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R Fahlbusch

Publications and source records attributed to R Fahlbusch.

At least 145 records · Page 8Linked to original sources
PubMed1995

Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop.

The growth of human cerebral meningiomas depends on various growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, platelet-derived growth factor (PDGF)-BB, insulin-like growth factor (IGF)-I and IGF-II, and acidic and basic fibroblast growth factors. The latter three have been shown to form autocrine loops that are thought to be a major component of uncontrolled growth in meningioma tissue. Suramin is known to prevent binding of a variety of growth factors to their receptors in mammalian tissue, thus abolishing para- and/or autocrine-mediated cell growth. The authors therefore tested the effect of suramin on the proliferation of cultured human meningioma cells. Suramin (10(-5) to 10(-4) M) significantly inhibited the growth of meningioma cells in culture. The maximum effect observed was with the higher dose (10(-4) M), which resulted in a 40% to 70% reduction in cellular proliferation. This effect was observed in all 15 tumor samples studied and was confirmed by [3H]thymidine uptake. In studies using DNA flow cytometry, suramin inhibited meningioma cell proliferation in five tumor samples by arresting cells in the S and G2/M phases of the cell cycle. Growth factor (EGF, IGF-I, and PDGF-BB)-induced cell proliferation was completely abolished in five tumor samples when 10(-4) M suramin was applied to meningioma cells. Western blot analysis of three tumor samples showed that the intracellular PDGF-BB content of meningioma cells was significantly reduced after treating the cells with 10(-4) M suramin. Binding of iodinated growth factors (that is, [125I]EGF, [125I]IGF-I, and [125I]PDGF-BB) to their receptor sites was prevented by suramin in a dose-dependent manner in 10 meningioma membrane fractions. Lowering of the intracellular PDGF content and prevention of extracellular growth factor receptor binding demonstrates that suramin disrupts autocrine loops and paracrine growth stimulation in meningioma tissue. These data provide evidence that growth of cerebral meningiomas in culture is strongly inhibited by suramin at a concentration of 10(-4) M. Suramin acts as a scavenger neutralizing exogenous growth factors; thus it can interrupt autocrine loops and paracrine stimulation of human meningioma cell growth. The evidence favors suramin as a therapeutic option for controlling meningioma proliferation in patients with inoperable and recurrent high-grade meningiomas.

Blotting, Western↗
PubMed1995

Prolactin-producing pituitary tumor: resistance to dopamine agonist therapy. Case report.

A 14-year-old girl presented with a rapidly growing, invasive prolactin-producing pituitary tumor that failed to respond to dopamine agonist medication. Histological, immunocytochemical, and ultrastructural studies of the surgically removed tissue revealed a pleomorphic, chromophobic, or slightly acidophilic pituitary tumor that was immunoreactive for prolactin and that, according to electron microscopy, consisted of atypical lactotrophs showing no evidence of cell shrinkage. In situ hybridization demonstrated large amounts of prolactin messenger ribonucleic acid (mRNA), moderate amounts of estrogen receptor mRNA and dopamine (D2) receptor mRNA, and an absence of growth hormone mRNA in the tumor cells. Because D2 receptor mRNA was present in the tumor, causes other than D2 receptor loss may have been responsible for the resistance of the lactotrophs to dopamine agonist administration.

Adenoma↗
PubMed1994

Posterior fossa neurovascular anomalies in essential hypertension.

Intraoperative observations, necropsy, and angiographic studies support the presumption that neurovascular compression of the left ventrolateral medulla may cause neurogenic hypertension. Pulsatile irritation of the ventrolateral medulla at the root-entry zone of cranial nerves IX and X increases blood pressure in animals. To identify and assess the distribution of neurovascular compression at the ventrolateral medulla in human beings, we did a prospective single-blind study in 24 patients with essential hypertension, in 14 patients with renal hypertension, and in 14 normal subjects. To detect neurovascular compression, we used axial and coronal double-echo and magnetic-resonance angiography sequences. Blood pressure control and duration of hypertension were not different in the two groups of patients. 20 patients with essential hypertension had magnetic tomographic evidence of left-sided neurovascular compression at the ventrolateral medulla; 2 patients with renal hypertension and 1 of the normal subjects had a positive finding on the left. On the right side, we found signs of neurovascular compression in 4 patients with essential hypertension, in 4 with renal hypertension, and in 2 of the normal subjects. With magnetic resonance tomography, it is possible to evaluate the neurovascular relations in the posterior fossa and detect neurovascular compression at the ventrolateral medulla. These data in living subjects give further evidence of an association between neurovascular compression at the left ventrolateral medulla and essential hypertension.

Adult↗
PubMed1994

Raymond's syndrome following petrosal sinus sampling.

