William J. Kupsky

The prognostic significance of postoperative residual tumor in ependymoma.

Between 1970 and 1989, 29 patients with intracranial ependymomas were evaluated and treated at the Childrens Hospital in Boston. With a median follow-up of 82 months, the actuarial survival rates at 5 and 10 years were 61 +/- 10% and 46 +/- 12%, respectively. Anaplastic histological findings were uncommon (2 of 29). Initial postoperative radiotherapy was given to 25 patients, with a median tumor dose of 5360 cGy. With a median time to recurrence of 22 months, local failure (within 2 cm of original enhancing mass) was the predominant pattern of relapse (15 of 16 failures). The presence of radiographic residual disease seen on postoperative magnetic resonance imaging or computed tomographic scans was the most important prognostic variable for patients with intracranial ependymoma. Analysis of the 19 patients who underwent postoperative imaging revealed a 75 +/- 15% 5-year freedom from progressive disease for 9 patients with no residual disease, as compared with 0% freedom from progressive disease for the 10 patients with gross residual disease (P = 0.03). In contrast, the surgical assessment of residual disease was not significant (P = 0.4). Age at presentation was also a significant prognostic factor. The overall actuarial survival rate at 12 years for infants 24 months or younger at diagnosis was 0%, as compared with 62 +/- 13% for older patients (P = 0.03). For non-anaplastic ependymomas, complete surgical resection followed by local-field, high-dose (greater than 54 Gy) radiotherapy appears to offer the greatest chance for long-term survival. Because of the markedly reduced survival rate for patients with radiologically apparent postoperative disease, maximal surgical resection and novel therapeutic endeavors appear warranted for this high-risk group. Future protocols should use postoperative imaging, not operative reports, to stratify patients with ependymoma.

Tumors of the choroid plexus in children

Primary neoplasms of the choroid plexus in children are surgically treatable, and the encouraging results of surgical removal, even for carcinoma, justify an aggressive surgical approach. Forty cases operated on over a span of 45 years have been reviewed in detail, including a rereading of all microscopic slides. The prognosis for children with papilloma has been excellent. The 5-year survival rate for children with carcinoma of the choroid plexus was 50%, and all deaths occurred within 7 months of operation. The patients whose carcinomas were totally removed had a better prognosis than did those with subtotal removal.

Prolonged Regional Nerve Blockade by Controlled Release of Local Anesthetic from a Biodegradable Polymer Matrix

Background:Prolonged nerve blockade is potentially useful in the management of many acute and chronic pain problems. Aside from infusions via an indwelling catheter, most currently available nondestructive techniques for prolonging local anesthetic action cannot provide more than 1–2 days of blockade. Bioerodible polymer matrixes have been used to deliver a variety of drugs in patients and animals for periods lasting weeks to years. Previously, dibucaine and bupivacaine were incorporated into copolymers of 1,3 bis(p-carboxyphenoxy) propane-sebacic acid anhydride (1:4), and demonstrated sustained release in vitro following incubation of the drug-polymer matrixes in phosphate-buffered solution (pH 7.4, 37° C). Methods:In the present study, cylindrical pellets made from polymer matrixes incorporated with buplvacaine-HCl were implanted surgically along the sciatic nerves of rats. Neural block was assessed by direct observation of motor skills and by leg-withdrawal latency to a hot surface. Biochemical and hlstologic examinations were performed 2 weeks after implantation. Results:Sensory and motor blockade was produced for periods ranging from 2 to 6 days. Contralateral control legs receiving polymer implants without drug showed no block. Blockade was reversible, and animals appeared to recover sensory and motor function normally. Biochemical indexes of nerve and muscle function were indistinguishable from contralateral controls. Conclusions:This biodegradable polymer system provides a promising new alternative for the delivery of local anesthetics to peripheral nerves to produce prolonged blockade for the management of acute and chronic pain.

