"Large cell/anaplastic" medulloblastomas: a Pediatric Oncology Group Study.

495 medulloblastomas (MBs) from 6 Pediatric Oncology Group (POG) protocols were reviewed to assess the incidence and prognostic significance of "large cell" and "anaplastic" variants. "Large cell" medulloblastomas (LC MBs) were those with focal or diffuse, large, round neoplastic cells with prominent nucleoli. "Anaplastic" MBs (A MBs) were those with nuclei that were also large but markedly atypical with coarse chromatin and irregular shapes. Twenty-one cases were identified in the combined LC/A MB group, comprising about 4% of all MBs. Survival curves and Kaplan-Meier estimates of survival probabilities were examined separately for the LC/A MB and control groups. The logrank test for detecting poorer survival in the 21 cases was significant (p < 0.0001). Fluorescence in situ hybridization for c-myc showed amplification in 4 of 11 cases of the LC/A phenotype and 1 additional case of high level gain at 8q24 was disclosed by comparative genomic hybridization. Comparative genomic hybridization confirmed c-myc amplification and found evidence for isochromosome 17q in 3 of 4 LC/A cases studied successfully. One additional tumor showed high level gain restricted to 2p13 consistent with n-myc amplification. Monosomy 22, common in atypical teratoid/rhabdoid tumors, was not found. These results suggest that LC/A MB phenotype could be, at least in part, a correlate of c-myc, and possibly n-myc, amplification. The study thus confirms original observations about the LC MB in regard to histological features, immunohistochemical findings, c-myc amplification, cytogenetic findings, and poor prognosis.

Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.

PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.

Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy of Pediatrics.

Febrile seizures are the most common seizure disorder in childhood, occurring in 2-5% of children. Despite their frequency, there has been little unanimity of opinion regarding the need for long-term antiepileptic therapy. As such, the American Academy of Pediatrics formulated a subcommittee to study the subject. A Practice Parameter was developed that addressed the issue of whether continuous or intermittent antiepileptic therapy is necessary for children with simple febrile seizures. The committee determined that with the exception of a high rate of recurrence, no long-term adverse effects of simple febrile seizures have been identified. The risk of developing epilepsy is extremely low and, even in those patients who do, there is no evidence that recurrent simple febrile seizures produce structural central nervous system damage. Also, there is no evidence that recurrent simple febrile seizures cause either learning problems or premature death. The committee concluded that although there is the evidence that continuous antiepileptic therapy with phenobarbital or valproic acid and intermittent therapy with diazepam are effective in reducing the risk of recurrence, the potential toxicities associated with antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term treatment is not recommended.

Carboplatin is effective therapy for young children with progressive optic pathway tumors: a Pediatric Oncology Group phase II study.

The Pediatric Oncology Group conducted a phase II study to evaluate the activity of carboplatin in children 5 years or younger with progressive optic pathway tumors (OPTs). Of the 51 patients accrued to this study, 1 was not eligible because the child was older than 6 years. Fifty patients were eligible and had either neuro-imaging or symptomatic evidence of progressive OPTs. Twenty-one of 50 had evidence of neurofibromatosis type I (NF-1). Therapy consisted of carboplatin 560 mg/m2 at 4-week intervals. Patients with stable disease or better after two courses were continued on therapy for 18 months or until progressive disease. Of the 50 eligible children, 39 had stable disease or better, and 34 completed the 18-month therapy. Our data are sufficient to conclude that the proportion of objective responses (complete, partial, or minor response or stable disease) exceeded 30% (P < 0.00001), and the approximate 95% confidence interval estimate of the objective response rate was 0.665 to 0.895. Twenty-one patients went off protocol because of progressive disease. Fifteen patients progressed during the 18-month therapy, and 6 patients progressed after completing therapy. Six children died with progressive disease. Major toxicities were neutropenia and thrombocytopenia, and 3 children experienced allergic reactions. Carboplatin is active and safe for the treatment of young children with progressive OPTs. The addition of other potentially active drugs may further increase the event-free survival for these children.

