Optimal paths on the road network as directed polymers.

We analyze the statistics of the shortest and fastest paths on the road network between randomly sampled end points. We find that, to a good approximation, the optimal paths can be described as directed polymers in a disordered medium, which belong to the Kardar-Parisi-Zhang universality class of interface roughening. Comparing the scaling behavior of our data with simulations of directed polymers and previous theoretical results, we are able to point out the few characteristics of the road network that are relevant to the large-scale statistics of optimal paths. Indeed, we show that the local structure is akin to a disordered environment with a power-law distribution which become less important at large scales where long-ranged correlations in the network control the scaling behavior of the optimal paths.

Pharmacogenetic modulation of combined hormone replacement therapy by progesterone-metabolism genotypes in postmenopausal breast cancer risk.

Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

Recall of diet during a past pregnancy.

The authors conducted a study of women's ability to recall diet during a past pregnancy. For a prospective study, women completed self-administered food frequency questionnaires (FFQs) before and during pregnancy (1989-1992). These women, mostly White and well-educated, were contacted 3-7 years later (1996-1997) for a retrospective dietary assessment performed by either telephone interview (n = 154) or self-administered FFQ (n = 115). Energy-adjusted Pearson correlations ranged from 0.10 to 0.49 for the telephone interview group and from 0.02 to 0.67 for the self-administered questionnaire group. When participants' intakes were ranked, quintile agreement (within one quintile) between original diet and recalled diet ranged from 60% to 69% in the telephone interview group and from 69% to 79% in the self-administered questionnaire group. Correlations and percentages of agreement were higher among women who used the same questionnaire for both dietary assessments than among those who used different questionnaires. These results suggest that diet during pregnancy is recalled with similar accuracy as or perhaps slightly lower accuracy than adult diet generally. This may reflect, in part, the influence of current (nonpregnancy) diet on recall of past (pregnancy) diet. While the results of this study may not be generalizable to those obtained from other populations, to the authors' knowledge it is the first study of recall of diet during pregnancy.

Cyclophosphamide-based, seven-drug hybrid and low-dose involved field radiation for the treatment of childhood and adolescent Hodgkin disease.

PURPOSE: The outlook for children and adolescents with Hodgkin disease (HD) is excellent with combined modality therapy. However, the long-term toxicities of multiagent therapy and radiation therapy remain of concern for these patients with curable disease. In an attempt to reduce long-term toxicities while preserving excellent cure rates, we developed a combined-modality protocol using a modified seven-drug hybrid and low-dose (2,000 cGy) involved field radiation therapy (RT). The hybrid used cumulative doses of alkylating agents and anthracyclines that were lower than those used in previous four-drug regimens and substituted a less leukemogenic agent, cyclophosphamide, for nitrogen mustard. PATIENTS AND METHODS: From 1991 through 1994 a cyclophosphamide, vincristine, procarbazine, and prednisone/adriamycin, bleomycin, and vinblastine hybrid was used to treat 29 patients with HD. Median age was 12 years (range 6-16 yrs). Patients who were postpubertal with early stage disease as determined by surgical staging were excluded. Treatment consisted of four cycles of therapy for stages I and IIA, six cycles for stages IIB and III, and eight cycles for stage IV. Twenty-two patients also received low-dose RT to areas of bulky disease. RESULTS: Twenty-eight patients (97%) had a complete response to chemotherapy. Five patients experienced relapse; two died from disease 27 and 29 months after initial diagnosis; three received additional therapy and are alive with no evidence of disease. Follow-up for all other patients is a median of 56 months (range 24-78 mos) from cessation of therapy and all have remained disease-free. At 5 years follow-up, actuarial disease-free survival is 82%, and the overall survival is 93%. There have been no clinically significant cardiac or pulmonary toxicities and no secondary malignancies. CONCLUSIONS: This therapy has resulted in 5-year overall survival and disease-free survival rates similar to regimens using higher doses of alkylating agents, anthracyclines, and radiation. Longer follow-up will be necessary to fully evaluate disease-free survival, organ damage, and quality of life.

What causes childhood brain tumors? Limited knowledge, many clues.

