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Background: Subsequent short-latency leukemias are well-described among survivors of childhood cancer. However, late (5-14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort., Methods: Subsequent leukemias, among 25,656 five-year survivors, were self-reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures., Results: Seventy-seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0-14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9-42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%-0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0-12.1) and VLL (SIR 5.9, 95% CI 3.9-8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m 2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0-9.9)., Conclusions: In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined., Objective: To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors., Design, Setting, and Participants: This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024., Exposures: Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants., Main Outcomes and Measures: Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type., Results: The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions., Conclusions and Relevance: In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

Background: Glucocorticoids used to treat childhood leukemia and lymphoma can result in osteonecrosis, leading to physical dysfunction and pain. Improving survival rates warrants research into long-term outcomes among this population., Objective: The objective of this study was to compare the physical function and quality of life (QOL) of survivors of childhood cancer who had an osteonecrosis history with that of survivors who had no osteonecrosis history and with that of people who were healthy (controls)., Design: This was a cross-sectional study., Methods: This study included St Jude Lifetime Cohort Study participants who were ≥ 10 years from the diagnosis of childhood leukemia or lymphoma and ≥ 18 years old; 135 had osteonecrosis (52.5% men; mean age = 27.7 [SD = 6.08] years) and 1560 had no osteonecrosis history (52.4% men; mean age = 33.3 [SD = 8.54] years). This study also included 272 people who were from the community and who were healthy (community controls) (47.7% men; mean age = 35.1 [SD = 10.46] years). The participants completed functional assessments and questionnaires about QOL., Results: Survivors with osteonecrosis scored lower than other survivors and controls for dorsiflexion strength (mean score = 16.50 [SD = 7.91] vs 24.17 [SD = 8.61] N·m/kg) and scored lower than controls for flexibility with the sit-and-reach test (20.61 [SD = 9.70] vs 23.96 [SD = 10.73] cm), function on the Physical Performance Test (mean score = 22.73 [SD = 2.05] vs 23.58 [SD = 0.88]), and mobility on the Timed "Up & Go" Test (5.66 [SD = 2.25] vs 5.12 [SD = 1.28] seconds). Survivors with hip osteonecrosis requiring surgery scored lower than survivors without osteonecrosis for dorsiflexion strength (13.75 [SD = 8.82] vs 18.48 [SD = 9.04] N·m/kg), flexibility (15.79 [SD = 8.93] vs 20.37 [SD = 10.14] cm), and endurance on the 6-minute walk test (523.50 [SD = 103.00] vs 572.10 [SD = 102.40] m)., Limitations: Because some eligible survivors declined to participate, possible selection bias was a limitation of this study., Conclusions: Survivors of childhood leukemia and lymphoma with and without osteonecrosis demonstrated impaired physical performance and reported reduced QOL compared with controls, with those requiring surgery for osteonecrosis most at risk for impairments. It may be beneficial to provide strengthening, flexibility, and endurance interventions for patients who have pediatric cancer and osteonecrosis for long-term function., (© 2020 American Physical Therapy Association.)

Background: Children with Down syndrome (DS) are at increased risk of developing acute leukemia and are more prone to acute toxicities. We studied the incidence and severity of chronic health conditions among survivors of childhood leukemia with DS compared with those without DS., Methods: Chronic health conditions reported by questionnaire were compared between 154 pediatric leukemia survivors with DS and 581 without DS, matched by leukemia, age at diagnosis, race/ethnicity, sex, radiation location and chemotherapy exposure using Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects were selected from 7139 5-year survivors of leukemia in the Childhood Cancer Survivor Study., Results: Risk of at least 1 late onset chronic health condition (grade 1-5) was similar in the DS population compared with the non-DS group (HR, 1.1; 95% CI, 0.7-1.5). Serious chronic health conditions (grade 3-5) were more common in DS survivors (HR, 1.7; 95% CI, 1.1-2.6), as were ≥ 3 chronic health conditions (grades 1-5) (HR, 1.7; 95% CI, 1.2-2.4). The 25-year cumulative incidence of any condition (grades 1-5) was 83% for DS survivors and 69% for non-DS survivors., Conclusion: Leukemia survivors with DS have therapy-related chronic health conditions comparable to those of similarly treated survivors without DS, with a few notable exceptions: 1) an increased risk of cataracts, hearing loss, and thyroid dysfunction compared with survivors without DS (though these are known risks in the DS population), 2) decreased risk of second cancers, and 3) increased risk of severe or multiple conditions. Practitioners should be aware of these risks during and after therapy. Cancer 2018;124:617-25. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Purpose: Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for breast cancer among these women., Patients and Methods: We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study., Results: With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both < .01)., Conclusions: Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study., (© 2015 by American Society of Clinical Oncology.)