The change in patterns of relapse in medulloblastoma

The authors reviewed 89 patients treated for cerebellar medulloblastoma between 1970 and 1989 to determine the impact of changing treatment (high‐dose posterior fossa radiation therapy and chemotherapy) on the pattern of failure in medulloblastoma. Between 1970 and 1983, 50 patients (median follow‐up, 110 months) were treated with surgery and postoperative craniospinal irradiation (CSI). Nineteen of the 50 (38%) recurred in the central nervous system (CNS). Isolated systemic (bone) metastases occurred in six. The median time to the development of bone metastases was 12 months. Since 1984, 39 patients (median follow‐up, 27 months) were treated with preradiation chemotherapy consisting of cisplatin and vincristine for 9 weeks before initiation of CSI. Nine of the 39 (23%) patients recurred in the CNS. There were no systemic failures in this cohort. The actuarial 5‐year disease‐free survival was 55 ± 7% for the earlier cohort and 72 ± 8% for the later cohort (P equals 0.3). Posterior fossa recurrence was associated with radiation therapy to this area. The cumulative incidence of posterior fossa relapse was 50 ± 13% in patients who received less than 5300 cGy and 18 ± 7% in those who received 5300 cGy or more (P equals 0.005). All six bone relapses were in patients treated with CSI alone and 5300 cGy or more to the posterior fossa for a 5‐year cumulative incidence of bone metastases of 18 ± 7% compared with 0% for patients treated with 5300 cGy or more and chemotherapy (P equals 0.03). The authors concluded that high‐dose radiation therapy has altered the pattern of relapse with an increase in systemic recurrence after radiation therapy alone that is now equivalent to the risk of recurrence in the posterior fossa. Chemotherapy may be indicated in an attempt to decrease this high risk of systemic metastases.

Cytogenetic evidence for a chromosome 22 tumor suppressor gene in ependymoma

Although ependymomas comprise 5-10% of pediatric brain tumors, consistent cytogenetic aberrations have not been identified in these neoplasms. We report karyotypes for two ependymomas. A predominantly well-differentiated ependymoma contained several numerical chromosome aberrations, including monosomy 22. In contrast, an anaplastic ependymoma had a more complex karyotype that included loss of one chromosome 22 homologue and a balanced translocation at q13.3 in the remaining 22 homologue. These findings suggest the location of an ependymoma tumor suppressor gene on the long arm of chromosome 22.

Prognostic factors in medulloblastoma, including DNA ploidy.

PURPOSEnDNA ploidy status, completeness of surgical resection, use of chemotherapy, adequacy of radiation therapy, metastatic stage, sex, and age at diagnosis were evaluated as predictors of relapse in 58 patients with cerebellar medulloblastoma.nnnMETHODSnFlow cytometry (FCM) and/or image analysis (IA) were used to characterize tumor DNA ploidy. Twelve tumors (21%) were found to be aneuploid, 11 (19%) tetraploid, and 35 (60%) diploid.nnnRESULTSnThe most significant predictors of relapse in univariate analyses were the adequacy of radiation (> or = 50 Gy) (P = .02), metastatic staging (P = .05), completeness of resection (P = .085), and DNA ploidy status (diploid/tetraploid v aneuploid; P = .11). When the 52 patients who received > or = 50 Gy were included in a multivariate Cox model analysis, those with diploid/tetraploid tumors had fewer recurrences than those with aneuploid tumors (relative risk, 0.33; 95% confidence interval, 0.12 to 0.89; P = .03). Patients with complete resections (P = .07), or with stage M0 disease (P = .06) had fewer recurrences than other patients, but these factors were not independent predictors of outcome. DNA ploidy status was correlated with age; 10 of the 12 aneuploid tumors were found in children ages 3 to 10 years. Age, sex, and the use of chemotherapy were not prognostically significant in these analyses.nnnCONCLUSIONnThe adequacy of radiation dose and DNA ploidy were the most important prognostic factors in this series. Contrary to previous reports, when corrected for adequacy of treatment, DNA aneuploidy was associated with a poor outcome. By multivariate analyses, DNA ploidy was an independent variable, even when controlling for extent of surgical resection and metastatic stage.

SELECTIVE INJURY OF THE GLOBUS PALLDUS IN CHILDREN WITH POST‐CARDIAC SURGERY CHOREIC SYNDROME

Occasionally children undergoing cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest develop a postoperative syndrome of acute chorea. The authors report the neuropathological findings in two such children surgically treated for congenital heart disease. Examination of the brain showed neuronal loss, reactive astrocytosis and degeneration of myelinated fibers (without frank necrosis) in the globus pallidus, primarily the outer segment, with sparing of other regions commonly susceptible to hypoxic‐ischemic necrosis. The localization and relative mildness of the brain damage suggest a susceptibility of the globus pallidus to injury in this setting and implicate disruption of pallidal pathways in the pathogenesis of post‐cardiac surgery choreic syndrome.

