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Frank Eggers, Robert Lukin, A. Alan Chambers, Thomas A. Tomsick and Raymond Sawaya

✓ A case of iatrogenic carotid-cavernous fistula secondary to a Fogarty catheter thrombectomy is presented. The literature and seven previously reported cases are reviewed.

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Dandy-Walker syndrome

Clinical analysis of 23 cases

Raymond Sawaya and Robert L. McLaurin

✓ A clinical analysis of 23 patients with Dandy-Walker malformation indicates that more than 85% of them were diagnosed at or before 1 year of age, and that the incidence of associated anomalies is approximately 50%, with a 17% incidence for agenesis of the corpus callosum. The significance of the presence of these anomalies is substantiated by the fact that of the seven deaths recorded, six were related to this disease and five were affected by associated anomalies. The high mortality rate (26%) is comparable to that of other series. The differential diagnosis with posterior fossa extra-axial cysts is discussed.

Ten patients were primarily treated with excision of the cyst membrane; all of them required subsequent shunting to control the intracranial pressure, demonstrating the futility of this approach. None of the patients treated with lateral ventricle shunting suffered an upward herniation of the posterior fossa contents, suggesting that combined shunting of the lateral and fourth ventricles is rarely necessary. The technical advantages of posterior fossa shunting alone are outlined. Of the 16 survivors, 14 were assessed for their mental development by means of standard psychometric testing. The results of the intelligence quotient (IQ) scoring have indicated that 71% of the patients have subnormal mental development (IQ < 83). There was no significant relationship between retardation and associated anomalies, although agenesis of the corpus callosum was related to poor intellectual development in the two patients so affected (IQ's of 50 and 73).

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Dan S. Heffez, Raymond Sawaya, George B. Udvarhelyi and Risa Mann

✓ Spinal cord compression by epidural extramedullary hematopoiesis (EMH) is a rare phenomenon. A case of acute compressive myelopathy is reported in a 72-year-old man with EMH secondary to sideroblastic anemia. Technetium colloid scanning was used to document extensive ectopic marrow formation. The patient improved following surgery and radiotherapy. A review of the literature revealed 23 other cases of symptomatic spinal epidural EMH. The underlying hematological disorder varied but was always of long duration. Eighty-eight percent of the patients were males. Symptoms lasted longer than 1 week in 90% of cases, and 91% demonstrated incomplete neurological deficits. Plain x-ray films were rarely helpful in establishing the diagnosis. Technetium sulfur colloid bone marrow scanning has been used successfully to detect EMH and has led to preoperative diagnosis in one case. Decompressive laminectomy with or without postoperative irradiation is the suggested therapy, although there is evidence that radiotherapy alone may be adequate in some cases. Good recovery is the rule despite long-standing neurological deficits.

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Monitoring of antifibrinolytic therapy following subarachnoid hemorrhage

The importance of CSF fibrin/fibrinogen degradation products

Raymond Sawaya, Victor Sonnino, Robert L. McLaurin and Gerardo Perrotta

✓ Ten cases of subarachnoid hemorrhage (SAH) from ruptured cerebral aneurysm are reported. Fibrin/fibrinogen degradation product (FDP) levels were determined simultaneously in blood and cerebrospinal fluid (CSF) at an average frequency of 1.7 days, extended over periods of 8 to 63 days. Successful antifibrinolytic therapy (AFT) correlated with FDP levels in CSF of less than 16 µg/ml. Five patients failed to respond to AFT. Levels of FDP in the CSF fluctuated widely in these five patients, and remained at or above 16 µg/ml for most of the monitoring period. Blood FDP levels were normal or minimally elevated, and could not be used in predicting or preventing rebleeding episodes. A hypothesis is presented to explain the significance of the presence of FDP's in CSF.

In spite of the many techniques employed in monitoring AFT and reviewed in this paper, little information has been gained to improve the results and therapeutic strategies. Among the different methods available, FDP measurements in the CSF have correlated best with rebleeding, and thus may be used in modifying and individualizing therapy. Suggestions are given for future studies.

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Raymond Sawaya, Thaddeus Mandybur, Illona Ormsby and John M. Tew Jr.

✓ This study was designed to evaluate the effect of an inhibitor of plasminogen activation on the growth of a human glioblastoma line grown in nude mice up to the seventh passage. The tumors produced plasminogen activators and showed histological characteristics similar to those of the original tumor. Three groups of mice were studied. Group A received 5% epsilon aminocaproic acid (EACA); Group B received 2.5% EACA; and Group C served as a control. There was no statistical difference among the three groups with regard to: 1) age at time of tumor transplantation; 2) the interval between implant and treatment; or 3) tumor volume at time of treatment. Blood measurements of EACA, performed in a limited number of animals, have shown that the drug at 5% concentration had reached toxic levels. Statistically significant differences between the three groups were noted in the following categories: 1) rate of tumor growth; 2) tumor volume at time of death, where Group A had smaller tumors than Group C; and 3) mean survival times of Groups A and B as compared to Group C.

A statistically significant negative correlation was found between the rate of tumor growth and the length of survival of animals in Group C, while no correlation could be found for either Group A or B, indicating that the antifibrinolytic therapy modified this important biological variable. This study supports the hypothesis that the fibrinolytic system plays a role in the growth and development of malignant gliomas and that interference with the fibrinolytic system may retard the growth of these tumors grown in nude mice.

