Congenital abnormalities in children with acute leukemia: a report from the Children's Cancer Group.

OBJECTIVE: To evaluate the risk of leukemia associated with congenital abnormalities, a series of matched case-control studies were carried out by the Children's Cancer Group. STUDY DESIGN: Eligible case patients for this analysis included individuals with a diagnosis of leukemia confirmed at a Children's Cancer Group member institution: 2117 diagnosed with acute lymphoblastic leukemia (ALL) and 605 diagnosed with acute myelogenous leukemia (AML). Case patients were compared with matched regional population control subjects selected by using a modified random digit dialing method. Data regarding congenital abnormalities in index children and their siblings were collected by telephone interview with the biologic mother. Relative risk was estimated by using the odds ratio (OR). RESULTS: More congenital abnormalities were reported in index case patients with ALL than in control subjects, with statistically significant increases in multiple birthmarks (OR = 1.35), Down syndrome (OR = 4.85), congenital heart defects (OR = 1.48), and pancreas-digestive tract abnormalities (OR = 2.52). Similarly, birth defects were reported more often among index case patients with AML than control subjects (OR = 2.90), with significant increases in multiple birthmarks (OR = 1.89), Down syndrome (OR = 76.80), mental retardation (OR = 14.47), and congenital heart defects (OR = 2.07). Exclusion of case patients with Down syndrome from the analysis did not change the statistically significant excess of pancreas-digestive tract abnormalities in case patients with ALL or the excess of multiple birthmarks observed in both case patients with ALL and those with AML. For both the ALL and AML analyses, no significant differences in the number of reported congenital abnormalities were seen between siblings of case patients and siblings of control subjects. CONCLUSION: Many of the observed associations with congenital abnormalities occurred in the children with Down syndrome, who are known to have an increased risk for leukemia. The higher reported frequency of birthmarks among case patients may suggest a genetic component to leukemia risk.

High birth weight and risk of specific childhood cancers: a report from the Children's Cancer Group.

OBJECTIVES: High birth weight has been associated with a number of childhood cancers. This study was conducted to test the hypothesis that elevated birth weight is associated with an increased risk of diagnosis-specific and age-specific groups of childhood cancers. METHODS: A case-control study, using a large Children's Cancer Group database, examined birth weight as a risk factor for childhood cancer. Birth weight information for the index child was available for 3711 cases and 816 control subjects. RESULTS: There was a statistically significant increased risk of acute lymphoblastic leukemia, Wilms' tumor, and neuroblastoma with increasing birth weight (p, trend = 0.006, 0.003, and 0.001, respectively). A statistically significant decreased risk of cancer was observed for soft tissue sarcoma (p, trend = 0.04). When data were stratified on the basis of age at diagnosis, many of these associations were apparent for children whose disease was diagnosed before the age of 2 years. Moreover, for acute myeloid leukemia, age at diagnosis was an important effect modifier. For children with acute myeloid leukemia whose disease was diagnosed before 2 years of age, there was a statistically significant increased risk with high birth weight (odds ratio = 2.5, 95% confidence interval 1.1 to 5.5); there was no increased risk of acute myeloid leukemia with high birth weight noted for children whose disease was diagnosed after 2 years of age (odds ratio 1.3, 95% confidence interval 0.8 to 2.2). CONCLUSIONS: Biologic studies are needed to address why high birth weight may increase risk (particularly at younger ages) of development of certain cancers.

Epidemiologic study of Langerhans cell histiocytosis in children.

OBJECTIVE: The etiology and pathogenesis of Langerhans cell histiocytosis (LCH) remain poorly understood. We conducted an exploratory epidemiologic study to investigate potential risk factors associated with LCH. STUDY DESIGN: We used a case-control study design to obtain data from parents of children with LCH (n = 459) who were members of the Histiocytosis Association of America and Canada. The two control groups consisted of 683 community control subjects and 3719 children with childhood cancers treated at participating Children's Cancer Group institutions. RESULTS: The median age at diagnosis of LCH was 1.8 years (range 0.1 to 14.6 years). Cases were categorized as multisystem LCH (MS-LCH) (n = 208) and single-system LCH (SS-LCH) (n = 198). Statistically significant associations included the following: infections in the neonatal period (MS-LCH, odds ratio (OR) = 2.2), solvent exposure (SS-LCH, OR = 54.9), childhood vaccinations (MS-LCH and SS-LCH, OR = 0.4), thyroid disease in the proband (MS-LCH and SS-LCH, OR = 21.6), and family history of thyroid disease (MS-LCH and SS-LCH, OR = 1.4). The association with thyroid disease in the proband was explained partially by the involvement of the pituitary, with the relative risk decreasing when patients with diabetes insipidus and thyroid involvement were excluded from analysis. CONCLUSIONS: This large hypothesis-generating study provides directions for future investigations in well-designed population-based or hospital-based epidemiologic studies.

