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Isabelle M. Germano, Richard L. Davis, Charles B. Wilson and Grant B. Hieshima

✓ Embolization with polyvinyl alcohol (PVA) is an accepted method of rendering complex arteriovenous malformations (AVM's) more amenable to surgery, but its effects on human vascular tissues have not been adequately documented. The authors reviewed the histopathology of 66 intracranial AVM's resected 1 to 76 days after embolization with PVA. The mean age of the patients was 36 years, and their AVM's were located in the cerebral hemispheres (92%), the cerebellum (6%), or the corpus callosum (2%). In 79% of cases, at least one vessel contained PVA particles; in most cases, the vessel was filled with sharp, angular PVA particles in a serpiginous pattern. Polyvinyl alcohol particles indented the endothelium in 69% of cases but were rarely found subendothelially. Clotted blood and fibroblasts were present among the particles, and abundant intraluminal mononuclear and polymorphonuclear inflammatory cells were found in all vessels containing PVA particles. Foreign-body giant cells appeared 2 to 14 days after embolization in the majority of cases. Patchy mural angionecrosis and necrotizing vasculitis were found in 39% of the cases. Recanalized lumina were seen in 18% of PVA-embolized vessels. Foreign materials resembling cotton fibers and other particulate substances, which were probably contaminants of the contrast solution or the embolic material, were found in 65% of the cases. These findings suggest a specific chain of events in the interaction between PVA and vessel wall components and may explain some important sequelae of embolization therapy.

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Stanley L. Barnwell, Christopher F. Dowd, Richard L. Davis, Michael S. B. Edwards, Philip H. Gutin and Charles B. Wilson

✓ The cases of seven patients with intramedullary, cryptic vascular malformations of the spinal cord are reported. In all patients, the clinical course was progressive; a Brown-Séquard syndrome was the most common presenting symptom complex. Magnetic resonance (MR) imaging was performed in all patients. The pattern seen most often was a focus of high signal (on both T1- and T2-weighted MR images) surrounded by a larger zone of low signal (best seen on T2-weighted images), and was remarkably similar for all patients. Six patients underwent surgical exploration; removal of the lesions halted the progression of symptoms in five patients, and one patient had worsened sensory function after surgery. Motor function did not decrease postoperatively in any patient. The one patient who refused surgery has continued to decline neurologically. Histopathological examination of surgical specimens showed a cavernous malformation in one patient, a venous malformation in one, venous varices in two, and organizing hematomas in two; these findings are markedly different from those in previously reported cases of cryptic vascular malformations.

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Samuel F. Ciricillo, Richard L. Davis and Charles B. Wilson

✓ The authors report the case of a patient harboring a posterior fossa neuroepithelial cyst who presented with positional facial weakness and syncope. The patient recovered rapidly after cyst fenestration and placement of an internal cyst-cisternal shunt. The pathogenesis and principles of diagnosis and management of these rare lesions are reviewed.

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Takao Hoshino, Michael Prados, Charles B. Wilson, Kyung Gi Cho, Kyu-Sung Lee and Richard L. Davis

✓ This study includes 182 patients with intracranial gliomas who received bromodeoxyuridine (BUdR), 200 mg/sq m intravenously, at the time of craniotomy but before tumor biopsy. The tumor specimens were stained for BUdR using the immunoperoxidase method; the BUdR labeling index (LI), or S-phase fraction, was calculated as the percentage of BUdR-positive cells. The median BUdR LI's for 127 primary moderately anaplastic astrocytomas, highly anaplastic astrocytomas, and glioblastomas (< 1%, 2.7%, and 7.3%, respectively; range 0% to 38.1%) were not significantly different from those of 55 similar recurrent tumors (< 1%, 4.3%, and 7.4%, respectively; range 0% to 30.5%). The mean LI was significantly higher in tumors from patients over 50 years of age than in tumors from younger patients (p < 0.001). This age-related difference in LI's was found in both groups of patients with astrocytomas but not in those with glioblastomas. Kaplan-Meier survival curves showed a significantly greater probability of survival among patients whose tumors had LI's of less than 1% than among those with LI's greater than 5%; survival probability of patients with tumor LI's of 1% to 5% was intermediate between the two extremes. Thus, the BUdR LI appears to reflect the proliferative potential more accurately than the histopathological diagnosis and should therefore be considered an important factor in determining the prognosis of individual patients with intracranial gliomas and in selecting their treatment.

