Retrospective family study of childhood medulloblastoma.

Medulloblastoma is the most common malignant central nervous system tumor of childhood and can occur sporadically or in association with inherited cancer susceptibility syndromes such as the nevoid basal cell carcinoma syndrome (NBCCS). To determine whether an association existed between the risk of developing medulloblastoma and undiagnosed syndromes, we retrospectively reviewed clinical data on 33 patients with medulloblastoma from a single institution and compared them with their unaffected relatives (n = 46). Six patients had tumors showing desmoplastic histology. Two of the six met diagnostic criteria for NBCCS. One NBCCS patient had a missense mutation of patched-1 (PTCH1); the other had no identifiable PTCH1 mutation. Two patients with isolated desmoplastic medulloblastoma had an insertion and splice site mutation, respectively, in suppressor of fused (SUFU). All patients with nondesmoplastic medulloblastoma histology received molecular testing for SUFU. None of these patients had an identifiable mutation in PTCH1 or SUFU. We performed a clinical evaluation for Greig cephalopolysyndactyly syndrome (GCPS) in four medulloblastoma families, who exhibited macrocephaly as the only finding consistent with the diagnosis of GCPS. Molecular analysis of GLI3 in these four families was negative. There was a paucity of clinical findings among the majority of medulloblastoma patients in this study group to suggest a definable cancer genetic syndrome. We conclude that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations are present at a low but significant frequency.

Prognostic factors and secondary malignancies in childhood medulloblastoma.

PURPOSE: Little is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed. PATIENTS AND METHODS: The records of all patients with childhood medulloblastoma diagnosed at Children's National Medical Center in Washington, DC from 1969 through 1997 were reviewed. RESULTS: The median follow-up time was 92 months (range 6-257 months). Overall survival was 59% at 5 years and 52% at 10 years. Univariate analysis showed that age at diagnosis, extent of surgical resection, presence of metastatic disease (M stage), ventriculoperitoneal shunt placement within 30 days from diagnosis, posterior fossa radiation therapy dose, and adjuvant chemotherapy significantly affected survival. Although based on small numbers, the risk of second neoplasms was significantly increased in this cohort. Multiple basal cell carcinomas developed in the areas of radiation therapy in two patients; these patients also had nevoid basal cell carcinoma syndrome (NBCCS) diagnosed. One other patient died of glioblastoma multiforme 8 years after treatment of medulloblastoma. A meningioma developed in another patient 10 years after radiation therapy. CONCLUSION: As survival of medulloblastoma patients improves, increased surveillance regarding secondary malignancies is required, especially because radiation-induced tumors may occur many years after treatment. These two cases of NBCCS also illustrate the importance of considering the concomitant diagnosis of NBCCS in young patients with medulloblastoma. In those patients, alternative therapy should be considered to minimize radiation therapy-related sequelae.

Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.

Sonographic detection of uterine and ovarian abnormalities in female survivors of Wilms' tumor treated with radiotherapy.

OBJECTIVE: The purpose of this study was to use sonography to evaluate the size of the ovaries and uterus in survivors of Wilms' tumor who underwent radiotherapy. SUBJECTS AND METHODS: Eighteen survivors of Wilms' tumor had their ovaries and uterus measured on sonography. Their ages at diagnosis and treatment ranged from 14 months to 6 years. Four girls were prepubertal (age, 5-9 years), 11 were postpubertal (age, 11-30 years), and three had primary ovarian failure (age, 15-23 years) at the time of imaging. Findings were compared with those of a control group of 25 prepubertal and 25 postpubertal girls and women. Gonadotropin levels were measured. RESULTS: Three patients who underwent whole abdomen radiotherapy had elevated levels of gonadotropin and primary ovarian failure. Neither ovary was seen in two of the three patients and both ovaries were abnormally small (< or = 1 cm3) in the third patient. The uterus was abnormally small (length, < or = 4 cm) in all three of these patients even though two were being treated with hormone replacement therapy. Ten postpubertal patients who underwent hemiabdomen radiotherapy had normal gonadotropin levels and a normal-sized uterus on sonography; the ovary on the side that received radiotherapy was not seen in three of the 10 patients or was abnormally small (< or = 1.4 cm3) in two of the 10 patients compared with all normal ovaries in the postpubertal control group (p < .0001). One postpubertal patient with bilateral renal bed radiotherapy had normal ovaries and a normal-sized uterus. Significantly more patients in the postpubertal and ovarian failure radiotherapy group (5 [36%] of 14 patients) had one or both ovaries not seen than the control group (none [0%] of 25 patients; p = .0014). The uterus was significantly smaller than normal in three (23%) of the 13 patients in the postpubertal hemiabdomen and ovarian failure radiotherapy group versus none of the 25 patients in the postpubertal control group (p = .0339). CONCLUSION: Postpubertal female survivors of Wilm's tumor who underwent radiotherapy as children may have one or two small or absent ovaries and a small uterus that can be detected by sonography. The response of the uterus to hormone replacement therapy can also be assessed on sonography.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

