Horst Traupe

Volumetric computed tomography (VCT): a new technology for noninvasive, high-resolution monitoring of tumor angiogenesis.

Volumetric computed tomography (VCT) is a technology in which area detectors are used for imaging large volumes of a subject with isotropic imaging resolution. We are experimenting with a prototype VCT scanner that uses flat-panel X-ray detectors and is designed for high-resolution three-dimensional (3D) imaging. Using this technique, we have demonstrated microangiography of xeno-transplanted skin squamous cell carcinomas in nude mice. VCT shows the vessel architecture of tumors and animals with greater detail and plasticity than has previously been achieved, and is superior to contrast-enhanced magnetic resonance (MR) angiography. VCT and MR images correlate well for larger tumor vessels, which are tracked from their origin on 3D reconstructions of VCT images. When compared with histology, small tumor vessels with a diameter as small as 50 μm were clearly visualized. Furthermore, imaging small vessel networks inside the tumor tissue improved discrimination of vital and necrotic regions. Thus, VCT substantially improves imaging of vascularization in tumors and offers a promising tool for preclinical studies of tumor angiogenesis and antiangiogenic therapies.

Identification of Embolic Stroke Patterns by Diffusion-Weighted MRI in Clinically Defined Lacunar Stroke Syndromes

Background— A number of clinical syndromes describing the presentation of deep brain infarcts are called lacunar syndromes resulting from small vessel occlusion (SVO). To verify the reliability of the clinical diagnosis “lacunar syndrome,” the value was investigated with diffusion-weighted MRI (DWI). Methods and Results— A total of 73 patients (mean age 66 years; range 35 to 83 years) with sudden onset of a classical lacunar syndrome were enrolled. On the basis of the DWI findings, patients were divided into 3 groups: group 1, single subcortical lesion (<15-mm lesion; 43 patients; 59%); group 2, large (≥15 mm) or scattered lesions in 1 vascular territory (16 patients; 22%); and group 3, multiple lesions in multiple vascular territories (14 patients; 19%). A stroke mechanism other than SVO could be identified in 17 (23%) patients. Cardiac work-up revealed a cardiac embolic source in 8 patients (11%). Duplex sonography revealed symptomatic stenosis in 9 patients (12%). Based on the work-up information, 29 patients (40%) were found to have a potential cause of stroke other than SVO. A significant correlation with >1 single lesion on DWI-MRI and a clinical proven embolic source was observed (P=0.002). In 9 patients with MRI suspicious for a pathomechanism other than SVO, no embolic source was found. Conclusions— The use of DWI-MRI improves the accuracy of the subtype diagnosis of stroke. Inaccuracy has to be expected in approximately one third if lacunar diagnosis is based on clinical and computed tomography findings. Most of these “false-positive” cases are attributable to large artery or cardiogenic embolic stroke.

New approach in strabismus surgery in high myopia

AIMS To develop appropriate methods of eye muscle surgery in highly myopic patients with esotropia and hypotropia, with respect to the pathological findings in high resolution magnetic resonance imaging (MRI). METHODS 35 patients with unilateral or bilateral high myopia and strabismus—that is, axial length of the globe averaged 29.4 mm. Multiple coronal, transverse, and parasagittal MRI image planes were obtained using a Siemens Magnetom 1.5 tesla MRI scanner. In 15 patients with a pathological plane of recti extraocular muscles found by MRI and confirmed intraoperatively, a new technique of eye muscle surgery was performed to re-establish the physiological muscle plane. This was checked postoperatively in addition to the measurement of alignment and motility by MRI. RESULTS The new MRI finding of a dislocation of the lateral rectus (LR) into the temporocaudal quadrant by 3.4 mm requires new surgical techniques. Only fixing the LR in the physiological meridian at the equator with a silicone loop (‘guide pulley’) or a non-absorbable suture is a causal therapy. This yields alignment and improves abduction and elevation. CONCLUSIONS If the described misalignment of the LR is detected by MRI, a common high dosage recess-resect procedure for esotropia may even aggravate the deviation. The most important aim of eye muscle surgery is to normalise the pathological path of the LR. The restoration of the physiological function of the dislocated LR is remarkable.

Serum cytokine levels do not correlate with disease activity and severity assessed by brain MRI in multiple sclerosis.