Little is known about the causes of brain tumors in children. Children with one of several genetic disorders including tuberous sclerosis and Li-Fraumeni syndrome are at increased risk, as are children who have received therapeutic irradiation to their head. The multifactorial causation of brain tumors, the inaccuracies of recall of past exposures, and the study of all pediatric brain tumors as a single etiologic entity may be contributing to the difficulty in identifying additional risk factors. The evidence that frequent cured meat consumption by the mother during pregnancy increases the risk is suggestive but not conclusive. For other potential risk factors, the evidence is limited and/or conflicting. These exposures and characteristics include pesticides, carcinogen metabolizing genes, and polyomaviruses.

Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma.

PURPOSE: To study the effectiveness of combined systemic chemotherapy and local ophthalmic therapy for retinoblastoma with the goal of avoiding enucleation and external-beam radiation therapy (EBRT). PATIENTS AND METHODS: This was a prospective, nonrandomized, single-arm clinical trial. Seventy-five eyes were followed in 47 children. Patients were treated with a six-cycle protocol of vincristine, etoposide, and carboplatin. Most (83%) also received ophthalmic treatment (cryotherapy, laser photocoagulation, thermotherapy, or plaque radiation therapy) during and/or after the chemotherapy. RESULTS: With a median follow-up of 13 months, event-free survival was 74%, with an event defined as enucleation and/or EBRT. Six children required EBRT in seven eyes (9%); five required enucleation of one eye (7%); five required a combination of EBRT and enucleation in six eyes (8%). Reese-Ellsworth groups 1, 2, and 3 eyes had excellent results, with avoidance of EBRT or enucleation in all 39. Treatment of groups 4 and 5 was less successful, with 33% of six eyes and 53% of 30 eyes, respectively, requiring EBRT and/or enucleation. Toxicities from chemotherapy were mild and included cytopenias (89%), fever and neutropenia (28%), infection (9%), and gastrointestinal symptoms, dehydration, and vincristine neurotoxicity (40%). No patients developed a second malignancy, metastatic disease, renal disease, or ototoxicity. CONCLUSION: In retinoblastoma patients with Reese-Ellsworth eye groups 1, 2, or 3, systemic chemotherapy used with local ophthalmic therapies can eliminate the need for enucleation or EBRT without significant systemic toxicity. More effective therapy is required for Reese-Ellsworth eye groups 4 and 5.

The descriptive epidemiology of craniopharyngioma.

OBJECT: In this report the authors describe the epidemiology of craniopharyngioma. METHODS: The incidence of craniopharyngioma in the United States was estimated from two population-based cancer registries that include brain tumors of benign and borderline malignancy: the Central Brain Tumor Registry of the United States (CBTRUS) and the Los Angeles county Cancer Surveillance Program. Information on additional pediatric tumors was available from the Greater Delaware Valley Pediatric Tumor Registry (GDVPTR). The overall incidence of craniopharyngioma was 0.13 per 100,000 person years and did not vary by gender or race. A bimodal distribution by age was noted with peak incidence rates in children (aged 5-14 years) and among older adults (aged 65-74 years in CBTRUS and 50-74 years in Los Angeles county). Survival information was available from GDVPTR and the National Cancer Data Base (NCDB), a hospital-based reporting system. In the NCDB, the 5-year survival rate was 80% and decreased with older age at diagnosis. Survival is higher among children and has improved in recent years. CONCLUSIONS: Craniopharyngioma is a rare brain tumor of uncertain behavior that occurs at a rate of 1.3 per million person years. Approximately 338 cases of this disease are expected to occur annually in the United States, with 96 occurring in children from 0 to 14 years of age.

Maternal diet during pregnancy and risk of brain tumors in children.

Nine studies of childhood brain tumors and maternal diet during pregnancy have focused on foods related to the N-nitroso-compound(NOC) hypothesis. An association between frequent consumption of cured meat by pregnant women and increased risk is a consistent finding in most of the studies. The data on fruit and vegetable consumption are less consistent, but suggest decreased risk. Studies that assess all aspects of maternal diet during pregnancy are needed to determine whether the observed associations remain after adjustment for other aspects of diet. Such comprehensive studies also may elucidate other dietary factors that affect the risk of brain tumors in children.

Paternal age and sporadic neurofibromatosis 1: a case-control study and consideration of the methodologic issues.