Human herpesviruses types 6 and 7 and febrile seizures.

The frequency was studied with which human herpesviruses types 6 and 7 (HHV-6 and HHV-7) occur in the cerebrospinal fluid (CSF) of patients with febrile seizures and matched control patients. CSF samples were prospectively collected from a case series of patients with febrile seizures and from age-, sex-, and race-matched control patients without febrile seizures, all of whom were evaluated in the emergency department of an urban, tertiary care, pediatric medical center. Using polymerase chain reaction, the samples were examined for the presence of viral DNA from HHV-6, HHV-7, herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), and cytomegalovirus (CMV). CSF from a subset of both groups was also examined for RNA from enteroviruses. During the 7-month, 2-week collection period, a total of 174 patients were evaluated for fever and seizures. Of these, 23 (13.2%) met the study criteria. Their mean age was 1.4 +/- 0.7 years. Sixteen (70%) of the 23 were male. The 23 patients were matched to 21 control subjects. None of the samples from the patients or control subjects had polymerase chain reaction evidence of HHV-6, HHV-7, HSV-1, or HSV-2. All samples from the patients were negative for CMV. One control subject was positive for CMV. The 10 patients and seven control subjects tested for enteroviral RNA were negative. Neither HHV-6 nor HHV-7 appears to be present in the CSF of patients with febrile seizures. What role, if any, they have in the pathogenesis of febrile seizures merits further study.

Prognostic factors in infants and very young children with intracranial ependymomas.

The Pediatric Oncology Group (1986-1990) conducted a study in which 48 children <3 years of age with intracranial ependymomas were treated with prolonged postoperative chemotherapy (CT) and delayed RT. Thirty-one children, 0-23 months of age at diagnosis (Gp A) received 2 years of CT followed by RT; while 17 children, 24-36 months of age at diagnosis (Gp B) received CT for 1 year followed by radiation. One-year survivals were 87% (Gp A) and 94% (Gp B) and 2-year survivals were 67% (Gp A) and 82% (Gp B). In subsequent years a significant divergence in survivals according to age has been noted (p = 0.04). Five-year survivals were 25.7% (Gp A) vs. 63.3% (Gp B). The curves began to diverge 1 year following diagnosis. Other than age, the only significant prognostic factor was degree of surgical resection: 5-year survivals were 66% (total resection) vs. 25% (subtotal resection). Neither the presence of metastases, degree of anaplasia nor the degree of surgical resection varied significantly according to age at diagnosis. The most likely reason for the difference in survivals between the two age groups relates to the timing of radiation following CT, i.e., 1-year delay in children 24-36 months of age compared to a 2-year delay in children 0-23 months of age. An alternative but less likely hypothesis is that ependymomas in the younger children have a more aggressive biology. In contrast, survivals in the 24- to 36-month group are much better than previous reports in the literature suggesting that prolonged postoperative CT may allow both a delay in CRT as well as provide improved survivals. Based on these results, future treatment trials should emphasize maximal surgical resection and a delay in radiation of no more than 1 year.

Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study.

