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Biomedical subjects

F T Vertosick

Publications and source records attributed to F T Vertosick.

At least 19 recordsLinked to original sources
PubMed1994

A comparison of the relative chemosensitivity of human gliomas to tamoxifen and n-desmethyltamoxifen in vitro.

Tamoxifen has been shown to inhibit the proliferation of human gliomas in vitro. This inhibition is independent of tamoxifen's known anti-estrogenic properties. Tamoxifen is an inhibitor of protein kinase C (PKC), a calcium- and phospholipid-dependent serine kinase which plays a critical role in the proliferation of certain cell lines. Gliomas overexpress PCK, and their growth rate is coupled to the level of this key enzyme. As such, the effect of tamoxifen may be mediated by its inhibitory effect on PKC. To further investigate this possibility, we compared the chemosensitivity of cultured glioma lines to both tamoxifen and N-desmethyltamoxifen (DMT). DMT is the major metabolite of tamoxifen in humans and is a ten-fold more potent inhibitor of PKC. Seven lines were tested using the standard MTT assay, which quantitates metabolically active cells colorimetrically using a tetrazolium dye. Four of the seven lines were also tested using a tritiated thymidine uptake assay. In the MTT assay, all seven lines showed significantly greater sensitivity to DMT, while three of the four lines tested in the thymidine uptake assay were more sensitive to DMT. Correlation between the two assays was good. The dose of tamoxifen required to produce a 50% inhibition of optical absorbance or thymidine uptake (ID50) was typically five- to ten-fold greater than the ID50 for DMT, approximating the relative strength of the two compounds as PKC inhibitors. In addition to providing some support for the ypothesis that triphenylethylenes inhibit gliomas via PKC inhibition, these findings have clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Colorimetry↗
PubMed1994

Correlation of thallium-201 single photon emission computed tomography and survival after treatment failure in patients with glioblastoma multiforme.

After initial radiotherapy for an intracranial malignant glioma, the majority of patients return at a later date with a recurrent, enhancing mass on computed tomography or magnetic resonance imaging. This mass represents either recurrent tumor, radionecrosis, or a combination of the two. The relative proportion of live versus dead tumor cells is difficult to determine from surgical specimens of another biopsy, although this has been the preferred method of assessing such "failed" patients. Recently, attention has turned to tomographic images of metabolic markers, i.e., positron emission tomography and thallium-201 (Tl-201) single photon emission computed tomography, as noninvasive methods of assessing relative tumor viability. To assess whether Tl-201 uptake in vivo can be used as a prognostic indicator in patients with glioblastoma multiforme, we measured the ratio of Tl-201 uptake in tumor to Tl-201 uptake in myocardium (T/C ratio) in 16 patients at the point of treatment "failure" and followed all the patients until they died. All patients died of neurological causes, and 11 of the 16 patients had documented viable tumor recurrence. There was a significant negative correlation between the T/C ratio at failure and the time interval between failure and death (r = -0.602, P = 0.014). Patients with T/C ratios of less than 0.3 lived an average of 13 months, whereas patients with T/C ratios of more than 0.3 lived an average of only 4 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Predicting behavior of an enzyme-linked immunoassay model by using commercially available neural network software.

Setting up new immunoassays can be a laborious and expensive task. A relatively new form of multivariate analysis known as neural networks can be applied to this problem with potential savings in reagents and technician time. Neural network software programs for personal computers are now available. We applied one such software package (Brainmaker) to a model ELISA system for measuring human serum albumin. Random combinations of four variable ELISA conditions (antigen concentration, primary and secondary antibody titers, and time for chromagen development) were used to train a three-layered feed-forward network. The trained network was then used to predict measured absorbances as a function of the four input variables in separate cross-validation sets. The network adequately predicted the effect of the input variables on the absorbance produced. With use of such methods, optimal conditions for the linear dependence of absorbance on antigen concentration can be evaluated on the computer rather than in the laboratory, with subsequent savings of time and money.

