Biomedical subjects

R Sawaya

Publications and source records attributed to R Sawaya.

At least 91 records · Page 5Linked to original sources

PubMed1995

Plasminogen activator inhibitor-1 in brain tumors: relation to malignancy and necrosis.

Tumor necrosis is a common feature of malignant neoplasms. The pathogenesis of tumor necrosis remains poorly documented. Recent evidence has shown a correlation between the presence of tumor necrosis and low content of tissue plasminogen activator in brain tumors and significantly higher levels of plasminogen activator inhibitor-1 (PAI-1) in human glioblastomas. We subjected fresh brain tumor tissue samples (n = 197) to an enzyme-linked immunosorbent assay to determine PAI-1 content. The results were correlated with the presence of edma and necrosis on imaging studies. The samples studied were from normal brain (n = 10), low-grade gliomas (n = 26), meningiomas (n = 47), acoustic neuromas (n = 18), glioblastomas (n = 45), metastases (n = 45), and areas of tumor necrosis (n = 6). The benign tumor samples (n = 96) had 3.5 times less PAI-1 than did the malignant tumors (n = 101). Tumor necrosis samples contained 3.8 times more PAI-1 than did the nonnecrotic malignant tumor samples (P < 0.000001). The benign meningioma samples showed a similar ratio compared with their malignant counterparts (0.35 versus 1.59 ng/mg, respectively, P = 0.0004). Regression analysis results showed a strong correlation between PAI-1 and necrosis (r = 0.47, P < 0.0000028) and, to a lesser extent, brain edema (r = 0.26, P = 0.001). A negative correlation between PAI-1 and tissue plasminogen activator levels almost reached statistical significance (P = 0.07). There was no correlation between PAI-1 content and the tumor size, duration of symptoms, or the sex or age of the patients. The results of this study indicate that malignant transformation is associated with a significant increase in PAlI1 and that PAI-1 may play an integral role in the pathogenesis of tissue necrosis, perhaps via the inhibition of tissue plasminogen activator and the promotion of microthrombosis.

Base Sequence↗

PubMed1995

Aggressive meningeal tumors: review of a series.

A series of 25 patients with aggressive meningeal tumors was studied to determine the efficacy of various management options. The median age of the patients was 52 years, with a range of 13 to 73 years. A marked male preponderance (64%) was noted. Twenty of 25 patients experienced recurrence during a median follow-up time of 47 months. Survival and freedom from recurrence varied with histological diagnosis. Recurrence was noted sooner in patients who had received partial resections on first presentation of tumor than in those who had received total resections at first presentation. Survival time was also shorter for patients who underwent partial resections at first presentation than for patients who underwent total resections. Patients' prognoses did not improve as a result of either chemotherapy or radiotherapy. Of six patients with extracranial metastases, the median time to metastasis was 102 months, with a 5-year metastasis-free rate of 85%. The most common sites of metastasis in these six patients were lung and bone. In each tumor type, histological features used in diagnosis and radiological features studied from computerized tomography and magnetic resonance imaging were evaluated, compared, and discussed. Of eight patients studied with an in vivo bromodeoxyuridine (BUdR) labeling index (LI), seven showed an LI of 1% or more. The authors support the incorporation of the BUdR LI into the diagnostic process to provide a better estimate of the potential for tumor recurrence.

Adolescent↗

PubMed1995

Management of intracranial plasmacytoma.

The authors report on a study of eight cases of intracranial plasmacytoma to identify the risk of progression to multiple myeloma and suggest the treatment required for cure of solitary lesions. The diagnosis of multiple myeloma or myelomatous changes was made in the immediate postoperative period in four patients (50%), two of whom had skull base lesions. Of the four remaining patients, three were treated with complete surgical resection and radiation therapy and had no recurrence of plasmacytoma or progression to multiple myeloma during mean follow up of 12 years (range 2-25 years); one patient underwent subtotal surgical resection and had recurrence of the tumor despite radiation therapy. It is concluded that multiple myeloma is unlikely to develop during the long term in patients with intracranial plasmacytoma who do not develop multiple myeloma or myelomatous changes in the early postoperative period. However, lesions that infiltrate the skull base are not likely to be solitary, and patients who harbor these neoplasms should undergo complete evaluation and close follow-up review to exclude multiple myeloma. A recurrence of solitary intracranial plasmacytoma is possible with subtotal surgical resection despite radiation therapy. Definitive treatment should consist of complete surgical resection with adjuvant radiation therapy.