PURPOSE: The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS: Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS: Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION: The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control.

BACKGROUND: The diencephalic syndrome (DS), which is manifested by progressive emaciation and failure to thrive in an apparently alert, cheerful infant, usually is due to a low grade hypothalamic glioma. Treatment with aggressive surgery and/or radiotherapy is variably successful in controlling disease and may result in severe neurologic sequelae. Chemotherapy recently has been shown to be effective in patients with low grade gliomas of childhood, but it is used infrequently in those with DS. METHODS: The authors evaluated the efficacy of a regimen of carboplatin and vincristine on improving weight, causing tumor shrinkage, and delaying the need for alternative therapies in seven children (ages 9-20 months; median age, 11 months) with DS. Five patients weighed less than the 5th percentile for their age at the start of the study, one weighed within the 10th percentile, and one weighed within the 25th percentile. RESULTS: At follow-up (range, 6-54 months; median, 28 months), the patients' weights had increased by 66-95% (median, 80%). On magnetic resonance imaging, four patients had a >50% reduction in tumor mass, one had a 25-50% reduction, and two had stable disease. In those patients with radiographic response to treatment, weight gain was accomplished with oral feedings in four of five patients, whereas those with stable disease required nasogastric, nasojejunal, or gastrostomy tube supplementation to maintain weight. Disease progression occurred at a median of 24 months after initiation of chemotherapy, and two patients remained free of progressive disease at last follow-up. Five patients were alive a median of 59 months from diagnosis. The need for radiation or other therapies was delayed in six of seven children. Therapy was tolerated without significant toxicities. CONCLUSION: The authors conclude that treatment of DS with a carboplatin and vincristine regimen results in demonstrable weight gain, may result in tumor shrinkage, and in some cases, significantly delays the need for alternative therapies.

Cancer in human immunodeficiency virus-infected children: a case series from the Children's Cancer Group and the National Cancer Institute.

PURPOSE: To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. METHODS: We retrospectively surveyed the Children's Cancer Group (CCG) and the National Cancer Institute (NCI) for cases of cancer that occurred between July 1982 and February 1997 in children who were HIV seropositive before or at the time of cancer diagnosis. We used Kaplan-Meier survivorship curves, hazard function estimates, and Cox proportional hazards models to evaluate survival. RESULTS: Sixty-four children (39 boys, 25 girls) with 65 tumors were reported. Thirty-seven children (58%) acquired HIV infection vertically (median age at cancer diagnosis, 4.3 years); 22 children (34%) acquired HIV through transfusion of blood or blood products (median age at cancer diagnosis, 13.4 years). Forty-two children (65%) had non-Hodgkin's lymphoma (NHL). Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. Other malignancies included acute leukemia (five children), Kaposi's sarcoma (KS; three children), Hodgkin's disease (two children), vaginal carcinoma in situ (one child), and tracheal neuroendocrine carcinoma (one child). Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The average monthly death rate after NHL diagnosis was 12% in the first 6 months, which decreased to about 2% thereafter. In contrast, the monthly death rate after leiomyosarcoma diagnosis increased from 5% in the first 6 months to about 20% thereafter. CONCLUSION: After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates; improved outcome for NHL, in particular, may depend on earlier diagnosis and therapy.

The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society.

The frequency of Langerhans cell histiocytosis (LCH) and a malignant neoplasm occurring in the same individual appears to be greater than previously recognized. To define the occurrence and the pattern of these events, a Study Group of the Histiocyte Society initiated a registry of patients in whom this association occurred synchronously or asynchronously. Evaluation of 54 patients detected two patterns of associations between LCH and other disorders. First, it is possible that therapy of LCH promotes a secondary malignancy. Second, it is possible that a genetic predisposition, with or without the immunosuppression associated therapy for the malignancy, plays a role in the development and expression of disseminated LCH. Data collected by the LCH-Malignancy Study Group may provide insights into the etiology and pathophysiology of LCH.

