Intratumoral consumption of indium-111-labeled platelets in a child with splenic hemangioma and thrombocytopenia.

The authors report Kasabach-Merritt syndrome (KMS) in a patient with thrombocytopenia and splenic hemangioma. A 13-month-old boy with a history of anemia, thrombocytopenia, and abdominal mass was admitted to the hospital. The scintigraphic studies showed that a large mass contiguous to the spleen was responsible for the platelet uptake. After partial splenectomy, the platelet count returned to normal. This report of KMS in a child with splenic hemangioma suggests that the scintigraphic studies are mandatory to confirm diagnosis. Indium-111-labeled platelets are useful in identifying hemangiomatous sequestration of platelets in patients with thrombocytopenia.

Mature plasma cells as indicator of better prognosis in multiple myeloma. New methodology for the assessment of plasma cell morphology.

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Indolent course as a relatively frequent presentation in T-prolymphocytic leukaemia. Groupe Français d'Hématologie Cellulaire.

T-prolymphocytic leukaemia (T-PLL) is a rare disorder with a poor outcome. Presentation features were studied in 78 T-PLL cases. Although 53 patients (group A) presented with typical progressive disease including rapidly increasing leucocytosis. 25 patients (group B) experienced an initial indolent clinical course with stable moderate leucocytosis. The morphology and antigenic profile of abnormal cells were similar in both groups, except for a lower incidence of CD45RO+ CD45RA- pattern in group B. A high incidence of inv(14)(q11;q32), t(14;14)(q11;q32) and i(8)(q10) chromosomal abnormalities were found in both groups. After an initial indolent phase (median 33 months; 6-103 months), 16 group B patients progressed to an aggressive stage with clinical and laboratory features similar to group A. Moreover, median survival after progression was short in both groups. In conclusion, T-PLL may start as an indolent disease similar to that reported in ataxia telangectasia. In this rare genetic disorder, some patients develop stable T-cell clones which progress toward T-PLL-like leukaemia. Moreover, ATM gene mutations have been reported in T-PLL. Thus, both diseases are likely to be closely related.

Myelodysplastic syndromes in childhood: is the FAB classification relevant? Report of 81 children from a French multicentre study. French Group of Cellular Hematology.

We reviewed the peripheral blood and bone marrow smears of 81 children with myelodysplastic syndrome (MDS). The morphological FAB classification was applicable in 59 children (72.8%): RAEB and RAEBt were the most frequent, 32 cases (39.5%). CMML was observed in 15 cases (18.5%) and in 25% of them, serological evidence for a recent EBV infection was demonstrated. In 22 cases (27.2%), the FAB classification was not convenient. In some of these children, dysmyelopoiesis was associated with constitutional disorders. Among these various inherited conditions, Down syndrome in which myelodysplasia is the expression of an abnormal clonal hematopoiesis, and mitochondrial cytopathies in which MDS is the hematological expression of a polyclonal multi-organ disease. The FAB classification does not appear to be satisfactory for all the disorders included in the group of childhood MDS and should be modified for specific use in children.

Erythrocyte spermine levels: a prognostic parameter in childhood common acute lymphoblastic leukemia.

Polyamines have been implicated to play a role in cell proliferation and in cancer development. Ninety percent of the circulating spermidine (Spd) and spermine (Spm) are transported by red blood cells (RBC). RBC Spd and Spm levels were prospectively determined in 63 unselected children with common acute lymphoblastic leukemia. The Spm and Spd levels were not correlated with white blood cell (WBC) count. On the basis of the polyamine levels it was possible to discriminate four groups with P< 10(-3). In C1, C2, C3 and C4 group the Spm level was respectively 90 (39-597), 3.75 (1-7.45), 9.95 (2.9-12.6) and 17(6.3-33.8). The probability of relapse-free survival (RFS) of the 58 children who entered complete remission was 55% +/- 9. For the groups C1 (n = 6), C2 (n = 16), C3 (n = 21) and C4 (n= 15) groups, the RFS was 25% +/- 20, 73% +/- 12, 73% +/- 13 and 32% +/- 13 respectively. For children with Spm levels <13/> or = 13nmol/8 x 10(9) RBC, event-free survival (EFS) was 54% +/- 11/33% +/- 10 and RFS was 64% +/- 12/38% +/- 11 respectively (P < 0.03, P < 0.005). Our clinical study shows clearly that an RBC spermine level could be used as parameter of prognosis at the time of diagnosis, particularly for patients with intermediary WBC count.

Multifactorial drug-resistance phenomenon in acute leukemias: impact of P170-MDR1, LRP56 protein, glutathione-transferases and metallothionein systems on clinical outcome.