Fifty-five patients with atypical teratoid/rhabdoid tumors of the central nervous system were studied to define the clinical and pathologic features of this newly described neoplasm. The lesion occurred primarily in children younger than 2 (mean age at diagnosis, 17 months). The neoplasms were located in the posterior fossa (36 patients) and the supratentorial compartment (17 patients) or were multifocal in both compartments (2 patients) at presentation. Histologically, the tumors were composed of small cells and large, pale cells in a jumbled architectural arrangement. The small cell component resembled medulloblastoma and occasionally had cords of cells in a mucinous background, simulating chordoma. The cytoplasm of the larger cells was conspicuous with a somewhat "rhabdoid" appearance, although rhabdoid features were not always prominent. Epithelioid features in the form of poorly formed glands or Flexner-Wintersteiner rosettes were noted in a minority of lesions. The neoplasms showed striking polyphenotypic immunoreactivity, including that for vimentin, glial fibrillary acidic protein, epithelial membrane antigen, cytokeratins, synaptophysin, chromogranin, and smooth muscle actin. Using a probe for chromosome 22, seven of eight scorable cases showed a solitary signal by fluorescence in situ hybridization (FISH) consistent with monosomy 22. The eighth scorable case showed three signals by fluorescence in situ hybridization and had a translocation involving chromosome 22 reported by conventional cytogenetics. In contrast to patients with medulloblastoma, the neoplasm with which these lesions are often confused, the outcome of the patients was uniformly poor. The mean postoperative survival of patients with atypical teratoid/rhabdoid tumors was only 11 months. Local recurrence, seeding of the cerebrospinal fluid pathways, or both, were common terminal events. This study underscores the distinctive clinical, histopathologic, immunohistochemical, and cytogenetic character of this unusually aggressive tumor.

Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study.

Between 1986 and 1990, the Pediatric Oncology Group conducted a study in which 198 children younger than 3 years of age with malignant brain tumors were treated with prolonged postoperative chemotherapy in an effort to delay irradiation and reduce long-term neurotoxicity. Children younger than 2 years of age received 24 months of chemotherapy followed by irradiation, and those between 2 and 3 years of age received 12 months of chemotherapy plus irradiation. Chemotherapy was given in 28-day cycles (AAB, AAB), with cycle A = vincristine (0.065 mg/kg) intravenously on days 1 and 8 and cyclophosphamide (65 mg/kg) intravenously on day 1, and cycle B = cisplatinum (4 mg/kg) intravenously on day 1 and etoposide (6.5 mg/kg) intravenously on days 3 and 4. Five of the 198 children developed second malignancies, with a cumulative risk at 8 years of 11.3% (95% confidence interval [CI], 0-39%). Four of the five second malignancies occurred in children younger than 2 years of age at diagnosis, with a cumulative risk at 8 years of 18.9% (CI, 0-70%). Initial diagnoses were choroid plexus carcinoma (2 children), ependymoma (1 child), desmoplastic infantile ganglioglioma (2 children), and medulloblastoma (1 child). Duration from diagnosis of initial tumor to second malignancy was 33, 35, 57, 66, and 92 months. Three children younger than 2 years of age developed lymphoproliferative disease, that is, myelodysplastic syndrome (2 children), both with monosomy 7 deletions, and acute myelogenous leukemia (1 child), after 24 to 26 cycles of chemotherapy, including 8 cycles of etoposide. Two of 3 received craniospinal irradiation (2,560/3,840 cGy) and (3,520/5,320 cGy). Time to second malignancy was 7 years 8 months, 4 years 9 months, and 2 years 9 months. Two children developed solid tumors, at 5 years 6 months and 2 years 11 months, respectively, after initiation of treatment. A sarcoma developed after 26 cycles of chemotherapy and no irradiation, and a meningioma developed after 12 cycles of chemotherapy and local craniospinal irradiation. Potential causative factors for this high rate of secondary malignancies include prolonged use of alkylating agents and etoposide with or without irradiation.

Acquired oral reading vocabulary following the onset of amnesia in childhood.

While the neuropsychological literature includes few cases of child-onset amnesia, 2 previous case studies suggest that these patients may be able to learn new information of a semantic or academic nature. The previous studies were, in large part, based on neuropsychological testing performed during adulthood and a retrospective review of academic achievement test scores during childhood. We present patient A.C., who acquired severe anterograde amnesia at age 10 years but demonstrated average levels of performance on tests of reading, spelling and arithmetic upon examination at age 19 years. Episodic and semantic memory test scores were severely impaired, but near normal performances were found on tests of implicit and procedural memory. In a prospective study, A.C. learned to read new irregular and pseudowords and retained this learning over a 1-month period, similar to the performance of age-matched controls. This demonstration of postmorbid, acquired oral reading vocabulary supports a previous conclusion that oral reading can progress in childhood following the onset of severe anterograde amnesia. The data also suggest that this new learning probably reflects nondeclarative memory processes rather than preservation of semantic memory, as was proposed in an earlier case study.