Objective – Chronic and acute dysregulation of the cytokine network has been described in multiple sclerosis (MS). Inflammatory lesions in the central nervous system of MS patients can be assessed by brain magnetic resonance imaging (MRI). This study has been performed to investigate whether changes of cytokines correlate with morphological changes as determined by MRI. Materials and methods – We included 46 patients with relapsing–remitting MS in the study. The serum concentrations of tumor necrosis factor‐β (TNF‐β), TNF receptor‐1 (TNFR‐1; 55 kDa) and TNFR‐2 (75 kDa), interleukin‐4 (IL‐4), interleukin‐10 (IL‐10) and interferon‐γ (IFN‐γ) were measured by enzyme linked immunosorbent assay in all patients. Each parameter was correlated with clinical findings and brain MRI parameters. We measured both the number (lesion load) and cumulated area (disease burden) of all lesions on brain MRI. In addition, the number and cumulated area of those lesions showing signs of activity [Gadolinium (Gd)‐enhancement, perifocal edema] were determined. Results – A non‐significant trend (P < 0.05) was found only for the correlation of serum IFN‐γ levels and the number of active MRI lesions showing both Gd‐enhancement and perifocal edema in the subgroup of patients (n=21) with active lesions. When corrected for multiple comparisons, this correlation was not significant anymore, as it was above the corrected P‐value of 0.001. We could not observe any further correlation of cytokine levels and MRI parameters. However, TNF‐β serum levels were significantly (P < 0.05) elevated in the patient subgroups with higher number of lesions and disease burden, respectively. Conclusion – Our data show that the determination of serum levels of the investigated cytokines and cytokine receptors is not useful as a tool to determine subclinical disease activity and severity as assessed by brain MRI.

Soluble and cell surface ICAM-1 as markers for disease activity in multiple sclerosis

Objective ‐ The intercellular adhesion molecule‐1 (ICAM‐1) is a member of the Ig supergene family. ICAM‐1 is expressed on various cells like peripheral blood lymphocytes, endothelial cells or thymic cells and the cell surface form is supposed to be shed into a soluble form. The expression of ICAM‐1 is induced by cytokines like Interleukin‐1, TNF alpha or interferon gamma. The aim of the study was to investigate whether changes of cell surface and soluble ICAM‐1 in the cerebrospinal fluid (CSF) and blood are indicative for disease activity in patients with multiple sclerosis (MS). Material and methods ‐ In all patients with relapsing‐remitting MS (relapse: n=31, remission: n= 11) and controls (n= 13) the expression of cell surface ICAM‐1 (c‐ICAM‐1) was determined by two colour flow cytometry. Soluble ICAM‐1 (s‐ICAM‐1) was measured by ELISA. Follow‐up examinations were done 3 months later. Results ‐ In 31 patients with a current relapse we found significantly decreased expression levels of c‐ICAM‐1 on leukocytes in CSF (P<0.001) and blood (P<0.10), when compared to those 11 individuals experiencing remission. In contrast we observed significantly (P<0.05) increased levels of s‐ICAM‐1 in CSF of patients with relapses. Comparing patients who had been in remission for more than 4 weeks (n= ll) with remission lasting longer than 3 months (n=28) we detected stable c‐ICAM‐1 expression on CD3 + T cells in blood. Conclusion ‐ Our results demonstrate for the first time that c‐ICAM‐1 on CD3 + T‐cells in CSF and blood is an activity marker in MS.

Analysis of Tumor Vessel Supply in Lewis Lung Carcinoma in Mice by Fluorescent Microsphere Distribution and Imaging with Micro- and Flat-Panel Computed Tomography

In lung carcinomas the blood supply varies depending on tumor type and stage and can develop from pulmonary or bronchial circulation, or both. To examine this in vivo, primary bronchogenic Lewis lung carcinoma cells were intratracheally instilled in C57BL/6 mice. Within 7 days, histological examinations showed progressive tumor growth at the peripheral parenchymal region. The relative contribution of tumor blood supply via the pulmonary and systemic arteries was studied in detail using fluorescent microspheres (10 microm). When compared to healthy lung parenchyma (13:1), Lewis lung carcinoma tumor tissue (52:1) showed a fourfold increase in pulmonary to systemic microspheres, indicating that the pulmonary arteries are the predominant tumor-feeding vessels. After filling the vessels with a vascular cast, the microanatomy of vessels being derived from the pulmonary artery was visualized with micro computed tomography. Flat-panel volumetric computed tomography provided longitudinal visualization of tissue bridges between the growing tumor and the pulmonary vasculature. In this model of peripheral parenchymal malignancy, new imaging techniques allowed effective visualization of lung tumor growth and vascularization in living mice, demonstrating a pulmonary blood supply for lung tumors.

