Biomedical subjects
Publications and source records attributed to R J Packer.
One half of brain tumors in children originate in the posterior fossa. Although a wide variety of lesions occurs, four tumor types account for more than 95% of cases. Knowledge of their modes of presentation, CT and MR features, and pattern of spread can usually lead to a correct diagnosis.
OBJECTIVE: To describe the neurologic manifestations of cocaine exposure in children and adolescents as the neurologic effects of cocaine have been described in adults and neonates. METHODS: During 1-year period, 41 children between the ages of 2 months and 18 years who had been exposed to cocaine, were examined in the emergency department at the Children's National Medical Center. Cocaine exposure was documented on urine samples; all were confirmed by urine gas chromatographic/mass spectrometric analysis. RESULTS: Nineteen (46%) of 41 had neurologic abnormalities, including seizures (7), obtundation (6), delirium (4), dizziness (1), drooling (1), and ataxia (1). In 14 others, the neurologic effects of cocaine were difficult to determine because of other concomitant medical conditions, including head injuries and severe abdominal or chest trauma. Two major age-related patterns were seen: (a) in each child < 5 years of age, seizures and obtundation; and (b) in 11 older children, delirium (3), dizziness (1), drooling (2), and lethargy (4). Seizures, occurring at ages 12 months to 8 years, were focal with secondary generalization in three and generalized in four. They were associated with fever in two children. Six children had no further seizures, and one developed a mixed-seizure disorder. Passive intoxication while being in a room in which "crack" was smoked was the most likely cause of exposure for young victims. Multiple drug abuse was not documented in any child with neurologic impairment. CONCLUSIONS: 1) Cocaine exposure is common in children in our urban setting; 2) neurologic manifestations frequently occur; 3) in children 8 years of age or younger, "passive" ingestion/inhalation is associated with focal and generalized seizures without evidence of structural brain injury; 4) cocaine may lower seizure threshold in children predisposed to seizures; 5) in children > 8 years of age, manifestations are similar to those in adults; 6) trauma and motor vehicle accidents were seen in the adolescent age group exposed to cocaine; and 7) urine toxicological study in cocaine exposure is recommended in all first-time seizures as well as first-time febrile seizures.
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BACKGROUND: Most children with brain stem gliomas (BSG) die within 18 months of diagnosis. Early experience suggested that hyperfractionated radiation therapy (RT) at a dose of 72 Gy, administered in 1-Gy fractions twice daily, possibly improved disease-free survival for children with BSG. METHODS: To better characterize the toxicity and possible efficacy of this dose and fractionation of RT, 53 assessable children with diffuse intrinsic or malignant BSG were treated. Survival figures also were combined with outcome in 36 patients treated in a previous pilot study. RESULTS: An objective response to treatment was observed in 28 of 53 (53%) patients; a partial response occurred in 7. No child died of treatment-related brain necrosis, although 7 of 53 did have intralesional cystic/necrotic changes within 6 weeks of completion of RT. The overall survival rate for patients in the study was 38% (+/- 6.5) at 1 year, 14% (+/- 5.4) at 2 years, and 8% (+/- 6.5) at 3 years. Leptomeningeal dissemination was observed in 4 of 48 (8%) children who had relapses. A greater than 2-month duration of symptoms before diagnosis was related to a better prognosis. There was no statistical association between any other clinical parameter, neuroradiographic finding, or pathologic finding and outcome. Combined with that in 35 patients treated in the pilot study, the survival rate in 88 children was 14% (+/- 5) at 3 years. CONCLUSIONS: The radiographic response rate is encouraging; however, it cannot be concluded that hyperfractionated RT, at this dose schedule and total dose, is superior to conventional RT.
BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.
A 3-year-old girl received conventional-dose external beam posterior fossa irradiation (5400 cGy in 30 fractions over 40 days) for good-risk medulloblastoma. Soon thereafter, she experienced an extraneural (occipital scar, cervical lymph nodes) and central nervous system (CNS) recurrence. Intensive cisplatin and cyclophosphamide chemotherapy led to rapid disappearance of the extraneural disease. Methotrexate was administered via a ventricular reservoir. After 2 months of chemotherapy, CNS toxicity progressed rapidly from ataxia to paraplegia to quadriplegia to central respiratory failure. Radiographic scans and autopsy material revealed brain stem necrosis. This unusual toxicity raises concern about the safety of aggressive systemic chemotherapy and intrathecal therapy, when given after conventional radiotherapy.
