Analysis of surgical management of calvarial tumours and first results of a newly designed robotic trepanation system.

This study was performed to evaluate the surgical strategy in patients with calvarial tumours, in order to design and modify a robot-assisted trepanation system. A total of 75 patients underwent craniectomy for the treatment of calvarial tumours during the 10-year period from 1993 to 2002. The patients' complaints, the size, location and histology of the tumour, and the various cranioplasty techniques used were analysed retrospectively. In a second procedure several craniectomies at typical locations according to the study's results were performed in a laboratory setting using a hexapod robotic tool, constructed at the Helmholtz-Institute, RWTH Aachen University, and plastic model heads. The workflow was documented and the reproducibility and the accuracy of the procedure were registered. A total of 83 surgical procedures were performed on 75 patients. The majority (87 %) of lesions treated surgically were located in the frontal, temporal and anterior parts of the parietal region. Histological examination revealed benign lesions in 66 % of the patients and dural involvement in 46 %. According to these results craniectomies were performed using the robotic system. Mean positioning accuracy of the robotic system while milling was 0.24 mm, with a standard deviation of 0.04 mm, and maximum error under 1 mm. Craniectomies leaving a 1-mm layer of the tabula interna intact to ensure a healthy dura were performed in several regions successfully. The majority of calvarial tumours, requiring surgical treatment in our patients, were located in cosmetically relevant areas in which drilling can be carried out with the robotic trepanation system. Consequently, the surgical approach had to be planned carefully in order to achieve a good cosmetic outcome.     

Fibronectin is an immunosuppressive substance associated with epithelial ovarian cancer.

BACKGROUND. Although the ascites of patients with ovarian cancer has been reported to contain immunosuppressive factors, the identity and source of this activity has not been determined. Previously, the authors showed that conditioned media from two of four epithelial ovarian cancer cell lines inhibits proliferation of mitogen-stimulated human lymphocytes. The physical characteristics of the inhibitory substance are unlike those of peptide growth factors but closely resemble those of fibronectin. METHODS AND RESULTS. In the current study, it was found that the two ovarian cancer cell lines that produce the inhibitory substance have more fibronectin on the cell surface and secrete significantly more immunoreactive fibronectin into their culture media than the other two ovarian cancer cell lines. In addition, the immunosuppressive activity was bound to a gelatin-Sepharose affinity column, known to bind fibronectin. Finally, in ascites from 20 patients with advanced epithelial ovarian cancer, fibronectin levels correlated with the ability to inhibit proliferation of lectin-stimulated lymphocytes (P < 0.001). CONCLUSIONS. Fibronectin is produced by some ovarian cancer cell lines and acts to inhibit proliferation of mitogen-stimulated lymphocytes. Additional studies are needed to clarify the role of fibronectin in ovarian cancer.     

Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha.

OBJECTIVE: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells. STUDY DESIGN: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test. RESULTS: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies. CONCLUSIONS: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.     

The CA 125 tumour-associated antigen: a review of the literature

CA 125 is an antigenic determinant on a high-molecular-weight glycoprotein recognized by a monoclonal antibody which was raised using an ovarian cancer cell line as an immunogen. During the last 5 years the studies reviewed in this paper have provided information concerning the nature, distribution and clinical significance of CA 125. The CA 125 determinant is expressed by epithelial ovarian tumours and various other pathological and normal tissues of Müllerian origin. The function of the glycoprotein expressing CA 125 remains unclear but the distribution of the antigen suggests that it may have a physiological role. The highest serum levels of CA 125 are found in ovarian cancer patients, but elevation of serum CA 125 may also be associated with other malignancies and benign and physiological states, including pregnancy, endometriosis and menstruation. Despite limitations of sensitivity and specificity serum CA 125 estimation is of clinical value in the pre-operative diagnosis and monitoring of ovarian malignancy and may be a prognostic indicator for this disease. The role of CA 125 in screening for early-stage ovarian cancer is currently under investigation. Recent reports suggest that serum CA 125 measurement may also be of value as a prognostic indicator in endometrial cancer and as a reflection of disease status in advanced endometriosis.     

Toxicity and immunogenicity of a verotoxin 1 mutant with reduced globotriaosylceramide receptor binding in rabbits.

