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.

Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia.

OBJECTIVE: As more children survive acute lymphoblastic leukemia (ALL), questions are raised regarding how the disease and its therapy affect their pubertal development. STUDY DESIGN: The National Institute of Child Health and Human Development-National Cancer Institute-Children's Cancer Group Leukemia Follow-Up Study used a historical cohort design to investigate menarche in 188 ALL survivors who were premanarchal at diagnosis, aged at least 18 years, at least 2 years after diagnosis, alive, and in remission. Female siblings of ALL survivors (n = 218) served as control subjects. RESULTS: Menarche occurred within the normal age range in 92% of survivors and 96% of the control subjects (p = 0.09). Early menarche occurred in four survivors (2%) and three control subjects (1%). Delayed, absent, or medically induced menarche was reported by 12 survivors (6%) and six control subjects (3%). Compared with the control subjects, survivors of ALL who received 1800 cGy cranial radiation before the age of 8 years had significantly earlier menarche, relative hazard (RH) of 2.2 (95% confidence interval: 1.4, 3.4 [p = 0.0003]). Survivors receiving 2400 cGy of craniospinal radiation with or without abdominal radiation had significantly later menarche than the control subjects, RH 0.4 (95% confidence interval: 0.3, 0.7 [p = 0.0002]). CONCLUSIONS: In this large cohort of ALL survivors, the risk of disordered menarche was low. However, younger subjects receiving 1800 cGy cranial radiation and those receiving 2400 cGy below the diaphragm required careful monitoring.

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.

Myelosuppression associated with co-trimoxazole as a prophylactic antibiotic in the maintenance phase of childhood acute lymphocytic leukemia.

Thirty-seven children with acute lymphocytic leukemia in clinical remission for at least 6 months completed a 1-year trial in which they were randomly assigned in a double-blind fashion to receive co-trimoxazole twice daily for 6 months followed by placebo for 6 months (18 patients) or placebo followed by co-trimoxazole (19 patients). Total amounts of maintenance chemotherapy administered during both periods were similar. During administration of co-trimoxazole significant reductions were documented in the patients' average total white blood count (P less than 0.001), absolute neutrophil count (P less than 0.001), absolute lymphocyte count (P = 0.009), and platelet count (P = 0.002) compared with values obtained during the placebo period. Patients had on the average 1.6 infections during the co-trimoxazole period compared with 2.5 infections during placebo administration (P = 0.008). It is concluded that, although co-trimoxazole is an effective prophylactic antibiotic in children with acute lymphocytic leukemia, the resultant myelosuppression could potentially hamper the administration of maintenance cancer chemotherapy.

Down syndrome and acute leukemia in children: a 10-year retrospective survey from Childrens Cancer Study Group.

Review of 5406 children with acute lymphoblastic (ALL) or nonlymphoblastic leukemia (ANLL) registered with Childrens Cancer Study Group (CCSG) since 1972 identified 115 patients (2.1%) with Down syndrome. The proportion of patients with Down syndrome was the same for ALL (2.1%) and ANLL (2.1%). Patients with ALL with and without Down syndrome did not differ significantly with respect to age at diagnosis, sex, race, morphology (FAB classification), cell surface markers, initial white blood cell count, pretreatment hemoglobin value, hepatomegaly, lymphadenopathy, presence of mediastinal mass, CNS disease at diagnosis, or prognostic group as defined by age and initial white blood cell count. Patients with ALL-Down syndrome less frequently had splenomegaly, had lower pretreatment platelet counts, and more often had normal or elevated IgG or IgA levels. In addition, they had a significantly lower rate of remission (81% versus 94%), a higher mortality during induction therapy (14% versus 3%), and a poorer overall survival with 5-year life table rates of 50% versus 65% (P less than 0.001). If an initial remission was achieved, there were no significant differences with respect to remission duration, survival, or disease-free survival. Patients with ANLL-Down syndrome were younger at diagnosis than those without Down syndrome. There was no significant difference in the remission rates between these patients. Analysis of findings in patients with ANLL provided results similar to those obtained for patients with ALL with regard to clinical outcome after achievement of an initial remission.

Serial thyroid function measurements in children with Hodgkin disease.

Thyroid function was measured serially in 28 children with Hodgkin disease diagnosed from 1971 to 1978. The patients' ages ranged from 4 to 16 years at diagnosis, and treatment consisted of chemotherapy only (four patients), radiation alone (15), or radiation plus chemotherapy (nine). None of the four children given chemotherapy only developed thyroid hypofunction, in contrast to 21 (88%) of the 24 children given high doses of radiation (P less than 0.001). Thyroid function in three patients with compensated hypothyroidism and in one child with primary hypothyroidism reverted to normal without thyroid replacement. One child given chemotherapy only and one child given radiation only became transiently hyperthyroid. These results indicate that patients given combined modality therapy for Hodgkin disease are at high risk for thyroid abnormalities. The results of long-term follow-up of thyroid function demonstrate, however, that all such thyroid abnormalities may not necessarily be permanent.