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Isabelle M. Germano, Masami Ito, Kyung G. Cho, Takao Hoshino, Richard L. Davis and Charles B. Wilson

✓ One hundred fifty-two intracranial gliomas of various types were reviewed in order to correlate the histopathological features with the proliferative potential of each tumor as reflected by the bromodeoxyuridine (BUdR) labeling index (LI). Patients undergoing surgical removal of gliomas were given a 30-minute intravenous infusion of BUdR (150 to 200 mg/sq m) to label S-phase tumor cells. The tumor specimens were stained immunohistochemically for BUdR and processed for routine histopathological diagnosis. The BUdR LI was calculated as the percentage of labeled cells among cells analyzed. Twenty-seven histological features in three categories (degenerative, vascular, and cellular changes) were considered. A significantly higher BUdR LI (p < 0.05) was found in tumors with necrosis than in those without this feature; tumors with both coagulative and liquefactive necrosis had the highest BUdR LI (p < 0.05). Increased vascularity was also associated with a higher BUdR LI (p < 0.05). Although tumors with abnormal mitotic figures had a significantly higher BUdR LI than those without, the number of mitoses did not correlate with a higher BUdR LI. These results suggest that the number of mitoses is not a good indicator of tumor growth rate. Necrosis and increased vascularity should be heavily weighted in predicting the proliferative potential of individual gliomas.

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Takao Hoshino, Luis A. Rodriguez, Kyung G. Cho, Kyu S. Lee, Charles B. Wilson, Michael S. B. Edwards, Victor A. Levin and Richard L. Davis

✓ The proliferative potential of low-grade astrocytomas was estimated in 47 patients. Each patient received an intravenous infusion of bromodeoxyuridine (BUdR), 150 to 200 mg/sq m, at the time of craniotomy to label cells in deoxyribonucleic acid (DNA) synthesis; the percentage of S-phase cells, or BUdR labeling index (LI), of each tumor was determined immunohistochemically. In 29 patients (60%), the tumors had BUdR LI's of less than 1%, indicating a slow growth rate; only three (10%) of these patients died of recurrent tumor during a follow-up period of up to 3½ years. In contrast, of the 18 patients (40%) whose tumors had BUdR LI's of 1% or more, 12 (67%) had a recurrence and nine died during the same follow-up period. These results show that the proliferative potential, as reflected by the BUdR LI, is an important prognostic factor that separates low-grade astrocytomas into two groups and provides a more scientific rationale for selecting treatment for individual patients.

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Victor A. Levin, Luis A. Rodriguez, Michael S. B. Edwards, William Wara, Hsiu-Chih Liu, Dorcas Fulton, Richard L. Davis, Charles B. Wilson and Pamela Silver

✓ Forty-seven patients with medulloblastoma were treated postoperatively with procarbazine, followed by craniospinal radiation therapy in combination with hydroxyurea. The radiation dose to the posterior fossa was 55 Gy; the spinal cord received 25 Gy and the whole brain 25 to 35 Gy (mean 33 Gy).

