Factor V Leiden and other hypercoagulable state mutations are not associated with osteonecrosis during or after treatment for pediatric malignancy.

OBJECTIVE: Osteonecrosis (ON) is a debilitating complication of cancer treatment in children and is usually associated with systemic steroid therapy. Defects of coagulation may be important in the pathogenesis of ON. This study evaluated the prevalence of factor V Leiden (FVL, 1691G-->A), the most common inherited thrombophilic state, the prothrombin 20210G-->A polymorphism, and the thermolabile methylene tetrahydrofolate reductase (MTHFR, 677C-->T) variant in a group of children in whom ON developed during or after treatment for cancer. STUDY DESIGN: Children in whom ON developed during cancer treatment at St Jude Children's Research Hospital were studied (n = 24). Genomic DNA was isolated, and polymerase chain reaction was performed to identify the FVL, prothrombin 20210, and thermolabile MTHFR mutations. RESULTS: Sixteen of 24 patients had acute lymphoblastic leukemia. The mean age at ON diagnosis was 14.4 +/- 3. 7 years. The mean interval between cancer diagnosis and ON diagnosis was 27 +/- 21 months. Twenty-two patients had received steroids for a mean duration of 24 +/- 15 weeks before having development of ON. No patient had a history of thrombosis. Five (21%) patients had a family history of thrombosis. Genetic analysis revealed 0 (0%) of 24 FVL, 1 (4.5%) of 22 prothrombin 20210, and 3 (13.6%) of 22 thermolabile MTHFR. None of these mutation frequencies was significantly different from our control frequencies or published values. CONCLUSIONS: Although procoagulant abnormalities in general and FVL in particular have been detected in a significant number of patients with ON of the jaw and Legg-Perthes disease, we did not identify an increased prevalence of FVL or other hypercoagulable state mutations in a cohort of children with ON that developed during or after treatment for a variety of cancers.

Predominance and characteristics of Burkitt lymphoma among children with non-Hodgkin lymphoma in northeastern Brazil.

The purpose of this paper was to define the histologic distribution, clinical features, and treatment response of childhood non-Hodgkin lymphoma (NHL) in northeastern Brazil. We reviewed medical records and histopathologic studies of 98 children treated for NHL from 1980 to 1987 at a major pediatric cancer center in Recife, Brazil. Treatment outcome was evaluated in relation to tumor burden (stage and serum LDH) and type of therapy (LSA2L2 vs other multiagent chemotherapy). There was a striking predominance of the small noncleaved cell (Burkitt) subtype, which occurred in 92 of the 98 children and adolescents diagnosed with NHL. Subsequent analyses focused on these patients. The majority (n = 84) had advanced (stage III/IV) disease at diagnosis. The abdomen was the most common site of disease (84 cases); jaw involvement was rare (three cases). Five-year event-free survival (excluding treatment refusals) was significantly better for patients with limited vs advanced stage disease (75 +/- 14% vs 42 +/- 6%; P < 0.04). Elevated serum LDH (>500 U/l) was associated with a poorer outcome (P = 0.008). The type of chemotherapy did not affect EFS (P = 0.95). Only 39% of patients are long-term survivors, reflecting the high rate of septic deaths (25% of patients) and parental refusal/abandonment of therapy (10%). Epstein-Barr virus (EBV) was detected in tumor cells from eight of the 11 cases studied. In clinical presentation, these cases resemble sporadic Burkitt lymphoma, yet in their apparent responsiveness to LSA2L2 therapy and association with EBV, they do not. Childhood NHL in northeastern Brazil is predominantly of the Burkitt subtype, and is associated with clinical features that appear to distinguish it from the endemic and sporadic forms of this tumor. These cases may represent a third or intermediate subtype of Burkitt lymphoma.

Chlorpromazine with and without lorazepam as antiemetic therapy in children receiving uniform chemotherapy.

We prospectively studied the efficacy and adverse effects of chlorpromazine (30 mg/m2 given intravenously) plus lorazepam (0.04 mg/kg given intravenously) versus chlorpromazine alone in a controlled, double-blind, randomized, parallel-design investigation in 25 children (1.5 to 17.3 years of age) with acute lymphoblastic leukemia. Response to other antiemetics in eight children refusing random assignment to treatment was also evaluated. All children were receiving intravenous infusions of teniposide plus cytarabine, the pharmacokinetics of which were characterized for each of the one to four courses. There were no differences between the 11 patients randomly assigned to receive chlorpromazine alone and the 14 randomly assigned to receive lorazepam plus chlorpromazine in the number of emesis episodes (6.0 vs 5.9; p = 0.53), frequency of dystonic reactions (3% vs 5%), or akathisia (13 vs 10%). The only serious adverse event, symptomatic hypotension, occurred in a boy receiving chlorpromazine plus lorazepam. An exploratory pharmacodynamic analysis revealed that the only variable that correlated with vomiting was cytarabine 1 1/2-hour plasma concentration (p = 0.007). Children who received either chlorpromazine plus lorazepam or chlorpromazine alone had fewer episodes of vomiting than those who received "conventional" antiemetic therapy (6.0 vs 8.6; p = 0.01). We conclude that the severity of emesis is related to the plasma concentration of cytarabine; that intravenously administered chlorpromazine is as effective as chlorpromazine plus lorazepam in preventing chemotherapy-induced vomiting; and that the potential for adverse effects with the addition of lorazepam may be a disadvantage.

Azithromycin for treatment of severe Cryptosporidium diarrhea in two children with cancer.

Two children with cancer received azithromycin for Cryptosporidium-associated diarrhea that was unresponsive to supportive care. One child had choleriform diarrhea requiring daily fluid replacement of up to 65% of his total body weight; the other had protracted diarrhea and wasting. In both cases, administration of azithromycin was followed by prompt clinical improvement.

Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia.

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.

Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone.

We determined retrospectively the frequency and risk of hyperglycemia in 421 children with leukemia who had received L-asparaginase and prednisone as part of their remission induction therapy. Forty-one patients (9.7%) developed this complication, 39 within one week after the first dose of L-asparaginase. Hyperglycemia resolved in all patients and in 32 before the end of the four-week induction period. Age, obesity, and Down syndrome each had a significant bearing on the frequency of hyperglycemia. Children 10 years of age or older were more likely to develop the complication than were younger children. When more than one factor was present in a child, the risk of hyperglycemia increased significantly. A family history of diabetes mellitus also appeared related to an increased risk of hyperglycemia. Childhood leukemia patients with any of the risk factors identified here should be closely monitored for glucosuria while receiving prednisone and L-asparaginase for remission induction.

Evans syndrome in childhood.

The combination of idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia is rare in childhood. Among 164 instances of ITP and 15 instances of AHA, 11 patients were found to have this combination. Three were found to have systemic lupus erythematosus, one had aplastic anemia, and seven had Evans syndrome. Neutropenia, at times associated with bacterial infections, occurred in four of the latter patients. Unlike most cases of ITP or AHA in childhood, the clinical course of Evans syndrome is usually chronic and relapsing. Treatment including corticosteroids, splenectomy, and immunosuppressive agents has been generally unsatisfactory. In view of the frequent presence of antibodies directed at red blood cells, platelets, neutrophils, and lymphocytes, immunopancytopenia may be a better term for this condition.