It has been suggested that pediatric patients treated with spinal irradiation may have an elevated risk of breast cancer. Among a cohort of 363 long-term survivors of a pediatric central nervous system tumor or leukemia treated with spinal irradiation, there was little evidence of an increased breast cancer risk., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

In a case-control study of infant leukaemia, we assessed agreement between medical records and mother's self-reported pregnancy-related conditions and procedures and infant treatments. Interview and medical record data were available for 234 case and 215 control mothers. Sensitivity, specificity and predictive values for maternal report were estimated for case and control mothers separately, taking the medical record as correct. For most perinatal conditions, sensitivity and specificity were over 75%. Low sensitivity was observed for maternal protein or albumin in the urine (cases: 12% [95% exact confidence interval (CI) 8%, 18%]; controls: 11% [95% CI 7%, 17%]) and infant supplemental oxygen use (cases: 25% [95% CI 11%, 43%]; controls: 24% [95% CI 13%, 37%]). Low specificity was found for peripheral oedema (cases: 47% [95% CI 37%, 58%]; controls: 54% [95% CI 43%, 64%]). Sensitivity for maternal hypertension appeared much lower for cases (cases: 46% [95% CI 28%, 66%]; controls: 90% [95% CI 70%, 99%]; P = 0.003). We did not detect other case-control differences in recall (differentiality), even though the average time between childbirth and interview was 2.7 years for case and 3.7 years for control mothers. Many conditions exhibited notable differences between interview and records. We recommend use of multiple measurement sources to allow both cross-checking and synthesis of results into more accurate measures., (© 2011 Blackwell Publishing Ltd.)

Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible., (© 2011 Blackwell Publishing Ltd.)

Previous investigations of cancer survivors report that the cumulative incidence of subsequent leukemia plateaus between 10 and 15 years after primary therapy. Risk beyond 15 years has not been comprehensively assessed, primarily because of lack of long-term follow-up. Among 5-year survivors from the Childhood Cancer Survivor Study cohort, 13 pathologically confirmed cases of subsequent leukemia occurred ≥ 15 years after primary malignancy, with a mean latency of 21.6 years (range, 15-32 years). Seven were acute myeloid leukemia (2 acute promyelocytic leukemia with t(15;17), 2 with confirmed preceding myelodysplastic syndrome), 4 acute lymphoblastic leukemia (2 pre-B lineage, 1 T cell, 1 unknown), and 2 other. Two acute myeloid leukemia cases had the 7q- deletion. The standardized incidence ratio was 3.5 (95% confidence interval, 1.9-6.0). Median survival from diagnosis of subsequent leukemia was 2 years. This is the first description of a statistically significant increased risk of subsequent leukemia ≥ 15 years from primary diagnosis of childhood cancer.

Background: Infant leukaemia is likely initiated in utero., Methods: We examined whether analgesic use during pregnancy was associated with risk by completing telephone interviews of the mothers of 441 infant leukaemia cases and 323 frequency-matched controls, using unconditional logistic regression., Results: With the exception of a reduced risk for infant acute myeloid leukaemias with non-aspirin non-steroidal anti-inflammatory drugs (NSAID) use early in pregnancy (odds ratios=0.60; confidence intervals: 0.37-0.97), no statistically significant associations were observed for aspirin, non-aspirin NSAIDs, or acetaminophen use in early pregnancy or after knowledge of pregnancy., Conclusion: Overall, analgesic use during pregnancy was not significantly associated with the risk of infant leukaemia.

