Showing papers by "Ulrich Bogdahn published in 1993"

The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma.

Abstract: This in vitro study was aimed at restitution of transforming growth factor (TGF)-beta 2-mediated suppression of T-lymphocyte activation within malignant gliomas. In early-passage tumor cell cultures of two glioblastomas (HTZ-153 and HTZ-209) and one malignant astrocytoma classified as World Health Organization Grade III (HTZ-243), autologous peripheral blood mononuclear cells were activated by interleukin-1 alpha and interleukin-2 in vitro (lymphokine-activated killer cells) and tested for cytotoxic and proliferative activity. In expression studies (Western blot and Northern hybridization) of all three tumors, TGF-beta could be detected at the protein and messenger ribonucleic acid (mRNA) levels. A polyclonal anti-TGF-beta neutralizing antibody did not enhance lymphocyte proliferation upon stimulation with tumor targets (3H-thymidine incorporation) and slightly stimulated lymphocyte cytotoxicity against autologous target cells. Preincubation of target cells for 12 hours with TGF-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides (S-ODN's) did, however, enhance lymphocyte proliferation up to 2.5-fold and autologous tumor cytotoxicity up to 60%, compared to controls not treated with S-ODN's. Incubation of tumor cells with TGF-beta 2-specific S-ODN's resulted in decreased TGF-beta-specific immunoreactivity in cultured glioma cells, in reduced TGF-beta 2 protein concentration (Western blot), and in a change in the expression pattern of TGF-beta 2 mRNA's. These observations may have implications for in vivo and in vitro activation of a cellular immune response against autologous malignant glioma cells.

Contrast-enhanced transcranial color-coded real-time sonography. Results of a phase-two study.

Abstract: Transcranial color-coded real-time sonography has been developed as a promising new bedside procedure to monitor central nervous system parenchymal and vascular pathology; the present study was designed to investigate the potential role of galactose microparticles (SH U 508 A) as a new ultrasound contrast-enhancing agent for transcranial sonography. Ten patients (four women and six men, 24-63 years of age) with a broad spectrum of central nervous system pathology were investigated by transcranial color-coded real-time sonography in a phase-two clinical study. After conventional ultrasound examination, all patients received a maximum of six injections of 10 ml with 200, 300, or 400 mg/mL SH U 508 A. The intracranial vessels were scanned by color flow imaging in the axial and coronal planes through a transtemporal acoustic bone window; in addition, the vertebrobasilar system was followed through the foramen magnum. SH U 508 A was well tolerated without side effects. In axial and coronal scans, the application of SH U 508 A resulted in detection of peripheral branches of the anterior, middle, and posterior cerebral arteries, as well as the posterior communicating and superior cerebellar arteries. In addition, the deep cerebral veins (i.e., inferior sagittal sinus, internal cerebral veins, great cerebral vein of Galen, straight sinus, and the confluence sinuum) were revealed. The transforaminal approach led to detection of the main infratentorial branches (anterior inferior, posterior inferior, and superior cerebellar arteries). One patient could not be insonated without contrast, but after SH U 508 A the trunks of the large intracranial arteries were detected. No obvious changes in the ultrasound pattern of the central nervous system parenchyma were observed. These preliminary data indicate that the use of a transpulmonary ultrasound contrast agent (SH U 508 A) may substantially broaden the spectrum and potential diagnostic utility of transcranial ultrasound by allowing detection of supratentorial peripheral central nervous system arteries, deep cerebral veins, and (through the foramen magnum) the entire vertebrobasilar system, including the cerebellar arteries.

Differentiation between ischemic and hemorrhagic stroke by transcranial color-coded real-time sonography.

Abstract: Transcranial color-coded real-time sonography was applied to 20 patients with ischemic stroke and 28 patients with spontaneous intracerebral hemorrhage In all patients the sonographic diagnosis corresponded closely to cranial computed tomography findings Recent hemorrhages were visualized as a hyperechodense mass The high contrast to minor echodense adjacent parenchyma led to a clear sonographic distinction Older clots were characterized by a continuous decrease of echodensity and subsequently were interspersed by hypoechodense zones In the acute stage of ischemic infarction, the vessel occlusion (17/20) and collateral vascular supply (10/20) could be depicted in the color-B-mode in two perpendicular planes and further verified by the Doppler mode Brain edema was not visualized Although in the acute stage no change of echo texture was observed within the infarction, hyperechodense regions (7/11) could be observed in some patients during the time course Complications of intracerebral hemorrhage and ischemic stroke, such as disturbance of cerebrospinal fluid circulation, midline shift, and compression of adjacent territories, were depicted by transcranial color-coded sonography These preliminary results illustrate that transcranial color-coded real-time sonography may be helpful in the early noninvasive differential diagnosis as well as long-term follow-up in patients with cerebrovascular disorders

Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules.