Clinical and neuroradiologic findings in infants with intracranial ependymomas. Pediatric Oncology Group.

Typical clinical characteristics, neuroradiologic findings, and initial neuroradiologic studies were reviewed for 40 patients <3 years of age with intracranial ependymomas, who were treated in the Pediatric Oncology Group (prolonged postoperative chemotherapy and delayed radiation for children <3 years of age with malignant brain tumors). The study included 16 females and 24 males, aged 3 to 35 months, who were diagnosed and registered in the study between 1986 and 1990. Commonly, patients presented with vomiting (70%), ataxia (53%), headache (28%), lethargy (28%), increased head circumference (23%), and irritability (23%). Duration of symptoms before diagnosis ranged from 1 day to 11 months. Thirty-five tumors (88%) were infratentorial; average tumor size was 4.3 (+/-1.4) x 4.2 (+/-1.7) x 4.1 (+/-1.8) cm at presentation. Noncontrast CT scans were performed on 23 patients; 13 (57%) were isodense to surrounding brain tissue and 13 (57%) were calcified. Contrast CT scans of 29 patients revealed that 28 (97%) were enhanced. Of the 15 T1-weighted MRI scans, 10 (67%) demonstrated low-signal intensity tumors, and 15 (94%) of the 16 T2-weighted scans revealed high-signal tumors. Forty-three percent of the tumors were cystic. Blood was observed within only 2 tumors and peritumoral edema was uncommon. Twenty-five percent of the ependymomas extended out to involve the dura, and 97% of the infratentorial tumors showed characteristic plasticity. Hydrocephalus was present in 34 (85%) children.

Response of recurrent medulloblastoma to low-dose oral etoposide.

PURPOSE: The outcome for patients with recurrent medulloblastoma has historically been poor, with most patients dying of disseminated disease. Here, we report on seven patients with recurrent medulloblastoma, most heavily pretreated with a variety of chemotherapeutic agents, including parenteral etoposide (VP-16), who showed responses to the administration of repeated courses of low-dose oral VP-16. PATIENTS AND METHODS: Seven patients age 4 to 16 years were treated with VP-16 after neuroradiographic and clinical evidence of tumor progression. Six had received prior irradiation. All seven had been pretreated with a variety of chemotherapeutic agents and schedules, including parenteral VP-16. VP-16 was administered orally as repeated 21-day courses at 50 mg/m2/d with a 7-day interval between courses. Evaluation consisted of neuroradiographic and clinical examination after completion of every two courses of therapy. Complete blood cell counts were performed weekly. RESULTS: The major toxicity of oral VP-16 was hematologic, with two patients requiring platelet transfusions due to thrombocytopenia and two requiring RBC transfusions. All seven patients developed treatment-related neutropenia. Two patients were supported with granulocyte colony-stimulating factor (G-CSF) between courses. One patient developed infectious epididymitis after course 2 and required intravenous antibiotics; this illness was complicated by Clostridium difficile colitis. There was one episode of fever associated with neutropenia. There were no treatment-related deaths. Of seven patients assessed, six have demonstrated partial responses (PRs) and the remaining patient had stable disease (SD). CONCLUSION: This report demonstrates the activity of oral VP-16 in the treatment of a small cohort of pretreated patients with recurrent medulloblastoma. This form of administration of oral VP-16 was well tolerated and produced modest toxicity.

Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience.