Inferior petrosal sinus sampling (IPSS) is used to evaluate the pituitary-dependency of Cushing's disease, and to predict the laterality of a microadenoma prior to transsphenoidal operation. A serious complication occurred in a 14-year-old boy: he suffered brain stem ischaemia with abducens nerve palsy and hemiparesis (Raymond's syndrome). The case prompted us to reconsider the indication for this investigation.

Abducens Nerve↗
PubMed1994

Involvement of protein kinase C in growth regulation of human meningioma cells.

In order to investigate the possible role of protein kinase C (PKC)-mediated signal pathways in growth regulation of meningiomas, we examined the effect of two PKC-activating phorbol esters, 12-O-tetradecanoyl-13-phorbol acetate (TPA) and phorbol 12, 13-dibutyrate (PDBu), and PKC inhibitor, staurosporine, on cell proliferation using low-passage human meningioma cells in culture. TPA (0.1 to 100 ng/ml) caused a dose-dependent stimulation of cell proliferation in six of eight meningioma cultures. At optimal concentrations of TPA, the cell growth ranged from 113% to 251% versus control. In contrast, PDBu (0.1 to 100 ng/ml) caused a significant inhibition of cell proliferation in three of five meningioma cultures. At optimal concentrations of PDBu, the cell growth ranged from 52% to 79% of control. Staurosporine exhibited a stimulation of cell proliferation (135% to 178%) in three of four meningioma cultures studied at a concentration of 10(-10) to 10(-9)M, although a tendency of growth inhibition was observed at a lower concentration. A time course of DNA synthesis in response to TPA, assessed by [3H] thymidine incorporation studies, revealed a time- and dose-dependent stimulation and/or inhibition which further depended on the serum concentration of the growth medium used. The overall results indicate that PKC-mediated signal pathways are closely involved in growth regulation of human meningioma cells. The results further suggest that the signalling processes consist of complex mechanisms which await to be elucidated.

Alkaloids↗
PubMed1994

Meningiomas and neurofibromatosis for the oncologist.

The goal of this review is to understand meningioma, one of the most frequent primary intracranial tumors, from an oncologic and neurosurgical point of view. The epidemiology, pathogenesis, cytogenetics, and molecular genetics are presented. The operative therapeutic possibilities, the recurrence rates in relation to the intracranial tumor localization, and the place of adjunctive therapies is discussed. Although the emphasis of this review is on developments in the past year, some historical references are provided.

Growth Substances↗
PubMed1994

In situ hybridization study of estrogen receptor messenger ribonucleic acid in human adenohypophysial cells and pituitary adenomas.

Estrogen receptor (ER) was demonstrated in nontumorous and adenomatous human pituitaries by autoradiography and biochemical assays. In the present study, we investigated ER mRNA by in situ hybridization applied on paraffin section of 9 nontumorous pituitaries obtained at surgery or autopsy and 109 surgically removed adenomas. In nontumorous pituitaries, in situ hybridization combined with immunocytochemistry revealed hybridization signal in GH-, PRL-, ACTH-, TSH-, and LH/FSH-immunoreactive cells, with the highest intensity in PRL-immunoreactive cells. ER mRNA was also localized in Crooke's cells, corticotrophs extending to posterior lobe, cells lining the pars intermedia cavities, and squamous nests of pars tuberalis. The neurohypophysis, endothelium, and connective tissue expressed no ER gene. ER mRNA was present in all adenoma types, including somatotroph, lactotroph, mixed somatotroph-lactotroph, mammosomatotroph, acidophil stem cell, functioning and silent corticotroph, thyrotroph, gonadotroph, null cell adenomas, and oncocytomas. The strongest signal was seen in some lactotroph and mammosomatotroph adenomas. In 9 lactotroph adenomas exposed to bromocriptine (long-acting repeatable injectable form), the hybridization signal was weak or absent, suggesting that suppression of ER gene plays a role in the inhibition of PRL synthesis and tumor growth.

Adenoma↗
PubMed1994

Normal structural dopamine type 2 receptor gene in prolactin-secreting and other pituitary tumors.

Dopamine, acting via its specific receptor (DRD2) in the anterior pituitary, tonically inhibits pituitary prolactin secretion and lactotroph proliferation. In addition, dopamine agonist therapy for pituitary prolactinomas results in reduction of prolactin secretion and tumor regression. These observations lead to the speculation that functional dopamine uncoupling may release lactotrophs from the inhibitory effects of dopamine and contribute to the development of prolactin (PRL)-secreting pituitary tumors. We hypothesized that such an uncoupling may occur by inactivating mutation(s) of the DRD2. To test our hypothesis, we examined 79 pituitary tumors, mostly prolactinomas and mixed GH/PRL-secreting, for mutations in the coding exons of the DRD2 gene. We used the polymerase chain reaction and analyzed the fragments for migration abnormalities on denaturing gradient gel electrophoresis, complemented by direct DNA sequencing. No mutations were demonstrated, and all migration abnormalities detected by denaturing gradient gel electrophoresis were due to polymorphisms within the DRD2 gene. In addition, allelic losses in the multiple endocrine neoplasia type 1 region in 11q13 could not be demonstrated in all five informative prolactinomas. We conclude that mutations in the DRD2 gene do not occur in PRL or GH/PRL-secreting pituitary tumors and that allelic loss of 11q13 is uncommon in prolactinomas.