Background: Little is known about the potential risk factors for infant leukemia. With its very young age at diagnosis, exposures occurring in the perinatal period are suspected. Parental infertility and infertility treatment have been studied with regard to childhood cancer in general, but rarely in individual cancer subtypes., Methods: A case-control study of infant leukemia was conducted through the Children's Oncology Group, including cases diagnosed from January 1996 to December 2006 and controls selected through random digit dialing and birth certificate tracing. Maternal phone interviews were conducted to obtain information about infertility, infertility treatment and demographic factors. All cases as well as subgroups defined by mixed lineage leukemia (MLL) translocation status and leukemia subtype were examined. Statistical analysis was performed using multivariate logistic regression models., Results: No significant associations between infertility or its treatment and combined infant leukemia were found. In subgroup analyses, there was a significant increase in the risk of MLL--leukemia for children born to women not trying to conceive compared with those trying for <1 year for all types combined [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.01-2.59] and for acute lymphoblastic leukemia (OR = 2.50, 95% CI = 1.36-4.61)., Conclusions: There were no positive associations between parental infertility or infertility treatment and infant leukemia. While this is the largest study to date, both selection and recall bias may have impacted the results. However, for infant leukemia, we can potentially rule out large increases in risk associated with parental infertility or its treatment.

Background: Children with Down syndrome (DS) have from 10 to 20 times the risk of developing acute leukemia than the general pediatric population. There is mixed evidence for associations between reproductive history or infertility and acute leukemia among children without DS., Methods: The authors conducted a case-control study of acute leukemia among children with DS to investigate possible risk factors in this population. From 1997 to 2002, 158 children aged <20 years with DS who had a diagnosis of acute leukemia (97 children with acute lymphoblastic leukemia [ALL] and 61 children with acute myeloid leukemia [AML]) were enrolled at Children's Oncology Group (COG) institutions. Controls with DS (n = 173) were selected from the cases' primary care clinic and frequency matched to cases on age. Telephone interviews were conducted with mothers of cases and controls assessing reproductive history, infertility, and infertility treatment., Results: Null results were observed overall and by subtype for reproductive factors, including previous pregnancy outcomes and contraceptive use, and for most infertility outcomes. There was an increased risk of AML among children with DS whose parents had ever tried for >/=1 year to become pregnant (odds ratio [OR], 2.22; 95% confidence interval [95% CI], 1.14-4.33). A 1-year increase in maternal age also was associated with AML (OR, 1.06; 95% CI, 1.01-1.12)., Conclusions: Although the questionnaire was limited in this area, the results suggested that the risk for AML may be raised in children with DS because of infertility. In that the risk of infertility, along with having a child with DS, increase with age, these results warrant more research.

Leukemias with MLL gene rearrangements predominate in infants (<1 year of age), but not in older children, and may have a distinct etiology. High birth weight, higher birth order, and prior fetal loss have, with varying consistency, been associated with infant leukemia, but no studies have reported results with respect to MLL status. Here, we report for the first time such an analysis. During 1999 to 2003, mothers of 240 incident cases (113 MLL(+), 80 MLL(-), and 47 indeterminate) and 255 random digit dialed controls completed a telephone interview. Odds ratios and 95% confidence intervals for quartile of birth weight, birth order, gestational age, maternal age at delivery, prior fetal loss, pre-pregnancy body mass index, and weight gain during pregnancy were obtained using unconditional logistic regression; P for linear trend was obtained by modeling continuous variables. There was a borderline significant linear trend of increasing birth weight with MLL(+) (P = 0.06), but not MLL(-) (P = 0.93), infant leukemia. Increasing birth order showed a significant inverse linear trend, independent of birth weight, with MLL(+) (P = 0.01), but not MLL(-) (P = 0.18), infant leukemia. Other variables of interest were not notably associated with infant leukemia regardless of MLL status. This investigation further supports the contention that molecularly defined subtypes of infant leukemia have separate etiologies.

