Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate.

To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.

Cardiorespiratory decompensation following methylprednisolone administration.

A 2-year-old white female receiving multidrug chemotherapy for treatment of a primitive neuroectodermal tumor developed acute hypotension, bradycardia, and shock following administration of ondansetron and high-dose methylprednisolone. The subsequent clinical course is described, and cardiovascular reactions to ondansetron and methylprednisolone are reviewed. While the etiology of this severe reaction is uncertain, it is possible that it represents an idiosyncratic reaction to the rapid administration of high-dose adrenal corticosteroids. Patients receiving high-dose corticosteroid therapy should be closely monitored, and slow rates of infusion are recommended.

Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia.

Idiopathic hypereosinophilic syndrome (IHES) is a heterogeneous group of disorders characterized by multisystem dysfunction and persistent, extreme eosinophilia of unknown cause. We describe a 9-1/2-year-old boy whose course included several unusual clinical features and terminated 2 years after diagnosis in acute lymphoblastic leukemia (ALL). Serial studies suggest that leukemia was not present earlier in his course. We speculate that this child may have had an evolving lymphoproliferative syndrome with a terminal blast crisis to which the eosinophilia was a nonmalignant leukemoid reaction.

Leukemia in a child with a history of medulloblastoma.

Leukemia of mixed lineage, was diagnosed in a 6.5-year-old boy with a history of medulloblastoma, 38 months after his initial cancer diagnosis. Therapy had included craniospinal radiation and nitrosourea-based chemotherapy. In addition, onset of leukemia was preceded by therapy with recombinant growth hormone for short stature. Although rare, leukemia is a treatment-related complication for patients with past brain tumors whose follow-up should therefore include surveillance with complete blood counts.

Cancer chemotherapy after solid organ transplantation.

To assess how well chemotherapy is tolerated after solid organ transplantation, we reviewed our experience at the Children's Hospital of Pittsburgh with five patients aged 1 to 12 years. Four patients had a liver transplant, indications for which were hepatoblastoma in two patients, hepatic failure secondary to Wilms' tumor chemoradiotherapy in one patient, and familial intrahepatic cholestasis in one patient. A fifth patient received a cardiac transplant for unresectable angiosarcoma of the right atrium. After transplant, chemotherapy was given for the treatment of the primary malignancy in four of the patients. The patient with familial intrahepatic cholestasis received chemotherapy for secondary lymphoproliferative disease that had not responded to the cessation of immunosuppression. All patients other than this patient were on immunosuppression with prednisone (0.5 to 2 mg/kg daily) and cyclosporine (to maintain serum levels at 800 to 1000 ng/ml radioimmunoassay) throughout the duration of chemotherapy. Courses of chemotherapy included one or more of the following agents: Adriamycin (Adr, 20 mg/m2 daily, three patients), Cyclophosphamide (Ctx, 1 gm/m2, one patient), cisplatin (CDDP, 90 mg/m2, one patient), Vincristine (Vcr, greater than 0.75 to 1.5 mg/m2, three patients), Actinomycin D (Act-D, 7.5 micrograms/kg, one patient), Ifosfamide (I, 1800 mg/m2, one patient) and Etoposide (VP-16, 100 mg/m2, one patient). All patients received greater than or equal to 3 courses (range, 3 to 9; mean, 5) of chemotherapy every 3 to 4 weeks. Dose reductions were made because of neutropenia in three patients but none were greater than 50%. Severe rejection was seen in one patient who had, however, manifested evidence of rejection prior to his first postoperative course of chemotherapy. No nephro or cardiac toxicity was seen. This preliminary experience suggests that chemotherapy is well tolerated after solid organ transplantation.

Juvenile chronic myelogenous leukemia with abnormalities of chromosomes 4 and 5.

A case of a boy with juvenile chronic myelogenous leukemia (CML) and independent clonal abnormalities of chromosomes 4 and 5 is presented. The characteristics and cytogenetics of CML are discussed, as is the involvement of chromosomes 4 and 5 in hematologic malignancies. The significance of these karyotypic findings in juvenile CML is explored.

Zinc status of children with sickle cell disease: relationship to poor growth.