Antibodies↗
PubMed1992

Long-term survival after the diagnosis of malignant glioma: a series of 22 patients surviving more than 4 years after diagnosis.

Long-term survival after the diagnosis of malignant glioma is uncommon but not rare. To define better the population of patients who have extended survival with this disease, we reviewed the records of 22 of our patients who survived more than 4 years after the biopsy-proven diagnosis of anaplastic astrocytoma, malignant mixed glioma, or glioblastoma multiforme. Surprisingly, 21 of the 22 patients are still alive and being actively followed by the authors. The long-term survivors were typically young and with minimal or no functional impairment at the time of diagnosis. Survivals ranged from 4.2 to 15.8 years. The quality of survival was generally good, with the surviving patients having a mean Karnofsky Performance Score of 76. Three-quarters of the patients had no enhancement or mass effect on their most recent computed tomography scans. A review of the available literature, together with our own series, suggests that death from recurrent disease is unusual in glioma patients who survive more than 4 or 5 years.

Adult↗
PubMed1992

The treatment of intracranial malignant gliomas using orally administered tamoxifen therapy: preliminary results in a series of "failed" patients.

In vitro studies have shown that the nonsteroidal antiestrogen tamoxifen can suppress deoxyribonucleic acid synthesis and cell proliferation in cultured human gliomas. This growth suppression is independent of its antiestrogenic properties. Tamoxifen may act through the inhibition of the enzyme protein kinase C, which transduces mitogenic signals from the cell surface to the nucleus. Based on these preclinical studies, we initiated a clinical trial of orally administered tamoxifen, 20 mg twice daily, to patients with recurrent, progressive malignant gliomas who were not candidates for other "failed" protocols, such as brachytherapy. No limits were placed on age, Karnofsky Performance Score (KPS), or expected survival. Thirty-two patients were entered in the study, 29 with a glioblastoma multiforme and 3 with an anaplastic astrocytoma. The mean age of the group was 48 years, and the mean KPS was 65. Median survival of the entire cohort from the onset of tamoxifen therapy was 17 weeks; the median survival of those patients with an initial KPS of 70 or more was 21 weeks. Seven patients survived for more than 6 months with no change in their baseline computed tomographic scans or KPS on tamoxifen, including 2 patients with computed tomographic evidence of regression during the course of therapy. There were no significant patient-reported side effects of the treatment. Three patients had thromboembolic complications during tamoxifen administration. We conclude that tamoxifen can be administered safely to these patients and may show some efficacy against glial neoplasms.

Administration, Oral↗
PubMed1991

The immune system as a neural network: a multi-epitope approach.

The term "neural network" has been applied to arrays of simple activation units linked by weighted connections. If the connections are modified according to a defined learning algorithm, such networks can be trained to store and retrieve patterned information. Memories are distributed throughout the network, allowing the network to recall complete patterns from incomplete input (pattern completion). The major biological application of neural network theory to date has been in the neurosciences, but the immune system may represent an alternative organ system in which to search for neural network architecture. Previous applications of parallel distributed processing to idiotype network theory have focused upon the recognition of individual epitopes. We argue here that this approach may be too restrictive, underestimating the power of neural network architecture. We propose that the network stores and retrieves large, complex patterns consisting of multiple epitopes separated in time and space. Such a network would be capable of perceiving an entire bacterium, and of storing the time course of a viral infection. While recognition of solitary epitopes occurs at the cellular level in this model, recognition of structures larger than the width of an antibody binding site takes place at the organ level, via network architecture integration of, i.e. individual epitope responses. The Oudin-Cazenave enigma, the sharing of idiotypic determinants by antibodies directed against distinct regions of the same antigen, suggests that some network level of integration of the individual clonal responses to large antigens does occur. The role of cytokines in prior neural network models of the immune system is unclear. We speculate that cytokines may influence the temperature of the network, such that changes in the cytokine milieu serve to "anneal" the network, allowing it to achieve the optimum steady-state in the shortest period of time.

Artificial Intelligence↗
PubMed1991

Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography.