The multidrug resistance phenomenon can be observed in cases which do not express the P170 protein and these cases are suspected as having activated different resistance phenomena. Four phenomena were studied at the time of diagnosis in a series of 35 lymphoblastic and 25 myeloblastic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MDR/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) and the metallothioneins (Mts). The results demonstrate that these phenomena are independent but their synergic activity can increase their impact on the outcome. P110/LRP56 positive cases demonstrated 48.8% complete remission (CR) rate compared to 71.4% for negative tests. When P170 and P110 were both positive or negative, the CR rates were 27.3% and 81.8% respectively (p = 0.0120), and survival curves were also different (p = 0.030). The CR rate in AML or ALL is weakly affected by GST pi, alpha or mu but relapses are more frequently observed for Positive-GST pi ALL (p = 0.0658). Patients with both P170 and GST pi positive reactions had a 53.3% CR rate compared to 78.9% for both negative reactions. Survival curves for these two groups were different. The CR rate in AMl was 100% for Mts positive and 43.7% for negative cases (p = 0.050), however the median survival was totally different for these two groups (p = 0.046). CR rates were 26.6% for patients who were P170 positive and Mts negative compared to 100% for P170 negative and Mts positive (p = 0.038) patients. Survival curves were also different (p = 0.0510). We conclude that these four mechanisms induce an independent drug resistance but their synergic action increase their impact on the outcome. The metallothioneins seem to have a major impact on the drug resistance phenomenon and its effect should be investigated with high priority, in the light of these results.

Influence of severity of chronic inflammatory joint disease on the pharmacokinetics of indomethacin and etodolac.

The goal of this study was to look for correlations between the severity of chronic inflammatory joint disease and pharmacokinetic parameters of nonsteroidal antiinflammatory drugs. Disease severity data (pain severity and magnitude of abnormalities in laboratory tests for inflammation) and pharmacokinetic data (area under the curve in the morning (AUCm) and maximum plasma concentration (Cmax) were collected during a prospective, randomized, double-blind, parallel-group study. Two groups of nine and 11 patients, respectively, were given 300 mg etodolac b.i.d or 50 mg indomethacin b.i.d. by the oral route, for three days, after a 36-hour placebo washout. Univariate analyses demonstrated statistically significant negative correlations between pharmacokinetic parameters of both study drugs and a number of disease severity parameters. In the multivariate analysis of data for etodolac, the sigma erythrocyte sedimentation rate contributed significantly to variations in all pharmacokinetic parameters and explained 100% of the variations in free S-enantiomer AUCm and in total and free S-enantiomer Cmax. For indomethacin, pain contributed to variations in Cmax values of the total and free forms; the sigma erythrocyte sedimentation rate was also a factor in variations in total indomethacin. These negative correlations suggest that severity of chronic inflammatory joint disease may influence the pharmacokinetics of nonsteroidal antiinflammatory drugs.

Multi-drug resistance (MDR) activity in acute leukemia determined by rhodamine 123 efflux assay.

We prospectively analyzed MDR functional activity by the Rh123 efflux assay in 84 de novo acute leukemias. Thirty of the 60 AML cases (50%) showed a positive dye efflux (in more than 10% of blast cells). In 19 cases, the dye efflux was superior to 30%. Twenty-four of the 30 efflux positive cases were CD34+ and could be studied in double staining. The mean percentage of effluxing CD34+ blast cells was 54%. There was a high correlation between CD34 expression and MDR activity (P < 10(-4)), MDR activity and PgP expression (P < 10(-6)). All the efflux negative samples were PgP negative. Nine efflux positive cases were PgP negative. Five of the 24 ALL were efflux positive. MDR activity did not correlate with FAB subtype (with the exception of AML3: 1/6 was efflux positive), age, white blood cell count or LDH level. Forty-seven AML patients were treated with conventional chemotherapy including cytarabine and an anthracycline. Thirty-one (66%) entered complete remission (CR). CR rate was statistically lower for efflux positive as compared to efflux negative patients, 46 vs 87% (P = 0.003), for PgP+ as compared to PgP- patients, 40 vs 78% (P = 0.01), for CD34+ as compared to CD34- patients, 45 vs 84% (P = 0.005). There was no correlation between P110 expression (32 AML cases studied) and FAB subtype, MDR status and clinical outcome. Two years survival was 20% for efflux positive patients as compared to 54% for efflux negative patients (P < 0.07), 15% for PgP+ vs 54% for PgP- patients (P < 0.04). The finding of efflux+/PgP- cases suggests the existence of other membrane efflux pumps. Rh123 efflux assay is straightforward in routine and could be included in MDR screening because of its potential interest in clinical outcome in AML.

Erythrocyte polyamine levels: an indication of successful engraftment of bone marrow in children.