Purpose: This report examines the incidence of and risk factors for strokes that occur in > or = 5-year survivors of childhood leukemia and brain tumors., Patients and Methods: The rate of first occurrence of self-reported late-occurring strokes was determined for leukemia survivors (n = 4,828), brain tumor survivors (n = 1,871), and a comparison group of a random sample of cancer survivor siblings (n = 3,846). Relative risks (RRs) and 95% confidence intervals (CIs) of stroke by treatment exposures were examined by multivariate analyses., Results: Thirty-seven leukemia survivors and 63 brain tumor survivors reported a late-occurring stroke. The rate of late-occurring stroke for leukemia survivors was 57.9 per 100,000 person-years (95% CI, 41.2 to 78.7). The RR of stroke for leukemia survivors compared with the sibling comparison group was 6.4 (95% CI, 3.0 to 13.8; P < .0001). The rate of late-occurring stroke for brain tumor survivors was 267.6 per 100,000 person-years (95% CI, 206.8 to 339.2). The RR of stroke for brain tumor survivors compared with the sibling comparison group was 29.0 (95% CI, 13.8 to 60.6; P < .0001). Mean cranial radiation therapy (CRT) dose of > or = 30 Gy was associated with an increased risk in both leukemia and brain tumor survivors in a dose-dependent fashion, with the highest risk after doses of > or = 50 Gy CRT., Conclusion: Survivors of childhood leukemia and brain tumors, particularly those with brain tumors treated with CRT at doses of greater than 30 Gy, are at an increased risk of stroke.

In contrast to the positive association found in three studies between maternal anaemia during pregnancy and childhood leukaemia, no such association was found in infant leukaemia (odds ratio 0.85, 95% confidence interval 0.53-1.37).

Studies suggest nearly a 20-fold increased risk of leukemia in individuals with Down syndrome. Most of this increased risk appears in the first few decades of life, with the highest incidence in children less than 5 years of age. It is unknown why children with Down syndrome are at such an increased risk of leukemia. With respect to environmental exposures, it will be important to investigate risk factors associated with childhood leukemia in general (including diagnostic x-rays, pesticides, and other occupational exposures) as well as experiences common to children with Down syndrome (including routine medical screening tests, increased susceptibility to infections, and increased vitamin deficiencies)., ((c) 2004 Wiley-Liss, Inc.)

Objective: We explored whether maternal medication use during pregnancy may be an important etiologic area for investigation in studies of infant leukemia., Methods: In this case-control study, associations were explored between specific medications as recorded in the medical records of 243 mothers of infants who were diagnosed with leukemia at < 18 months of age and 393 mothers ol infants without leukemia identified through random digit dialing. Cases included 157 acute lymphoblastic (ALL), 77 acute myeloid (AML), and nine other leukemias. A total of 27 different drugs that were prescribed for at least six women were analyzed., Results: Overall, non-statistically significant negative associations (Odds ratios, OR < 0.5) were observed with amoxicillin, nystatin, clomiphene, levothyroxine, cefaclor, and trimethobenzamide HCL. When cases were restricted to either myeloid or lymphoblastic leukemia, cotrimoxazole was prescribed for five ALL case mothers and no matched controls; no association with cotrimoxazole was observed with AML., Conclusions: Given the number of comparisons, chance cannot be ruled out for any of the associations found here. However, a strength of this study is the lack of recall bias. The disparate data observed between AML and ALL in some instances may indicate areas of interest; they will be explored further in a case-control study of infant leukemia that is currently underway.