The epidemiology of Langerhans cell histiocytosis.

Little progress has been made in finding the causes of LCH. Epidemiologic studies are difficult because of the rarity of this disease. Although several associations have been demonstrated in case-control studies, particularly that with thyroid disease, no causal relationships have been documented. Additional case-control studies may uncover the to-date missing lead that may prove fruitful for epidemiologic investigation.

Increased incidence of cancer in infants in the U.S.: 1980-1990.

BACKGROUND: During the decade between 1980-1990, the rate of cancer in children in the U.S. increased. It is unknown whether cancer in infancy, which is biologically and clinically different from cancer in older children, also increased. METHODS: To evaluate changes in cancer incidence in infants in the U.S. age < 1 year, data from the Surveillance, Epidemiology, and End Results (SEER) program and the U.S. Bureau of the Census were used to construct age specific, population-based cancer incidence rates. RESULTS: Overall, the annual cancer rate in infants increased from 189 cases per million infants between 1979-1981 to 220 between 1989-1991. At both timepoints, female infants had higher cancer rates than male infants. Although the rates for female infants remained stable at 223 between 1979-1981 versus 236 between 1989-1991, rates for male infants increased from 158 to 205 during the same timepoints. Male infants had increased rates of central nervous system (CNS) tumors (P < 0.05), neuroblastoma, and retinoblastoma; female infants had increased rates of teratomas (P < 0.01) and hepatoblastomas. Between 1979-1981, the three most common types of cancer in infants were neuroblastoma, leukemia, and renal tumors (27%, 15%, and 14%, respectively), and were neuroblastoma, CNS tumors, and leukemia between 1989-1991 (27%, 15%, and 13%, respectively). CONCLUSIONS: This study shows that the rate of certain types of cancer in infants in the U.S. is increasing. Studies of both genetic and environmental factors are needed to explain these increased rates and the changing distribution of cancer in the first year of life.

Pathways Linking Treatment Intensity and Psychosocial Outcomes among Adult Survivors of Childhood Leukemia.

To determine the pathways between treatment intensity (age at diagnosis, dosage of chemotherapy [intrathecal methotrexate; IT-MTX] and cranial radiation [CRT]) and various psychosocial outcomes, review of medical records and structured interviews were carried out in 510 adult survivors of childhood leukemia. Structural equation modeling revealed that higher treatment intensity during childhood (indicated by treatment with high-dose CRT, low-dose IT-MTX, and adjusted by younger age at diagnosis) predicted more health- compromising behaviors as adults through lower educational achievement. Additionally, higher childhood treatment intensity predicted current negative mood both directly and via changes in perceived limitations. The present study's findings suggest that higher treatment intensity during childhood may serve as a risk factor for adult survivors' health-compromising behaviors through neuropsychological deficits that arise from cancer treatment.

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

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

Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas.

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 +/- 6% at 2 years and 68 +/- 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 +/- 11% vs. 75 +/- 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 +/- 7% compared with a rate of 39 +/- 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

Comparison of psychologic outcome in adult survivors of childhood acute lymphoblastic leukemia versus sibling controls: a cooperative Children's Cancer Group and National Institutes of Health study.

PURPOSE: To determine psychologic outcome, with the focus on emotional or mood state, of young adult survivors of childhood acute lymphoblastic leukemia (ALL) compared with sibling controls and to identify vulnerable subgroups at highest risk for negative mood. PATIENTS AND METHODS: Adult survivors (n = 580), aged > or = 18 years, who were treated before age 20 years on Children's Cancer Group (CCG) protocols for ALL and 396 sibling controls were administered a structured telephone interview and the Profile of Moods State (POMS), a standardized measure of affective state. RESULTS: Survivors had higher total mood scores (which indicates greater negative mood) than sibling controls (P<.01) and reported more tension (P< .01), depression (P<.01), anger (P<.01), and confusion (P<.01), but not more fatigue or less vigor. Female, minority, and unemployed survivors reported the highest total mood disturbance. Overall, survivors were more likely to be unemployed (P<.05) or working less than half-time (P<.01) compared with controls. CONCLUSION: This large, sibling-controlled, multisite study of young adult survivors of childhood ALL treated on CCG protocols after 1970 found significant increased negative mood in survivors, not accounted for by reported energy level differences, which suggests that these emotional effects are not likely the result of current illness. Survivors are less likely to be fully employed. Female, minority, and unemployed survivors are at greatest risk for emotional sequelae, a finding that indicates the need for targeted, preventive intervention.