Sporadic neurofibromatosis 1 (NF1) occurs in the absence of a family history of the disease and usually results from a new mutation in the germ cell of one of the parents, most commonly the father. Older paternal age may increase the risk for a new germinal NF1 mutation, but the results of studies to address this question conflict. We investigated paternal age in sporadic NF1 by using a case-control study design. Patients who were seen at two specialty NF clinics in Houston, Texas, born between 1970 and 1992 and living in the Houston area and surrounding counties, were studied. Birth certificates with information on the father were found for 89 cases. For each case, two birth certificates were chosen at random from the same year and county of birth. In this way, the control group of 178 individuals was formed. Fathers of patients with NF1 were 1.5 years older than fathers of control subjects at the birth of the child, but the difference was only of borderline statistical significance (P = 0.07). This paternal age difference was not changed by adjustment for socioeconomic status or maternal age. These and previous data are consistent with either a small paternal age effect in sporadic NF1 or a bias such as that resulting from the selection of cases and/or controls.

The descriptive epidemiology of craniopharyngioma.

The incidence of craniopharyngioma in the United States was estimated from two population-based cancer registries that include brain tumors of benign and borderline malignancy: the Central Brain Tumor Registry of the United States (CBTRUS) and Los Angeles county. Information on additional pediatric tumors was available from the Greater Delaware Valley Pediatric Tumor Registry (GDVPTR). The overall incidence of craniopharyngioma was 0.13 per 100,000 person years and did not vary by gender or race. A bimodal distribution by age was noted with peak incidence rates in children (aged 5-14 years) and among older adults (aged 65-74 years in CBTRUS and 50-74 years in Los Angeles county). Survival information was available from GDVPTR and the National Cancer Data Base (NCDB), a hospital-based reporting system. In the NCDB, the 5-year survival rate was 80% and decreased with older age at diagnosis. Survival is higher among children and has improved in recent years. Approximately 338 cases of craniopharyngiomas are expected to occur annually in the United States, with 96 occurring in children from 0 to 14 years of age.

Screening for neuroblastoma is ineffective in reducing the incidence of unfavourable advanced stage disease in older children.

Neuroblastoma exhibits many characteristics which would suggest that preclinical detection may improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. All 476,603 children born in the province of Quebec during a 5-year period of time (1 May 1989 to 30 April 1994) were eligible for determinations of urinary catecholamine metabolites at 3 weeks and 6 months of age. Children with positive screening were referred to one of four paediatric cancer centres in Quebec for uniform evaluation and treatment. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in Quebec and two comparable population-based controls during the same period of time using similar ascertainment procedures. Compliance with screening in Quebec was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Up to 31 July 1995 with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically prior to screening at 3 weeks of age and 55 detected clinically after 3 weeks of age having normal screens (n = 52) or never screened (n = 3). Based on data from concurrent control populations, 54.5 cases of neuroblastoma would have been expected in Quebec during the study period for an SIR of 2.17 (95% CI 1.79-2.57, P < 0.0001). For the two control groups, the overall SIR was 1.00 (NS). SIRs for Quebec by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR = 2.85, 95% CI 2.26-3.50), with no reduction in incidence in subsequent years. We conclude that screening for neuroblastoma markedly increases the incidence in infants without decreasing the incidence of unfavourable advanced stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce the mortality of this disease.

A population-based study of the usefulness of screening for neuroblastoma.

