Chronic myelocytic leukaemia with unusual (27 years) complete remission terminating in acute undifferentiated leukaemia: a clinical and karyotypic study.

A case of clinically typical CML (300 x 10(6)/l leukocytes, 400 x 10(6)/l platelets, splenomegaly) is presented. After complete remission induced by busulphan, no clinical or haematological abnormalities were observed for 27 years until the development of acute leukaemia (type M1), which was rapidly fatal after a brief chemotherapy-induced remission. The cytogenetic findings were also original: no chromosome Ph1 (during remission 3 years after the onset of the disease), no translocation (banding study 5 years later), and no bcr/abl rearrangement (during the terminal phase).

Stimulatory effect of thyroid hormone on RA-induced granulocytic differentiation in leukemic cells.

Retinoic acid, vitamin D3, and dexamethasone are known inducers of myeloid leukemic cell differentiation. Recent evidence indicates that these drugs mediate their biological effects through binding to a nuclear receptor which belongs to the steroid/thyroid hormone receptor superfamily. This paper shows that the ligands of the other receptors of this family, estrogens, progesterone, androgens and thyroid hormone, do not induce leukemic cell differentiation. However, thyroid hormone potentiates, by one order of magnitude, the dose-response effect of retinoic acid in HL-60 cells.

Modulation of IL-8, IL-1 beta, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AML) characterized by the presence of the t(15;17) translocation and the resulting PML/RAR alpha fusion proteins. To date APL is the only AML which is sufficiently sensitive to all-trans retinoic acid (ATRA) differentiating effect. We have recently reported that APL express and secrete hematopoietic growth factors (HGF) such as IL-1 beta, TNF alpha, and IL-6. In vivo ATRA alone allows achievement of complete remission in APL patients. One of ATRA therapy's drawbacks is the increase of peripheral blast cells often associated with the ATRA leukocyte activation syndrome. To determine if this specific side-effect was linked to an increase of HGF release by APL cells, we studied the modulation of cytokine production by APL cells, we studied the modulation of cytokine production by APL samples (n = 12) before and after incubation with ATRA. ATRA failed to modulate TNF alpha, IL-6 or GM-CSF secretion levels; however, IL-8 levels decreased in 11 cases, and in four cases up-regulation of IL-1 beta and G-CSF protein expression was observed. These modulations were found to be linked to ATRA sensitivity as ATRA failed to modulate cytokine production in non-APL cells (n = 8). Interestingly, the increase of IL-1 beta and G-CSF production in the presence of ATRA was highly correlated to an increase in APL cell count in vitro and in vivo hyperleukocytosis, resulting in fatal outcome. IL-1 beta, TNF alpha, IL-6, and IL-8 are known to be implicated in leukocyte activation. The results of this study suggest that ATRA-induced hyperleukocytosis and ATRA leukocyte activation syndrome in APL may be inherent to the secretion of specific hematopoietic growth factors by the APL cells.

Induction of high-affinity GM-CSF receptors during all-trans retinoic acid treatment of acute promyelocytic leukemia.

Differentiation of normal myeloid cells is accompanied by the increase of high-affinity GM-CSF receptors necessary for progenitor proliferation/differentiation and mature neutrophil function. All-trans retinoic acid (ATRA) induces terminal differentiation of acute promyelocytic leukemia cells (AML3 subtype). We report in this study that AML3 cells, like other AML subtypes, harbor high-affinity GM-CSF R (n = 138.3 +/- 69.3 sites/cell, Kd = 76.9 +/- 68.8 pM). In all cases, incubation with ATRA induces either an increase in the number of affinity of GM-CSF R (n = 212.7 +/- 116.2 sites/cell, Kd = 43.2 +/- 22.5 pM). The data presented show that modulation of GM-CSF receptors cells is correlated to the degree of ATRA-induced granulocytic differentiation but not to increased cell growth.

Pregnancy and paroxysmal nocturnal hemoglobinuria.

Our study concerns eight pregnancies, six of which were successful, in four patients with paroxysmal nocturnal hemoglobinuria (PNH). Several complications of PNH during pregnancy were prevented: chronic anemia, folate and iron deficiency, and deep-vein thrombosis. During puerperium, acute hemolytic crises, most probably triggered by delivery, were observed in two patients. Thrombotic complications could be prevented by early initiation of an anticoagulant therapy after delivery. The only neonatal complication, observed in two cases, was isoimmune hemolytic anemia related to the multiple blood transfusions received before and during pregnancy. These results show that successful pregnancies are possible in women with PNH provided that both the obstetricians and physicians in charge monitor the pregnancies closely.