BACKGROUND: Children younger than 5 years who have posterior fossa (PF) primitive neuroectodermal tumors (PNET) have a poor prognosis. Because the use of low-dose craniospinal radiation therapy (CSRT) alone has been associated with a higher relapse rate in these patients, and because standard dose CSRT is associated with profound late sequelae, the authors embarked on a study using a combination of low-dose CSRT and adjuvant chemotherapy. METHODS: Between January 1988 and March 1990, ten patients with PF PNET were treated on an institutional pilot trial. The trial included 1800 cGy radiation therapy (RT) to the craniospinal axis, a PF boost to 5040-5580 cGy and chemotherapy consisting of vincristine weekly during RT. This was followed by vincristine, cisplatin, and lomustine for eight cycles administered every 6 weeks. Patients between 18 and 60 months of age without evidence of tumor dissemination were eligible for study. Follow-up is available to October 1992, with a median follow-up of 4 years from diagnosis. All patients have completed therapy. RESULTS: Actuarial survival at just more than 4 years is 69%. Three of the ten patients have died after experiencing relapse. In one, the relapse developed in the spine and brain outside the PF; in the second, concurrently in the PF, brain, and spine; and in the third, only in the spine. In one of the three, one of two initial cerebrospinal fluid cytologic examinations showed one clump of tumor cells, and the other sample appeared normal. Neuropsychologic testing has been a routine aspect of the study. A mean intelligent quotient (IQ) score of 103 in six patients surviving at least 1 year is unchanged from the baseline group score of 107. Five children have been tested at baseline and at 2 years after RT; for these children, baseline IQ was 101 and 2-year IQ was 102. These results stand in sharp contrast to earlier studies from this institution that found children younger than 7 years at diagnosis showing marked IQ losses after RT at 1 and 2-year follow-up. CONCLUSIONS: The results of this study suggest that 1800 cGy CSRT in conjunction with the chemotherapy used may produce less neurocognitive damage, perhaps at the expense of relapse along the craniospinal axis. Better means of improving survival without increasing toxicity are needed.
BACKGROUND: A higher total dose of radiation therapy administered in fractionated lower individual doses twice daily (hyperfractionated radiation therapy) has been reported to improve survival for children with brain stem gliomas. However, this higher dose of radiation therapy may cause more sequelae. METHOD: Eighty-eight children with brain stem gliomas were treated with 100 cGy twice daily to a total dose of 7200 cGy. Patients were carefully followed up for treatment-related clinical or radiographic worsening. RESULTS: Thirteen (15%) had intralesional cystic/necrotic changes within 8 weeks of completion of treatment. Children with these changes had a variable clinical course, including steady deterioration in one child; initial improvement, followed by progressive deterioration in three; and initial improvement, followed by deterioration, with subsequent improvement or prolonged stabilization of condition without additional antineoplastic treatment in nine. CONCLUSION: This latter "triphasic" course suggests that "early" worsening after hyperfractionated radiation therapy at 7200 cGy may be a sequelae of therapy, rather than a symptom of progressive tumor growth. This has substantial implications for patient care and evaluation of the efficacy of treatment.
