Biomedical subjects
Publications and source records attributed to A T Meadows.
More children than ever before are being cured of cancer, thanks to aggressive use of multimodal therapy. Of prime concern are the potential long-term deleterious effects of such treatment. Sequelae may include impairment of growth or other aspects of development, damage to various organ systems, or a second cancer. Guidelines for surveillance and counseling are described.
This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13-institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.
Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.
A matched case-control study was conducted by the Children's Cancer Study Group to investigate the role of parental occupation in the etiology of sporadic heritable and nonheritable retinoblastoma. Eligible cases were those patients with retinoblastoma diagnosed in 1982-1985 at any of the Children's Cancer Study Group member hospitals. Telephone interviews of 201 parents of cases and their pair-matched controls selected by random digit dialing were completed. Of the 201 cases, 19 were familial, 67 were sporadic heritable, and 115 were nonheritable. The 19 familial cases were excluded from the analysis. Paternal employment in the military [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.1-8.8, P = 0.04] and in the metal industry (OR infinity, 95% CI 1.4-infinity, P = 0.02) was associated with sporadic heritable retinoblastoma (N = 67). For nonheritable retinoblastoma (N = 115), a significant association was observed for a job cluster consisting mostly of welders and machinists (OR 4.0, 95% CI 1.1-22.1, P = 0.04). Occupations of maternal grandparents were also studied and an association was observed with farming and nonheritable retinoblastoma (OR 10.0, 95% CI 1.4-433, P = 0.02). Many comparisons were made and the number of significant findings did not exceed that expected by chance. Thus, the results need to be interpreted very cautiously. However, the findings related to metal exposure corroborate observations on other childhood cancers.
Gestational and familial risk factors were investigated for their association with astrocytoma, the most frequently occurring brain tumor in children. A case-control study of 163 matched pairs was performed. Cases under 15 years of age at diagnosis in 1980-1986 were identified through the tumor registries of 8 hospitals in Pennsylvania, New Jersey, and Delaware. Controls were selected by random digit dialing and were matched to cases for age, race, and telephone area code and exchange. Maternal antinausea medications increased the risk of childhood astrocytoma [OR (odds ratio) = 2.0, P = 0.04]. Cured meat consumption during pregnancy was more common among cases (OR = 1.9, P = 0.07), and a significant trend with increasing frequency of consumption was observed (P = 0.04). Results for gestational exposure to marijuana (OR = 2.8, P = 0.07) were of borderline significance. Gestational exposure to neurally active medications, alcohol, and tobacco were not risk factors. There was a significant trend for cases to be of higher birth weight (P = 0.03). Mental retardation (OR = 3.0, P = 0.04) and cancer (OR = 1.7, P = 0.02) in a relative of the child significantly increased the risk of astrocytoma. Significantly increased risks were observed for brain tumors in relatives of children 0-4 years of age at diagnosis (OR = 6/0, P = 0.04). A significant protective effect was observed for maternal history of miscarriage or stillbirth (OR = 0.5, P = 0.01). The results of this study suggest that some gestational and familial factors may increase the risk of childhood astrocytoma.
The renal tubular Fanconi syndrome developed in five patients with Wilms tumor after treatment with ifosfamide, a derivative of cyclophosphamide. Glomerular filtration rates were severely decreased. Renal function was investigated because of the development of rickets. All patients had undergone reduction of renal mass by nephrectomy. None had preexisting renal tubular injury. The syndrome developed at cumulative doses of ifosfamide of 39 to 99 gm/m2. Low serum bicarbonate and phosphate concentrations with glucosuria, aminoaciduria, and hypochloremic metabolic acidosis were the manifestations of the Fanconi syndrome. Bicarbonate and phosphate replacement resulted in bone healing, but recovery of tubular and glomerular function did not occur. Monitoring of these laboratory values during ifosfamide therapy could allow earlier replacement therapy to prevent severe bone disease.
A matched case-control study of neuroblastoma investigated parental occupational risk factors. Cases diagnosed in 1970-1979 were identified through tumor registries in the Greater Philadelphia area. Controls were selected by random digit dialing and were matched to cases on race, birth date, and telephone exchange. Parents of 104 matched pairs were interviewed by telephone. In contrast to results of a previous study, no significant associations were noted for paternal employment in a job cluster of occupations in electricity, electronics, insulation, utility, and printing; in jobs with electromagnetic field exposure; or in jobs as workers in electronics. Six cases and one control, however, had a father or mother who worked in electrical or electronic products assembly.