Seventeen tumors recurred. Only one initial recurrence was in the spinal subarachnoid space; 10 (59%) were in the posterior fossa, and four (24%) were supratentorial. The estimated 5-year disease-free survival probability was 55%; the 5-year overall survival rate was 66%. Myelotoxicity occurred in 38% of patients, but in only one case was it severe enough to warrant reducing the total dose of radiation. It was concluded that good-risk medulloblastoma patients may be treated with radiation dosages as low as 25 Gy to the spinal axis and to the whole brain without increasing the risk of recurrence outside the posterior fossa. Chemotherapy with procarbazine followed by radiation therapy and hydroxyurea during radiation therapy was well tolerated and may play a role in reducing radiation dosages outside the posterior fossa.

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Ali K. Choucair, Victor A. Levin, Philip H. Gutin, Richard L. Davis, Pamela Silver, Michael S. B. Edwards and Charles B. Wilson

✓ To determine the percentage of patients who developed multiple central nervous system (CNS) gliomas during postoperative radiation therapy and chemotherapy, the authors reviewed the records of 1047 patients treated between December 2, 1976, and August 16, 1985, who had an original diagnosis of supratentorial glioblastoma multiforme or other anaplastic glioma. The occurrence of multiple lesions was verified by neurodiagnostic studies (computerized tomography or myelography) or by findings at operation or autopsy. Twelve patients (1.1%) who presented with multiple lesions were excluded from this analysis. There were 405 patients with glioblastoma multiforme; their median age was 46.5 years (range 22 to 70 years). Eighteen (5%) of these patients had multiple CNS lesions, five of which were in the spinal cord. The median time from diagnosis to detection of the second lesion in this group was 59.5 weeks (range 10 to 182 weeks). There were 630 patients with anaplastic glioma (which included mixed malignant glioma and highly anaplastic, gemistocytic, moderately anaplastic, and anaplastic astrocytomas); their median age was 30 years (range 2 to 62 years). Fifty-four (8.6%) of these patients had multiple lesions, 10 of which were in the spinal cord; only one case of extraneural metastasis was found. The median time from diagnosis to detection of the second lesion in this group was 101 weeks (range 14 to 459 weeks). These results show that more than 90% of CNS gliomas recur at the site of the original tumor. Considering the high frequency of intellectual dysfunction after whole-brain radiation therapy, the use of focal radiation fields appears to be the most judicious approach to the treatment of patients with gliomas.

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Takao Hoshino, Tadashi Nagashima, Judith A. Murovic, Charles B. Wilson, Michael S. B. Edwards, Philip H. Gutin, Richard L. Davis and Stephen J. DeArmond

✓ Thirty-eight patients undergoing surgical removal of neuroectodermal tumors of the central nervous system were given a 1-hour intravenous infusion of bromodeoxyuridine (BUdR), 150 to 200 mg/sq m, to label tumor cells in the deoxyribonucleic acid (DNA) synthesis phase (S-phase). The excised tumor specimens were divided into two portions: one was fixed with 70% ethanol and embedded in paraffin and the other was digested with an enzyme cocktail to make a single-cell suspension. The paraffin-embedded tissues were stained by an indirect peroxidase method using anti-BUdR monoclonal antibody (MA) as the first antibody. Single-cell suspensions were reacted with fluorescein isothiocyanate (FITC)-conjugated anti-BUdR MA's for flow cytometric analysis. S-phase cells that had incorporated BUdR into their DNA were well stained by both methods. The percentage of BUdR-labeled cells, or S-phase fraction, was calculated in tissue sections by microscopic examination and in single-cell suspensions by flow cytometric analysis. The biological malignancy of the tumors was reflected in the S-phase fractions, which were 5% to 20% for glioblastoma multiforme, medulloblastoma, and highly anaplastic astrocytoma, but less than 1% in most moderately anaplastic astrocytomas, ependymomas, and mixed gliomas. Two juvenile pilocytic astrocytomas and two low-grade astrocytomas from children had high S-phase fractions despite the fairly benign and slow-growing nature of these tumors. These results indicate that the S-phase fraction obtained immunocytochemically with anti-BUdR MA's may provide useful information in estimating the biological malignancy of human central nervous system tumors in situ.