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Mario Zuccarello, Raymond Sawaya, Robert Lukin and Gabrielle deCourten-Myers

✓ A 24-year-old man developed a spontaneous cerebellar hematoma 5 years after the implantation of cerebellar electrodes. No vascular malformations were found either intraoperatively or radiographically. The histopathological findings of the cerebellar tissue obtained at biopsy from the region surrounding the electrodes support the hypothesis of a causal relationship between the spontaneous cerebellar hemorrhage and chronic cerebellar stimulation.

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Raymond Sawaya, Mario Zuccarello and Robert Highsmith

✓ This study was undertaken to confirm the presence of alpha-1-antitrypsin (α 1-AT) in human brain tumors and to attempt to elucidate its significance. Seventy-seven consecutive unselected patients with various brain tumors were entered in this study. The α 1-AT and α 2-macroglobulin contents of the tumor extracts were qualitatively assessed by Ouchterlony immunodiffusion techniques. Plasminogen activator (PA) activity was assayed electrophoretically on sodium dodecyl sulfate gels. The patients were divided into two groups according to the positivity of their tumors to α 1-AT. Sixty-eight percent of the tumors were positive for α 1-AT, and all specimens were negative for α 2-macroglobulin. Clinical and biological parameters obtained in all study patients failed to show statistically significant differences between the two groups with the exception of PA activity (p = 0.001), the peritumoral edema as seen on computerized tomography, and the preoperative serum fibrinogen level. These three parameters were higher in the group with specimens positive to α 1-AT.

This study supports the hypothesis that α 1-AT is produced primarily by tumor cells in proportion to the regional proteolytic and inflammatory activity, and may protect the tumor cells.

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Raymond Sawaya and Robert Highsmith

✓ Fresh human brain-tumor samples were assayed for their plasminogen activator (PA) content. Specific molecular weight patterns were identified for each of five common brain tumors and for normal brain, suggesting a cell-specific origin of the various PA forms. Malignant tumors contained higher PA activity and a larger number of molecular weight patterns than benign tumors, with the exception of acoustic neurinomas. Irradiated tumors contained lower PA activity than nonirradiated tumors. Finally, a slight but definite correlation between brain edema and PA activity was detected. The future role of brain-tumor PA's for diagnostic and therapeutic purposes is discussed.

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Raymond Sawaya, O. Juhani Rämö, Mei Lin Shi and George Mandybur

✓ Fresh brain-tumor samples were obtained at operation and analyzed for their content of tissue type plasminogen activator (tPA) using an activity assay (gel chromatography zymogram) and an enzyme-linked immunospecific assay. The specimens were taken from 23 glioblastomas, 35 metastatic tumors, 42 meningiomas, 16 low-grade gliomas, and seven acoustic neurinomas; seven specimens were from normal brain.

A strong correlation was found between the results of the two assays (r = 0.77, p < 0.0001). There was a threefold difference in the tPA content of the benign tumors as compared to malignant tumors (p = 0.0006), the latter having less tPA. Histologically benign meningiomas contained higher tPA than malignant meningiomas (p = 0.01); however, the difference between low-grade gliomas and high-grade gliomas was less evident. Overall regression analysis data have shown an inverse relationship between the tissue content in tPA and the presence and degree of tumor necrosis and peritumoral brain edema (p = 0.004 and p = 0.0004, respectively). This finding was most consistent in the glioblastoma group where the correlation coefficient values were r = 0.53 and r = −0.55, respectively. There was no significant correlation between the tissue tPA content and the age and sex, steroid use, or plasma tPA of the patients or the duration of symptoms.

In summary, this is the first demonstration of tPA in a large series of human brain tumors and in normal brain. The differences observed have clear biological significance and, although the source of tPA in tumor tissue is still unknown, a relative reduction in tPA in tumor tissue may play an integral role in the development of tissue necrosis and tissue edema. The lack of tPA in tumor necrosis was not due to tissue destruction and cell death since urokinase was readily detectable in that tissue.

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Rajesh K. Bindal, Raymond Sawaya, Milam E. Leavens and J. Jack Lee

✓ The authors conducted a retrospective review of the charts of 56 patients who underwent resection for multiple brain metastases. Of these, 30 had one or more lesions left unresected (Group A) and 26 underwent resection of all lesions (Group B). Twenty-six other patients with a single metastasis who underwent resection (Group C) were selected to match Group B by type of primary tumor, time from first diagnosis of cancer to diagnosis of brain metastases, and presence or absence of systemic cancer at the time of surgery. Statistical analysis indicated that Groups A and B were also homogeneous for these prognostic indicators. Median survival duration was 6 months for Group A, 14 months for Group B, and 14 months for Group C. There was a statistically significant difference in survival time between Groups A and B (p = 0.003) and Groups A and C (p = 0.012) but not between Groups B and C (p > 0.5). Brain metastasis recurred in 31% of patients in Group B and in 35% of those in Group C; this difference was not significant (p > 0.5). Symptoms improved after surgery in 65% of patients in Group A, 83% in Group B, and 84% in Group C. Symptoms worsened in 13% of patients in Group A, 6% in Group B, and 0% in Group C. Groups A, B, and C had complication rates per craniotomy of 8%, 9%, and 8%, and 30-day mortality rates of 3%, 4%, and 0%, respectively. Guidelines for management of patients with multiple brain metastases are discussed. The authors conclude that surgical removal of all lesions in selected patients with multiple brain metastases results in significantly increased survival time and gives a prognosis similar to that of patients undergoing surgery for a single metastasis.