The use of cimetidine for the treatment of pruritus in polycythemia vera.

Thirty-four patients with polycythemia vera complicated by pruritus were treated with 900 mg of cimetidine daily for 30 days and their responses to treatment were evaluated. The conditions of 15 (44%) were improved, with 12 patients stating that pruritus completely disappeared. Nineteen patients either showed no improvement or had increasing symptoms. No toxic effects were reported. The positive responses seen are encouraging and suggest that controlled studies are indicated to further evaluate the effectiveness of H2 antagonists.

Hydroxyurea suicide study of the kinetic heterogeneity of colony forming cells in human bone marrow.

The kinetics of granulomonocyte colony forming cells have been studied in unfractionated normal human bone marrow by hydroxyurea suicide and in cells separated by velocity sedimentation. Sequential studies revealed two subpopulations of colony forming cells, having different sizes and different multiplication potentialities. There are large cells with a high suicide rate which develop small granulocyte and monocyte colonies during the first week of culture in semi-solid agar. Smaller cells develop larger colonies of granulocytes, monocytes and eosinophils between 2 and 3 weeks of culture. Only granulocyte progenitors have a substantial suicide rate in this small cell population. This population is also less responsive to stimulation than is the large cell class, which is a more highly differentiated progeny. The role of these different kinetics of colony forming cells is discussed in the context of the heterogeneity of the in vitro differentiation of neutrophil, monocyte and eosinophil lines.

Percentage of free serum prostate-specific antigen: a new tool in the early diagnosis of prostatic cancer.

Prostate-specific antigen (PSA) is a protease able to bind to serum antiproteases as alpha 1 antichymotrypsin (ACT). Free PSA (FPSA) corresponds to the fraction of total PSA (TPSA) which is unbound to ACT. Specific detection of the FPSA seems to be a valuable tool in the distinction between prostatic cancer (PCa) and benign prostatic hyperplasia (BPH). Our aim was to evaluate retrospectively the FPSA/TPSA ratio in comparison to TPSA or FPSA determination, using two new immunoradiometric assays (PSA-RIACT and FPSA-RIACT, CIS bio international, Gif Sur Yvette, France) in the early diagnosis of PCa. 256 men, with TPSA levels between 0.7 and 44.7 ng/ml (median age = 69 years), including 164 sera obtained from patients with BPH and 92 sera from patients with untreated PCa were assayed. All diagnoses were histologically confirmed and patients tested before any adjuvant treatment. The evaluation of the median FPSA/TPSA ratio in the two groups showed significantly different values (BPH group: 24.2%, PCa group: 12.1%, P < 0.0001). By R.O.C. (Receiver-Operating-Characteristics) analysis, we show that the FPSA/TPSA ratio is the method of choice for discriminating BPH and PCa, since the area under curve is the greatest for the FPSA/TPSA ratio curve, as compared to the TPSA or FPSA curves (P < 0.0001). The best accuracy (number of true positive + true negative/total = 82.4%) was obtained with a FPSA/TPSA ratio < or = 15% with high odds ratio (20.5; confidence interval (CI): 11.2; 37.7). Of interest, similar results were also confirmed even in the subpopulation with serum TPSA levels between 2.5 and 10 ng/ml (161 patients including 99 BPH and 62 PCa). We thus confirm that combined serum measurement of FPSA and TPSA is of particular interest in the early diagnosis of PCa for patients with non-suspicious digital rectal examination and a TPSA value between 2.5 and 10 ng/ml. In those patients, biopsy should be reserved to the cases with FPSA/TPSA below 15%, which allows significant odds ratio (12.8; CI: 5.2; 31.4). Otherwise, to avoid the risk of missing any PCa, usual follow-up with combined TPSA and FPSA determination would be required with the same criteria of biopsy (i.e. FPSA/TPSA ratio < or = 15% when TPSA value is between 2.5 and 10 ng/ml; or TPSA > 10 ng/ml).

Prognostic factors in acquired aplastic anemia. A study of 352 cases.

The prognostic factors of short- and long-term survival have been studied in 352 patients with aplastic anemia of all grades of severity. This group was homogeneous with regard to the clinical and laboratory survey, and the treatment used [high-dose androgen therapy]. The "hierarchy" of the individual prognostic parameters has been established: current severe infection, granulocyte count, percentage of the nonmyeloid cells on the bone marrow slides, platelet count, reticulocyte count, 59Fe utilization, and stromal disorganization on the bone marrow biopsy specimen. As these parameters are interrelated, a multiparametric analysis enables us to define groups of patients with different short-term evolution and to derive a prognostic index from these data. The use of such an index, however, allows a correct prediction in only 73 per cent of the cases, better in the milder than in the more severe cases. It is possible that the short-term evolutive tendency (improvement or worsening during the first six weeks of therapy) may contribute supplementary information useful for prognosis and the choice of treatment. After the first three months critical period, the mortality rate no longer depends on the initial severity of the disease but exclusively on the clinical and hematologic improvement. Thus, comparing the hematologic data obtained initially and after three months of androgen therapy allows us to correctly predict the long-term evolution.