We report 25 verified cases of well-differentiated cerebral astrocytomas in adults treated between 1978 and 1988. All patients were diagnosed by computed tomographic (CT) scans, with 5 undergoing a craniotomy for debulking and 20 undergoing a biopsy alone. The median survival for the entire group was 8.2 years, the longest survival yet reported for a series of patients with these tumors. A review of the literature suggests that the longer survival observed in more recent series is the result of the earlier diagnosis of tumors afforded by modern brain imaging. Twenty of our patients presented with seizures in the absence of any other focal findings and would probably not have had a biopsy in the era before CT scans until their tumors had progressed. Only 8% of our patients had papilledema at the time of presentation, in contrast to almost half of the patients with low-grade astrocytomas reported before 1975, supporting the hypothesis that patients in the CT era are diagnosed earlier. None of our patients died from progressive low-grade disease. One patient died from a squamous cell cancer, and 7 died as a consequence of their tumors dedifferentiating into a more malignant astrocytoma or glioblastoma multiforme, with a median time of approximately 5 years after the diagnosis. Our findings, together with the available data in the literature, suggest that death from a focal low-grade astrocytoma, in the absence of malignant degeneration, may be a rare event. Consequently, future therapeutic efforts should be targeted at preventing dedifferentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Anti-estrogen antibodies in systemic lupus erythematosus: a quantitative evaluation of serum levels.

We measured the beta-estradiol binding capacity of serum gamma-globulins in four subject groups; 1) normal men, 2) normal women who had never taken oral contraceptives, 3) normal women who had a history of oral contraceptive use and, 4) patients with systemic lupus erythematosus (SLE). We used dextran-coated charcoal to strip endogenous estradiol from serum proteins, added 3H-estradiol, and measured its association with proteins in various electrophoretic fractions following zone separation on agarose gels. Most of the bound radioactivity was present in the albumin, beta and gamma-globulin fractions. Binding to gamma-globulins was elevated in SLE patients, and normal controls who had taken oral contraceptives, as opposed to other controls (p less than 0.005). Gamma-region radioactivity could be removed by protein-G adsorption prior to zone electrophoresis. Isoelectric focusing revealed a pattern of tritiated-E2 binding consistent with polyclonal B-cell activation in all groups. There was no correlation between the extent of gamma-region binding and the total serum immunoglobulin level for any of the groups studied, nor was there a correlation between E2 binding and anti-DNA titers in the SLE group. The average anti-estradiol antibody concentrations in SLE sera (assuming equimolar binding) was 105 ng/ml (95% CL = 92-118), whereas their average anti-DNA antibody concentration was in the microgram/ml range. Thus, quantitatively, the level of anti-estradiol antibodies is at least an order of magnitude lower than the anti-DNA antibodies characteristic of this disease.

Adolescent↗
PubMed1991

Response of low-passage human malignant gliomas in vitro to stimulation and selective inhibition of growth factor-mediated pathways.

The proliferation of many nonglial tumors in vitro depends on the presence of nanomolar concentrations of one or more growth factors. To define the growth factor requirements of malignant glial tumors, the authors examined the response properties of four low-passage human malignant glioma lines to the following mitogens: epidermal growth factor (EGF), acidic and basic fibroblast growth factors (FGF's), insulin-like growth factor I (IGF-I), nerve growth factor (NGF), platelet-derived growth factor (PDGF), 12-O-tetradecanoyl-13-phorbol acetate (TPA), and serum. Each of the tumors showed increased deoxyribonucleic acid (DNA) synthesis (assessed by acid-precipitable [3H]-thymidine incorporation) in response to PDGF with a maximum effect at 50 ng/ml. Three tumors responded to EGF, three to IGF-I, two to acidic FGF, two to basic FGF, and two to TPA with maximum effects at 10, 50, 1, 1, and 10 ng/ml, respectively. None of the tumors responded to NGF. In the responsive tumors, optimum concentrations of EGF, IGF, TPA, acidic FGF, and basic FGF induced, at most, a two- to fourfold increase in [3H]-thymidine incorporation, which was only 30% to 50% of the response seen in 10% serum. In contrast, PDGF increased DNA synthesis eight- to 10-fold, equaling the effect of 10% serum. Measurements of cell proliferation also demonstrated a significant response to PDGF in each of the tumors. Appropriate concentrations of an anti-PDGF neutralizing antibody inhibited baseline DNA synthesis and proliferation in the absence of added growth factors, suggesting the possible role of PDGF in autocrine stimulation of these cells. However, this antibody produced only slight inhibition of serum-induced mitogenesis. Trapidil, an agent reported to inhibit the effects of PDGF, and polymyxin B, an inhibitor of protein kinase C, strongly inhibited baseline as well as PDGF- and serum-induced mitogenesis. It is concluded that, in the malignant gliomas studied, PDGF may be acting as a dominant mitogen to enhance DNA synthesis, and may function in autocrine stimulation. However, other factors contained in serum can also contribute to cell division.