Objective: To evaluate and compare psychological outcomes in long-term survivors of pediatric leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma and sibling controls., Methods: Adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma (N = 5736) and sibling controls (N = 2565) were administered a long-term follow-up questionnaire allowing assessment of symptoms associated with depression and somatic distress., Results: The majority of respondents in this study did not demonstrate symptomatology indicative of depression or somatic distress. Survivors, however, were significantly more likely than sibling controls to report symptoms of depression and somatic distress. Women were significantly more likely to indicate symptoms of depression and somatic distress than were men; however, this difference did not vary by survivor/sibling status. Similarly, socioeconomic (SES) variables predicted symptomatic levels of depression and somatic distress for both survivors and siblings, and these effects did not vary by survivor/sibling status. Among leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma survivors, in addition to gender and SES, the only treatment variable that predicted scores indicating depressive symptomatology was exposure to intensive chemotherapy. Exposure to intensive chemotherapy also predicted scores indicative of somatic distress symptoms. No other medical variables, including diagnostic category, age at diagnosis, time since diagnosis, and duration of treatment, predicted symptomatic scores for depression and somatic distress., Conclusions: This large, sibling-controlled, multisite study of young adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma found that survivors had significant increased risk for reporting symptoms of depression and somatic distress and that intensive chemotherapy added to this risk. However, being a cancer survivor did not compound the effects of gender and SES variables on the 2 outcomes measured. The ability of SES, gender, and treatment-related variables to predict psychological symptoms in this cohort of childhood survivors and sibling controls calls for future research into varied biological and psychosocial pathways by which cancer influences future psychosocial functioning.

The causes of acute leukemia and lymphomas are still largely unknown. These malignancies account for approximately 6% of cases of cancer in the US population, and active research efforts are now underway to define etiologically important genetic or environmental factors for these conditions. Recent epidemiologic studies have focused on international variations, secular trends, genetic syndromes, familial aggregation, chromosomal abnormalities, environmental exposures, and unique subgroups defined either demographically or biologically.

Archival slides are a potentially useful source of DNA for mutation analyses in large population-based studies. However, it is unknown whether specimen age or histological stains alter the accuracy of Taq polymerase or induce secondary mutations in sample DNA. To address this question, we evaluated five methods for extraction of genomic DNA from archival bone marrow slides of 17 leukemia patients and analyzed exons 1 and 2 of the N- and K-ras genes for the presence of mutations. Of the five methods, optimal DNA purification was achieved by boiling and phenol:chloroform extraction. N-and K-ras exons 1 and 2 were independently amplified using 35 cycles of PCR, and 6-12 clones for each exon were isolated and individually sequenced for each patient. Mutations were confirmed by repeat extraction, cloning, and sequencing. Sixteen of 17 patient samples were successfully amplified (94%), including slides up to 29 years old. Twelve slides had been stained with Wright-Giemsa, I stained with toluidine blue, and 4 were unstained. A total of 16 single-base mutations were identified of 33,840 nucleotides sequenced. No insertions or deletions were identified. Six of 16 single-base mutations were previously described activating mutations in codon 13 of N-ras exon 1. The 10 other mutations were in other regions of the N- and K-ras genes and were not reproduced after repeat extraction, cloning, and sequencing. The frequency of these other alterations was I of 3384 bp. This value is comparable with the inherent error frequency for Taq polymerase. Our findings suggest that high fidelity DNA amplification can be achieved using archival hematological slides as old as 29 years and can be reliably used in genetic analyses.

Objectives: As there are some suggestions that a family history of cancer or autoimmune disease might be associated with an increased risk of leukemia in children, we explored this possibility using data from a matched case-control study conducted by the Children's Cancer Group., Methods: We compared the family history of cancer and autoimmune diseases of 302 infant leukemia cases (diagnosed within the first 18 months of life) with that of 668 individually matched controls in the United States and Canada., Results: Although not significant, cancer history in parents was found to be associated with an elevated risk of infant leukemia (odds ratio [OR] = 1.4, 95 percent confidence interval [CI] = 0.6-3.6), predominantly acute myeloid leukemia (AML) (OR = 2.2, CI = 0.6-9.0). Cancer history among second-degree relatives was also related to a nonsignificantly elevated risk of AML. Family history of autoimmune diseases, on the other hand, was generally not found to be related to the risk of infant leukemia., Conclusion: This study provided no strong evidence that family history of cancer or autoimmune disease is a major risk factor for infant leukemia.

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.