BACKGROUND: Neuroblastoma has many characteristics which suggest that preclinical detection might improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. As an early endpoint, we report whether screening could reduce the incidence of poor-prognosis neuroblastoma in children with advanced-stage disease over 1 year of age. METHODS: All 476,603 children born in the province of Quebec during the 5-year period of May 1, 1989, to April 30, 1994, were eligible for urinary assay of homovanillic acid and vanillylmandelic acid at 3 weeks and 6 months of age. Children with a positive screen were referred to one of four paediatric cancer centres in the province for uniform evaluation and treatment if necessary. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in the province and two similar population-based controls, the state of Minnesota and the province of Ontario, during the same period of time and with similar ascertainment procedures. FINDINGS: Compliance with screening in Quebec province was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Through July 31, 1995, with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically before screening at 3 weeks of age, and 55 detected clinically after 3 weeks of age having normal screens (52) or never screened (3). Retrospective analysis of stored samples confirmed that 49 of 52 patients missed by screening had levels of catecholamine metabolites that were too low to be detected at 6 months or earlier. Based on US Surveillance, Epidemiology and End Results data, 54.5 cases of neuroblastoma would have been expected in Quebec province during the study period, for an SIR of 2.17 (95% CI 1.79-2.57, p < 0.0001). For the two control groups, 43 and 80 cases of neuroblastoma were detected, respectively, compared with 37.9 and 85.4 expected, overall SIR 1.00 (not significant). SIRs for Quebec province by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR 2.85, 2.26-3.50), with no reduction in incidence in subsequent years. Limiting analysis to only patients diagnosed over 1 year of age with advanced-stage disease, 22 cases were detected in Quebec province versus 14.4 expected (SIR 1.52, 0.95-2.23). Data in the two control groups show no significant increase or decrease in any-stage disease in children under or over the age of 1 year, except for an increase in early-stage disease in Minnesota children over 1 year: 10 versus 3.8 expected (SIR 2.67, 1.27-4.58). INTERPRETATION: Screening for neuroblastoma increases the incidence in infants without decreasing the incidence of unfavourable advanced-stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce mortality for this disease.

Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effect of recombinant human erythropoietin (EPO) and iron supplementation on transfusion requirements in pediatric patients with sarcoma who were receiving chemotherapy, we performed a double-blind, placebo-controlled, randomized trial. METHODS: Twenty-four pediatric patients with malignant solid tumors were randomly assigned to receive either placebo (saline solution) or EPO for a 16-week study period. The starting dose was 150 IU/kg per dose three times a week and was escalated by 50 IU/kg per dose increments monthly until packed red blood cell (PRBC) transfusion independence was achieved or a dosage of 300 IU/kg per dose was reached. Iron supplementation was prescribed at a dose of 6 mg of elemental iron per kilogram daily. The primary study end point was the comparison of PRBC transfusion requirements in the two groups. RESULTS: Of 24 patients, 20 were evaluable for response. The median PRBC transfusion requirement during the 16-week period was 23 ml/kg in EPO-treated patients versus 80 ml/kg in placebo patients (p = 0.02). The median number of single-donor platelet units transfused was zero in the EPO-treated patients compared with four in the placebo group (p = 0.005). No statistical difference in the intensity of bone marrow suppression was seen, as measured by the median number of complete blood cell counts with an absolute neutrophil count of < 1000 cells/microliter. CONCLUSIONS: Treatment with EPO and iron significantly reduces PRBC transfusions in pediatric patients receiving concomitant chemotherapy for malignant sarcomas. A decrease in the number of platelet transfusions was also seen and deserves further study.

Increasing incidence of childhood cancer: report of 20 years experience from the greater Delaware Valley Pediatric Tumor Registry.

As little is known about the aetiology of cancer in children, analysis of time trends may be useful. Recent data on time trends for paediatric cancers are very limited. We report here on trends in the incidence of 15 categories of cancer in children under 15 years of age from 1970 to 1989, using data from the Greater Delaware Valley Pediatric Tumor Registry in the US. Total cancer incidence increased 1% per year (P < 0.001). Neither acute lymphocytic leukaemia, acute myelocytic leukaemia, nor total leukaemia incidence changed significantly. In contrast, the incidence of central nervous system (CNS) tumours rose 2.7% per year (P < 0.001). All three subgroups of this category, glioma, primitive neuroectodermal tumor (PNET)/medulloblastoma, and other CNS tumours, showed increases. For glioma and PNET/medulloblastoma, trends differed by age, race, and/or gender. Among the other childhood cancers, significant increases were observed for non-Hodgkin lymphoma and neuroblastoma. For osteosarcoma and retinoblastoma, no overall change in incidence was observed, although decreases were observed in some age and race subgroups. The rise in CNS tumour incidence confirms previous reports from the US and Great Britain. The lack of change for acute lymphocytic leukaemia conflicts with other data from the US, but diagnostic changes appear to explain at least part of the discrepancy. The increase in neuroblastoma has also been observed in Great Britain. In contrast to our finding, investigators in the US and Great Britain have reported no rise in non-Hodgkin lymphoma. Analyses for more of the childhood cancers from other registries would aid in detecting and interpreting incidence trends in recent years.