Choroid plexus tumors in the breast cancer-sarcoma syndrome.

Choroid plexus neoplasms are rare epithelial tumors of the central nervous system. A carcinoma of the choroid plexus occurred in a child from a family with the breast cancer–sarcoma syndrome (Li‐Fraumeni or SBLA syndrome), an inherited condition characterized by the development of diverse neoplasms (sarcoma, breast cancer, brain tumors, leukemia, adrenal cortical carcinoma, and others). Choroid plexus carcinomas were identified in two kindreds previously reported with the syndrome. the literature contains reports of choroid plexus neoplasms occurring in families and in individuals with multiple primary tumors. Choroid plexus neoplasm may be a manifestation of the inherited proclivity to tumor development in the breast cancer–sarcoma syndrome.

Seizures in Children with Supratentorial Astroglial Neoplasms

We reviewed the records of 98 consecutive patients, 18 years of age or younger, with pathologically confirmed supratentorial astroglial neoplasms at the Childrens Hospital, Boston, to evaluate the importance of seizures in their presentation and natural history. Tumors were diagnosed using the WHO criteria as pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas, glioblastomas, giant cell glioblastomas, oligoastrocytomas and gangliogliomas. Our results were as follows. (1) Fifty percent of children had seizures as part of their presentation and 30% had seizures as their only presenting phenomenon. (2) The seizures varied in nature, but complex (55%) or simple (28%) partial seizures were by far the most common types, occurring in 77% of cases. (3) Preoperative electroencephalography (EEG) accurately lateralized to the tumor side in 88% of the cases and localized to the correct lobe in 56%. (4) Tumors involving cerebral cortex significantly correlated with seizures at presentation as compared to noncortical locations; 59% of patients with cortical tumors presented with seizures, and only 15% of patients with noncortical tumors experienced seizures. Lesions in the temporal and frontal lobes had the highest incidence of seizures. (5) Patients with gangliogliomas and oligoastrocytomas had the highest incidence of seizures, 88 and 86%, respectively, whereas patients with anaplastic astrocytoma had the lowest incidence, 21%. (6) Histopathologic calcification was associated with seizures at presentation approaching significance (p = 0.06). (7) Seizures at presentation were significantly associated with good prognosis (p = 0.02).

201Tl/99mTc-HMPAO SPECT imaging of treated childhood brain tumors

To assess whether thallium-201 thallous chloride (Tl) can detect childhood tumors and whether diagnostic effectiveness improves with combined blood flow imaging, 28 children (1.0-18.6 years) were studied using single photon emission computed tomography (SPECT): Tl (1.3-1.8 mCi intravenously), followed in 13 of the patients by technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO; 8-18 mCi intravenously). Tl-uptake was markedly increased with histologically confirmed recurrent brain tumors (N = 12). Tl-avid tumors comprised several histologic types, including 6 astrocytomas/gliomas as well as nonastrocytic neoplasms, such as medulloblastoma and ependymoma. A questionable false-positive study was observed with a treated medulloblastoma. Tl failed to detect 5 tumors (i.e., 2 medulloblastomas, 1 ependymoma, 1 malignant schwannoma, and initially 1 low-grade astrocytoma). The sensitivity and specificity of 201Tl-SPECT for detection of childhood brain tumors was 76.9% and 93.3%, respectively. The mean tumor-to-normal brain ratio for Tl was 2.5 +/- 0.5 (N = 7). In some of the patients, 201Tl-SPECT allowed a more precise assessment of the functional state of the tumor than was possible with computed tomography and magnetic resonance imaging. HMPAO distribution was variously normal, increased or decreased at the site of tissue abnormality, and abnormal blood flow was demonstrated in the remaining neuraxis, in 3 of the 7 patients. Changes in tissue perfusion did not correlate with Tl findings, but were evaluated in only one false-negative study.