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PURPOSE: This study investigates the response rate to and toxicity of carboplatin and vincristine in children with recurrent low-grade gliomas (LGGs) or patients younger than 60 months with newly diagnosed LGGs. PATIENTS AND METHODS: Twenty-three children with recurrent and 37 children with newly diagnosed LGGs were treated with a 10-week induction cycle of carboplatin and vincristine, followed by maintenance treatment with the same drugs. Patients were evaluated for response to treatment and toxicity. RESULTS: Twelve of 23 (52% +/- 10%; 95% confidence interval [CI], 0.32 to 0.72) assessable children with recurrent disease had an objective response to treatment, which included a greater than 50% reduction in tumor size in seven of 23 (30% +/- 10%; 95% CI, 0.10 to 0.50). Twenty-three of 37 (62% +/- .08; 95% CI, 0.46 to 0.78) of newly diagnosed patients had an objective response, 16 of 37 (43% +/- 0.08%; 95% CI, 0.27 to 0.59) with greater than 50% reduction in tumor size. The majority of those with an objective response had diencephalic tumors (n = 29), but children with thalamic (n = 2), cortical (n = 1), and brain stem (n = 2) LGGs also responded to treatment. Of the 35 patients with objective response to treatment, the maximum response was seen in 25 after completion of induction and in the remaining 10 after two to six cycles of maintenance treatment. Forty-nine of 53 (92% +/- .04%) patients who were stable or improved after induction remain without progressive disease (PD). Hematologic toxicity was common, but resulted in cessation of therapy in only one patient. Six children have been removed from the study because of allergic reactions, which were considered to be carboplatin-associated. CONCLUSION: Carboplatin and vincristine have activity in children with recurrent and newly diagnosed progressive LGGs. Objective responses to treatment after chemotherapy can be seen. This drug regimen is relatively well tolerated, and further studies are indicated to define the role of this combination of drugs in children with newly diagnosed LGGs.
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Children's Cancer Group Protocol CCG-9882 was designed to determine the effectiveness of hyperfractionated radiation for the treatment of children and young adults with brain stem gliomas. The study opened for the accrual of patients on September 21, 1988, and was closed on June 30, 1991. The first 54 children in the study were treated with irradiation doses of 100 cGy given twice daily to a total dosage of 7200 cGy. The next 66 children were treated with a similar daily regimens to a total of 7800 cGy. Tumors were diagnosed by clinical and radiographic criteria. Decisions about the need for surgery were left to the discretion of the treating neurosurgeon; tissue diagnosis did not alter the therapy in patients with diffuse infiltrating tumors. We reviewed the neuroradiology and neurosurgery reports as well as the pathological specimens of children entered on the study. By magnetic resonance (MR) imaging criteria, tumors involved the majority of the brain stem in 76% of cases; only three patients had tumors localized to the midbrain or medulla. Operations were performed on 56 of 120 patients (47%). Cerebrospinal fluid shunts were inserted in 27 (23%) of the children; insertion of a shunt was the only operation in 11, and a shunt was inserted in conjunction with a tumor operation in 16. Tumor operations were performed in 45 (38%) of the patients; 24 had stereotactic biopsies, and 21 had craniotomies. Of the 21 patients who had craniotomies, only biopsies were performed in 11; partial tumor resections were performed in 5 patients and subtotal resection in 5.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Current therapy for children with medulloblastoma includes craniospinal radiation therapy (CSRT) with or without adjuvant chemotherapy. The difference in growth of children after the two different therapeutic modalities is unknown. METHODS: The growth of 38 prepubertal children who survived medulloblastoma was reviewed retrospectively. Fifteen of these patients received CSRT alone; 23 received chemotherapy in addition to the radiation therapy. RESULTS: The average growth velocity of all patients with medulloblastoma during the 4 years of the study was below the mean for age and sex in all patients except one. Most patients grew at velocities more than two standard deviations below the mean. The overall growth of children who received chemotherapy in conjunction with CSRT was significantly worse than the growth of those who received only CSRT. The children who received chemotherapy showed little or no improvement in growth velocity by year 4; those who did not receive chemotherapy had some improvement. CONCLUSIONS: These findings suggest that chemotherapy potentiates the deleterious effects of radiation on growth.
Chiasmatic/hypothalamic gliomas usually are histologically benign astrocytomas that may recur many years after diagnosis and treatment. Three children with chiasmatic/hypothalamic gliomas who were treated at the authors' institution returned 9.5, 11.5, and 2 years, respectively, after radiation therapy (RT) because visual and neurologic deterioration developed. Neuroradiographic studies, including arteriography in two of the patients, showed large mass lesions. These were presumed to be recurrence of tumor, and chemotherapy was administered. Pathologic examination of two children who died and of the third who had a biopsy revealed only a minimal amount of residual, histologically benign astrocytoma, whereas the bulk of the specimen consisted of numerous vessels of variable size. These probably represented incorporation of the rich vasculature in the chiasmal region into the tumor, which underwent degeneration secondary to RT. Radiographic methods did not distinguish progressive tumor growth from the vasculopathy and led to inappropriate clinical diagnoses and treatment.