The verotoxins (VT1 and VT2), produced by strains of enterohemorrhagic Escherichia coli, have been implicated in the pathogenesis of hemorrhagic colitis and the hemolytic uremic syndrome. To better understand the role of globotriaosylceramide (Gb3) receptor binding by the verotoxins in disease production, we examined the clinicopathologic effects of an intravenously (i.v.) administered verotoxin 1 mutant holotoxin (Phe30Ala) in rabbits. The substitution of alanine for phenylalanine 30 in the VT1 B subunit has been shown previously to reduce both Gb3 binding affinity and capacity in vitro. This reduction in receptor binding corresponded to a 10(5)-fold reduction in the toxic activity of VT1 on a Vero cell monolayer. In this study, purified 125I-labeled Phe30Ala was administered i.v. to rabbits to determine its specific distribution in rabbit tissues. In contrast to the rapid elimination of i.v. administered 125I-VT1 from the bloodstream, 125I-Phe30Ala had a 52-fold-longer half-life in serum and failed to localize preferentially in the gastrointestinal tract and central nervous system (CNS). Rabbits challenged with Phe30Ala at a dose equivalent to 10 times the 50% lethal dose (LD50) of VT1 showed no visible clinical symptoms typical of VT effect after 7 days. Administration of Phe30Ala at a dose equivalent to 100 times the LD50 of VT1, however, caused both clinical and histopathologic features indistinguishable from VT1 toxemia in rabbits, although the onset of symptoms was delayed. Rabbits were immunized with Phe30Ala and challenged i.v. with either 125I-VT1 or 125I-VT2. The specific uptake of 125I-VT1 in the gastrointestinal tract and CNS was totally inhibited in Phe30Ala immune rabbits. Only a partial decrease in target organ uptake was observed in Phe30Ala immune rabbits challenged with 125I-VT2. From this study, we conclude that Gb3 binding is responsible for target organ localization of VT1 and disease production in the rabbit. The ability of Phe30Ala to induce both strong antibody and protective responses against VT1 suggests that VT mutants with reduced receptor binding properties may be useful in vaccine strategies. A further reduction in the toxicity of Phe30Ala would be required for its use as a natural toxoid to protect against human verotoxigenic E. coli infections.     

Irreversible H2-antagonism of the four isomeric butyl analogues of mifentidine

It has been hypothesized that bidentate hydrogen bonding plays an important role in the interaction of imidazolylphenylformamidines with the H₂-receptor. The present study, in which the degree of pseudoirreversible H₂-antagonism of the four isomeric butyl substituted mifentidine analogues was determined on the spontaneously beating right atrium of the male guinea-pig, lends further support to this hypothesis. In solution the EE/EZ ratio is different for the four isomeric butylated mifentidine analogues. The rank order of the percentage of E,E conformation, which favors a bidentate interaction, of the formamidine moiety parallels the rank order of pseudo-irreversible H₂-antagonism.     

A beta adrenoceptor with atypical characteristics is involved in the relaxation of the rat small intestine

In several studies in guinea pig ileum or rat colon a beta adrenoceptor with characteristics distinct from beta-1 or beta-2 receptors has been observed and has been denoted as "atypical" beta adrenoceptor. In this study the relaxation of the rat small intestine was investigated, using isolated segments of the rat jejunum. Several beta-1 or beta-2 agonists and antagonists were tested on the rat jejunum preparation, and it was found that nonselective and selective antagonists for beta-1 or beta-2 receptors showed a relatively low affinity, compared to their affinity for beta-1 or beta-2 receptors. BRL 37344, an agonist which has been reported to be selective for the atypical beta adrenoceptor, was more potent although a partial agonist compared to isoprenaline, whereas it is clearly less active than isoprenaline on beta-1 or beta-2 receptors. These findings indicate that beta adrenergic relaxation of the rat small intestine is mediated via atypical beta adrenoceptors. Efforts were made to confirm these findings with binding studies on small intestinal 45,000-g membranes. Competition radioligand binding experiments were performed with the radiolabeled ligand [125I]iodocyanopindolol and the various antagonists which were also tested in the intact rat jejunum preparations. Receptor binding experiments only revealed beta adrenoceptors of the beta-2-subtype, which does not correspond with the results obtained in the jejunum relaxation. Probably the beta-2 receptors found in the binding studies are located on circular smooth muscle cells or on epithelial cells, whereas longitudinal smooth relaxation is mediated by atypical beta adrenoceptors. Atypical beta adrenoceptors were not measured in binding studies probably because [125I]iodocyanopindolol is an unsuitable ligand to label atypical intestinal beta adrenoceptors.