Faculty Bibliography

Regional glucose metabolic rate constants and blood-to-brain transport of rubidium were estimated using positron emission tomography in an adolescent patient with a brain tumor, before and after chemotherapy with intravenous high-dose methotrexate. Widespread depression of cerebral glucose metabolism was apparent 24 hours after drug administration, which may reflect reduced glucose phosphorylation, and the influx rate constant for 82Rb was increased, indicating a drug-induced alteration in blood-brain barrier function. Associated changes in neuropsychological performance, electroencephalogram, and plasma amino acid concentration were identified in the absence of evidence of systemic methotrexate toxicity, suggesting primary methotrexate neurotoxicity

Primary CNS germ cell tumors present several biologic and therapeutic concerns. Their predilection to midline locations (pineal and suprasellar) has discouraged until recently attempts at biopsy, much less radical surgical resection. Their heterogeneity (germinomas, embryonal carcinoma, endodermal sinus tumor, choriocarcinoma and malignant teratoma) has made uniform treatment planning unrealistic. Their rarity (less than 50 cases per year in USA) precludes a large institutional experience. More recently, with the use of microsurgical techniques, major resections are possible and accurate pretreatment histologic diagnosis can be established. Following surgery, patients should be staged with cerebrospinal fluid (CSF) cytology, serum and CSF tumor markers (alpha-fetoprotein and human beta-chorionic gonadotrophin) and myelography. The majority of patients will present with disseminated disease and require craniospinal radiotherapy. Chemotherapy should eventually prove to be an effective adjuvant treatment modality, not only for the highly radiosensitive germinoma with a good prognosis (5-year survival greater than 60%) following radiotherapy alone, but also for the radioinsensitive nongerminoma germ cell variants where longterm survival is unusual. Chemotherapy agents such as cyclophosphamide, cisplatin, vinblastine, VP-16 and bleomycin appear to be useful for patients with newly diagnosed and recurrent disease

The growth hormone (GH) responses to (A) GRF 1-44, 1 microgram/kg i.v., (B) L-dopa and either arginine, insulin, or glucagon, and (C) exercise were evaluated in 10 children (3 girls, 7 boys; ages 10 years to 15 years, 8 months), 2-10.75 years following cranial irradiation for medulloblastoma (8 patients), pineoblastoma (1 patient), and a fourth ventricular ependymoma (1 patient). Nine of the 10 children had abnormal growth rates. All children were euthyroid at the time of the study. The mean 0-60-min peak GH response to GRF (10.06 +/- 2.6 ng/ml) in the patients was less than the mean peak GH response (29 +/- 2.3 ng/ml) in the control children (n = 7). In 6 patients (5 with poor growth rates), a decreased GH response was noted to GRF and all other tests. Of the remaining patients, all with poor growth rates, two patients demonstrated an adequate response to GRF and pharmacologic testing; one patient had a normal GH response to GRF with a low GH response to pharmacologic testing; and one patient had a low response to GRF, despite a normal response to both exercise and pharmacologic testing. The decrease in mean peak GH response to GRF in the patient population confirms that radiation to the hypothalamic-pituitary region produces abnormalities in growth hormone release. Furthermore, in these patients, discordant GH responses to GRF and pharmacologic or physiologic tests can be observed. The abnormality in growth hormone release may result from a hypothalamic dysfunction in GRF release and/or damage to GH secretory pituicytes

PCNU, the latest nitrosourea analogue to be subjected to clinical trials, held promise as a superior chemotherapy agent for brain tumors because of more favorable biochemical and cytotoxic characteristics in laboratory studies. Thirty-nine children with a variety of recurrent primary CNS tumors, all of whom had evaluable disease, participated in a phase II PCNU trial. Their mean age was 9.7 (3-20) years. PCNU was administered as a 2 hour intravenous infusion in one of 2 dose schedules at 6-7 week intervals; 100-125 mg/m2 for minimally treated patients and 70-90 mg/m2 for heavily treated patients. Response was assessed after 2 courses of chemotherapy after attempting to taper the steroid dose. The overall objective response rate was 18% (7/39) for a mean of 5.9 months (2+ -12). Only partial responses were observed. Disease-specific responses rates were: brainstem glioma--18% (3/17); cerebral glioma--27% (3/12); ependymoma--1/1; and primitive neuroectodermal tumors--(0/9) including 5 medulloblastomas, 2 pineoblastomas and 3 cerebral primitive neuroectodermal tumors. Toxicity was primarily hematologic and clinically significant thrombocytopenia (less than 50,000 mm3) was encountered in 30/38 (79%) patient trials. Modest activity of PCNU in recurrent childhood gliomas is confirmed. Our response rates, using objective CT criteria, are somewhat lower than those reported for BCNU and CCNU. Because of comparable hematologic toxicity and efficacy, intravenous PCNU does not appear to offer a clinical advantage to existing nitrosoureas for children with recurrent brain tumors using a 2 hour intravenous infusion schedule

Invasion of the meninges is a relatively common complication of head and neck rhabdomyosarcoma (RMS), while RMS arising primarily within the brain or meninges is rare. We report the case of an 11-year old child with a primary 'primitive' frontal lobe tumor, subsequent leptomeningeal spread and fatal intratumoral hemorrhage; the diagnosis of RMS was discovered only at postmortem examination. The literature contains a total of 34 reported cases of primary intracranial RMS. This tumor has been observed to arise in a variety of central nervous system (CNS) locations in patients of all ages, but most commonly within the posterior fossa of children. Leptomeningeal dissemination and spontaneous intratumoral hemorrhage are important clinical features. Postoperative chemotherapy and craniospinal radiation may improve the anticipated poor prognosis of patients treated with surgery and radiation alone. The diagnosis of RMS may be missed unless electron microscopic and specific immunohistochemical studies are applied to 'undifferentiated' or 'primitive' CNS tumors

A transient acute neurologic syndrome occurred in 22 patients receiving high-dose methotrexate (HDMTX) (8 to 9 g/m2) for a variety of malignancies. The neurologic signs were similar in all cases. The syndrome occurred an average of six days after the second or third weekly treatment. Common findings included behavioral abnormalities, focal sensorimotor signs, and abnormal reflexes. Signs often alternated from one side to the other. Evaluations including computed tomography (CT) scan, lumbar puncture, hemogram, and blood chemistry were normal. The EEG revealed some slowing in all cases. The cause of this syndrome is unknown. It is transient and usually does not recur. Its appearance does not preclude further treatment with HDMTX

Intravenous high-dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high-dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high-dose methotrexate neurotoxicity in the rat characterized by a profound dose-dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographic abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high-dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions

Endocrine evaluations were performed prospectively in 22 patients with medulloblastoma (ages 2 1/2 to 23 1/2 years at diagnosis), after craniospinal radiation with or without adjuvant chemotherapy. The mean craniospinal hypothalamic-pituitary). and thyroid radiation doses were 3600 and 2400 rads, respectively. Fourteen (73%) of 19 patients who had not yet completed their growth experienced a decrease in growth velocity. However, only three of 10 of these children, who underwent growth hormone stimulation tests, had evidence of deficient growth hormone responses, suggesting that growth hormone secretory or regulatory dysfunction, rather than absolute growth hormone deficiency, is present in the majority of these children. Elevated thyroid-stimulating hormone levels were noted in 15 of 22 patients; one patient had hypothalamic hypothyroidism. Thus, the late effects of therapy for medulloblastoma include frequent endocrine morbidity involving hypothalamic-pituitary and thyroid dysfunction