Unlike childhood leukemia diagnosed at later ages, where there is an excess risk in males, there is a notable female predominance in infant leukemia. Since abnormalities involving the MLL gene are frequent in infants with leukemia, we asked whether there are gender differences with respect to MLL gene status. Data were combined from seven published molecular studies that examined MLL abnormalities in infants with leukemia. Of 239 cases with conclusive information, there was a female predominance in cases with an MLL abnormality (female:male ratio 1.3); this was in marked contrast to cases with normal germline MLL (female:male ratio, 0.7). These potential gender-dependent MLL frequencies should be explored in large populations of infant leukemia and, if confirmed, future investigations could be directed toward potential etiologic mechanisms.

This study was performed to evaluate participation rates and characteristics of participants in a case-control study of infant leukaemia. Eligible cases were identified throughout the United States, and two controls were selected for each case using a structured protocol for telephone random digit dialling. The non-participation rate, once a household agreed to provide an address to receive a letter explaining the study, was 7.9% for cases and 19.8% for controls. When comparing demographic differences between participants and non-participants, parents of eligible cases that participated were more likely than non-participating case parents to be white (P = 0.01) and to be currently married (P = 0.03); parents of eligible controls who participated were more likely than non-participating parents of eligible controls to have a higher education level (P < 0.01), more children under the age of 10 years (P = 0.05) and to be white (P < 0.01). These data have application for future studies involving infants with a serious disease and the use of random digit dialling for the selection of infant controls.

Epidemiologic studies frequently obtain exposure information through subjects' self-report (personal interview or mailed questionnaire). The authors used data from a case-control study of infant leukemia, to assess the validity and reliability of maternally reported information on birth characteristics such as birth weight, reproductive history, and medical procedures. Cases were gathered from the Children's Cancer Group, a United States and Canadian cooperative clinical trails group with approximately 100 member and affiliate institutions, during 1983-1988. Telephone interviews were completed for 302 cases and 558 matched controls. Medical records of the index pregnancy were obtained for 287 cases and 467 controls. Correlations between medical charts and maternal interview were high for birth weight (r = 0.98, kappa = 0.9) and gestational age (r = 0.86, kappa = 0.6). Mean differences between the two sources were small, -10.5 g for birth weight and -0.36 weeks for gestational age. Reproductive history and medical procedures had high to moderate reliability. Problems after delivery and pregnancy complications generally had low validity and reliability. Little evidence of differential misclassification was found. Time between delivery and interview ranged from zero to 8 years and did not greatly affect reliability. This study suggests that validity and reliability of maternally reported pregnancy and delivery information may differ with the nature of the factor of interest, but is affected little by time from birth or case-control status.

Nearly 80 percent of infant leukemias present with an abnormality involving the MLL gene at 11q23. Moreover, secondary acute myeloid leukemias (AML) that occur as the result of chemotherapy agents, which are known to inhibit DNA topoisomerase II, often manifest the same MLL abnormalities. It has been hypothesized that de novo infant leukemias may occur as a result of maternal exposure to agents in diet and medications that inhibit DNA topoisomerase II. Three epidemiologic studies of childhood leukemia with similar methodologies were conducted in the United States and Canada over the past 10 years by the Children's Cancer Group (CCG). Of the total 771 mothers of infants diagnosed at one year of age or less (< 12.5 months) who originally were interviewed (303 infant cases and 468 matched controls) across the three studies, follow-up questionnaire data on maternal exposure to potential DNA topoisomerase II inhibitors during pregnancy were available on 84 cases and 97 matched controls in the US. For maternal diet, a composite variable was created that consisted of 10 foods identified alpha priori as containing DNA topoisomerase II inhibitors. There were no significant trends with increasing maternal consumption for either the overall group, or the acute lymphoblastic leukemia (ALL) stratum. However, within the AML stratum, there was a statistically significant positive association (P trend = 0.04) with increasing consumption of DNA topoisomerase II-inhibitor containing foods (odds ratio [OR] = 9.8, 95 percent confidence interval [CI] = 1.1-84.8; OR = 10.2, CI = 1.1-96.4; for medium and high consumption, respectively). Other potential topoisomerase II inhibitors were explored; no significant findings were found. Results of this preliminary study, in combination with molecular data, should be used in future investigations of childhood leukemia (particularly, infant) to justify the incorporation of a detailed dietary history.