Although survivals of infants with malignant brain tumors are worse than any other age group, one possible exception to this rule are the malignant gliomas. Eighteen children less than 3 years of age with malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma and malignant glioma) were treated on the Pediatric Oncology Group regimen of prolonged postoperative chemotherapy and delayed irradiation, (1986-1990). Of 10 children evaluable for neuroradiologic response, 6 had partial responses (> 50% reduction) to two cycles of cyclophosphamide and vincristine. Progression free survivals at 1,3 and 5 years were 54.25% +/- 12, 43% +/- 16 and 43% +/- 23 respectively. Survivals at 5 years were 50% +/- 14. Four children were not irradiated after 24 months of chemotherapy due to parental refusal and none have developed recurrent disease. Neither degree of surgical resection, presence or absence of metastases, nor pathology influenced survival but this may reflect small sample size. This study suggests that some malignant gliomas in infants are chemotherapy sensitive and may be associated with a good prognosis. Why infants with these high-grade gliomas fare better than adults is not clear. It is likely that there is something intrinsically different about them that cannot be identified on routine pathologic examination.

Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma. A Combined Children's Cancer Group-Pediatric Oncology Group Study.

PURPOSE: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T1, T2 and T3A), minimal postoperative residual tumor, and no evidence of dissemination (M0). METHODS AND MATERIALS: Between June 1986 and November 1990, the Children's Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose. RESULTS: Following an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation. CONCLUSIONS: In patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma. Pediatric Oncology Group.

Eleven infants with pineoblastomas were treated with prolonged postoperative chemotherapy in an attempt to delay radiation and reduce neurotoxicity. These infants were part of the Pediatric Oncology Group infant brain tumor study but the outcome of infants with pineoblastomas was not previously reported. Ages ranged from 1 month to 35 months, with eight of 11 < or = 12 months at diagnosis. Four had + cytology and three had + myelograms at diagnosis. The majority had partial surgical resection (25-75% reduction in tumor) and 10 had shunts. Chemotherapy consisted of two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. Craniospinal radiation was planned following completion of either 2 years of chemotherapy (children less than 24 months at diagnosis) or following one year (children 24-36 months at diagnosis). Neuroimaging results following two cycles of cyclophosphamide and vincristine were one partial response, five stable disease, and five progressive disease. There were no responders in the leptomeninges. All children ultimately failed chemotherapy (2 months-11 months). Nine failed in the primary site. Of those eight children in whom a metastatic workup was performed at time of progression, all had evidence of leptomeningeal disease. Six received radiation following failure on chemotherapy. All failed either in the primary site, leptomeninges or extraneurally (peritoneal cavity). All children died. Survival following diagnosis ranged from 4 months to 13 months. This chemotherapy regimen was neither effective in controlling tumor in the primary site nor in treating or preventing leptomeningeal spread.

Postoperative chemotherapy and delayed radiation in infants and very young children with choroid plexus carcinomas. The Pediatric Oncology Group.

Eight infants with choroid plexus carcinomas were treated with surgery, prolonged postoperative chemotherapy and delayed radiation. The results suggest that some infants with choroid plexus carcinomas can be successfully treated with multimodality therapy, even allowing children with less than a gross total resection to have prolonged disease-free intervals.

Etiologies of central diabetes insipidus in children.

The last major review of the etiologies of central diabetes insipidus in children was performed a quarter century ago, prior to the development of modern neuroimaging techniques. We retrospectively reviewed the records of children with central diabetes insipidus identified at Children's Hospital of Buffalo from 1979 to 1992. Of the 35 patients identified, 27 were males and 8 were females. Their ages ranged from 3 weeks to 20 years. Nineteen children had brain tumors, 7 had cerebral malformations, 3 had central nervous system infections, 1 had traumatic brain injury, and 5 were considered idiopathic. Patients with brain death were excluded from the review. Thirty-one of 35 patients developed diabetes insipidus in conjunction with other endocrinopathies. Brain tumor and its treatment account for the most common cause. Cranial magnetic resonance imaging has improved the identification of structural lesions and the understanding of the pathophysiology of central diabetes insipidus.