Relationship between Fc receptor IIA polymorphism and infection in children with sickle cell disease.

OBJECTIVE: Despite penicillin prophylaxis and vaccination, infection with encapsulated organisms remains a leading cause of morbidity and death in children with sickle cell disease. The role of Fc receptors in the clearance of encapsulated organisms is well documented. The His(H)-Arg(R) polymorphism at amino acid 131 of the Fc gamma RIIA receptor alters binding affinity for human IgG2 and influences infection with encapsulated organisms in children without sickle cell disease. We hypothesized that the genotype for high-affinity human IgG2 binding (H/H131) is underrepresented in children with sickle cell disease who had encapsulated organism infection. DESIGN: We studied 60 black children with sickle cell disease from four participating centers who had a history of encapsulated organism infection. Genomic DNA from peripheral blood was subjected to amplification by polymerase chain reaction and to sequence analysis for identification of the Fc gamma RIIA genotype, and the genotype distribution was then compared with our data from ethnically matched control subjects. RESULTS: Contrary to our hypothesis, the H/H131 genotype was overrepresented in all individuals (p = 0.046) and in particular in the 11 individuals with a history of Haemophilus influenzae type b infection (64% H/H131, 27% H/R131, 9% R/R131; p = 0.002), in comparison with ethnically matched control subjects (14% H/H131, 60% H/R131, 26% R/R131). In the 51 individuals with a history of Streptococcus pneumoniae infection, the genotype distribution was not statistically significantly different from that of the control population. CONCLUSIONS: The H/H131 Fc gamma RIIA genotype is overrepresented in black children with sickle cell disease and a history of H. influenzae type b infection but not in those with S. pneumoniae infection.

Informing subjects of epidemiologic study results. Children's Cancer Group.

OBJECTIVE: To assess the feasibility and process of providing feedback to parents regarding the results of epidemiologic research, in particular to look at the importance and clarity of the information provided, parental reactions to the results, and utilization of the data provided. METHODOLOGY: Parents who participated in an epidemiologic study of pediatric brain tumors (patient and control mothers) were sent a letter summarizing the results of the study and the Parent Study Results Survey to complete and return. The final sample used for analyses was 109 (patient) and 90 (control) mothers. Analyses were conducted to determine differences between patient and control mothers and differences among subsets defined by educational level and vital status of the patient. RESULTS: Mothers rated the importance and clarity of the information very highly, although patient mothers were more likely than control mothers to want more information and a telephone contact. Patient and control mothers were similar in reported sadness, anxiety, and being overwhelmed, but patient mothers felt less satisfied and relieved. Patient mothers expressed feeling more guilt nad anger than control mothers, although even the levels among the patient mothers were only moderate. Close to half of all mothers commented on the inconclusiveness of the study results. Nearly all mothers indicated they would suggest that other parents participate in epidemiologic research. CONCLUSIONS: It is valuable to many parents that they receive information about results of research in which they have participated. We found little evidence of strong negative effects to a detailed feedback letter. We recommend that evaluative data be used to guide the process of informing research participants about study results and that investigators consider making feedback letters a standard part of research protocols.

Breast cancer and other second neoplasms after childhood Hodgkin's disease.