Testicular function was evaluated in 60 long-term survivors of childhood acute lymphoblastic leukemia (ALL). All the patients were treated on two consecutive Children Cancer Study Group protocols and received identical chemotherapy and either 18 or 24 Gy radiation therapy (RT) to one of the following fields: craniospinal plus 12 Gy abdominal RT including the gonads (group 1); craniospinal (group 2); or cranial (group 3). The median age at the time of their last evaluation was 14.5 years (range, 10.5 to 25.7), which took place a median of 5.0 years (range, 1 to 10.3) after discontinuing therapy. The incidence of primary germ cell dysfunction as judged by raised levels of follicle-stimulating hormone (FSH) and/or reduced testicular volume was significantly associated with field of RT; 55% of group 1, 17% of group 2, and 0% of group 3 were abnormal (P = .002). Leydig cell function, as assessed by plasma concentrations of luteinizing hormone (LH) and testosterone, and pubertal development, was unaffected in the majority of subjects regardless of RT field. These data indicate that in boys undergoing therapy for ALL, germ cell dysfunction is common following testicular irradiation and can occur following exposure to scattered irradiation from craniospinal RT. In contrast, Leydig cell function appears resistant to direct irradiation with doses as high as 12 Gy.
A model is presented to predict adult stature in children treated successfully for cancer outside the CNS. The model is based on radiation dose in Gray adjusted for location of therapy and attained stature (GALA); ideal adult stature (IAS), assuming the patient had not developed cancer, calculated by the Roche-Wainer-Thissen (RWT) method (which uses patient stature and weight before developing cancer, and parent stature data); a femur correction if both the acetabula or heads of both femurs were irradiated (FEMUR); and sex. The model was constructed using data from 49 patients with a mean time from completion of therapy to follow-up of 8.9 years (range, 3.3 to 15.4 years). Thirteen patients received no radiotherapy. All model coefficients were highly significant (P less than .001), and the model appears to be an excellent predictor of adult stature, with a multiple correlation coefficient of 0.84 (R2 = .74) between corrected adult stature (CAS) based on the most recent follow-up stature available for the patient projected to final adult stature, compared with the model's predicted adult stature (MPAS), based only on initial data at presentation and subsequent radiation treatment. Patients who did not receive radiotherapy did not have loss of stature, ie, there was no significant difference between IAS and CAS, (P less than .71; n = 13), but patients who received radiotherapy had shorter statures than would be expected from the healthy population model (P less than .0004; n = 36). The magnitude of the loss in stature appears to be well explained by the dose and location of radiation, the stature already achieved at the time of radiotherapy, along with IAS, FEMUR, and sex. We believe this model will help clinicians to predict the growth effects of radiotherapy in children with cancer not involving the CNS.
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A matched case-control study of retinoblastoma was conducted by the Children's Cancer Study Group (CCSG) to investigate the hypotheses that postconception exposures affect the risk of the nonheritable (post-zygotic origin) form of this disease and that preconception exposures affect the risk of the sporadic heritable (prezygotic origin) form. Eligible cases were those patients with retinoblastoma diagnosed in 1982-1985 at any of the CCSG member hospitals. Cases were classified as familial heritable, sporadic heritable, or nonheritable based on family history, tumor laterality, and cytogenetic analysis. Telephone interviews of parents of 201 cases and their pair-matched controls selected by random digit dialing were completed. Analysis of possible risk factors for the 67 sporadic heritable cases and the 115 nonheritable cases was performed. (The 19 familial cases were excluded). For the nonheritable group, gestational exposure to X-ray [odds ratio (OR) = 2.3, P = 0.08] and morning sickness medication (OR = 2.8, P = 0.02) and low maternal educational level (OR = 5.5, P = 0.03) were associated with increased risk; anemia (OR = 0.3, P = 0.02) and multivitamin use (OR = 0.4, P = 0.03) during pregnancy and periconceptional use of barrier contraceptive (OR = 0.1, P = 0.02) or spermicide (OR = 0.2, P = 0.02) were associated with decreased risk. In the sporadic heritable group, observations included a negative association with multivitamins during pregnancy (OR = 0.2, P = 0.02) and nonsignificant positive associations with preconception gonadal X-ray (maternal, OR = 2.0, P = 0.30; paternal, OR = 1.8, P = 0.42) and older parental age (case-control difference 1.0-1.2 years, P = 0.24-0.27). Many of the associations support study hypotheses, although the possibility of recall bias and chance findings suggest cautious interpretation.
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.