Base Sequence↗
PubMed1994

Human acoustic neuromas secrete interleukin-6 in cell culture: possible autocrine regulation of cell proliferation.

Interleukin-6 (IL-6) secretion by cell cultures of human acoustic neuromas was examined. Secretory rates varied from 0.02 to 5.4 ng/10(5) cells per 4 days, depending on the tumor. The IL-6 immunoreactivity eluted from a Sephadex G-100 column in a major peak corresponding to an M(r) of 30,000 and a lesser peak corresponding to an M(r) of 50,000. Western blot analysis revealed three IL-6 immunoreactive bands with M(r)s corresponding to 53,000, 29,000, and 24,000. Tumor necrosis factor-alpha, interleukin-1-beta, and cholera toxin all stimulated IL-6 secretion. An antisense phosphorothioate oligonucleotide against IL-6 messenger RNA inhibited both [3H]thymidine uptake and IL-6 secretion by acoustic neuroma cells in culture. In addition, [3H]thymidine uptake was inhibited by a specific polyclonal antibody against IL-6. We conclude that human acoustic neuroma cells produce and secrete IL-6, which may act in an autocrine manner to stimulate cellular proliferation.

Adult↗
PubMed1994

Growth hormone gene structure in human pituitary somatotrophinomas: promoter region sequence and methylation studies.

The structure of the GH gene in human somatotrophinomas was examined in terms of promoter region sequence and degree of methylation. In six tumours, the promoter sequence did not differ from that observed in the corresponding genomic (white blood cell-derived) DNA, suggesting that it is unlikely that excessive GH production is due to a point mutation within this region. In contrast, Southern blot analysis using the methylation-sensitive restriction enzymes HpaII and HhaI revealed lower levels of methylation of the GH gene in somatotrophinomas when compared with that found in DNA derived from normal pituitary glands. We conclude that hypomethylation of the GH gene in human somatotrophinomas may play at least a partial role in excessive GH production.

5-Methylcytosine↗
PubMed1994

Intrasellar pituitary tissue pressure, tumour size and endocrine status--an international comparison in 107 patients.

In a two-centre study, intrasellar pituitary tissue pressure was measured at transsphenoidal surgery in 107 patients with pituitary adenomas or intrasellar cysts. 'Normal' ISP in patients under anaesthesia with small microadenomas (< 5 mm diameter) or a partial empty sella was 12 +/- 3 mmHg. Raised ISP (> 15 mmHg) was found in 75% of cases. The highest pressures were recorded in tumours with parasellar invasion (30 +/- 2; p < 0.01) irrespective of size and extension in other directions. In non-invasive lesions there was no correlation between the level of raised ISP and tumour size. Hypopituitarism and stalk compression syndrome were both associated with higher ISP than patients with normal pituitary function.

Adenoma↗
PubMed1994

Accumulation of inositol phosphates in low-passage human meningioma cells following treatment with epidermal growth factor.

In order to elucidate some of the signal transduction processes in human meningioma cells, the authors studied the effect of epidermal growth factor (EGF) and bromocriptine on inositol phospholipid hydrolysis, using low-passage human meningioma cells in culture. Epidermal growth factor is a well-studied mitogenic factor for meningioma cells, whereas bromocriptine is known to have an inhibitory effect on meningioma cell proliferation. The addition of EGF to meningioma cells caused stimulation of inositol phosphate accumulation in a dose-dependent manner at 60 minutes posttreatment, with the maximum effect (120% to 167% of control) achieved at a concentration of 10 ng/ml. Extraction of separate inositol phosphates accumulation in a dose-dependent manner at 60 minutes posttreatment, with the maximum effect (120% to 167% of control) achieved at a concentration of 10 ng/ml. Extraction of separate inositol phosphates revealed that inositol monophosphate (IP1) and inositol bisphosphate (IP2), but not inositol trisphosphate (IP3), accounted for the increase at 60 minutes. Kinetic analysis of EGF-stimulated inositol phospholipid hydrolysis showed that a sharp and transient increase in IP3 from 5 to 12 minutes post-EGF and a transient but more gradual increase in IP2 from 2 to 12 minutes post-EGF were followed by a gradual and steady increase in IP1, which was significantly greater than control after 5 minutes. On the other hand, long-term studies showed a down-regulation of inositol phosphate accumulation (a 64% decrease vs. control) after 7 days of treatment with EGF (10 ng/ml). Bromocriptine (5 microM) exhibited no significant effect on inositol phosphate accumulation at 60 minutes in four of five meningiomas studied. However, of two meningiomas studied with bromocriptine in combination with EGF, both showed a significant additive increase in inositol phosphate accumulation compared to those treated with EGF alone. The results suggest a close involvement of inositol phospholipid turnover in human meningioma cells in response to mitogenic stimulation by EGF.