Adult↗

PubMed1995

Reoperation for recurrent metastatic brain tumors.

Results of reoperation in 48 patients who developed recurrent brain metastases between January 1984 and April 1993 are presented. Median time from first craniotomy to diagnosis of recurrence (time to recurrence) was 6.7 months. Median Karnofsky performance scale (KPS) score prior to reoperation was 80. Recurrence was local in 30 patients, distant in 16 patients, and both local and distant in two patients. Median survival time after reoperation was 11.5 months. There were no operative mortalities. Multivariate analysis revealed that presence of systemic disease (p = 0.008), KPS scores less than or equal to 70 (p = 0.008), time to recurrence of less than 4 months (p = 0.008), age greater than or equal to 40 years (p = 0.51), and primary tumor type of breast or melanoma (p = 0.028) negatively affected patient survival time. These five factors were used to develop a grading system (Grades I-IV). Patients categorized in Grade I had a 5-year survival rate of 57%, whereas the median survival time of patients in Grades II, III, and IV was 13.4, 6.8, and 3.4 months, respectively (p < 0.0001). Overall, 26 patients developed a second recurrence after reoperation. Seventeen patients underwent a second reoperation, whereas nine did not. Patients undergoing a second reoperation survived a median of 8.6 additional months versus 2.8 months for those who did not (p < 0.0001). This study concludes that reoperation for recurrent brain metastasis can prolong survival and improve quality of life. A second reoperation can also increase survival. Five factors influence survival: status of systemic disease, KPS score, time to recurrence, age, and type of primary tumor. The grading system using these five factors correlates with survival time. Reoperation should be approached with caution in Grade IV patients because of their poor prognosis.

Adolescent↗

PubMed1995

Advances in surgery for brain tumors.

Significant advances in the management of neurosurgical disorders during the past decade have enhanced the safety of intracranial surgery, resulting in the ability of most patients with brain tumors to undergo successful resection now. Among these advances are stereotactic surgical procedures and intraoperative monitoring devices; future directions in neurosurgery include the application of advances in robotics and virtual reality. The surgical considerations and complications that accompany these advances are factors that the neurosurgeon must evaluate along with the choice of management.

Adult↗

PubMed1994

Expression and localization of urokinase-type plasminogen activator receptor in human gliomas.

Urokinase-type plasminogen activator receptors (uPARs) play an important role in tumor invasion by localizing degradative enzymes at the invasive zone. In the present study, we examined the presence and distribution of uPARs in human gliomas in vivo. The amounts of uPARs were measured by radioreceptor assays and Northern blotting and were significantly higher in anaplastic astrocytomas and glioblastomas than they were in normal brain tissues and low-grade gliomas. In situ hybridization was performed to investigate the cellular source of uPAR mRNA in various types of astrocytomas and normal brain tissues. uPAR mRNA was localized in astrocytoma cells and endothelial cells within tumor tissue, especially near sites of vascular proliferation and at the leading edges of tumors. uPAR mRNA was also expressed in tumor cells near necrotic areas. Expression was barely detectable in low-grade astrocytomas and normal brain tissues. These results suggest that expression of uPAR in the invading astrocytoma cells may play a significant role in the invasive behaviors of glioblastomas.

Base Sequence↗

PubMed1994

Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo.

Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amount of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.

Astrocytoma↗

PubMed1994

Expression and cellular localization of messenger RNA for plasminogen activator inhibitor type 1 in human astrocytomas in vivo.