Parental occupational exposures for Wilms' tumor were investigated in a pair-matched case-control study. The timing of the exposures in relation to the child's conception and birth was studied, as were the two forms of Wilms' tumor: genetic (prezygotic origin) and nongenetic (postzygotic origin). Cases who were under 15 yr of age at diagnosis during 1970 to 1983 were identified through the registries of three main hospitals treating childhood cancer in the Greater Philadelphia area. Controls were selected by random digit dialing and were matched to cases on race, birth date, and telephone area code and exchange. Because of a low participation rate among blacks, results are reported only for the 88 white matched pairs whose parents participated in telephone interviews. Children whose fathers held jobs in a job cluster that consisted mostly of machinists and welders were at significantly increased risk. The increase was highest for preconception exposure (odds ratio = 5.3, P = 0.006). The effect of preconception exposure was higher for the 26 genetic cases than for the 42 nongenetic cases. The other 20 cases were excluded from the subgroup analyses for various reasons. Further analyses did not elucidate an exposure common to machinists and welders that might explain the findings.
One-hundred sixty children under the age of 6 years presented for diagnostic evaluation regarding neurofibromatosis-1 (NF-1). Using the National Institutes of Health Consensus Conference criteria, 151 (94%) of the children were classified on initial examination: 112 were diagnosed as having NF-1 and 39 were found to be unaffected (all 39 have remained asymptomatic on follow-up). Nine could not be classified (3 have subsequently met minimal diagnostic criteria on follow-up). Clinical manifestations of NF-1 include cafe au lait spots (97%), freckling in the axillary or inguinal region (81%), Lisch nodules (30%), neurofibromas (15%), pseudoarthrosis (6%), and optic nerve gliomas (4%). More than minimal diagnostic criteria were met by 80% of the children who had a positive family history and by 32% of those who did not. Thus, the clinical diagnosis of NF-1 is possible in the child who is under 6 years of age, and the National Institutes of Health criteria are useful and applicable.
The majority of childhood cancer patients now can expect to survive into early adulthood, cured of their cancer. Current adult survivors are a diverse group in terms of diagnosis, age at diagnosis, and types of treatment. It is estimated that by 1990, 1 in every 1,000 twenty-year-olds will have had cancer, making it important to describe the long-term psychosocial adjustment of this population. Patients who were diagnosed between 1948 and 1975 while less than 16 years of age, who were currently 18 years or older, had been off therapy for at least 5 years, and had no known brain damage were eligible for this survey and were identified through the tumor registry at the Children's Hospital of Philadelphia (CHP). Initially, the parents were contacted by letter. Ninety-five (57%) of the 167 eligible patients participated in a telephone interview, which covered educational achievement, occupational status, interpersonal relationships, marital status, pregnancies, employee benefits and insurance, and medical and health behaviors. Respondents were not different from nonrespondents in terms of sex, year of diagnosis, age at diagnosis, diagnoses, stage of illness, or type of treatments. There were no differences in terms of education, marital status, fertility issues, or occupational status by diagnosis group, age at diagnosis, or treatments. The patients were compared to siblings over 18 years of age in terms of education and marital status. No significant differences in sex distribution or years of education between patients and siblings were found. The siblings were, as a group, older than the patients and were more likely to be married. In general, these patients were functioning normally, but there are many unexplored areas of interpersonal relationships and productivity that need further study before conclusions regarding psychosocial adjustment of childhood cancer survivors can be drawn.
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This study presents data on psychologic adjustment (self-concept, depression, locus of control, family environment, and parental distress) for a sample of 8- to 16-year-old long-term cancer survivors (n = 138) and their mothers, and for a sample consisting of a matched group of healthy children (n = 92) and their mothers. The null hypothesis of no group differences between survivors and control subjects was tested with respect to these variables. It was hypothesized that survivors with severe late effects would have poorer self-concepts, a more external locus of control, and more depressive symptoms than children with no or mild-to-moderate late effects. The children completed the Piers-Harris Self-Concept Scale, the Nowicki-Strickland Locus of Control Scale, and the Children's Depression Inventory. Mothers completed the Family Environment Scale and the Derogatis Stress Profile. The majority of former patients are functioning within normative limits on these standardized measures, although their scores were lower than those in the comparison group. One-way analyses of variance on the dependent measures indicate that the children with severe medical late effects have a poorer total self-concept, more depressive symptoms, and a more external locus of control than those with no or mild-to-moderate late effects. Therapies for childhood cancer are now well standardized and many long-term deleterious effects are known, so children at risk can be identified readily and steps taken early in treatment to prevent or mitigate future psychologic problems.
Young adolescent (10-15 year old) survivors of childhood cancer and their families (n = 35) completed self-report measures of perceived self-competence, social support, child behavior, parental distress, and family adaptability and cohesion, at two data points, 6 months apart. Relative to instrument norms and a comparison group (n = 13), survivors and their families scored within normative levels. The overall lack of group differences is discussed in terms of the implications of tests of the null hypothesis for families with chronically ill children. Changes over time for the survivors suggest a decline in available social support. Parents of survivors who received educational assistance reported less family adaptability and more distress than parents of survivors not receiving these services.