We studied the evolution of erythrocyte polyamine levels after 17 autologous bone marrow transplants (BMT) in 16 children with malignant diseases. We found that the time to the end of aplasia (0.5 x 10(9) granulocytes per liter) could be divided into 2 distinct periods. The first is characterized by low erythrocyte spermidine (Spd) and spermine (Spm) levels; the second is characterized by normal levels of polyamines. Spd and Spm levels were correlated (r = 0.74) during the second period, but not during the first period or in the control group. Furthermore, the time when Spd concentration was > or = 7 nmol/8 x 10(9) erythrocytes (19 +/- 7) was correlated (r = 0.64) with the advent of end of aplasia (30 +/- 10). We found no correlation between the numbers of CFU-GM and duration of aplasia levels or the duration of period A. The establishment of normal erythrocyte spermidine levels is the earliest index of successful marrow engraftment.

Plasmacytoid CD8 lymphoma: morphologic and immunologic characterization.

This study describes a 79 year-old female suffering from fever and lymphadenopathy. A lymph node biopsy showed diffuse infiltration of medium-sized cells with plasmacytoid features. The immunologic phenotype determined by cytometric analysis and immunochemistry showed suppressor T antigen (CD2, CD3, CD7, CD8) expression. Absence of CD5 expression characterized this abnormal T cell proliferation. Gamma T cell receptor rearrangement without immunoglobulin heavy-chain gene rearrangement confirmed the T lineage of these plasmacytoid cells and their clonality. Immunological studies are necessary for identification of this T lymphoma with B microscopic findings.

P-glycoprotein (P-170) and CD34 expression in adult acute myeloid leukemia (AML).

We investigated the prognosis value of CD34 and P-170 expression in blast cells of adult patients affected by de novo acute myeloid leukemia (AML). CD34 antigen was analyzed by indirect immunofluorescence (IFI) and alkaline phosphatase-labeled streptavidin biotine (AP-LSAB) in 62 patients (median age: 51 years). P-170 expression was determined by AP-LSAB in 51 cases using JSB1 and C219 monoclonal antibodies. All patients were treated with conventional chemotherapy induction regimen. Follow-up was from 6 to 79 months. Complete remission (CR) rate was not statistically different between CD34+ and CD34- patients (67 vs. 84%, p = 0.2). The duration of CR and survival were not influenced by CD34 expression. Karyotype abnormalities were more frequent among MDR+ patients (65 vs. 21%, p < 0.01). CR rate was statistically lower in MDR+ patients as compared to MDR- patients (63 vs. 96%, p = 0.01). Median disease-free survival (DFS) was shorter for MDR+ patients but the difference was not significant (5 vs. 10 months, p = 0.09). Patients who were positive for both parameters CD34 and P-170, had a poor prognosis with a 50 vs. 100% CR rate for CD34/P-170 negative patients, (p = 0.002), a lower median DFS (3 vs. 12 months, p = 0.01) and overall survival (OS) (3 vs. 14.5 months, p = 0.01). Results of cytogenetic analysis did not influence CR rate but the relapse rate was higher, although not significant, for the patients with unfavorable karyotype (63 vs. 33%). The seven CD34+/MDR+ patients with poor prognosis karyotype had a statistically lower CR rate, median DFS and OS than the 7 CD34-/MDR- patients with normal or favorable karyotype (CR: 29% vs. 100%, p = 0.02), (DFS: 3 vs. > 12 months, p = 0.01), (OS: 4 vs. > 12 months, p = 0.02). Our data indicate that P-170 but not CD34 expression is predictive for a lower CR rate. The identification of a bad prognosis subgroup of CD34+/MDR+ AML patients (and especially those with poor prognosis karyotype) has to be confirmed on larger series using uniform methodology.

Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: prognostic implications.

Immunocytochemical detection of the multidrug resistance (MDR)-associated membrane protein (P-170) was performed at time of diagnosis in a series of 36 children and 23 adults with acute lymphoblastic leukemia (ALL) using two monoclonal antibodies JSB1 and C219. Immunophenotypes were obtained in all cases and karyotypes were analyzed in 37 cases. Detection with JSB1 or with C219 led to similar results in terms of positive cells and cases, but the intensity of staining was higher with JSB1. In the populations studied, the rate of first complete remission differed between MDR-positive and MDR-negative in adult patients only (56% v 93%, respectively, P = .05). Of the 16 MDR-positive patients who had presented a first complete remission, 13 (81%) relapsed, compared with 13 of 35 (37%) MDR-negative (P = .008) patients. A higher rate of relapse among MDR-positive compared with MDR-negative patients was observed in adults and in children taken separately (adults 100% v 46%; children 73% v 32%, respectively). The survival rates (Kaplan-Meier method) were significantly higher in MDR-negative compared with MDR-positive populations as a whole (P = .002) and among children (P = .05) and adults (P = .03) taken separately. Event-free survival curves followed this trend. The percentage of second complete remission was very low in the MDR-positive group (15%) compared with 38% for the MDR-negative group. These results were shown by multivariate analysis to be independent of age, immunophenotypes, and karyotypes and clearly show the importance of MDR phenotype detection in ALL.