Significance of bone-marrow scintigraphy in aplastic anemia: concise communication.

Tc-99m colloid and In-111 transferrin were used in a semiquantitative scintigraphic study of bone-marrow activity in 76 patients with aplastic anemia, the majority of which were severe cases. The results are compared with other known prognostic parameters and with a predictive index formulated from a prior multi-parametric analysis performed in 352 cases. In 47 cases parallel abnormality of Tc and In uptakes was noted and was well correlated with other prognostic factors. Indium uptake is apparently a good indicator of the severity of aplasia; extension of active erythroid tissue, demonstrated with this method, is correlated with prognosis. In nine cases, excessive In uptake is explained by dyserythropoiesis associated with granulo- and thrombocytopenia (Fanconi's anemia in most cases). In 20 of our patients, TcSC uptake was excessive compared with that of In and with other prognostic factors. Statistically, this phenomenon carries an unfavorable prognosis but its physiological meaning remains to be defined.

Advantages of SPECT in technetium-99m-sestamibi parathyroid scintigraphy.

UNLABELLED: We demonstrate several advantages of SPECT in parathyroid scintigraphy. METHODS: Forty-four parathyroid 99mTc-MIBI scintigrams were obtained before surgery in 43 patients suffering from hyperparathyroidism. For each patient, we obtained dynamic views and planar and SPECT images of the neck and thorax. For 15 patients, we also acquired a delayed static view of the neck 2 hr after tracer injection. Abnormal thyroid-area glands were detected with factor analysis of dynamic structure (FADS) of the initial dynamic acquisition. In the 15 patients with delayed views of the neck, we compared FADS and the double-phase study results to detect glands in the thyroid uptake area. Glands outside the thyroid area were demonstrated on planar views. The location of enlarged glands was more precisely defined on the tomographic slices. The anatomic and histologic findings and the evolution of hypercalcemia after surgery were taken as reference. RESULTS: Sixty-four abnormal glands were found during surgery, including 39 observed in patients who underwent reoperation for persistent or recurrent hyperparathyroidism. Twenty-two of these glands were in an abnormal location, including 10 in the mediastinum. SPECT allowed the detection of three glands not demonstrated on planar views or FADS. Fifty-eight glands were correctly localized scintigraphically, including 34 in patients who underwent reoperation. Therefore, SPECT raised the sensitivity from 86% to 90.5% and from 79.5% to 87% in the reoperated patients. Tracer uptake in the low mediastinal area was better analyzed on tomographic slices than on planar views. Only seven false-positive results were depicted by planar views or FADS; none were depicted on SPECT. CONCLUSION: A combination of FADS and SPECT permits detection of small glands, even in a posterior location, inside or outside the thyroid area. This scintigraphic method enables the surgeon to define more precisely details about the location of the enlarged gland and contributes to improved parathyroid surgery.

Identifying abnormal parathyroid glands in the thyroid uptake area using technetium-99m-sestamibi and factor analysis of dynamic structures.

UNLABELLED: A rapid (25 min) single tracer scintigraphic method to localize parathyroid gland abnormalities was evaluated in 24 patients with hyperparathyroidism. METHODS: Scintigraphy was performed with 99mTc-sestamibi prior to surgery. A 25-min dynamic series centered on the neck was acquired immediately after injection of 99mTc-MIBI. Two planar static views were obtained after 1 and 2 hr. To identify abnormal parathyroid tissue in the thyroid uptake area, a factor analysis of dynamic structure (FADS) was applied to the dynamic acquisition. The results were compared to the analysis of the two planar static views. RESULTS: FADS demonstrated abnormal uptake of the tracer in the thyroid area for 26 of the 31 parathyroid glands found to be abnormal at surgery (5/6 adenomas, 21/25 hyperplastic glands). In three cases, FADS demonstrated parathyroid uptake despite the absence of parathyroid tissue at surgery. FADS revealed as specific and more sensitive than the visual analysis of the two static views, since only 13/30 glands were still visible after 1 hr, and 5/26 after 2 hr. Furthermore, a study with two static views was found to be less sensitive for the detection of hyperplastic glands. CONCLUSION: FADS99mTc-MIBI is performed in less time than existing scintigraphic protocols. It is a promising method to detect abnormal parathyroid glands in the cervical area with a single tracer.