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.

Uterine anomalies in Wilms' tumor survivors.

BACKGROUND: The association between Wilms' tumor (WT) and genitourinary (GU) anomalies has long been appreciated; however, associated GU anomalies have been described almost exclusively in males. METHODS: To investigate whether females with WT also have an increased prevalence of GU anomalies, the authors evaluated the uterine anatomy of 24 WT survivors using magnetic resonance imaging and ultrasonography. RESULTS: Two of 24 female survivors (8%) had anomalies. One had a septate uterus, and a limited molecular analysis of her constitutional DNA revealed no mutations or deletions of the tumor suppressor gene WT1. Another survivor with the WAGR syndrome (WT, aniridia, GU anomalies, and retardation), with the characteristic 11p13 deletion including WT1, had a uterine anomaly (hypoplastic vs. unicornuate). CONCLUSIONS: Because uterine malformations are rare in the general population, this finding suggests an association between WT and uterine malformations and also may partially explain the fertility deficit previously demonstrated in adult female WT survivors. Pelvic ultrasonography in adult female WT survivors can alert survivors and clinicians to possible fertility problems that may lead to problem pregnancies and adverse pregnancy outcomes.

Maternal and perinatal risk factors for childhood brain tumors (Sweden).

Childhood brain tumors (CBT) include a diversity of rare neoplasms of largely unknown etiology. To assess possible maternal and perinatal risk factors for CBT according to subtype, we carried out a nested (within Swedish birth-cohorts, 1973-89) case-control study, utilizing data from the nationwide Birth Registry. We ascertained incident brain tumor cases through linkage of the nationwide Birth and Cancer Registries and randomly selected five living controls from the former, matching each case on gender and birthdate. There were 570 CBT cases, including 205 low grade astrocytomas, 58 high grade astrocytomas, 93 medulloblastomas, 54 ependymomas, and 160 'others.' Risks for all brain tumors combined were elevated in relation to: (i) three maternal exposures-oral contraceptives prior to conception (odds ratios [OR] = 1.6, 95 percent confidence interval [CI] = 1.0-2.8), use of narcotics (OR = 1.3, CI = 1.0-1.6), or penthrane (OR = 1.5, CI = 1.1-2.0) during delivery); (ii) characteristics of neonatal distress (a combined variable including low one-minute Apgar score, asphyxia [OR = 1.5, CI = 1.1-2.0]) or treatments for neonatal distress (use of supplemental oxygen, ventilated on mask, use of incubator, scalp vein infusion, feeding with a jejunal tube [OR = 1.6, CI = 0.9-2.6]); and (iii) neonatal infections (OR = 2.4, CI = 1.5-4.0). Higher subtype-specific risks, observed for a few risk factors, did not differ significantly from the risk estimates for all subtypes combined for the corresponding risk factors. Childhood brain tumors were not associated significantly with other maternal reproductive, lifestyle, or disease factors; perinatal pain, anesthetic medications, birth-related complications; or with birthweight, birth defects, or early neonatal diseases. These findings suggest several new leads, but only weak evidence of brain tumor subtype-specific differences.

Birth defects in offspring of adult survivors of childhood acute lymphoblastic leukemia. A Childrens Cancer Group/National Institutes of Health Report.