Family history of cancer and seizures in young children with brain tumors: a report from the Childrens Cancer Group (United States and Canada).

The occurrence of cancer and neurological disorders in first- and second-degree relatives of children in the United States and Canada diagnosed with brain tumor before age six was investigated. A pair-matched case-control study with 155 astrocytoma and 166 primitive neuroectodermal tumor (PNET) cases was performed. Cases were identified through the Childrens Cancer Group. Controls were selected by random-digit dialing and matched to cases on age, race, and telephone area code and exchange. Childhood cancers were more common in PNET relatives compared with the general population (standardized incidence ratio [SIR] = 2.5, 95 percent confidence interval [CI] 1.1-4.8, P = 0.02) and with control relatives (odds ratio [OR] = 3.0, CI = 0.5-30, P = 0.29). For astrocytoma, nonsignificant excesses of brain tumor, leukemia/lymphoma, and childhood cancer occurred among case relatives compared with control relatives, but not compared with the general population. Astrocytoma cases were significantly more likely than controls to have a relative with seizures (OR = 2.5, CI = 1.2-4.9, P = 0.009), especially childhood seizures (OR = 3.4, CI = 1.2-12, P = 0.02), epilepsy (OR = 3.0, CI = 0.9-13, P = 0.08), and febrile convulsions (OR = 4.5, CI = 0.9-43, P = 0.07). A family history of stroke was not a risk factor for either type of brain tumor. These results suggest that some childhood brain tumors may result from a genetic susceptibility and that some risk factors may affect childhood astrocytoma and PNET differently.

The CCSG prospective study of venous access devices: an analysis of insertions and causes for removal.

This is an interval analysis of the 2-year prospective multicenter Childrens Cancer Study Group study of 1,141 chronic venous access devices in 1,019 children with cancer. Device type was external catheter (EC) 72%, totally implantable (TID) 28%, and did not differ for diagnosis or age except more double-lumen devices in bone marrow transplant protocols (77%) and more TIDs in children less than 1 year old (17.7%). Insertion characteristics evaluated in 1,078 (95%) were: operating room placement 99%; general anesthesia 98%; cutdown 67%; percutaneous 33%; atrial position 50%, caval position 50%; and perioperative antibiotics 48%. Vein entry was the external jugular 33%, internal jugular 22%, subclavian 35%, cephalic 7%, and saphenous 3%. Insertion was difficult or very difficult in only 10% and operative complications occurred in only 0.7%. Degree of difficulty bore no relationship to device type or patient age. The reasons for removal in 736 devices (67%) were due to complications in 39%, of which infections were the most frequent. There was some variance between centers ranging from 8.5% to 31% for infection; 2.8% to 24% for dislodgment; and 0% to 13% for occlusion. ECs had a higher risk of dislodgment; elective removals were more frequent in TIDs; there was no difference in infection as a cause for removal between ECs and TIDs. Dislodgment was associated with the shortest distance of the cuff to the skin exit (mean, 4 cm): less than or equal to 2 cm, 49%; greater than 2 cm, 28% (P = .009) and occurred most frequently in the younger patient (18.9%, 0 to 1 years; 0.5%, greater than 8 years.

Frequency of 13q abnormalities among 203 patients with retinoblastoma.

We studied peripheral blood lymphocyte karyotypes of 203 patients with retinoblastoma. Twelve (5.9%) had a constitutional chromosomal abnormality involving 13q, of whom six had unilateral and six had bilateral disease. Two patients had mosaic deletions, eight had nonmosaic deletions, one had a de novo translocation, and one had a 13q14 deletion and a de novo direct insertion (10;6). Of the total, 4.9% of unilateral and 7.5% of bilateral patients had 13q abnormalities. None of 19 familial retinoblastoma patients had a visible cytogenetic abnormality. The unilateral patients with 13q abnormalities represent prezygotically determined (potentially heritable) cases which would have been classified as postzygotic (sporadic) without cytogenetic analysis. The observed 1% frequency of mosaic deletions is lower than that previously reported.

Pharmacokinetics of intravenously administered piperacillin in preadolescent children.

