[Development of psychological and intellectual performance in transplanted sickle cell disease patients: a prospective study from pretransplant period to 5 years after HSCT]. / Développement psycho-intellectuel des enfants drépanocytaires ayant reçu une allogreffe de cellules souches hématopoïétiques.

RATIONALE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD). Cerebral vasculopathy was the principal indication for transplantation. These children could present impaired neuropsychological development related to different causes, hence the value of exploring their intellectual capacities before and after transplantation. MATERIAL AND METHODS: Prospective longitudinal study from 1992 to 2006 in all transplanted SCD patients. The patients were assessed using Wechsler scales with four different indices: verbal comprehension, perceptual reasoning, working memory, and processing speed (PSI), providing a full-scale intellectual quotient (IQ). RESULTS: Fifteen SCD patients (8 females and 7 males; mean age, 8.9 years) were evaluated before and 36 and 60 months after transplantation. All were from Africa and lived in France. All patients except 2 had experienced ischemic stroke before HSCT. The median full-scale IQ was 87, 94, and 94 before transplantation and 36 months and 60 months after HSCT, respectively. DISCUSSION: At pre-HSCT evaluation, full-scale IQ was considered as "low average". This relatively poor result could be related to impairment of PSI, which reflects frequent graphic and motor abnormalities related to the previous stroke experienced by almost all patients. At 3 years after HSCT, all indices including IQ had increased. Only the PSI had decreased, this observation being potentially related to previous stroke and to the depression frequently experienced by the transplant recipient patient after the acute phase, when the disease is cured. At 5 years after HSCT, the median full-scale IQ was stable and the PSI had increased. CONCLUSION: At the end of follow-up, the patients improved their physical and psychological well-being. This allowed them to build projects for the future and to manifest the desire of becoming an adult. Bone marrow transplantation in this cohort of children with SCD and severe cerebral vasculopathy is associated with improved performance as measured by the Wechsler scale.

Household exposure to pesticides and risk of childhood acute leukaemia.

OBJECTIVES: To investigate the relation between childhood acute leukaemia and household exposure to pesticides. METHODS: The study included 280 incident cases of acute leukaemia and 288 controls frequency matched on gender, age, hospital, and ethnic origin. The data were obtained from standardised face to face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics. RESULTS: Acute leukaemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukaemia (OR = 1.9, 95% CI 1.2 to 3.3). CONCLUSION: The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukaemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.

Immune reconstitution after haematopoietic transplantation with two different doses of pre-graft antithymocyte globulin.

Antithymocyte globulin is widely used before haematopoietic transplantation with HLA-matched unrelated donors or mismatched relatives to prevent rejection and graft-versus-host disease (GVHD). However, optimal dosage is still under debate. Thirty-one consecutive children, mainly with haematological malignancies, were transplanted in a single institution with such donors, selected by HLA-A -B compatibility by serology and DRB1* by DNA typing. Antithymocyte globulin (Thymoglobuline; Sangstat) was infused at days -3, -2, -1. Total dosage varied: 16 patients received a median of 7.5 mg/kg (2.5 to 10.5: low-dose group), and 15 a median of 15.5 mg/kg (14.4 to 19.4: high-dose group). Post-transplant GVHD prophylaxis consisted of cyclosporine, short-course methotrexate and steroids. CD3(+), CD4(+) and CD19(+) cell reconstitution was slower in the high-dose group. Median time to reach 100 CD4(+) cells was 8 months vs 4 months (P = 0.03). Median time to normal CD19(+) cells was 16 months vs 8 months (P = 0.01). CD16(+)CD56(+) and CD8(+) cell reconstitution was similar. Nine patients in the high-dose group and two in the low-dose group experienced life-threatening opportunistic infections (P = 0.009). Although obtained from a limited number of patients, our data suggest that a higher pre-graft dose of antithymocyte globulin may negatively influence immune reconstitution.

Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.

MALT lymphoma of labial minor salivary gland in an immunocompetent child with a gastric Helicobacter pylori infection.

We report a pediatric case of a mucosa-associated lymphoid tissue lymphoma of the labial minor salivary gland in an immunocompetent patient. Chronic gastritis with Helicobacter pylori was disclosed and managed with antibiotic therapy. With eradication of Helicobacter pylori there was complete remission of the lymphoma.

Expansion of polyclonal B-cell precursors in bone marrow from children treated for acute lymphoblastic leukemia.