Antibodies↗
PubMed1991

Brain tumor biology and therapy.

There is renewed interest in boron neutron capture therapy of gliomas, while enthusiasm for immunotherapeutic modalities, such as interferon, has begun to wane. Basic research into glioma biology is shedding light on the proliferative pathways which may be amenable to future therapeutic manipulation. Recent evidence has confirmed the benefit of surgical excision in patients with solitary brain metastases. Great technical advances are occurring in radical skull base surgery; however, the indications for such surgery remain poorly defined, particularly for patients with malignant lesions.

Brain Neoplasms↗
PubMed1990

Effect of tamoxifen on DNA synthesis and proliferation of human malignant glioma lines in vitro.

Previous studies in our laboratory have shown that proliferation of human malignant gliomas in vitro depends in part upon the activation of protein kinase C (PKC) and, conversely, can be blocked by inhibitors of PKC. Here, we examined the effect of tamoxifen, a known PKC inhibitor, on DNA synthesis and proliferation of an established human glioma line (U138) and two low passage cultures of explanted human glioblastomas. Tamoxifen produced a profound, dose-dependent inhibition of both [3H] thymidine incorporation and cell proliferation, with a 50% effective dose of 20 ng/ml under serum-free conditions and 50 to 200 ng/ml in the presence of 10% serum. These tumors were estrogen receptor negative and showed no mitogenic response to estradiol. Furthermore, concentrations of estradiol as high as 10 micrograms/ml had no effect on the tamoxifen-induced inhibition. This suggests that the mechanism of growth inhibition by tamoxifen in these gliomas did not involve an estrogen receptor-mediated process but may instead result from its inhibition of PKC. In view of the profound effect of tamoxifen on cultured gliomas at concentrations that can safely be achieved therapeutically, further in vitro and in vivo studies of this agent are warranted.

Cell Division↗
PubMed1990

The risk and efficacy of anticoagulant therapy in the treatment of thromboembolic complications in patients with primary malignant brain tumors.

Twenty-three patients with malignant glial neoplasms were treated with anticoagulant therapy for thromboembolic complications. Fifteen patients had deep vein thrombosis alone, and 8 patients had both deep vein thrombosis and pulmonary embolism. Serum prothrombin times were maintained at 1.25 times control for an average of 5.8 months per patient, for a total patient exposure to warfarin therapy of 132 patient-months (11 patient-years). Only 1 patient suffered a recurrent pulmonary embolism, and this occurred during an episode of gastrointestinal bleeding, when anticoagulant therapy had to be discontinued prematurely. All patients were followed with serial computed tomographic or magnetic resonance imaging scans, and no patient showed radiographic evidence of intratumoral hemorrhage either during or after warfarin therapy. One patient, who died from a large recurrent glioblastoma, was found at autopsy to have scattered foci of intratumoral hemorrhage. This series, together with a review of the available literature, suggests that oral anticoagulant therapy is both a safe and effective means of treating thromboembolic complications in patients with residual malignant glial tumors.

Adult↗