We studied the pharmacokinetics of piperacillin in 37 preadolescent children (mean age 52 months, range 1 month to 11 years) after 50 mg/kg IV doses. Pharmacokinetic parameters were determined after the initial dose in 18 instances and after subsequent doses in 32 instances. There were no significant differences between the initial doses and the subsequent doses in the plasma piperacillin concentrations at comparable times, the elimination rate constants, the elimination-phase plasma half-lives, the total body clearances, the apparent volumes of distribution, or the areas under the concentration curves. At the end of a 30-minute infusion of the drug, the plasma concentration was 166.2 +/- 42.2 mg/L (mean +/- SD) and ranged from 91.6 to 268.3 mg/L. The mean half-life was 31.0 +/- 9.4 minutes. The half-life of piperacillin in children 1 to 6 months of age (47.2 minutes) was significantly longer than in older children (28.8 minutes) (P less than 0.05). Likewise, the total body clearance of the drug in the younger age group (71.7 ml/min/m2) was significantly lower than in the older children (130.8 ml/min/m2) (P less than 0.05). The mean renal clearance of the drug was only 63% (range 39% to 85%) of the total body clearance, suggesting a variable but substantial nonrenal route of elimination. The intravenous administration of 50 mg/kg piperacillin every four hours results in adequate plasma concentrations for the treatment of most infections caused by gram-negative and gram-positive organisms.

Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children.

The relative bioavailability of intravenously administered chloramphenicol succinate and orally administered chloramphenicol palmitate was compared in 18 children, age 2 months to 14 years. The area under the serum concentration vs time curve of chloramphenicol and urinary excretion of chloramphenicol succinate were determined in each child under steady-state conditions while receiving chloramphenicol succinate and again while receiving chloramphenicol palmitate. The mean AUC was significantly greater during oral therapy compared to intravenous therapy (110 vs 78 mg hr/L, P less than 0.001). The relative bioavailability of chloramphenicol succinate was 70% compared to chloramphenicol palmitate. This could be explained by the mean loss of 36% of the intravenous dose in the urine as unhydrolyzed chloramphenicol succinate. The intravenous dose of chloramphenicol succinate did not correlate with AUC (r = 0.193). However, there was a significant correlation between the oral dose of chloramphenicol palmitate and AUC (r = 0.429, P = 0.025). The bioavailability of orally administered chloramphenicol palmitate is superior to that of chloramphenicol succinate given intravenously. Furthermore, there is a greater correlation between dose and amount of active drug in the body when the oral preparation is used. Oral administration of chloramphenicol palmitate appears to offer significant therapeutic advantages in patients who can tolerate medication given orally.

Diffusion of moxalactam into the cerebrospinal fluid in children with bacterial meningitis.

We studied the penetration of moxalactam into the cerebrospinal fluid of 16 children (age range one month to 4 1/2 years) who were being treated for bacterial meningitis. Two hours after single intravenous doses of 15 or 25 mg/kg, moxalactam was detectable in the CSF in only one of 11 instances; however, following three doses (50 mg/kg each) moxalactam was detectable in eight of 17 instances. In these eight instances CSF concentrations of moxalactam ranged between 1.5 and 18.9 micrograms/ml (mean 7.7) and the CSF/plasma ratio ranged from 2.6 to 36% (mean 17.7). There was no relation between the stage of meningitis or the CSF cell count and the diffusion of the drug into the CSF. However, the diffusion of the drug significantly correlated with the CSF protein content. In view of the unpredictability of moxalactam penetration into CSF, caution should be exercised in using it alone in the treatment of meningitis.

Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children.

The metabolism and elimination of chloramphenicol-3-monosuccinate was studied in 45 infants and children, ages 3 days to 16 years, during intravenous administration. The apparent half-life of chloramphenicol was extremely variable, ranging from 1.7 to 12.0 hours with a mean of 5.1 hours. Apparent half-lives were inversely correlated with age. Chloramphenicol-S serum concentration declined biexponentially in most patients, with an estimated mean initial half-life of 0.7 hours and a subsequent longer mean half-life of 2.2 hours. Chloramphenicol-S persisted in serum up to six hours after a dose, and comprised a significantly larger fraction of total chloramphenicol in the serum of infants under one month of age than in older infants and children. A widely variable fraction of the administered chloramphenicol-S dose, with a mean of 33%, was excreted in the urine unchanged and was, therefore, not bioavailable in active form. Mean renal clearance of chloramphenicol-S was 259.5 ml/minute/1.73 M2, four times the mean creatinine clearance, indicating active tubular secretion. Variable hydrolysis and renal elimination of nonhydrolyzed chloramphenicol-S reduces the bioavailability of the antibiotic and appears to contribute substantially to the wide variation in apparent half-life and poor correlation between dose and serum concentration of free chloramphenicol.