Abstract: The cell lines of three neuroectodermal tumors, two glioblastomas (HTZ-146, HTZ-17) and one melanoma (HTZ-19) were established and screened for the expression of growth factors by northern blotting and immunochemical methods. All three tumors were positive for platelet-derived growth factor- (PDGF-) A-, -B-chain, and basic fibroblast growth factor (bFGF) messenger ribonucleic acids. Cultured cells as well as original tumor material were also positive for PDGF-AA-, PDGF-BB, and bFGF protein, as shown by immunochemistry. To investigate the possible pathophysiological role of PDGF and bFGF, antisense technology was employed with chemically modified nuclease-stable 14-mer phosphorothioate oligodeoxynucleotides. Proliferation of all three tumors was reduced to a different extent with antisense phosphorothioate oligodeoxynucleotides in vitro, targeted against PDGF-A-chain-, -B-chain-, and -bFGF-messenger ribonucleic acid. These data indicate autocrine stimulatory loops for PDGF and bFGF, which may be blocked, may have different relevance in neuroectodermal tumors in vitro, and may have conceivable future therapeutic implications.

Imaging of the vertebrobasilar system by transcranial color-coded real-time sonography

Abstract: The vertebrobasilar system was investigated in 75 persons by TCCS to evaluate the applicability and diagnostic capacity of this transcranial Duplex technique. Transforaminal and transtemporal acoustic windows were employed to identify the vertebral arteries, basilar artery (PCA) and major branches of the vertebrobasilar system. The frequency of identifying the basilar artery and the PCA ranged from 84 to 94% but was poor for the distal segment of the basilar artery (45.3%). The origin of the basilar artery was disclosed by transcranial Duplex sonography at an average depth of 7.0 cm (range 6.0 to 8.0 cm). The assignment of the obtained flow signals to specific vascular segments was improved by this new technique. In addition, four persons received a maximum of six intravenous injections of a transpulmonary stable sonographic contrast agent (SHU 508 A) to enhance Doppler signal intensity derived from the vertebrobasilar system. The vascular trunk and all major branches of the vertebrobasilar system were identified in these four persons. We conclude that TCCS of the vertebrobasilar system will improve reliability of transcranial sonographic examination.

Tolerance and cerebrospinal fluid pharmacokinetics of intrathecally administered human natural interleukin-2: a phase I trial.

Abstract: Recombinant interleukin-2 (rIL-2) is at present widely applied in the immunotherapy of various advanced cancers. As a number of side effects following the administration of rIL-2, either alone or in combination with lymphokine-activated killer (LAK-) cells, have been reported, a preparation of human leukocyte-derived and fully glycosylated interleukin-2 was used in the present study. We have recently demonstrated in cats that this natural IL-2 (nIL-2) is well tolerated and that the distribution and elimination half-lifes following intrathecal (i.th.) application are considerably longer than those after intravenous (i.v.) injection. To determine whether these long half-lifes and the good tolerance of i.th. given nIL-2 are also found in man, four patients with meningeosis neoplastica received repeated injections of human nIL-2 i.th.. Cerebrospinal fluid samples were drawn at different time intervals from either the lateral ventricle or lumbar subarachnoid space. The doses of nIL-2 ranged from 2 x 10(4) to 4 x 10(5) IU per injection. Only minor side effects were noted in one patient. The half-lifes for distribution and elimination of i.th. given nIL-2 ranged between 0.5-1.7 hours and 4.9-14.4 hours respectively. A linear relationship exists between the i.th. dose of nIL-2 and the area under the cerebrospinal fluid activity time profile curve.

In vitro studies on interaction of 4-hydroperoxyifosfamide and 2-mercaptoethanesulphonate in malignant gliomas

Abstract: Drug interference of ifosfamide and sodium 2-mercaptoethanesulphonate (MESNA) was studied in three malignant glioma cell cultures (HTZ-17, HTZ-209B, and HTZ-243) by a recently developed in vitro method for evaluation of multimodal treatment interactions. Glioma cell cultures were treated in monolayer 96-well tissue-culture plates for 2 h each, with 4-hydroperoxyifosfamide and MESNA combined in both sequences, or alone. Concentrations ranged from 0.01 μM to 50 μM in single-modality exposures, and from 0.01 μM to 10 μM in combination exposures. After five population doubling times, DNA synthesis was determined by a standard [3H]Tdr-incorporation liquid-scintillation-counting protocol. Data points were evaluated for mono- and combined treatment dose effects (adapted with a probit function), and a model-free three-dimensional response surface was created that was compared to the theoretical additive, anticipated response surface. Local additivity was analysed for any ratio of combined treatment. No tumour effects were seen with MESNA in single-drug exposure, whereas ifosfamide resulted in more than 90% inhibition of tumour DNA synthesis. In combination experiments, MESNA could be confirmed to be inert: the anticipated theoretical combination response surfaces formed a three-dimensional extension of the single-drug ifosfamide dose/response curves — the experimental combination response surfaces displayed an identical appearance (P≤0.05). In conclusion, these results indicate no drug interference of MESNA and ifosfamide in malignant glioma cells.

Prognostic Factors and Surgical Indications in Spontaneous Lobar and Putaminal Hematomas

Abstract: Since McKissock et al. published their historical study in 1961 [9] which showed no benefit from surgical treatment, the role of surgery in the treatment of spontaneous intracerebral hematomas has remained a matter of debate. After the introduction of computed tomography (CT) still no generally recognized criteria for a surgical indication are available despite several recent studies [1,4, 5, 7, 10]. Facing the ethical problems of a prospective randomized trial the following questions were investigated by a retrospective clinical study: What is the impact of clinical and radiological factors on patients outcome? Are there subgroups defined by these prognostic parameters which are significantly different after conservative or surgical treatment?