[Auto-immune idiopathic thrombocytopenic purpura in children. Apropos of 100 cases]. / Le purpura thrombopénique idiopathique auto-immun de l'enfant. A propos de 100 observations.

The authors report the results of a retrospective study concerning 100 children with immune thrombocytopenic purpura who were referred between January 1981 and January 1991. Twenty-seven children had a chronic evolution with a significantly high risk: girls aged 9 years or more, hospitalization longer than 10 days, or patients with a history of frequent ecchymoses. The risk of haemorrhage was highest at the early phase of the disease and when the platelet count was below 25 G/l. The need for laboratory tests has been controversial and the authors suggest a simplified list of tests after having demonstrated the limited value of tests attempting to document the prepurpuric infectious episode or associated disease. The number of responders was comparable in the group receiving corticosteroids (78%) and in that receiving intravenous immunoglobulins (76.5%), as was the number of complete remissions in both groups (40.4% and 50%, respectively). 20.5% of the patients receiving intravenous immunoglobulins experienced a chronic evolution versus 29.8% in the group receiving corticosteroids (no significant difference). Seventeen patients underwent splenectomy with excellent result, particularly in one child who underwent urgent splenectomy because of intracranial haemorrhage.

Evaluation of the dysmyelopoiesis in 336 patients with de novo acute myeloid leukemia: major importance of dysgranulopoiesis for remission and survival.

Myelodysplastic features and myeloperoxidase (MPO) deficiency have been investigated in a series of 336 cases of de novo acute myeloid leukemia (AML) to clarify their impact on the outcome of such patients and to compare with the previous results from the literature. Dysplastic features were defined according to the FAB criteria. Trilineage disease (TLD) was observed in 11.6% of patients (39 cases), and the complete remission rate (CR) was 56.4% for TLD patients compared to 74.4% for patients without any dysplastic features (p = 0.03). The effects of dysgranulopoiesis (DysM) alone or in combination were assessed using a logistic regression analysis. This analysis revealed that only DysG had any effect on CR rate (p = 0.013). The CR rate for patients with DysG was 56.6% and 71.5% for patients without DysG. We were unable to find any correlation between MPO deficiency, dysplastic features and CR rate. Cytogenetic analysis could be assessed for 119 patients. For patients with DysG, 10 karyotypes were normal and 20 were abnormal compared to 48 normal and 41 abnormal for patients without DysG (p = 0.05). We conclude that the presence of DysG in de novo AML exerts a negative effect on the ability to achieve a CR and is related to a higher frequency of cytogenetic abnormalities.

Heterogeneity of acquired idiopathic sideroblastic anaemia (AISA).

Clinical, haematological and outcome data were studied in 84 patients with acquired idiopathic sideroblastic anaemia (AISA) from a registry of 613 consecutive myelodysplastic syndromes (MDS) recorded by five institutions in western France. Two groups could be identified and compared: 'pure' erythroblastic AISA (AISA-E: 59 pts), and AISA with myelodysplastic features, i.e. dysgranulo and/or dysmegakaryopoiesis (AISA-M: 25 pts). Results were also compared to those of a series of 71 cases of refractory anaemia without sideroblastosis (RA) carried out from the same registry. Dyserythropoiesis was present in 90% of all AISA subtypes, dysgranulopoiesis in 88% of the AISA-M cases; dysmegakaryopoiesis was observed in 44% of AISA-M. Ten patients with both forms of AISA showed high platelet counts. These cases appeared particular in that four of them were associated with a splenomegaly and/or a hyperleucocytosis. They had to be distinguished from myeloproliferative syndromes. Outcome comparison of AISA-E with AISA-M showed a significant discrepancy of survival duration (60 vs 38 months respectively). Progression towards refractory anaemia with excess of blasts or acute leukaemia, was significantly higher for AISA-M than for AISA-E. The risk of transformation increased to 24% for the AISA-M group similarly to those of RA patients (17%). We conclude that AISA must be divided into two categories, 'pure' AISA and AISA-M, because survival duration and risk of transformation are different.

[Orbital and muscular relapse of Burkitt's lymphoma]. / Rechute orbitaire et musculaire d'un lymphome de Burkitt.

We report the case of a child presenting with abdominal Burkitt's lymphoma in whom a relapse presented as orbital and muscle involvement. This clinical feature is extremely rare. Two muscle and one orbital biopsies were necessary to obtain proper diagnosis. A new extension check-up showed bone marrow invasion and normal cerebrospinal fluid. This relapse was successfully treated by conventional chemotherapy and consolidated with high-dose chemotherapy, total body irradiation and autologous bone marrow transplantation. Eighteen months after transplantation, the child may be considered as definitively cured.