BACKGROUND: Patients who survive Hodgkin's disease are at increased risk for second neoplasms. As survival times increase, solid tumors are emerging as a serious long-term complication. METHODS: The Late Effects Study Group followed a cohort of 1380 children with Hodgkin's disease to determine the incidence of second neoplasms and the risk factors associated with them. RESULTS: In this cohort, there were 88 second neoplasms as compared with 4.4 expected in the general population (standardized incidence ratio, 18.1; 95 percent confidence interval, 14.3 to 22.3). The estimated actuarial incidence of any second neoplasm 15 years after the diagnosis of Hodgkin's disease was 7.0 percent (95 percent confidence interval, 5.2 to 8.8 percent); the incidence of solid tumors was 3.9 percent (95 percent confidence interval, 2.3 to 5.5 percent). Breast cancer was the most common solid tumor (standardized incidence ratio 75.3; 95 percent confidence interval, 44.9 to 118.4), with an estimated actuarial incidence in women that approached 35 percent (95 percent confidence interval, 17.4 to 52.6 percent) by 40 years of age. Older age (10 to 16 vs. <10 years) at the time of radiation treatment (relative risk, 1.9) and a higher dose (2000 to 4000 vs. <2000 cGy) of radiation (relative risk, 5.9) were associated with significantly increased risk of breast cancer. The estimated actuarial incidence of leukemia reached a plateau of 2.8 percent (95 percent confidence interval, 0.8 to 4.8 percent) 14 years after diagnosis. Treatment with alkylating agents, older age at the diagnosis of Hodgkin's disease, recurrence of Hodgkin's disease, and a late stage of disease at diagnosis were risk factors for leukemia. CONCLUSIONS: The risk of solid tumors, especially breast cancer, is high among women who were treated with radiation for childhood Hodgkin's disease. Systematic screening for breast cancer could be important in the health care of such women.

p53 gene mutations in pediatric brain tumors.

We investigated the frequency of p53 mutations in 47 pediatric brain tumors of various histologic subtypes that were collected over a period of 5 years. The specimens included 15 primitive neuroectodermal tumors (PNETs), 17 low grade astrocytomas, one anaplastic astrocytoma, three glioblastomas (GBMs), one mixed glial tumor, eight ependymomas, one choroid plexus carcinoma, and one gangliocytoma/ganglioneuroma. Mutations were identified by single strand conformation polymorphism analysis of exons 4-8 and verified by sequencing. Mutations were present in 2 of 3 cases of GBM, but not in 17 low grade astrocytomas (P = 0.02, Fisher's exact test). One GBM demonstrated a germline GGC to AGC transition (gly to ser) at codon 245 with loss of the wild-type allele. A second GBM contained a CGG to TGG transition (arg to trp) at codon 248, also with loss of the wild-type allele, but normal tissue was not available for comparison. In addition, one of 15 PNETs retained heterozygosity but demonstrated a somatic CGT to TGT transition (arg to cys) at codon 273. p53 mutations were absent in other histologic subtypes and in two cases with multiple primary cancers. These data are consistent with earlier findings that p53 mutations are rare in PNETs, which are primarily pediatric tumors. In contrast to adult gliomas, p53 mutations in pediatric gliomas appear restricted to the GBMs. The lack of p53 mutations in pediatric low grade astrocytomas suggests not only histological differences, but also a different molecular pathogenesis in adult and pediatric patients.

Neurologic and other disorders in relatives of pediatric patients with CNS tumors.

Abnormalities of embryogenesis and nervous system development may cause or contribute to the development of childhood brain tumors. To identify genetic or environmental factors that may be associated with etiologies of childhood central nervous system tumors, we examined family histories of 165 children with such tumors for the presence of neurologic disorders, including neural tube defects, mental retardation, seizures, and central nervous system tumors, as well as other cancers and birth defects. Only 1 patient, with the neurofibromatosis-Noonan syndrome, was confirmed to have an underlying syndromic diagnosis associated with central nervous system tumorigenesis. Families of 2 probands with posterior fossa primitive neuroectodermal tumors reported relatives with olivopontocerebellar atrophy. Although increased incidences of study disorders were not identified in this population, it is possible that within individual families one or more of these disorders is related to childhood central nervous system tumorigenesis.

Assessment of environmental and genetic factors in the etiology of childhood cancers: the Childrens Cancer Group epidemiology program.

The occurrence of cancer during childhood represents one of the leading causes of death within the pediatric and adolescent age group. It is estimated that approximately 8000 children will be diagnosed annually with cancer in the United States. Epidemiologic research addressing the etiology of childhood cancer has been limited because of the difficulties in identifying a sufficiently large study population. Moreover, the use of retrospectively ascertained childhood cancer cases in epidemiologic investigations has restricted the incorporation of biological and clinical parameters. The Childrens Cancer Group has developed an active program in epidemiologic research, with over a decade of experience demonstrating the feasibility and strengths of conducting analytic epidemiologic studies within a cooperative clinical trials network. The availability of detailed clinical and biologic data on cases diagnosed within the cooperative group facilitates the transfer of state-of-the-art technology to epidemiologic research.