We examined the zinc status of 80 children with sickle cell disease (SCD) and 44 disease-free sibling controls aged 3 to 18 years. For both patients and controls, variations in serum zinc by age, type of hemoglobinopathy, and growth status were measured. The mean serum zinc concentration of patients was significantly lower than for controls (77.8 +/- 9.9 vs. 82.2 +/- 9.8 micrograms/dl, mean +/- 1SD, P less than .05). Serum levels of alkaline phosphatase (AP) and retinol-binding protein (RBP), two zinc-dependent proteins, were also lower among patients (AP: 171 +/- 66 vs. 243 +/- 97 IU/L, P less than .001; RBP: 1.92 +/- .9 vs. 2.77 +/- .9 mg/dl, P less than .001). Patients greater than or equal to 12 years of age (n = 34) had significantly lower zinc levels than those less than 12 years (74.5 +/- 8.4 vs. 80.3 +/- 10.3 micrograms/dl, P less than .01), and children with homozygous SCD (Hb SS, n = 55) had a more pronounced deficiency than those with a variant hemoglobinopathy (76.3 +/- 8.9 vs. 81.5 +/- 11.5, micrograms/dl, P less than .05). Patients classified as having "poor" growth (height-for-age less than 5th percentile, n = 24) had a lower serum zinc level than those with "normal" growth (72.8 +/- 8.0 vs. 79.8 +/- 10.0 micrograms/dl, P less than .01). Dietary intake data, body mass index, and serum total protein and albumin levels were similar for patients and controls, suggesting that zinc deficiency in SCD does not relate to inadequate dietary intake. The origin of low serum zinc levels in children with SCD is more likely to relate to factors such as increased urinary zinc excretion, chronic intravascular hemolysis, and/or zinc malabsorption.

Rhabdomyosarcoma in Roberts syndrome.

A 23-month-old child diagnosed as having Roberts syndrome, born to consanguineous parents, developed a sarcoma botryoides. Cytogenetic evaluation of peripheral blood lymphocytes and tumor cells showed premature centromere separation, which is characteristic of Roberts syndrome.

Oral trimethoprim/sulfamethoxazole for prevention of bacterial infection during the induction phase of cancer chemotherapy in children.

We conducted a randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral trimethoprim/sulfamethoxazole (TMP/SMX) in the prevention of bacterial infections in children with cancer. Sixty-three patients with acute leukemia were studied during the induction phase of chemotherapy; 28 patients with solid tumors who were starting intensive chemotherapy were also enrolled and treated for 2 months. There was no significant difference in the frequency of febrile episodes between the 43 children receiving trimethoprim/sulfamethoxazole and the 48 receiving placebo. However, when the group of 74 children who experienced granulocytopenia (absolute granulocyte count less than 500/microL) was analyzed separately, significant reductions in the frequencies of confirmed bacteremia (2.6% v 20.0%, P = .02) and febrile episodes (35.9% v 65.7%, P = .01) were observed in the trimethoprim/sulfamethoxazole group. Furthermore, life table analysis showed that children with leukemia receiving trimethoprim/sulfamethoxazole had significantly more days without fever and without bacteremia. No benefits from prophylaxis were recognized in the subgroup with solid tumors. Although the frequency of oral thrush was greater (P = .02) in the trimethoprim/sulfamethoxazole group (25.6%) than in the placebo group (6.3%), invasive fungal infection did not occur. Although the mean duration of granulocytopenia was greater among those receiving trimethoprim/sulfamethoxazole (13.7 v 9.0 days, P = .05), this did not appear to increase the overall risk for bacterial infection. These data suggest that trimethoprim/sulfamethoxazole reduces the frequency of bacteremia and febrile episodes in granulocytopenic children undergoing induction chemotherapy for acute leukemia.

Growth patterns by age and sex in children with sickle cell disease.

We examined growth patterns by age and sex in 133 children and adolescents with sickle cell disease. These patients are estimated to be representative of the total population aged 1 to 18 years with sickle cell disease in a large metropolitan area. Median height and weight curves constructed from serial growth data available for all 133 children demonstrated impairment in height and weight at all ages and in both sexes. Analysis of growth trends by age reveals a pattern of increasing deficit with increasing age; boys are more severely affected than girls. Growth velocity curves constructed for a series of 13 adolescents with sickle cell disease illustrate the marked delay in the onset of the normal pubertal growth spurt in these patients.