Spinal cord compression in Wilms' tumor is a rare event, generally caused by invasion of the canal by paraspinal lesions or metastatically involved vertebral bodies. This case report reviews the clinical presentation, radiologic evaluation, and emergent therapy in two cases of spinal cord compromise involving patients with widely metastatic Wilms' tumor. One of these is the only known report of intradural metastasis in a child with this malignancy. Both cases illustrate the importance of anticipating and rapidly responding to neurologic complications that may arise in patients with aggressively metastatic Wilms' tumor.
The presentation, growth patterns, and response to therapy of 11 consecutive children with choroid plexus carcinomas were analyzed, and the results were compared with the outcome reported in other series. Patients were a median of 26 months of age at diagnosis. Two patients had thalamic tumors, one had a posterior fossa primary, and the rest had ventricular lesions. Five of 11 (45%) children remain in continuous progression-free remission a median of 48 months from diagnosis. Four of the five in continuous remission had a "gross total" surgical resection, and only one received radiation therapy. Five of six patients with subtotal resections relapsed despite postoperative treatment with radiation therapy (three) and chemotherapy (one). The response to treatment with radiation therapy or chemotherapy at relapse was disappointing, with only one child (treated with etoposide) responding. In combination with other series, 11 of 14 children had prolonged progression-free survival after gross total resection (only two of whom received adjuvant therapy) compared with two of 20 after less than total resections, independent of the type of adjuvant therapy given. Adjuvant therapy for children with choroid plexus carcinomas is of unproven benefit, and this must be considered when analyzing innovative treatment trials for such children, especially for those with totally resected tumors. Patients with partially resected lesions fare poorly with present forms of treatment.
Cognitive function and school achievement were studied prospectively over 3 to 4 years in 19 children treated for brain tumors with whole-brain radiotherapy; 14 of 19 also received adjuvant chemotherapy. For the group as a whole, mean IQ fell from a baseline of 104 to 92 at follow-up (p < 0.01). Age was inversely correlated with change in IQ over time (r = 0.71; p < 0.001). Children younger than 7 years at diagnosis had a mean IQ loss of 27 points, while children over 7 years at diagnosis showed no significant decrease in IQ. Decline in IQ occurred between baseline and year 2 of follow-up; none could be documented between years 2 and 4. All children younger than 7 years at diagnosis were receiving special education at follow-up; 50% of the children over 7 years at diagnosis were receiving supplemental educational services.
Twenty patients, aged 6 months to 20 years, with low-grade astrocytoma (LGA) participated in a chemotherapy trial of vincristine (VCR) and etoposide (VP-16). Fourteen children had recurrent progressive disease at entry on study. Prior treatment consisted of surgical resection alone (6), surgical resection and irradiation (4), surgical resection, irradiation and chemotherapy (2), surgery and chemotherapy (1), and irradiation and chemotherapy (1). Six patients were treated at initial diagnosis of LGA because they were less than 5 years old (5) or for a second primary tumor (1). Four recurrent patients and 3 newly diagnosed patients underwent surgical debulking of their tumors immediately prior to study entry. Tumors were located in the optic nerve/chiasm/hypothalamus (8), brain stem/cerebellum (4), cerebral hemispheres (3), midline structures (3), and spinal cord (2). The treatment plan administered in an out-patient setting consisted of weekly VCR 1.5 mg/m2 for 7 to 8 weeks and VP-16 100 mg/m2 for 5 days repeated every 6 weeks for a total of 18 months of therapy. Responses were evaluated by computerized tomography or magnetic resonance imaging. Of the 20 patients, 1 exhibited a partial response maintained for 12+ months, 3 exhibited minor responses maintained for a period of 10+ to 35 months, and 11 maintained stable disease for 10 to 42 months. Of the 11 patients with stable disease, 2 were withdrawn early from the study without further therapy. Five of the 20 patients developed progressive disease; for 4 of these 5, this occurred during the first course of therapy. Subsequently, these 5 died due to tumor.(ABSTRACT TRUNCATED AT 250 WORDS)