Bromocriptine↗
PubMed1994

Secretion of interleukin-6 by human meningioma cells: possible autocrine inhibitory regulation of neoplastic cell growth.

Using cell culture techniques, the authors have previously shown that human meningioma cells secrete an autocrine growth stimulator related to platelet-derived growth factor. Here, they further demonstrate potential autocrine inhibitory regulation of meningioma cell growth by interleukin (IL)-6. Constitutive IL-6 production was detected in all meningiomas studied, in the form of protein as well as IL-6-specific messenger ribonucleic acid. The IL-6 immunoreactivity in conditioned medium from three different meningioma cultures eluted from a Sephadex G-100 column was evidenced by a single peak corresponding to a molecular weight of about 32 kD. Interleukin-6 secretion was remarkably stimulated by tumor necrosis factor-alpha, IL-1 beta, and IL-4, and was also influenced by a combination of epidermal growth factor and bromocriptine. Recombinant IL-6 exhibited a significant dose-dependent inhibitory effect on meningioma cell proliferation. The maximum effect was observed at concentrations of 10 to 100 pg/ml, with the decrease in thymidine incorporation ranging from 21% to 35% versus control. Addition of an anti-IL-6 antibody enhanced the growth-stimulating effect of meningioma-derived conditioned medium. The rate of IL-6 secretion tended to show an inverse correlation with meningioma growth rate. The results presented here and the previous results suggest that the regulation of meningioma cell proliferation is defined by a complex network of autocrine stimulation, autocrine inhibition, and influences from multiple exogenous factors.

Blotting, Northern↗
PubMed1993

The role of transsphenoidal microsurgery in the management of sellar and parasellar meningioma.

We report on eight meningiomas that have been operated on via the transsphenoidal route since May 1988. Six patients harbored cavernous sinus meningiomas with intrasellar extension. The intrasellar tumor extension and the parasellar tumor portion medial to the carotid artery were removed. Decompression of the pituitary gland with normalization of prolactin levels was achieved in all patients. It is a well-tolerated approach to confirm the diagnosis and still allows the option of major transcranial surgery in the event of tumor progression. Additionally, we report complete tumor removal in two rare cases with intrasellar and suprasellar merely subdiaphragmatic meningiomas.

Adult↗
PubMed1993

Recent advances in the molecular biology of growth-hormone secreting human pituitary tumours.

The application of DNA technology has led to significant progress in our understanding of the aetiology of GH-secreting pituitary tumours. X-chromosome inactivation and RFLP analysis has revealed that GH-secreting tumours are monoclonal in origin and thus arise as a consequence of a somatic mutation within a single cell. Using PCR and sequence analysis, such a mutation has been identified in 30-40% of tumours. This is the so-called gsp mutation in which the gene for the alpha s subunit of the Gs protein is converted to an oncogene the expression of which results in constitutive adenyl cyclase activity and thus excessive cAMP production. In our own studies, we demonstrate that it is unlikely that a defect within the promoter region of the GH gene will prove to be a cause of excessive GH secretion in acromegaly. In contrast, we have shown that the GH gene is hypomethylated in tumour derived DNA and this may account, at least in part, for abnormal GH gene expression.

Clone Cells↗
PubMed1993

TRH/GnRH test in acromegaly. Long-term follow-up experience with successfully treated patients.

We investigated the rate of recurrence in acromegaly in 20 patients who were found to have a TRH and GnRH induced GH response postoperatively after primarily successful transsphenoidal selective adenomectomy in a retrospective study. All operations had been carried out by the same neurosurgeon (R.F.). Successful therapy was defined as basal GH-levels < or = 2 ng/ml and no evidence of residual tumour in the postoperative neuroradiological examination. The follow-up period ranged from 5 to 14 years (mean 7.7 years). At the last follow-up visit an OGTT was performed and SmC measured. In spite of the long-follow-up period we did not find patients with recurrent acromegaly in this investigation. We conclude that, in contrast to previous studies, a stimulation of GH in the TRH/GnRH test does not necessarily predict likely recurrence of acromegaly in patients with an adequate suppression of GH during an OGTT following operative microsurgical treatment.

Acromegaly↗