Flat-panel volumetric computed tomography: a new method for visualizing fine bone detail in living mice.

In this report, we present a new noninvasive 3-dimensional (3D) imaging technology for in vivo monitoring of the skeletal development of mice: flat-panel volumetric Computed Tomography (fpvCT). Long-term investigations of 4 mice are presented, with up to 14 scans of each mouse from postnatal day 0 to 86. Examinations of a newborn and an adult mouse, performed with fpvCT and clinical multislice CT (MSCT), demonstrate the superior image quality of high-resolution fpvCT.

Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma.

We performed a whole genome scan in a family with maternally transmitted paraganglioma (PGL3). The family included five patients with histologically proven paraganglioma and one patient with imaging findings consistent with a paraganglioma. In addition, there were 33 clinically unaffected family members. Of these eight could be examined by magnetic resonance imaging. Our investigations indicate that PGL3 is located in 1q21-q23 for several reasons: 1) two-point linkage analysis yielded the highest LOD score of 2.25 at 1q21-q23 (marker D1S2675); 2) haplotype analysis was most consistent for 1q21-q23 markers; and 3) the locus was excluded from more than 97% of the genome using a total of 381 highly polymorphic markers.

A Combination Hybrid-Based Vaccination/Adoptive Cellular Therapy to Prevent Tumor Growth by Involvement of T Cells

Cancer immunotherapy with dendritic cell-tumor cell fusion hybrids induces polyclonal stimulation against a variety of tumor antigens, including unknown antigens. Hybrid cells can prime CTLs, which subsequently develop antitumor responses. The aim of this study was to enhance the known antitumor effect of hybrid vaccination (HC-Vacc) and hybrid-primed adoptive T-cell therapy (HC-ACT) using the poorly immunogenic Lewis lung carcinoma (LLC1) model. The strategy used was a combination of a double HC-Vacc alternating with HC-ACT (HC-Vacc/ACT). Using flat-panel volumetric computer tomography and immunohistochemistry, we showed a significant retardation of tumor growth (85%). In addition, a significant delay in tumor development, a reduction in the number of pulmonary metastases, and increased survival times were observed. Furthermore, the tumors displayed significant morphologic changes and increased apoptosis, as shown by up-regulation of gene expression of the proapoptotic markers Fas, caspase-8, and caspase-3. The residual tumor masses seen in the HC-Vacc/ACT-treated mice were infiltrated with CD4+ and CD8+ lymphocytes and showed elevated IFNgamma expression. Moreover, splenic enlargement observed in HC-Vacc/ACT-treated mice reflected the increased functionality of T cells, as also indicated by increased expression of markers for CTL activation, differentiation, and proliferation (Cd28, Icosl, Tnfrsf13, and Tnfsf14). Our findings indicate that the combination therapy of dendritic cell-tumor cell HC-Vacc/ACT is a very effective and a promising immunotherapeutic regimen against poorly immunogenic carcinomas.

Cell surface bound and soluble adhesion molecules in CSF and blood in multiple sclerosis: correlation with MRI-measures of subclinical disease severity and activity

BACKGROUND The expression of soluble cell adhesion molecules (AM) in cerebrospinal fluid (CSF) and blood and their significance as measures of disease activity has been extensively studied in patients with multiple sclerosis (MS). In previous studies, we found that cell surface bound AM on mononuclear cells (MNC) in CSF and blood might be useful markers of clinical disease activity in MS patients. OBJECTIVE To analyze the correlation of cell surface bound and soluble AM in CSF and blood with magnetic resonance imaging (MRI) markers of subclinical disease severity and activity in patients with MS. METHODS Expression levels of cell surface bound AM on peripheral blood and CSF MNC were determined by flow cytometry analysis in 77 (CSF: 33) MS patients. Concentration levels of the soluble forms of AM were measured by enzyme-linked immunosorbent assay (ELISA). In corresponding cerebral gadolinium (Gd)-enhanced MRI scans, we determined both measures of subclinical disease severity and subclinical disease activity. RESULTS The expression levels of cell surface bound AM in peripheral blood correlated inversely with parameters for subclinical disease severity and activity on cerebral MRI scans as well as with the disease duration. Furthermore, we found significant correlations between serum levels of soluble AM and patient age but not with disease duration. CONCLUSIONS Our results suggest that subclinical disease progression may be associated with a decrease of the expression of cell surface bound AM on peripheral blood MNC. This might be a result of activated MNC migration into the CNS.