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Rudolf Fahlbusch, Michael Buchfelder and Uwe Schrell

✓ During a period of 3 years, 25 patients with intra- and extrasellar macroprolactinomas were pretreated with dopamine agonists for a period of 2 to 6½ weeks prior to transsphenoidal microsurgical tumor resection. Dopamine agonists were administered orally to 17 patients, intramuscularly to three patients, and both orally and intramuscularly to five patients. Repeated computerized tomography (CT) examinations revealed that all neoplasms except one cystic tumor were reduced in size during the course of dopamine-agonist administration. No complications attributable to medical pretreatment were observed. Tumor shrinkage increased the efficacy of surgery, especially in cases with considerable extrasellar extension of the adenomas. Within 3 months following adenomectomy, prolactin levels were adjusted to normal levels in 19 patients by additional low-dose treatment with dopamine agonists. Thin-collimation CT assessments performed at least 3 months after surgery showed no evidence of residual tumor tissue in 23 patients. It is concluded that administration of dopamine agonists for some weeks prior to surgery is a useful adjunct to transsphenoidal microsurgery for macroprolactinomas. The new injectable form of bromocriptine is particularly valuable for this purpose.

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Hormonal dependency of cerebral meningiomas

Part 1: Female sex steroid receptors and their significance as specific markers for adjuvant medical therapy

Uwe M. H. Schrell, Eric F. Adams, Rudolf Fahlbusch, Robert Greb, Gustav Jirikowski, Reinhard Prior and Flavio J. Ramalho-Ortigao

✓ Female sex steroid receptors were examined in 50 human cerebral meningiomas. For estrogen receptors, high-affinity binding sites (dissociation constant (Kd): 0.05 to 0.2 nM) were found in the cytosolic fraction with a capacity of less than 4 fmol/mg protein in 10 meningiomas using a dextran-coated charcoal (DCC) assay. In the same cytosolic fraction, the solid-phase enzyme immunoassay revealed only one cytosol with a positive colorimetric reaction equal to 5 fmol/mg protein. However, in the nuclear compartment, none of the tumors stained positively for estrogen receptors with immunohistochemical techniques. In addition, the most convincing evidence for the absence of estrogen receptors was obtained by in situ hybridization using an oligonucleotide probe complementary to a fraction of the human receptor messenger ribonucleic acid (mRNA). In none of the 50 meningiomas was the expression of estrogen mRNA coding for the estrogen receptor detected.

For progesterone receptors, high-affinity binding sites (Kd: 0.3 to 2.6 nM) were found in 49 of the 50 tumors using a DCC assay. In the same cytosols, solid-phase enzyme immunoassay revealed that each tumor was positive for progesterone receptors. However, in the nuclear compartment, only five tumors had partially positive staining for progesterone receptors with immunohistochemical techniques.

Within the confines of this study, it is concluded that: 1) the estrogen receptor is generally absent in meningioma tissue, and 2) the progesterone receptor is mainly absent in the nuclear compartment, leading to the conclusion that the cytosolic progesterone receptor may be an inactive form. This study suggests that female sex steroid receptors are not primarily involved in the proliferative rate of cerebral meningiomas and that they are of no current significance as markers for adjuvant medical therapy of most meningiomas.

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Hormonal dependency of cerebral meningiomas

Part 2: In vitro effect of steroids, bromocriptine, and epidermal growth factor on growth of meningiomas

Eric F. Adams, Uwe M. H. Schrell, Rudolf Fahlbusch and Paul Thierauf

✓ Cell culture and biochemical techniques have been employed to examine the effects of steroids, bromocriptine, and epidermal growth factor (EGF) on the growth and proliferative potential of meningiomas. In cell culture, the growth of meningiomas was not altered by progestogens, antiprogestogens, or 17β-estradiol. The progestogen, norethisterone, had no effect on the uptake by meningioma cell cultures of 3H-thymidine. Furthermore, cytosolic deoxyribonucleic acid (DNA) polymerase activity of meningiomas did not correlate with the progesterone receptor status of the same tumors. In contrast, the androgen antagonists, cyproterone acetate and 11-α-hydroxyprogesterone, and the dopamine agonist, bromocriptine, all inhibited the in vitro growth of meningioma cells. The growth of meningioma cell cultures was stimulated by EGF, and there was a positive correlation between the EGF content and DNA polymerase activity in meningioma cytosols. These results demonstrate that female sex steroids do not influence growth of meningiomas in vitro, whereas antiandrogens and bromocriptine have an antiproliferative effect. Consequently, bromocriptine and antiandrogens may have a role in the medical treatment of meningiomas. In addition, these results suggest that EGF may be involved in the genesis and/or progression of meningiomas.