In vivo platelet kinetics in 31 diabetic patients. Correlation with the degree of vascular impairment.

In vivo platelet survival was estimated, in 31 diabetic patients, using 51Cr-labelled autologous platelets. A mathematical analysis attempted to measure the "potential" life span (senescence process) and the degree of a superimposed aleatory destruction (consumption process). The potential platelet life span in diabetics did not differ from normal values. However, excessive consumption was observed in one third of the studied cases, without correlation with the age of the patients, the clinical duration of diabetes, and the degree of vascular impairment. Thus, platelet kinetic studies did not provide presently useful indications, in a particular patient, regarding the prognosis of the vascular disease, and the justification of anti-aggregant therapy.

Prognostic value of the combined suicide level of granulocyte progenitors and the labelling index of precursors in preleukemic states and oligoblastic leukemias.

Although abnormalities in granulopoiesis detected by means of bone marrow cytology, culture and kinetic studies have provided prognostic data in preleukemic states and oligoblastic leukemias, this information cannot be applied to individual cases. In order to determine the indications for treatment and the form it should take in a given case, data would be required concerning the probability of impending transformation into acute leukemia. In 45 studies involving 34 patients who were followed for 10-42 months, a combination of a rise in the proportion of granulocyte precursors in S-phase, indicated by a colony-forming cell suicide rate of over 40%, and a low labelling index of myeloblasts and promyelocytes, was always followed by the onset of acute leukemia within 10 months. Sequential studies in 13 patients revealed an increase in cluster-forming cells and in the suicide level in the second study. The changed kinetics of granulopoietic proliferation may provide an indication for chemotherapy.

Bone marrow culture in aplastic anemia.

Blood and bone marrow granulocyte colony forming units (CFUc) were assayed in 46 patients with aplastic anemia, and the serum was examined for its inhibitory action on normal CFUc growth. All patients showed a gross reduction in colonies and clusters in incidence and absolute number in the bone marrow and blood. Two proliferative abnormalities of CFUc in aplastic anaemia were identified: a significantly higher than normal cluster to colony ratio (P less than 0.05) and a higher than normal ratio of granulocytes to total aggregates in the bone marrow. Eleven out of 34 patients tested had serum inhibitory to normal CFUc. These patients were indistinguishable from the rest on haematological and CFUc culture characteristics, and no correlation between the results of CFUc assay and haematological severity was found. The results suggest that the CFUc is abnormal in aplastic anaemia, the reduction in pool size being related to a failure of self-renewal, but an immunological role in the pathogenesis of aplastic anaemia remains unproven. The close relationship of CFUc incidence to the percentage of granulocyte precursors in the marrow, together with the failure of the CFUc assay to predict clinical severity, limits the practical use of the assay to the confirmation of diagnosis in aplastic anaemia.

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.

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.

Effect of combination chemotherapy, duration of methotrexate administration, and patient's age on methotrexate pharmacokinetics.

The kinetics of methotrexate were studied in a group of 59 patients after infusion of high doses. From the triexponential analysis of the serum concentration curve, rate constants and relative concentrations in non-circulating pools were calculated, using a linear 'mammillary' three-compartment model. No significant variation as a function of dose (300-6,000 mg/m2) was observed. In circumstances the rapidly exchanging pool was a reflection of the circulating pool, suggesting that it is an extravascular, protein-bound pool of methotrexate. Considerable variations of the relative concentration and rate constants of the slowly exchanging pool were observed to be a function of the duration of methotrexate infusion, the presence of other drugs, and the patient's age. If this compartment is assumed to include the target cells for methotrexate, then the large variations observed could be responsible for individual differences in toxicity and/or effectiveness.

Bone marrow scintigraphy as a useful method for estimating the physiological status of bone marrow and spleen in polycythaemia vera.

Bone marrow scintigraphy is a simple and noninvasive examination useful to define the status of the bone marrow and spleen in polycythaemia vera (P.V.). Despite the absence of specificity of Indium 111 labelled transferrin (In-Tf) for myelopoietic tissue, there is a close correlation between bone marrow In-Tf uptake and bone marrow cellularity and between splenic In-Tf uptake and splenic metaplasia. The results of scintigraphy are compared to clinical data, radioactive iron kinetics, bone marrow and spleen histology and the course of the disease. The diagnostic and prognostic value of bone marrow scintigraphy is discussed, particularly at the stage of transformation of P.V. into postpolycythaemia myeloid metaplasia (Post-P.V.M.M.).

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.