Disease↗
Chromosome studies in polycythemia vera patients.
One hundred thirty-five polycythemia vera (PV) patients (30 untreated by chemotherapy and 105 treated) were studied cytogenetically . The incidence of clonal chromosomal abnormalities was 20.7% (28 patients in nonleukemic phase). The incidence of 20q - was 3.7% (5 patients). The presence of cytogenetically abnormal clones did not allow prediction of the evolution of the disease. In a few cases, abnormal clones disappeared at the time of later studies. Although nonrandom, the majority of clonal chromosomal abnormalities are believed to be secondary events in PV patients.
Aged↗