Several epidemiologic studies have demonstrated that high birthweight is associated with an increased risk of infant leukemia; however, the reason for this relationship is unclear. Biologic data demonstrate that birth weight is correlated positively with circulating levels of insulin-like growth factor-1 (IGF-1). IGF-1 is important in blood formation and regulation and has been shown to stimulate the growth of both myeloid and lymphoid cells in culture. Since infants who develop leukemia are likely to have had at least one transforming event occur in utero, we hypothesize that high levels of IGF-1 may both produce a larger baby and contribute to leukemogenesis.

Background: Whether parental drinking and smoking during pregnancy are associated with an increased risk of cancer in offspring is controversial. There are some indications that maternal alcohol consumption is associated with an elevated risk of acute myeloid leukemia (AML) appearing in very young children. Evidence for an association between maternal smoking during pregnancy and risk of leukemia in offspring has been inconsistent., Purpose: Using data from a Children's Cancer Group case-control study, we evaluated relationships between infant leukemia risk and parental alcohol consumption and/or cigarette smoking during pregnancy or during the month prior to it., Methods: Three hundred two leukemia cases (203 acute lymphoid leukemias [ALLs], 88 AMLs, and 11 other leukemia types) diagnosed in children at 18 months of age or younger and 558 individually matched, regional (i.e., same telephone area code and exchange number) controls were included in the analysis. Information concerning parental alcohol consumption and smoking behavior during the index pregnancy and during the month prior to it was collected by telephone interviews with the mothers of all case and control subjects and the fathers of 250 case and 361 control subjects. Odds ratios (ORs) were used to measure the risk of infant leukemia associated with parental smoking and drinking; tests for trend were used to assess dose-response relationships. The data were analyzed further after stratifying the leukemia cases according to histologic and morphologic types. Reported P values are from two-sided tests of statistical significance., Results: Maternal drinking during pregnancy (compared with not drinking) was associated with ORs of 1.43 (95%) confidence interval [CI] = 1.00-2.04) for ALL and 2.64 (95% CI = 1.36-5.06) for AML. A dose-response relationship was observed for total maternal alcohol consumption during pregnancy and risk of AML (P < .01). Alcohol-related risk appeared to be most pronounced for children who developed AML with a morphology of M1 (myeloblastic with minimal maturation) or M2 (myeloblastic with maturation (OR = 7.62; 95% CI = 2.03-28.64). Paternal alcohol consumption did not confer an increased risk of infant leukemia. Maternal smoking during pregnancy (compared with not smoking) was negatively associated with infant leukemia risk (OR = 0.66 and 95% CI = 0.46-0.94 for total leukemia; OR = 0.45 and 95% CI = 0.21-0.96 for AML), whereas paternal smoking 1 month prior to pregnancy (compared with not smoking during the same period) was related to an elevated risk of ALL (OR = 1.56; 95% CI = 1.03-2.36)., Conclusions: Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML. Maternal smoking, however, does not elevate risk for either AML or ALL., Implications: The data suggest that in utero exposure to alcohol may contribute to leukemogenesis involving myeloid cells.