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Uwe M. H. Schrell, Panos Nomikos and Rudolf Fahlbusch

✓ Preliminary studies have shown that the dopamine D1 receptor is expressed in cerebral meningioma tissue. The current study presents evidence that the iodinated dopamine D1 antagonist [125I]SCH-23982 bound to dopamine binding sites in 33 of the 45 human cerebral meningiomas examined for this. Saturation curves and the linearity of the Scatchard analysis indicate that [125I]SCH-23982 binds to a homogeneous population of binding sites. Competition curves reveal the presence of a dopamine D1 receptor by rank order of various dopaminergic and nondopaminergic antagonists ((+)-SCH-23390 > (±)-SKF-83566 > (cis)-flupentixol > (+)-butaclamol > chlorpromazine > 1-sulpiride > mianserin > (−)-butaclamol). Stereoselectivity was evaluated by (+)- and (−)-butaclamol. The mean (± standard deviation) dissociation rate constant was 369 ± 196 pM with a density of 31.9 ± 12.5 fmol/mg membrane protein among 33 meningiomas.

The dopamine D2 receptor was not present in the 30 meningiomas examined for this. These findings indicate that the dopamine D1 receptor identified is expressed alone and is therefore regulated independent of a D2 receptor in cerebral meningioma tissue. Although the function of the dopamine D1 receptor in cerebral meningiomas has not so far been defined, previous studies have suggested that the D1 receptor might be involved in the control of proliferative growth of meningiomatous tissue.

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Tomoki Todo, Eric F. Adams and Rudolf Fahlbusch

✓ In a previous study, the authors demonstrated that meningioma cells secrete platelet-derived growth factor (PDGF)-like molecules that stimulate their own growth in an autocrine manner. Based on that finding, a study was undertaken to examine the effect of trapidil, a drug known to have an antagonistic action against PDGF, on cell proliferation of human meningiomas in culture. Trapidil showed a dose-dependent inhibition of meningioma cell proliferation in the absence of any exogenous mitogenic stimulation. The maximum effect was observed at a concentration of 100 µg/ml, with the decrease in cell growth ranging from 16% to 54% compared to control samples. Trapidil similarly inhibited the basal deoxyribonucleic acid (DNA) synthesis assessed by [3H]-thymidine incorporation in three of seven meningiomas. While the conditioned medium generated from meningioma cells remarkably stimulated the proliferation of meningioma cells (166% to 277% of control), this effect was strikingly inhibited by the addition of trapidil. Trapidil also inhibited conditioned medium-stimulated DNA synthesis, even when there was no effect on basal DNA synthesis. Furthermore, trapidil significantly inhibited the epidermal growth factor (EGF)-stimulated proliferation of meningioma cells. This inhibitory effect on EGF-stimulated cell proliferation was also observed in nontumorous fibroblasts, demonstrating that trapidil is not an antagonist specific to PDGF. The addition of trapidil (30 µg/ml) in combination with bromocriptine (1 µM) showed an additive inhibitory effect on the meningioma cell growth compared to trapidil or bromocriptine alone. The overall results suggest that trapidil exhibits an inhibitory effect on meningioma cell proliferation through blocking the mitogenic stimulation induced by autocrine or exogenous growth factors, and may be considered as a possible new approach to the medical treatment of meningiomas.

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Christian Strauss, Johann Romstöck, Christopher Nimsky and Rudolf Fahlbusch

✓ Intraoperative electrical identification of motor areas within the floor of the fourth ventricle was successfully carried out in a series of 10 patients with intrinsic pontine lesions and lesions infiltrating the brain stem. Direct electrical stimulation was used to identify the facial colliculus and the hypoglossal triangle before the brain stem was entered. Multichannel electromyographic recordings documented selective stimulation effects. The surgical approach to the brain stem was varied according to the electrical localization of these structures. During removal of the lesion, functional integrity was monitored by intermittent stimulation. In lesions infiltrating the floor of the fourth ventricle, stimulation facilitated complete removal. Permanent postoperative morbidity of facial or hypoglossal nerve dysfunction was not observed. Mapping of the floor of the fourth ventricle identifies important surface structures and offers a safe corridor through intact nervous structures during surgery of brain-stem lesions. Reliable identification is particularly important in mass lesions with displacement of normal topographical anatomy.

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Tomoki Todo and Rudolf Fahlbusch

✓ 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 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 µM) 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.

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Tomoki Todo, Eric F. Adams, Brian Rafferty, Rudolf Fahlbusch, Theodor Dingermann and Herbert Werner

✓ 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-α, IL-1β, 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.