We investigated the expression and cellular localization of plasminogen activator inhibitor type 1 (PAI-1) in human astrocytoma in vivo. Northern blot and densitometric quantitation of PAI-1 mRNA indicated that PAI-1 transcripts were significantly higher in human malignant astrocytomas and especially in glioblastomas than in low-grade gliomas and normal brain tissues in vivo. Using in situ hybridization with paraffin-embedded surgical specimens of human gliomas and normal brain tissues, PAI-1 mRNA was abundantly expressed in glioblastomas. PAI-1 mRNA was localized mainly in tumor cells and endothelial cells. The distribution of PAI-1 mRNA expression was particularly abundant around areas of vascular proliferation and in remnant tumor cells surrounding necrotic foci. PAI-1 mRNA was also expressed in both the tumor and endothelial cells of anaplastic astrocytomas, whereas it was not expressed or only weakly expressed in low-grade astrocytomas or normal brain tissues. These results suggest that high expression of PAI-1 is associated with the malignant progression of astrocytic tumors and that excessive PAI-1 expression might be associated with intratumoral necrosis in glioblastomas.

Astrocytoma↗

PubMed1994

Induction of tissue-type plasminogen activator and 72-kDa type-IV collagenase by ionizing radiation in rat astrocytes.

Radiation-induced damage in the central nervous system (CNS) is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of the process is still poorly understood. In this study, we irradiated rat astrocytes with single doses of X-rays and then estimated the levels of tissue plasminogen activator (tPA) and collagenase in serum-free medium and cell extracts at different times. Fibrin zymography revealed increased levels of intracellular tPA activity at 12 hr after irradiation. Gelatin zymography showed continuously increasing levels of extracellular 72-kDa type-IV collagenase after irradiation. Quantitative enzymatic activities by densitometry showed a 3- to 4-fold elevation in the level of the intracellular tPA activity at 12 hr and a 5- to 6-fold increase in the level of the extracellular 72-kDa type-IV collagenase activity at 48 hr. An ELISA with specific antibodies for tPA and 72-kDa type-IV collagenase indicated a 5-fold increase in the level of tPA at 12 hr and a more-than-7-fold increase in the level of 72-kDa type-IV collagenase at 48 hr. This study adds considerable credibility to the proposed role of plasminogen activators and type-IV collagenase in the development of CNS damage after radiotherapy for brain tumors.

Animals↗

PubMed1994

Role of plasminogen activator and of 92-KDa type IV collagenase in glioblastoma invasion using an in vitro matrigel model.

The invasive nature of human gliomas represents a major factor in preventing their total resection. The exact nature of the underlying mechanisms of tumor cell invasion are still unclear. In this study, we have quantitatively assayed a glioblastoma cell line for its ability to migrate through a polycarbonate filter coated with matrigel which contains a complex of multiple basement membrane components. At 48 h the glioblastoma cell line (U251) showed a rate of invasiveness of 42% and also dependent on the concentration of matrigel. The U251 cell line produced a urokinase type plasminogen activator and a 92-KDa type IV collagenase. Both enzymes were inhibited by the addition of uPA and 92-KDa type IV collagenase antibodies. Those same antibodies reduced the invasion rate of U251 cells from 42% to 12 and 21%, respectively. Similarly, the addition of epsilon-aminocaproic acid (a plasmin inhibitor) or tissue inhibitor of metalloprotease (TIMP2, a collagenase inhibitor) reduced the invasiveness of U251 cells from 42% to 14% and 10%, respectively. Additionally, the other two glioblastoma cell lines (LG11, UWR1) and astrocytes showed a rate of invasiveness at 41%, 61% and 12%, respectively. Finally, the addition of hyaluronic acid to the matrigel, a constituent of brain extracellular matrix, enhanced the rate of invasion. These findings provide evidence for the role of serine proteases and metalloproteases in facilitating the invasion of extracellular matrix components by glioblastoma cell line and suggest a therapeutic role for protease inhibitors in attempting to minimize the invasive propensity of gliomas.

Aminocaproic Acid↗

PubMed1994

Prognostic significance of proteolytic enzymes in human brain tumors.

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

Brain↗

PubMed1994

Activities, localizations, and roles of serine proteases and their inhibitors in human brain tumor progression.