Whether low level radiation exposure before conception increases the risk of leukemia in offspring has been much debated. No study has specifically evaluated the effect of parental preconception diagnostic X-ray exposure in the development of leukemia among infants. Mothers of 302 infant leukemia cases (diagnosed at < or = 18 months of age) and 558 individually matched regional controls, and fathers of 250 cases and 361 controls, were independently interviewed to obtain information on X-ray exposures. Paternal preconception X-ray exposure was associated with an increased risk of infant leukemia, higher risks being linked to exposures closer to conception. X-ray related leukemia risk varied with exposure site and histopathological type, the highest risk being for acute lymphocytic leukemia related to two or more X-rays of the lower gastrointestinal (GI) tract and lower abdomen (odds ratio, 3.78; 95% confidence interval, 1.49-9.64). A positive association was observed between acute lymphocytic leukemia and number of paternal X-rays of the lower GI and lower abdomen (trend test, P < 0.01), upper GI (P = 0.04), and chest (P = 0.08). Exposures of head and neck and limbs were unrelated to risk. The risk of acute myelogenous leukemia was unrelated to paternal X-ray exposure, except for a marginally significant association (trend test, P = 0.07) for upper GI X-rays. No consistent association between maternal X-ray exposure and infant leukemia was observed. The results of this study suggest that paternal low level radiation exposure before conception is associated with an increased risk of infant leukemia, although the nature of this association needs to be further evaluated.

Objective: To determine whether pituitary-derived human growth hormone treatment increases the subsequent risk of developing leukemia and lymphoma., Design: Cohort study., Setting: United States., Participants: A total of 6284 recipients of pituitary-derived human growth hormone distributed by the National Hormone and Pituitary Program between 1963 and 1985., Main Outcome Measures: Leukemia and lymphoma., Results: Three cases of leukemia occurred in 59,736 patient-years of follow-up from the start of growth hormone therapy to case ascertainment at interview; this number was not significantly higher (P = .23) than the 1.66 cases expected in the US age-, race-, and gender-matched general population. Three additional cases, found in an extended follow-up that provided 83,917 person-years of risk, yielded a minimum rate of leukemia that was significantly increased (six cases found, 2.26 expected; P = .028). The relative risk of leukemia in pituitary growth hormone recipients compared with the general population was 1.8 (90% confidence interval [CI], 0.82 to 7.5) for the defined follow-up and 2.6 (90% CI, 1.2 to 5.2) for the extended follow-up. Five of the six subjects who developed leukemia had antecedent cranial tumors (four craniopharyngioma, one astrocytoma) as the cause of growth hormone deficiency, and four had received radiotherapy. There was no increase in leukemia in patients with idiopathic growth hormone deficiency. The association of leukemia and craniopharyngioma was significant (P < .001). There was no excess of lymphoma in the cohort., Conclusions: This cohort of growth hormone recipients had a significantly increased rate of leukemia compared with the age-, race-, and gender-matched general population. However, the upper bound CI of the relative risk in our population (5.2) is well below the other estimates (7.6). Compared with the general population, our study population had more possible risk factors for leukemia (radiation, tumor) that may have contributed to the excess observed. The clustering of cases of leukemia in craniopharyngioma patients should be further evaluated.

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.

Epidemiologic studies of the childhood leukemias have provided information relevant to several aspects of the care and follow-up of these children. The observations made regarding in utero radiation and ALL risk have certainly curtailed the use of routine obstetric diagnostic radiographs; observations regarding the association between birth weight, fetal loss, and other gestational events provide added enthusiasm for further research into basic biologic events occurring during fetal development; and the genetic patterns of disease supply critical information for genetic counseling and follow-up of affected patients and families. Additionally, the continued epidemiologic surveillance of children with cancer serves to form the foundation from which we will assess any future changes in childhood cancer incidence or pattern. Although not discussed here, the epidemiology of late effects, including second malignancies, reproductive function, and neuropsychologic functioning will assume a more prominent role as more children survive ALL and move into adulthood. While analytic studies have yet to yield an association as strong as the lung cancer/cigarette association in adults, future research designed to isolate biologically homogeneous disease populations for study may lead us to new and important associations. The continued cooperation of large pediatric oncology groups and private physicians is crucial as these future investigations are undertaken.

The discovery of cytosine arabinoside, and then the anthrocycline antibiotics, 6-thioguanine, vincristine, cyclophosphamide, and other drugs, has added to the armamentarium of known effective agents. The use of combination chemotherapy, the recognition of the need during induction for virtual marrow aplasia to obtain a remission, and recognition of the predilection of the disease for the central nervous system requiring prophylaxis constitute major advances. The impediment to long-term survival is the lack of effective maintenance therapy.