BACKGROUND: It is not known if therapy for acute lymphoblastic leukemia (ALL) during childhood increases the risk of birth defects in the offspring of adult survivors. The Childrens Cancer Group (CCG), in collaboration with the National Institutes of Health (NIH), conducted a retrospective cohort study of adults successfully treated for childhood ALL to determine if their offspring had an increased incidence of birth defects compared with the offspring of their sibling controls. METHODS: Study subjects were patients who had been enrolled on CCG ALL protocols, who were treated for ALL prior to age 20, who survived at least 2 years, and who were at least age 18. Survivors (N=593) and sibling controls (N=409) were interviewed by telephone. RESULTS: The mean age of survivors was 22.6 years; the mean age of controls was 25.2 years. Among survivors, 93 (15.7%) had given birth to or fathered a total of 140 live-born offspring, (mean age, 3.4 years), and 122 (29.8%) sibling controls had given birth to or fathered a total of 228 live-born offspring (mean age, 5.9 years). There was no difference in the rate of birth defects between offspring of survivors and offspring of controls (3.6% [5 of 140] vs. 3.5% [8 of 228]; relative risk, 1.02; 95% confidence interval, 0.34, 3.05). No specific ALL therapy was associated with an increased rate of birth defects. Only female survivors reported offspring with birth defects (P=0.0735). CONCLUSIONS: Adult survivors of childhood ALL in our study were not at greater risk for having offspring with birth defects compared with sibling controls. Although this is the largest group of ALL survivors studied to date, the number of offspring is still not large enough to detect small but significant differences in rare events such as birth defects. Studies following this cohort into later adulthood and studies of additional ALL survivors are necessary to adequately quantify the risks.

Treatment of children with newly diagnosed brain stem gliomas with intravenous recombinant beta-interferon and hyperfractionated radiation therapy: a childrens cancer group phase I/II study.

BACKGROUND: Prognosis for the majority of children with brain stem gliomas is dismal. In previous studies, recombinant beta-interferon (r beta IF) has been shown to be effective for children with recurrent brain stem gliomas and may also act synergistically with radiotherapy (RT). METHODS: Thirty-two children with diffuse intrinsic brain stem gliomas were treated with (r beta IF) and 7200 centigray (cGy) of hyperfractionated RT (100 cGy twice-daily fractions) to determine the toxicity of treatment and the tolerance of the brain stem to this regimen, as well as to assess survival. Patients were treated with r beta IF 3 times per week during RT and then for 8 weeks following RT. Initially, a dose escalation trial was performed. RESULTS: Interferon was initially begun at 12.5 x 10(6) IU/m2 and escalated up to 400 x 10(6) IU/m2. The safe starting dose was determined to be 100 x 10 (6) IU/m2. Due to unacceptable toxicity, the maintenance dose was reduced to 200 x 10 (6) IU/m2. Therapy was relatively well tolerated, although 13 of the patients required dose modifications due to hepatic or hematologic toxicity. Four of the patients had to discontinue treatment due to this toxicity. One patient died while receiving maintenance IF of encephalopathy, seizures, and brain stem dysfunction; believed possibly due to the r beta IF. Thirty of the 32 patients have developed progressive disease. The median time to progression from study entry was five months and the median time to death was 9 months. CONCLUSIONS: We conclude that r beta IF plus hyperfractionated therapy can be tolerated by children with newly diagnosed brain stem gliomas, although there is occasional dose-limiting hepatic, blood, and central nervous system toxicity. This therapy did not result in a higher rate of disease control.

'Complicated migraine-like episodes' in children following cranial irradiation and chemotherapy.

Neurologic sequelae may occur months to years after cranial irradiation. The site of primary damage is probably the vascular endothelium. Over a 2.8-year period, four children with brain tumors, a mean of 11 years of age at diagnosis (range, 6.5 to 15.5 years), had new onset of severe intermittent unilateral headaches associated with nausea, episodic visual loss, hemiparesis, aphasia, or hemisensory loss. The headaches lasted 2 to 24 hours. All patients had previously received whole-brain (2,400 to 3,600 cGy) and additional local boost (1,800 to 3,100 cGy) cranial irradiation, as well as cisplatin-, lomustine-, and vincristine-containing chemotherapy regimens. Symptoms began 1.2 to 2.8 years after the diagnosis, when all had stable disease and were off treatment. MRI studies were unchanged, and CSF cytology, EEGs, echocardiograms, and magnetic resonance angiograms were normal in all. Cerebral angiograms, performed in three children, were normal but led to severe headaches and neurologic deficits (hemiparesis in one and visual loss in two) that resolved after 24 to 48 hours. Response to antimigraine and antiplatelet medications was variable. We conclude that (1) "complicated migraine-like episodes" may occur in children after cranial irradiation and chemotherapy as a sequela of therapy; (2) these headaches may not be the harbinger of impending strokes, severe intracranial vasculitis, or tumor recurrence; and (3) while cerebral angiography may be useful in differential diagnosis, it may cause transient worsening of symptoms.