The plasminogen activation system consists of plasminogen activators and their inhibitors, serine proteases, and serpins. The proteases and inhibitors regulate a variety of processes in tissue morphogenesis, differentiation, cell migration, and cancer cell invasiveness and metastasis. One of the plasminogen activators, urokinase-type plasminogen activator (uPA), binds to a specific surface and provides a localized cell surface proteolytic activity required for the destruction of extracellular matrix, which is a vital step in tumor cell invasion. The proteolytic activity of uPA is modulated by its cell surface receptor, as well as by plasminogen activator inhibitor type-1 (PAI-1) and, to a lesser degree, by other inhibitors. The role of plasminogen activators and their inhibitors in cancer invasion can be demonstrated in the development and progression of malignant brain tumors. Our findings indicate that uPA and PAI-1 expression are dramatically upregulated in malignant brain tumors in parallel with the histological progression of the tumors. The results suggest that these molecules may contribute to tumor invasion in addition to their significant role in angiogenesis. An evaluation of the plasminogen activation system could add diagnostic and prognostic significance to the evaluation of individual patients.

Brain Neoplasms↗

PubMed1994

Modulation of fibrinolysis by ionizing radiation.

Radiation-induced damage to the central nervous system is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of this process is still poorly understood. A series of experiments were, therefore, conducted, including irradiation to primary rat astrocytes (in vitro) and rat spinal cords (in vivo). The levels of plasminogen activators (uPA and tPA) and their inhibitors (PNI and PAI-1) were determined by fibrin zymography, ELISA, amidolytic activity assay, complex formation, and Western blot analysis. Fibrin zymography revealed the presence of M(r) 48,000 (uPA) and M(r) 68,000 (tPA) lytic bands that were increased in irradiated samples. Three- to four-fold higher levels of tPA and 8- to 10-fold higher levels of uPA were detected in irradiated samples. Western blot analysis confirmed the presence of a 51-kDa band (PAI-1) in irradiated samples. PAI-1 is undetectable in nonirradiated spinal cord. Serum-free medium and cell and spinal cord extracts of nonirradiated samples showed a 43-kDa band (PNI), the intensity of which is decreased in irradiated samples. Four- to five-fold decreased levels of PNI were detected in irradiated serum-free media and cell extracts, but no levels of PNI were detected in irradiated spinal cord extracts. This study provides additional information regarding the proposed roles of plasminogen activators and their inhibitors in the development of CNS damage after irradiation.

Animals↗

PubMed1994

Management of metastatic brain tumors.

BACKGROUND: Brain metastases are the most common neurological complication of systemic cancer. They represent a serious cause of morbidity and mortality and a significant challenge for neurosurgeons. They outnumber all other intracranial tumors combined and, with advances in technology and treatment of systemic cancer, are on the increase as cancer patients live longer. METHODS: We have reviewed the major factors that influence the occurrences of metastases in the central nervous system: primary cancer, patient age and sex, clinical aspects of presentation, basic diagnostic modalities, diagnostic imaging (computed tomography and magnetic resonance imaging), and treatment considerations. In discussing these different aspects, we emphasize the efficacy of different treatment options, including recent information regarding multiple metastases that broadens the scope of surgical implications. The criteria we present are directed toward considerations made by general surgeons, as well as those made by neurosurgeons. CONCLUSIONS: Although radiotherapy remains the main therapeutic modality, surgical excision has increasingly shown advantages in certain settings, as has stereotactic radiosurgery. Chemotherapy is less effective, but its advantages are reviewed, as are the implications of recurrent metastases.

Brain Neoplasms↗

PubMed1994

Immunohistochemical localization of plasminogen activator inhibitor type 1 in human brain tumors.

We investigated the immunohistochemical localization of plasminogen activator inhibitor type 1 (PAI-1) in surgical specimens of 41 human intracranial tumors. Malignant tumors (7 glioblastoma multiforme, 5 anaplastic gliomas, 4 malignant meningiomas, and 9 metastatic tumors) showed consistently stronger PAI-1 immunohistoreactivity than benign or low-grade tumors (5 low-grade gliomas, 8 benign meningiomas, and 3 Schwannomas). Strong PAI-1 positivity was confined to glomeruloid-shaped proliferative vessels seen in high-grade gliomas and metastatic tumors. Blood vessels near necrotic foci and some zones of necrosis also showed strong PAI-1 positivity. PAI-1 localizes in the vascular basement membrane and perivascular connective tissue, while endothelial cells themselves show weak positivity. None of the specimens showed PAI-1 reactivity within the tumor cells per se. Localization of PAI-1 in proliferating vessels suggests that PAI-1 may be involved in angiogenesis.