In a series of 12 patients (mean age: 3 years at diagnosis) receiving chemotherapy for acute lymphoblastic leukemia, bone marrow examinations performed during hematopoietic recovery following treatment-induced agranulocytosis or completion of maintenance treatment showed at least 15% of non malignant immature cells which were sometimes hardly distinguishable from leukemic cells. No comparable data was observed in patients treated with G-CSF. The cytological features of these cells as well as their immunophenotyping were defined. Results showed that the majority of cells expressed HLA-DR, CD19, CD10 and cytoplasmic IgM but not the CD34 markers. This predominant and homogeneous pre-B cell population which likely represents the expansion of a minor population detectable in normal bone marrow is phenotypically indistinguishable from leukemic cells. The pattern of IgH gene rearrangements studied by PCR amplification of the CDRIII region showed that these cells were polyclonal. Except in one patient, minimal residual disease was not detected using probes specific for IgH or TCR gene rearrangement of the malignant clone. In children during the hematopoietic recovery after chemotherapy, immature marrow cells in great numbers, even with an highly homogeneous immunophenotype identical to the malignant clone's, are not sufficient for the diagnosis of relapse.

Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia.

OBJECTIVE: The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881. RESULTS: After 1 month of oral treatment at a dose of 50 mg.m-2.day-1, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g.m-2 (bolus dose of 0.2 g.m-2 followed by an 8-h infusion of 0.8 g.m-2) in 11 patients: systemic clearance was 23.02 1.h-1, volume of distribution was 0.75 l.kg-1, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol x 10(8) packed RBC) or within 24 h of infusion (223 pmol x 10(8) packed RBC). The CSF concentration was 3.78 mumol.1(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16). In patients receiving the oral dose of 50-165 mg.m-2.day-1 of 6-mercaptopurine, CSF concentrations were below 0.18 mumol.1(-1), 1-24 h after drug intake (n = 67), and the CSF to plasma ratio was not calculated. CONCLUSION: Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n[symbol: see text]5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses.

Prospective monitoring and quantitation of residual blasts in childhood acute lymphoblastic leukemia by polymerase chain reaction study of delta and gamma T-cell receptor genes.

We have developed a strategy based on polymerase chain reaction (PCR) for detecting all possible gamma T-cell receptor (gamma TCR) rearrangements and the most common delta TCR rearrangements found in B-lineage and T-acute lymphoblastic leukemia (T-ALL). The segments amplified from blasts are then directly sequenced to derive clonospecific probes. From a series of 45 patients aged 1 to 15 years (42 B-lineage ALL, 3 T-ALL), 35 (83%) could be followed for minimal residual disease with at least one clonospecific probe. Detection of clonal markers using clonospecific probes routinely allowed the detection of 1 to 10 blasts out of 10(5) cells as determined by serial dilutions of the initial samples. Residual disease was quantitated by a competitive PCR assay based on the coamplification of an internal standard. Twenty children were prospectively followed for periods varying from 7 to 30 months. In most children, a progressive decrease of the tumor load was observed, and blasts became undetectable within 6 months after the initiation of treatment. A slower kinetics of decrease in tumor cells was found in three children. These three patients relapsed with blasts that continued to display the initial clonospecific markers. Three other children had a central nervous system relapse despite the absence of detectable medullary residual disease. The use of both delta and gamma TCR genes as clonal markers, as well as simplification in the methods to detect and quantify residual blasts reported here, will allow the study of the large number of patients required to determine the role of the detection of minimal residual disease by PCR in the follow-up of childhood ALL.

[Breast feeding and hypernatremic dehydration. 3 case studies]. / Allaitement maternel et déshydratation hypernatrémique. Etude de 3 observations.

Despite the well-recognized advantages of breast-feeding, a rare but life-threatening complication may occur with failure to thrive resulting in severe malnourishment or hypernatremic dehydration. We report 3 more cases. Two of them with severe hypernatremic dehydration and cachexia were treated using peritoneal dialysis rather than intravenous fluids in order to rapidly correct the severe metabolic acidosis but slowly the serum osmolarity. Although insufficient breast-milk volume appears to prevail over positive sodium balance in the pathway to hypernatremic dehydration, high sodium concentrations were found in breast milk as previously reported. However, the discovery of a low lactose content inversely related to that of sodium in breast-milk, suggests more complex disturbances in lactation and may draw up new hypothesis in the pathogenesis of this challenging syndrome.