Brain Neoplasms↗

PubMed1994

Prognostic significance of bromodeoxyuridine labeling in primary and recurrent glioblastoma multiforme.

To evaluate the prognostic significance of bromodeoxyuridine (BUdR) labeling index (LI) and to estimate tumor proliferative potential, BUdR LI was examined in 98 patients having a primary diagnosis of glioblastoma multiforme (GBM); 55 underwent infusion of 200 mg/m2 of BUdR at the time of the primary resection and 49 underwent infusion at the time of the second resection. The tumors of six patients were labeled at both operations. The tumor specimens were stained with hematoxylin and eosin for histopathology and by immunohistochemical methods to determine the ratio of labeled to unlabeled cells, i.e., BUdR LI. The median BUdR LIs for the primary and recurrent GBM were significantly different at 6.8 and 2.6%, respectively (P < 0.0001). However, there was no significant association between BUdR LI at the first or second operation and survival (log rank, P = 0.12; Cox regression analysis, P = 0.91; log rank, P = 0.55; Cox regression analysis, P = 0.17, respectively). Patients who underwent a second operation within 10 months of the first operation had a lower BUdR LI than did patients with a longer interval between procedures (P = 0.078; Spearman rank correlation, 0.26). The aggressive biological behavior of GBM is dependent on complex cellular kinetics, not simply on the number of cells within the S phase of the cell cycle. Caution should be used when determining prognosis with BUdR LI in GBM.

Adult↗

PubMed1994

Postoperative mutism in neurosurgery. Report of two cases.

Mutism is defined as a state in which a patient is conscious but unwilling or unable to speak. It has been reported to occur in association with a multitude of conditions, including trauma, epilepsy, tumors, stroke, psychoses, and brain surgery. The cases of two patients who became mute in the immediate postoperative period are presented. The first patient developed mutism following removal of a parasagittal meningioma, and the second following removal of a posterior fossa medulloblastoma. It is believed that transient injury may have occurred to the supplementary motor cortex in the first case and to the dentate nuclei in the second case. It is interesting that these two areas are connected via pathways involving the ventrolateral nucleus of the thalamus, and that lesions of this thalamic nucleus can also lead to mutism. It therefore appears plausible that interruption of these pathways may be involved in the pathogenesis of mutism. Although mutism is an infrequent complication of brain surgery, neurosurgeons should be aware that it may occur following removal of lesions in these areas and that it is generally a transient condition.

Brain Neoplasms↗

PubMed1994

Plasminogen activator inhibitor-1 in the pathogenesis of delayed radiation damage in rat spinal cord in vivo.

The pathophysiology of radiation-induced damage to the central nervous system (CNS) is poorly understood. Preliminary data suggest that fibrinolytic inhibitors are involved in the development of necrosis. In this study, cervical spinal cord irradiation was studied in 90 rats by measuring plasminogen activator inhibitor (PAI)-1 on Days 2, 7, 30, 60, 90, 120, 130, or 145 after irradiation. Paralysis due to radiation necrosis developed in all animals kept alive for 140 to 150 days. Assay of PAI-1 was by Western blot, enzyme-linked immunosorbent assay (ELISA), and complex formation with 125I-labeled urokinase. No PAI-1 was detected in normal spinal cord tissue or in irradiated spinal cord up to Day 90. However, PAI-1 was detected at Day 120 and was marked by elevated ELISA levels at the time of paralysis. Western blot showed detectable PAI-1 (51 kD) at Day 120 and very significant levels at the time of paralysis. Complex formation with 125I-labeled urokinase was also detected at Day 120 with similar results. Immunohistochemical studies showed that PAI-1 was highly concentrated within and immediately adjacent to zones of necrosis at 145 days and was absent in normal tissue. This study adds considerable weight to the proposal that PAI-1 is closely associated with the pathogenesis of CNS radiation necrosis.

Animals↗